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Sample records for safety tolerability immunogenicity

  1. Safety, Tolerability, and Immunogenicity of Interferons

    Directory of Open Access Journals (Sweden)

    Michael G. Tovey

    2010-04-01

    Full Text Available Interferons (IFNs are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1, have found wide application for the treatment of chronic viral hepatitis and remitting relapsing multiple sclerosis respectively. Type II IFN, or IFN gamma, is used principally for the treatment of chronic granulomatous disease, while the recently discovered type III IFNs, also known as IFN lambda or IL-28/29, are currently being evaluated for the treatment of chronic viral hepatitis. IFNs are in general well tolerated and the most common adverse events observed with IFNα or IFNβ therapy are “flu-like” symptoms such as fever, headache, chills, and myalgia. Prolonged treatment is associated with more serious adverse events including leucopenia, thrombocytopenia, increased hepatic transaminases, and neuropsychiatric effects. Type I IFNs bind to high-affinity cell surface receptors, composed of two transmembrane polypeptides IFNAR1 and IFNAR2, resulting in activation of the Janus kinases Jak1 and Tyk2, phosphorylation and activation of the latent cytoplasmic signal transducers and activators of transcription (STAT1 and STAT2, formation of a transcription complex together with IRF9, and activation of a specific set of genes that encode the effector molecules responsible for mediating the biological activities of type I IFNs. Systemic administration of type I IFN results in activation of IFN receptors present on essentially all types of nucleated cells, including neurons and hematopoietic stem cells, in addition to target cells. This may well explain the wide spectrum of IFN associated toxicities. Recent reports suggest that certain polymorphisms in type I IFN signaling molecules are associated with IFN-induced neutropenia and thrombocytopenia in patients with chronic hepatitis C. IFN

  2. Safety, Tolerability and Immunogenicity of Pentavalent Rotavirus Vaccine Manufactured by a Modified Process.

    Science.gov (United States)

    Martinón-Torres, Federico; Greenberg, David; Varman, Meera; Killar, John A; Hille, Darcy; Strable, Erica L; Stek, Jon E; Kaplan, Susan S

    2017-04-01

    Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2-8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2-8°C. This study (ClinicalTrials.gov identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2-8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A. The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results. RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.

  3. Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants.

    Science.gov (United States)

    Block, Stanley L; Klein, Nicola P; Sarpong, Kwabena; Russell, Stephen; Fling, John; Petrecz, Maria; Flores, Sheryl; Xu, Jin; Liu, Guanghan; Stek, Jon E; Foglia, Ginamarie; Lee, Andrew W

    2017-02-01

    This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.

  4. Comparison of assay formats for drug-tolerant immunogenicity testing.

    Science.gov (United States)

    Butterfield, Anthony M; Chain, Jana S; Ackermann, Bradley L; Konrad, Robert J

    2010-12-01

    Immunogenicity testing is required for safety assessment of biotherapeutic drugs. Because levels observed during biotherapeutic administration can approach the mg/ml range, establishing drug tolerance is significantly important for assay development. Three assay formats for immunogenicity assessment were tested with respect to drug tolerance: Meso Scale Discovery(®) bridging (MSDB), solid-phase extraction with acid dissociation (SPEAD) and affinity capture elution (ACE). Six biotherapeutic drugs were analyzed by the three methods; four monoclonal antibodies, one Fc fusion protein and one Pegylated protein. Overall, ACE performed best for assays involving therapeutic monoclonal antibodies and also functioned well for therapeutic proteins. Despite several advantages, the MSDB assays displayed a potentially significant hook effect. SPEAD was comparable in performance to ACE for the biotherapeutic drugs tested, but suffers the disadvantage of being reagent-intensive. Novel assay formats offer significant advantages for immunogenicity testing, particularly in the design of assays that are tolerant to circulating levels of the biotherapeutic drug.

  5. Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults.

    Science.gov (United States)

    Gasparini, Roberto; Conversano, Michele; Bona, Gianni; Gabutti, Giovanni; Anemona, Alessandra; Dull, Peter M; Ceddia, Francesca

    2010-04-01

    This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults.

  6. Safety, tolerability, and immunogenicity of 7-valent pneumococcal conjugate vaccine in older infants and young children in China who are naive to pneumococcal vaccination: Results of a phase 4 open-label trial.

    Science.gov (United States)

    Li, Rongcheng; Huang, Lirong; Mo, Shunping; Li, Junchun; Zhou, Xin; Chen, Zhangjing; Liang, John; Young, Mariano; Giardina, Peter C; Scott, Daniel A

    2015-07-09

    This postlicensure study was conducted to assess immunogenicity and safety of PCV7 catch-up regimens in previously unvaccinated older infants and young children in China. Healthy children 121 days to vaccination and 1 and 12 months postvaccination. The incidence of clinically important adverse events (AEs) and serious AEs (SAEs), AEs leading to study withdrawal, and protocol-related AEs were assessed throughout the study. Prevaccination serotype-specific GMCs were generally low in subjects children 24 to 90% of subjects had IgG≥0.35 μg/mL for each PCV serotype. At 12-month follow-up, IgG GMCs ranged from 0.65 to 5.19, and all remained above prevaccination IgG GMC; >70% of subjects had IgG≥0.35 μg/mL. Older children generally had the most robust immune response both at 1 month postvaccination and during 12-month follow-up. PCV7 was well tolerated. Pyrexia, which was mild to moderate in severity, was the most common AE. Two subjects reported SAEs (n=4), and there was 1 study withdrawal; none of these were considered treatment related. In China, PCV7 catch-up vaccinations given to older infants and young children naive to pneumococcal vaccines resulted in a robust immune response to all serotypes; this response persisted after 1 year. PCV7 was well tolerated in Chinese infants and children. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Immunogenicity and safety of an acellular pertussis, diphtheria ...

    African Journals Online (AJOL)

    Immunogenicity and safety of an acellular pertussis, diphtheria, tetanus, inactivated poliovirus, Hib-conjugate combined vaccine (Pentaxim™) and monovalent hepatitis B vaccine at 6, 10 and 14 weeks of age in infants in South Africa.

  8. Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial.

    Science.gov (United States)

    Ramsauer, Katrin; Schwameis, Michael; Firbas, Christa; Müllner, Matthias; Putnak, Robert J; Thomas, Stephen J; Desprès, Philippe; Tauber, Erich; Jilma, Bernd; Tangy, Frederic

    2015-05-01

    immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded. The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings. Themis Bioscience GmBH. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Immunogenicity and safety of a live attenuated varicella vaccine in ...

    African Journals Online (AJOL)

    To investigate the safety of live attenuated varicella vaccine (aka strain) and the optimal virus titre/ dose required for immunogenicity in healthy South African children. ... Six subjects who were initially seropositive maintained or increased their titres post-vaccination; 3 of the 6 showed a booster response (a ;:;, 4-fold increase ...

  10. Safety and immunogenicity of two Haemophilus influenzae type b ...

    African Journals Online (AJOL)

    Objectives. Haemophilus influenzae type b (Hib) infection remains a major public health problem inthe developing world. We evaluated the safety and immunogenicity of a new PRP-CRM197 conjugate Hib vaccine (Vaxem Hib, Chiron Vacdnes), compared with theHibTITER vaccine (WyethLederle Vaccines), following the ...

  11. Immunogenicity and safety of a live attenuated varicella vaccine in ...

    African Journals Online (AJOL)

    Objectives. To investigate the safety of live attenuated varicella vaccine (aka strain) and the optimal virus titre/ dose required for immunogenicity in healthy South African children. Design. Double-blind randomised clinical study using two different lots of varicella vaccine, each at two different titres. Subjects were randomly ...

  12. Efficacy, safety and immunogenicity of biosimilars in inflammatory bowel diseases: A systematic review.

    Science.gov (United States)

    Martelli, Laura; Peyrin-Biroulet, Laurent

    2016-10-14

    Anti-tumor necrosis factor (anti-TNF) monoclonal antibodies have revolutionized the treatment of inflammatory bowel diseases (IBD). However, because of their complexity, their production is expensive contributing to their high price. As the patent protection of these therapies has expired in several countries, biosimilars have been developed to reduce the healthcare costs. The aim of this article is to review the literature on the safety, efficacy and immunogenicity of biosimilars in IBD. A PubMed literature search was performed using the following terms until May 2016: 'biosimilars', 'CT-P13', 'infliximab', 'Crohn's disease', 'ulcerative colitis', 'inflammatory bowel diseases', 'efficacy', 'safety', 'immunogenicity'. Additionally, abstracts from international meetings were also reviewed. A total of eleven studies in IBD patients provided real-world evidence on the efficacy, safety and immunogenicity profile of biosimilars in IBD patients. Based on available evidence, CT-P13 is efficacious and well tolerated in IBD patients in a real-life setting. The vast majority of studies only included IBD patients who had never received biological therapies. Information regarding the interchangeability between CT-P13 and its originator is currently being investigated in the NOR-SWITCH trial. Otherwise, the immunogenicity profile of CT-P13 seems to be similar to the originator. The infliximab biosimilar seems to be efficacious, safe and with a similar immunogenicity profile as the originator in IBD. Large prospective post-marketing studies are needed to assess the long-term safety profile of CT-P13. The use of infliximab biosimilars may lead to major healthcare cost savings.

  13. Safety and immunogenicity of a CRM or TT conjugated meningococcal vaccine in healthy toddlers.

    Science.gov (United States)

    Bona, Gianni; Castiglia, Paolo; Zoppi, Giorgio; de Martino, Maurizio; Tasciotti, Annaelisa; D'Agostino, Diego; Han, Linda; Smolenov, Igor

    2016-06-17

    MenACWY-CRM (Menveo(®); GlaxoSmithKline) and MenACWY-TT (Nimenrix(®); Pfizer) are two meningococcal vaccines licensed in the European Union for use in both children and adults. While both vaccines target meningococcal serogroups A, C, W and Y, immunogenicity and reactogenicity of these quadrivalent meningococcal conjugate vaccines may differ due to differences in formulation processes and chemical structure. Yet data on the comparability of these two vaccines are limited. The reactogenicity and immunogenicity of one dose of either MenACWY-CRM or MenACWY-TT were evaluated in healthy toddlers aged 12-15 months. Immunogenicity was assessed using serum bactericidal antibody assays (SBA) with human (hSBA) and rabbit (rSBA) complement. A total of 202 children aged 12-15 months were enrolled to receive one dose of MenACWY-CRM or MenACWY-TT. Similar numbers of subjects reported solicited reactions within 7 days following either vaccination. Tenderness at the injection site was the most common local reaction. Systemic reactions reported were similar for both vaccines and mostly mild to moderate in severity: irritability, sleepiness and change in eating habits were most commonly reported. Immunogenicity at 1 month post-vaccination was generally comparable for both vaccines across serogroups. At 6 months post-vaccination antibody persistence against serogroups C, W, and Y was substantial for both vaccines, as measured by both assay methodologies. For serogroup A, hSBA titers declined in both groups, while rSBA titers remained high. Despite differences in composition, the MenACWY-CRM and MenACWY-TT vaccines have comparable reactogenicity and immunogenicity profiles. Immediate immune responses and short-term antibody persistence were largely similar between groups. Both vaccines were well-tolerated and no safety concerns were identified. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Safety, immunogenicity and infectivity of new live attenuated influenza vaccines.

    Science.gov (United States)

    Isakova-Sivak, Irina; Rudenko, Larisa

    2015-01-01

    Live attenuated influenza vaccines (LAIVs) are believed to be immunologically superior to inactivated influenza vaccines, because they can induce a variety of adaptive immune responses, including serum antibodies, mucosal and cell-mediated immunity. In addition to the licensed cold-adapted LAIV backbones, a number of alternative LAIV approaches are currently being developed and evaluated in preclinical and clinical studies. This review summarizes recent progress in the development and evaluation of LAIVs, with special attention to their safety, immunogenicity and infectivity for humans, and discusses their perspectives for the future.

  15. Reappraisal of the Immunogenicity and Safety of Three Hepatitis A Vaccines in Adolescents.

    Science.gov (United States)

    Yoon, Seo Hee; Kim, Han Wool; Ahn, Jong Gyun; Kim, In Tae; Kim, Jong-Hyun; Kong, Kyoung Ae; Kim, Kyung-Hyo

    2016-01-01

    Although the overall incidence of hepatitis A in Korea has been decreasing, adolescents remain highly vulnerable to its outbreaks. This study was conducted to compare the immunogenicity and safety of three hepatitis A vaccines in Korean adolescents. Healthy anti-hepatitis A virus seronegative subjects aged 13 to 19 yr were randomized in three equal groups to receive two doses of Avaxim™, Epaxal®, or Havrix®, 6 to 12 months apart. Seroconversion rates one month after the first dose were 98%, 95%, and 93% for Avaxim™, Epaxal®, and Havrix®, respectively. Seroconversion rates reached 100% for all vaccine groups one month after the second dose. Anti-HAV geometric mean concentrations (GMCs) were 7,207.7 mIU/mL (95% CI, 6023.1-8684.7), 1,750.5 mIU/mL (95% CI, 1362.9-2248.3), and 1,953.5 mIU/mL (95% CI, 1459.4-2614.7) after two doses of Avaxim™, Epaxal®, and Havrix® respectively. Avaxim™ was significantly more immunogenic than Epaxal® and Havrix®, whereas there were no significant differences in antibody responses between Epaxal® and Havrix®. Local and systemic solicited adverse events (AEs) were mostly of mild-to-moderate intensity and resolved within 5 days. No serious AEs were reported. In conclusion, all three vaccines are highly immunogenic and well-tolerated in Korean adolescents. (Clinical Trial Registry NCT00483470).

  16. Immunogenicity and safety of the 9-valent HPV vaccine in men

    DEFF Research Database (Denmark)

    Castellsagué, X; Giuliano, A R; Goldstone, S

    2015-01-01

    OBJECTIVES: This study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16-26 years of age in comparison to young women 16-26 years of age (the population that was used to establish 9v......HPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16-26 year old women to 16-26 year old men. METHODS: This study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men...... having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6...

  17. Immunogenicity and safety of the 9-valent HPV vaccine in men.

    Science.gov (United States)

    Castellsagué, X; Giuliano, A R; Goldstone, S; Guevara, A; Mogensen, O; Palefsky, J M; Group, T; Shields, C; Liu, K; Maansson, R; Luxembourg, A; Kaplan, S S

    2015-11-27

    This study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16-26 years of age in comparison to young women 16-26 years of age (the population that was used to establish 9vHPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16-26 year old women to 16-26 year old men. This study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6) of 9vHPV vaccine. Serum samples were collected for anti-HPV assays. Safety information was collected for ∼ 12 months. The geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 for HM were non-inferior to those of women at Month 7. For all vaccine HPV types, Month 7 GMTs were numerically lower in MSM than in HM. Over 99.5% of subjects were seropositive at Month 7 for each vaccine HPV type. Administration of 9vHPV vaccine to both 16-26 year old men and women was generally well tolerated. These results support bridging the efficacy findings with 9vHPV vaccine in young women 16-26 years of age to men 16-26 years of age. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Immunogenicity and safety of a quadrivalent meningococcal polysaccharide CRM conjugate vaccine in infants and toddlers

    Directory of Open Access Journals (Sweden)

    Miguel Tregnaghi

    2014-09-01

    Conclusions: MenACWY-CRM vaccination regimens in infants and toddlers were immunogenic and well tolerated. No clinically meaningful effects of concomitant administration with routine infant and toddler vaccines were observed.

  19. A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta

    NARCIS (Netherlands)

    Abdolvahab, Mohadeseh Haji; Brinks, Vera; Schellekens, Huub

    2014-01-01

    Interferon beta may induce antibodies in multiple sclerosis patients and the incidence of immunogenicity depends on the type of product. These antibodies can reduce the efficacy of interferon beta. Two transgenic immune tolerant mouse models for human interferon beta (hIFNβ) (C57Bl/6, and

  20. Safety and immunogenicity of an MF59™-adjuvanted subunit influenza vaccine in elderly Chinese subjects

    Directory of Open Access Journals (Sweden)

    Pellegrini Michele

    2008-02-01

    Full Text Available Abstract Background The safety and immunogenicity of an MF59™-adjuvanted subunit influenza vaccine (Sub/MF59™; FLUAD®, Novartis Vaccines was evaluated among elderly Chinese subjects (≥ 60 years of age. After a preliminary Phase I, open-label study (n = 25 to assess safety 1–14 days post-vaccination, a comparative observer-blind, randomised, controlled clinical trial (n = 600 was performed to assess safety and immunogenicity versus a non-adjuvanted subunit influenza vaccine (Subunit; Agrippal®, Novartis Vaccines. Subjects were randomised (2:1 to receive Sub/MF59™ or Subunit. Results Both vaccines were well tolerated, with no vaccine-related serious adverse events reported during the Phase I trial. During the observer-blind study, local and systemic reactions were generally similar for both vaccines 1–22 days post-vaccination; however, injection-site induration was more frequent among the Subunit group (P Conclusion MF59™-adjuvanted subunit influenza vaccine is well tolerated by elderly Chinese subjects and induces a higher level of immunogenicity than a non-adjuvanted subunit influenza vaccine in this population that is at high risk of influenza-related complications. Clinical trial registry http://www.clinicaltrials.gov, NCT00310648

  1. Safety and immunogenicity of a candidate parvovirus B19 vaccine.

    Science.gov (United States)

    Bernstein, David I; El Sahly, Hana M; Keitel, Wendy A; Wolff, Mark; Simone, Gina; Segawa, Claire; Wong, Susan; Shelly, Daniel; Young, Neal S; Dempsey, Walla

    2011-10-06

    Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydropsfetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 μg dose of parvovirus B19 recombinant capsid; 2.5 and 25 μg doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5-9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. [Immunogenicity and safety of DTaP-IPV//PRP-T combined vaccine in infants in China].

    Science.gov (United States)

    Li, Yan-ping; Li, Feng-xiang; Hou, Qi-ming; Li, Chang-gui; Li, Ya-nan; Chen, Fu-sheng; Hu, Xue-zhong; Su, Wen-bin; Zhang, Shu-min; Fang, Han-hua; Ye, Qiang; Zeng, Tian-de; Liu, Tao-xuan; Li, Xiu-bi; Huang, Yun-neng; Deng, Man-ling; Li, Rong-cheng; Zhang, Yan-ping; Esteban, Ortiz

    2011-08-01

    The aim of this study was to demonstrate the immunogenicity and safety of diphtheria, tetanus, pertussis (acellular, component), poliomyelitis (inactivated) vaccine (adsorbed) and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV//PRP-T) combined vaccine compared with commercially available DTaP (diphtheria, tetanus and pertussis), Haemophilus influenzae type b (Hib), tetanus conjugate and IPV monovalent vaccine. Subjects were randomly divided into three groups, Group A and Group B were DTaP-IPV//PRP-T combined vaccine (PENTAXIM(TM)) vaccinated at 2, 3, 4 months of age or 3, 4, 5 months of age respectively; Group C was commercially available DTaP. Hib tetanus conjugate (Act-HIB(TM)) and IPV (IMOVAX PolioTM(TM)) vaccines vaccinated at 3, 4, 5 months of age. All groups received booster dose at 18 to 20 months of age, with antibody titers tested. Non-inferiority analysis was demonstrated in terms of seroprotection/seroconversion rates between Group A, Group B respectively and Group C. Safety information was collected after each vaccination to assess the safety of investigational vaccines. The non-inferiority of DTaP-IPV//PRP-T combined vaccine vaccinated at 2, 3, 4 or 3, 4, 5 months of age versus DTaP, Hib tetanus conjugate and IPV vaccine was demonstrated for all vaccine antigens in both primary and booster phases in terms of seroprotection/seroconversion rates. DTaP-IPV//PRP-T combined vaccine was well tolerated. The rate of solicited/unsolicited severe adverse reactions was very low and similar to the control vaccines. DTaP-IPV//PRP-T combined vaccine was highly immunogenic with good safety profile in Chinese infants, which was comparable to the commercially available control vaccines.

  3. Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults.

    Science.gov (United States)

    Moutschen, Michel; Léonard, Philippe; Sokal, Etienne M; Smets, Françoise; Haumont, Michèle; Mazzu, Pasqualina; Bollen, Alex; Denamur, Francoise; Peeters, Pascal; Dubin, Gary; Denis, Martine

    2007-06-11

    Two double-blind randomised controlled studies (phase I and I/II) were performed to assess for the first time the safety and immunogenicity of a recombinant subunit gp350 Epstein-Barr virus (EBV) vaccine in 148 healthy adult volunteers. All candidate vaccine formulations had a good safety profile and were well tolerated, with the incidence of solicited and unsolicited symptoms within a clinically acceptable range. One serious adverse event was reported in the phase I trial which was considered to be of suspected relationship to vaccination. The gp350 vaccine formulations were immunogenic and induced gp350-specific antibody responses (including neutralising antibodies).

  4. A novel peptide-based pan-influenza A vaccine: a double blind, randomised clinical trial of immunogenicity and safety.

    Science.gov (United States)

    Francis, James N; Bunce, Campbell J; Horlock, Claire; Watson, Jeannette M; Warrington, Steven J; Georges, Bertrand; Brown, Carlton B

    2015-01-03

    FP-01.1 is a novel synthetic influenza A vaccine consisting of six fluorocarbon-modified 35-mer peptides that encapsulate multiple CD4+ and CD8+ T-cell epitopes and is designed to induce an immune response across a broad population. FP-01.1 was evaluated for safety and immunogenicity in a randomised, double-blind, placebo-controlled, dose-escalation, phase I clinical study in healthy adult volunteers (n=49). IFNγ ELISpot assays and multicolour flow cytometry were used to characterise the immune response. FP-01.1 was safe and well tolerated at all doses tested with a similar adverse event profile in actively vaccinated subjects compared with controls. Maximum immunogenicity was in the 150 μg/peptide dose group where a robust response (243 spots/million PBMC) was demonstrated in 75% subjects compared with 0% in placebo controls. All six peptides were immunogenic. FP-01.1 induced dual CD4+ and CD8+ T cell responses and vaccine-specific T cells cross-recognise divergent influenza strains. This first-in-human study showed that FP-01.1 has an acceptable safety and tolerability profile and generated robust anti-viral T cell responses in a high proportion of subjects tested. The results support the further clinical testing of FP-01.1 prior to clinical, proof-of-concept, live viral challenge studies. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Reappraisal of the Immunogenicity and Safety of Three Hepatitis A Vaccines in Adolescents

    Science.gov (United States)

    2016-01-01

    Although the overall incidence of hepatitis A in Korea has been decreasing, adolescents remain highly vulnerable to its outbreaks. This study was conducted to compare the immunogenicity and safety of three hepatitis A vaccines in Korean adolescents. Healthy anti-hepatitis A virus seronegative subjects aged 13 to 19 yr were randomized in three equal groups to receive two doses of Avaxim™, Epaxal®, or Havrix®, 6 to 12 months apart. Seroconversion rates one month after the first dose were 98%, 95%, and 93% for Avaxim™, Epaxal®, and Havrix®, respectively. Seroconversion rates reached 100% for all vaccine groups one month after the second dose. Anti-HAV geometric mean concentrations (GMCs) were 7,207.7 mIU/mL (95% CI, 6023.1-8684.7), 1,750.5 mIU/mL (95% CI, 1362.9-2248.3), and 1,953.5 mIU/mL (95% CI, 1459.4-2614.7) after two doses of Avaxim™, Epaxal®, and Havrix® respectively. Avaxim™ was significantly more immunogenic than Epaxal® and Havrix®, whereas there were no significant differences in antibody responses between Epaxal® and Havrix®. Local and systemic solicited adverse events (AEs) were mostly of mild-to-moderate intensity and resolved within 5 days. No serious AEs were reported. In conclusion, all three vaccines are highly immunogenic and well-tolerated in Korean adolescents. (Clinical Trial Registry NCT00483470) PMID:26770041

  6. Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics.

    Science.gov (United States)

    De Groot, Anne S; Terry, Frances; Cousens, Leslie; Martin, William

    2013-11-01

    Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target 'foreign' sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xeno-sequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics 'quality by design', may lead to the development of ever more clinically effective, but less immunogenic, biologics.

  7. Immunogenicity and safety of a quadrivalent meningococcal polysaccharide CRM conjugate vaccine in infants and toddlers.

    Science.gov (United States)

    Tregnaghi, Miguel; Lopez, Pio; Stamboulian, Daniel; Graña, Gabriela; Odrljin, Tatjana; Bedell, Lisa; Dull, Peter M

    2014-09-01

    This phase III study assessed the safety and immunogenicity of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, administered with routine vaccines starting at 2 months of age. Healthy infants received MenACWY-CRM in a two- or three-dose primary infant series plus a single toddler dose. In addition, a two-dose toddler catch-up series was evaluated. Immune responses to MenACWY-CRM were assessed for serum bactericidal activity with human complement (hSBA). Reactogenicity and safety results were collected systematically. After a full infant/toddler series or two-dose toddler catch-up series, MenACWY-CRM elicited immune responses against the four serogroups in 94-100% of subjects. Noninferiority of the two- versus three-dose MenACWY-CRM infant dosing regimen was established for geometric mean titers for all serogroups. Following the three-dose infant primary series, 89-98% of subjects achieved an hSBA ≥ 8 across all serogroups. Immune responses to concomitant routine vaccines given with MenACWY-CRM were noninferior to responses to routine vaccines alone, except for pertactin after the two-dose infant series. Noninferiority criteria were met for all concomitant antigens after the three-dose infant series. MenACWY-CRM vaccination regimens in infants and toddlers were immunogenic and well tolerated. No clinically meaningful effects of concomitant administration with routine infant and toddler vaccines were observed. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. The safety and immunogenicity of Quadrivalent HPV (qHPV) vaccine in systemic lupus erythematosus.

    Science.gov (United States)

    Dhar, J Patricia; Essenmacher, Lynnette; Dhar, Renee; Magee, Ardella; Ager, Joel; Sokol, Robert J

    2017-05-09

    This study evaluated the safety and immunogenicity of qHPV vaccine in SLE. Subjects: 34 women ages 19-50years (yrs.) with mild to moderate SLE & minimally active or inactive SLE received qHPV vaccine at the standard dosing schedule. active SLE disease (SELENA-SLEDAI>2), history of severe SLE disease, deep venous thrombosis, on >400mg/day of hydroxychloroquine, on >15mg/day of prednisone, or active infections. Patients were monitored for adverse events (AE), SLE flare, generation of thrombogenic antibodies and thrombosis. Antibody (Ab) levels to HPV 6, 11, 16 & 18 were measured by HPV competitive Luminex Immunoassay and Geometric Mean Titers (GMTs) were calculated for each HPV type. Seroconversion was assessed for those seronegative at baseline. The women in the study: African-American (79%), mean age=38.1years, mean age at diagnosis of SLE=28.6years, 35.3% had a history of smoking, 91% had 4 or more sexual partners, 50% had a history of sexually transmitted diseases, and 27.3% used condoms on a regular basis. Vaccine site reactions (VSRs) occurred in 62%, all mild. Ninety-seven percent experienced at least 1 non vaccine adverse event (nvAE) with a total of 493 nvAEs in 33 patients, of which 90% were mild and none were related to vaccine or SLE. There were 9 serious AEs, none were related to vaccine or SLE, all resolved. No patient experienced an SLE flare, thrombosis, or generation of thrombogenic antibodies. Seroconversion rate was 100% with mean GMTs comparable to Gardasil® package insert data. In this SLE vaccine study, qHPV vaccine was generally safe, well tolerated, and highly immunogenic. This clinical trial is registered on Clinical Trials.gov under number, NCT01741012 and was conducted under the FDA IND BB14113. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Immunogenicity and safety of ZOSTAVAX® approaching expiry potency in individuals aged ≥50 years

    Science.gov (United States)

    Arnou, Robert; Fiquet, Anne; Thomas, Stéphane

    2011-01-01

    Background: Age is a major risk factor for herpes zoster (HZ) and its potential long-term complication post-herpetic neuralgia (PHN). Due to the significant burden of HZ and PHN on patients' quality of life, it is vital that effective and well-tolerated vaccines are available to prevent HZ in older adults. ZOSTAVAX® vaccine was developed to prevent HZ and PHN in individuals ≥50 years (y) of age, and its clinical efficacy and safety have been demonstrated. Aims and Methods: This phase 4, open-label, multicenter study was undertaken to assess the immunogenicity and safety of a single dose of ZOSTAVAX (refrigerator-stable formulation) given within 6 mo of its expiry date in individuals ≥50 y of age. The geometric mean fold rise (GMFR) from pre-vaccination to 4 weeks post-vaccination in varicella zoster virus (VZV) antibody titers was calculated. An acceptable antibody response was defined as a lower 95% confidence interval (CI) of GMFR >1.4. solicited and unsolicited injection-site reactions and systemic adverse events were recorded. Results: The GMFR in VZV antibody titers was 3.1 (95% CI: 2.6, 3.8), satisfying the criterion for an acceptable VZV antibody response to ZOSTAVAX (minimum requirement: 1.4 GMFR). An acceptable rise in VZV antibody titers was observed in individuals of 50–59 y of age (GMFR 3.9; 95% CI: 2.9, 5.1) and in those ≥60 y of age (GMFR 2.5; 95% CI: 1.9, 3.2). ZOSTAVAX was well tolerated; no serious adverse events were reported. Conclusion: ZOSTAVAX elicits an acceptable immune response in immunocompetent individuals ≥50 y of age when stored as directed and administered during the 6 mo prior to expiration. PMID:21941091

  10. Immunogenicity and safety of ZOSTAVAX(®) approaching expiry potency in individuals aged ≥50 years.

    Science.gov (United States)

    Arnou, Robert; Fiquet, Anne; Thomas, Stéphane; Sadorge, Christine

    2011-10-01

    Age is a major risk factor for herpes zoster (HZ) and its potential long-term complication post-herpetic neuralgia (PHN). Due to the significant burden of HZ and PHN on patients' quality of life, it is vital that effective and well-tolerated vaccines are available to prevent HZ in older adults. ZOSTAVAX(®) vaccine was developed to prevent HZ and PHN in individuals ≥50 years (y) of age, and its clinical efficacy and safety have been demonstrated. This phase 4, open-label, multicenter study was undertaken to assess the immunogenicity and safety of a single dose of ZOSTAVAX (refrigerator-stable formulation) given within 6 mo of its expiry date in individuals ≥50 y of age. The geometric mean fold rise (GMFR) from pre-vaccination to 4 weeks post-vaccination in varicella zoster virus (VZV) antibody titers was calculated. An acceptable antibody response was defined as a lower 95% confidence interval (CI) of GMFR > 1.4. Solicited and unsolicited injection-site reactions and systemic adverse events were recorded. The GMFR in VZV antibody titers was 3.1 (95% CI: 2.6, 3.8), satisfying the criterion for an acceptable VZV antibody response to ZOSTAVAX (minimum requirement: 1.4 GMFR). An acceptable rise in VZV antibody titers was observed in individuals of 50-59 y of age (GMFR 3.9; 95% CI: 2.9, 5.1) and in those ≥60 y of age (GMFR 2.5; 95% CI: 1.9, 3.2). ZOSTAVAX was well tolerated; no serious adverse events were reported. ZOSTAVAX elicits an acceptable immune response in immunocompetent individuals ≥50 y of age when stored as directed and administered during the 6 mo prior to expiration.

  11. Safety and Immunogenicity of rSh28GST Antigen in Humans: Phase 1 Randomized Clinical Study of a Vaccine Candidate against Urinary Schistosomiasis

    OpenAIRE

    Gilles Riveau; Dominique Deplanque; Franck Remoué; Anne-Marie Schacht; Hubert Vodougnon; Monique Capron; Michel Thiry; Joseph Martial; Christian Libersa; André Capron

    2012-01-01

    Background Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Metho...

  12. Immunogenicity of different stressed IgG monoclonal antibody formulations in immune tolerant transgenic mice

    Science.gov (United States)

    Filipe, Vasco; Jiskoot, Wim; Basmeleh, Abdul Hafid; Halim, Andhyk; Schellekens, Huub; Brinks, Vera

    2012-01-01

    The presence of protein aggregates in biopharmaceutical formulations is of great concern for safety and efficacy reasons. The aim of this study was to correlate the type and amount of IgG monoclonal antibody aggregates with their immunogenic potential. IgG degradation was obtained by freeze-thawing cycles, pH-shift cycles, heating, shaking and metal-catalyzed oxidation. The size, amount, morphology and type of intermolecular bonds of aggregates, as well as structural changes and epitope integrity were characterized. These formulations were injected in mice transgenic (TG) for human genes for Ig heavy and light chains and their non-transgenic (NTG) counterparts. Anti-drug antibody (ADA) titers were determined by bridging ELISA. Both unstressed IgG and freeze-thawed formulation did not induce measurable ADA levels. A mild antibody response was obtained in a fairly small percentage of mice, when injected with shaken, pH-shifted and heated formulations. The metal-catalyzed oxidized IgG formulation was the most immunogenic one, in both ADA titers and number of responders. The overall titers of NTG responders were significantly higher than the ones produced by TG mice, whereas there was no significant difference between the overall number of TG and NTG responders. This study reinforces the important role of protein aggregates on immunogenicity of therapeutic proteins and provides new insight into the immunogenic potential of different types of IgG aggregates. The results indicate that the quality of the IgG aggregates has more impact on the development of an immune response than their quantity or size. PMID:22951518

  13. Safety and immunogenicity of TetractHib (a vaccine combining DTP ...

    African Journals Online (AJOL)

    The safety and immunogenicity of TETRActHIB (a vaccine combining diphtheria and tetanus toxoids-pertussis vaccine (DTP) with Haemophilus influenzae type b (Hib) conjugate vaccine (polyribosyl ribitol phosphate conjugated to tetanus protein) (PRP-T)) was assessed in 131 Cape Town infants immunised at 6, 10 and 14 ...

  14. Safety and immunogenicity of indigenous recombinant hepatitis B vaccine (Shanvac-B) in comparison with commercially available vaccine.

    Science.gov (United States)

    Joshi, N; Kumar, A; Sreenivas, D V; Palan, S; Nagarjuna Kumar, Y R

    2000-01-01

    To assess the clinical safety, reactogenicity and immunogenicity of an indigenously developed recombinant hepatitis B vaccine (Shanvac-B; Shantha Biotechnics) and to compare it with another commercially available vaccine (Engerix-B, SmithKline Beecham) in healthy adults. 120 healthy adults randomLy received 20 micrograms of either Engerix-B (Group A; n = 61) or Shanvac-B (Group B; n = 59) in 0, 1, 2 months schedule. Anti HBs was assessed using commercially available AUSAB kits (Abbott Laboratories) one month after each dose. Protective seroconversion rates after first, second and third dose were 10%, 62.7% and 91.4%, respectively in Group A and 22.4%, 68.9% and 96.4% in Group B, respectively. The geometric mean titer (GMT) after the third dose was significantly high in Group B (419 mIU/mL) than in Group A (140 mIU/mL; p < 0.001). The GMT was significantly higher in women in both the groups. The indigenous vaccine was found to be clinically safe and well tolerated without significant side effects. The recombinant hepatitis B vaccine (Shanvac-B) developed in India is safe, well tolerated, and highly immunogenic, with high seroconversion and GMT response.

  15. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults.

    Science.gov (United States)

    Pépin, Stéphanie; Donazzolo, Yves; Jambrecina, Alen; Salamand, Camille; Saville, Melanie

    2013-11-12

    Although two antigenically distinct B strain lineages of influenza have co-circulated globally since the mid-1980s, trivalent influenza vaccines (TIVs) contain only one, resulting in frequent mismatches. This study examined the safety and immunogenicity of an inactivated quadrivalent influenza vaccine (QIV) candidate. This was a phase III, randomized, active-controlled, multicenter trial in adults during the 2011/2012 influenza season. Enrollment was stratified to include equal numbers of subjects 18-60 and >60 years of age. Subjects were randomized 5:1:1 to be vaccinated with the QIV, the licensed TIV, or an investigational TIV containing the alternate B strain lineage. Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination. 1116 subjects were vaccinated with QIV, 226 with the licensed TIV, and 223 with the investigational TIV. For all four vaccine strains, antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains. For both B strains, post-vaccination antibody responses to the QIV were superior to the responses to the TIVs lacking the corresponding B strain. The QIV met all European Medicines Agency criteria for all four vaccine strains. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for the QIV and pooled TIV groups. The most commonly reported solicited reactions were injection-site pain, headache, and myalgia, and most solicited reactions were mild or moderate and appeared and resolved within 3 days of vaccination. No treatment-related serious adverse events or deaths were reported. The inactivated QIV was well tolerated without any safety concerns. For all four vaccine strains, antibody responses to the QIV were superior to the responses to TIV for the unmatched strains and non-inferior for the matched strains. QIV could therefore help address an unmet need due to mismatched B strains in previous influenza vaccines. EudraCT: 2011

  16. Safety and immunogenicity of New Zealand strain meningococcal serogroup B OMV vaccine in healthy adults: beginning of epidemic control.

    Science.gov (United States)

    Thornton, V; Lennon, D; Rasanathan, K; O'Hallahan, J; Oster, P; Stewart, J; Tilman, S; Aaberge, I; Feiring, B; Nokleby, H; Rosenqvist, E; White, K; Reid, S; Mulholland, K; Wakefield, M J; Martin, D

    2006-02-27

    As the first step towards control of a strain specific epidemic of meningococcal disease in New Zealand (NZ), this study, an observer-blind, randomised controlled trial in 75 healthy adults, evaluated safety and immunogenicity of two different dosages of a meningococcal group B vaccine administered in a three dose regime. The "tailor-made" outer membrane vesicle (OMV) vaccine (candidate vaccine) developed using a New Zealand meningococcal group B strain (B:4:P1.7b,4) was well tolerated with no vaccine related serious adverse events. Similar local and systemic reactions were observed in those receiving the New Zealand candidate vaccine and the control parent Norwegian vaccine (MenBvac). A four-fold rise in serum bactericidal antibodies (SBAb) against the vaccine strain 4-6 weeks after the third vaccination was achieved in 100% of New Zealand candidate vaccine 2,519 microg participants and in 87% of 50 microg participants. The safety and immunogenicity profile observed in this study of healthy adults enabled studies in children to be initiated using 25 microg dosage.

  17. A review of immunogenicity and tolerability of live attenuated Hepatitis A vaccine in children.

    Science.gov (United States)

    Rao, Sameer; Mao, J S; Motlekar, Salman; Fangcheng, Zhuang; Kadhe, Ganesh

    2016-12-01

    Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored.

  18. An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants.

    Science.gov (United States)

    Fox, Christopher B; Haensler, Jean

    2013-07-01

    With the exception of alum, emulsion-based vaccine adjuvants have been administered to far more people than any other adjuvant, especially since the 2009 H1N1 influenza pandemic. The number of clinical safety and immunogenicity evaluations of vaccines containing emulsion adjuvants has correspondingly mushroomed. In this review, the authors introduce emulsion adjuvant composition and history before detailing the most recent findings from clinical and postmarketing data regarding the effects of emulsion adjuvants on vaccine immunogenicity and safety, with emphasis on the most widely distributed emulsion adjuvants, MF59® and AS03. The authors also present a summary of other emulsion adjuvants in clinical development and indicate promising avenues for future emulsion-based adjuvant development. Overall, emulsion adjuvants have demonstrated potent adjuvant activity across a number of disease indications along with acceptable safety profiles.

  19. Safety and immunogenicity of an inactivated whole virus Vero cell-derived Ross River virus vaccine: a randomized trial.

    Science.gov (United States)

    Aichinger, Gerald; Ehrlich, Hartmut J; Aaskov, John G; Fritsch, Sandor; Thomasser, Christiane; Draxler, Wolfgang; Wolzt, Michael; Müller, Markus; Pinl, Fritz; Van Damme, Pierre; Hens, Annick; Levy, Jack; Portsmouth, Daniel; Holzer, Georg; Kistner, Otfried; Kreil, Thomas R; Barrett, P Noel

    2011-11-21

    Ross River virus (RRV) is endemic in Australia and several South Pacific Islands. Approximately 5000 cases of RRV disease, which is characterized by debilitating polyarthritis, are recorded each year in Australia. This study describes the first clinical trial of a candidate RRV vaccine. An inactivated whole-virus Vero cell-derived RRV vaccine was tested in 382 healthy, RRV-naïve adults in a phase 1/2 dose-escalation study at ten sites in Austria, Belgium and The Netherlands. Subjects were equally randomized to receive 1.25 μg, 2.5 μg, 5 μg, or 10 μg aluminum hydroxide-adjuvanted or non-adjuvanted RRV vaccine, with a second dose after three weeks and a booster at six months. Vaccine immunogenicity was determined by measurements of serum IgG and neutralizing antibody titers. Vaccine tolerability and safety were monitored over the entire study period. The optimal vaccine formulation was the adjuvanted 2.5 μg dose, as calculated using a repeated mixed model analysis of covariance comparing log-transformed RRV-specific IgG titers between different dose groups. Geometric means of RRV-specific serum antibodies measured 21 days after the third vaccination with the 2.5 μg adjuvanted formulation were 520.9 (90% CI 377.2-719.4) as determined by IgG ELISA and 119.9 (82.6-173.9) as determined by virus neutralization assay, resulting in seropositivity rates of 92.9% (82.6-98.0) and 92.7% (82.2-98.0), respectively. All vaccine formulations and doses were well tolerated after the first, second and third vaccination. The adjuvanted, inactivated whole-virus Vero cell-derived Ross River virus vaccine is highly immunogenic in RRV-naïve adults and well tolerated at all dose levels. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Randomized Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18-49 Years of Age.

    Science.gov (United States)

    Dunkle, Lisa M; Izikson, Ruvim; Patriarca, Peter A; Goldenthal, Karen L; Muse, Derek; Cox, Manon M J

    2017-12-05

    Seasonal influenza vaccines are transitioning to quadrivalent formulations including the hemagglutinins of influenza A subtypes H1N1 and H3N2 and B lineages Yamagata and Victoria. A new quadrivalent recombinant influenza vaccine (RIV4) was compared directly with a standard-dose, egg-grown, quadrivalent-inactivated influenza vaccine (IIV4) for immunogenicity and safety in adults 18-49 years of age. The coprimary endpoints for noninferiority were hemagglutination inhibition seroconversion rates and postvaccination geometric mean titer ratios for each antigen using US regulatory criteria. Reactogenicity solicited for 7 days, other safety events collected for 28 days, and serious or medically attended adverse events collected for 6 months after vaccination comprised the safety evaluation. The immunogenicity of RIV4 was comparable to that of IIV4; the coprimary noninferiority criteria were met for 3 antigens, and the antibody responses to the fourth antigen, influenza B/Brisbane/60/2008, were low in each group, making comparisons uninterpretable. Systemic and injection site reactions were mild, transient, and similar in each group, whereas none of the spontaneously reported adverse events, serious or nonserious, were considered related to study vaccine. This first head-to-head comparison of recombinant versus inactivated quadrivalent influenza vaccines in 18-49 year old adults showed comparable immunogenicity, safety, and tolerability for both vaccines.

  1. Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa.

    Science.gov (United States)

    Loxton, André G; Knaul, Julia K; Grode, Leander; Gutschmidt, Andrea; Meller, Christiane; Eisele, Bernd; Johnstone, Hilary; van der Spuy, Gian; Maertzdorf, Jeroen; Kaufmann, Stefan H E; Hesseling, Anneke C; Walzl, Gerhard; Cotton, Mark F

    2017-02-01

    Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 (n = 36) or BCG Danish strain (n = 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8+ IL-17+ T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.). Copyright © 2017 Loxton et al.

  2. Tolerability and safety aspects of mirtazapine.

    Science.gov (United States)

    Nutt, David J

    2002-06-01

    The tolerability and safety profile of the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine reflects its unique pharmacological profile. The 5-HT(2) blocking effect contributes towards its anxiolytic effects and benefits on sleep, as well as preventing the sexual dysfunction that may occur with non-specific stimulation of the serotonin system by drugs such as the selective serotonin reuptake inhibitors (SSRIs). In addition, 5-HT(3) blockade by mirtazapine helps to prevent nausea and vomiting. Weight gain is the most commonly reported side-effect of mirtazapine, although there is evidence to suggest that this is not a significant problem during long-term treatment. In conclusion, mirtazapine has a good tolerability and safety profile that demonstrates several benefits over other antidepressants. Copyright 2002 John Wiley & Sons, Ltd.

  3. Immunogenicity and safety of a novel quadrivalent meningococcal conjugate vaccine (MenACWY-CRM) in healthy Korean adolescents and adults.

    Science.gov (United States)

    Lee, Hoan Jong; Chung, Moon-Hyun; Kim, Woo Joo; Hong, Young Jin; Choi, Kyong Min; Lee, Jina; Oh, Chi Eun; Welsch, Jo Anne; Kim, Kyung-Hyo; Hong, Ki Bae; Dagnew, Alemnew F; Bock, Hans; Dull, Peter M; Odrljin, Tatjana

    2014-11-01

    This phase III placebo-controlled study evaluated the immunogenicity and safety of MenACWY-CRM vaccination in healthy Korean adolescents and adults. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination against all four meningococcal serogroups. The IgG concentration specific for serogroup W capsular polysaccharide was measured in a subset of subjects in a post-hoc analysis. Adverse reactions were monitored throughout the study. Four hundred and fifty subjects were randomized 2:1 to receive MenACWY-CRM (N=297) or a saline placebo (N=153). MenACWY-CRM induced a good immune response against all four serogroups, with seroprotection rates (hSBA titers ≥8) of 79%, 99%, 98%, and 94% for serogroups A, C, W, and Y, respectively. Seroresponse rates were high for serogroups A, C, and Y, i.e. 76%, 86%, and 69%, respectively; the rate for serogroup W was 28%. MenACWY-CRM vaccine induced serum bactericidal antibodies against all four serogroups in a majority of subjects regardless of their baseline hSBA titers. MenACWY-CRM was generally well tolerated with most reactions being transient and mild to moderate in severity. Findings of this first study of a quadrivalent meningococcal polysaccharide conjugate vaccine in Korean adults and adolescents demonstrated that a single dose of MenACWY-CRM was well tolerated and immunogenic, as indicated by the percentages of subjects with hSBA titers ≥8 (79%, 99%, 98%, and 94% of subjects) and geometric mean titers (48, 231, 147, and 107) against serogroups A, C, W, and Y, respectively, at 1 month post-vaccination.

  4. Safety and immunogenicity of two subunit influenza vaccines in healthy children, adults and the elderly: a randomized controlled trial in China.

    Science.gov (United States)

    Zhu, Feng Cai; Zhou, Weizhong; Pan, Hongxing; Lu, Lily; Gerez, Lisya; Nauta, Jos; Giezeman, Katinka; de Bruijn, Iris

    2008-08-18

    The burden of influenza is well known in the elderly and at-risk patients, but also in children. Especially in those under 5 years old, influenza may cause severe morbidity and mortality. Influenza infections and complications can be reduced by vaccination. In a randomized, endpoint-blinded, parallel group trial the immunogenicity and safety was studied of two trivalent inactivated surface antigen (subunit) influenza vaccines Influvac and Agrippal in healthy children as well as in adults and the elderly. An open safety part in 30 children aged 3-12 years and 30 adults aged 18-60 years vaccinated with Influvac was followed by an endpoint-blind, parallel group part in 300 healthy children aged 3-12 years, 300 healthy adults aged 18-59 years, and 240 healthy elderly persons aged 60 years or over, in which subjects were randomized 2:1 to vaccination with either Influvac or Agrippal. The primary immunogenicity endpoint was the geometric mean titer (GMT) 4 weeks after vaccination. Both Influvac and Agrippal induced high anti-hemagglutinin antibody titers in the children and in the adult and elderly subjects. Seroprotection rates were >85% and seroconversion rates >70% for both vaccines in all three age groups for all three-virus strains. The GMT ratios after vaccination indicated that the immunogenicity of Influvac was at least comparable with that of Agrippal in all three age groups. Both vaccines were well tolerated and safe. In this trial, Influvac and Agrippal were immunogenic, safe and well tolerated in healthy children as well as in adults and elderly people.

  5. Safety and immunogenicity of a novel quadrivalent meningococcal CRM-conjugate vaccine given concomitantly with routine vaccinations in infants.

    Science.gov (United States)

    Klein, Nicola P; Reisinger, Keith S; Johnston, William; Odrljin, Tatjana; Gill, Christopher J; Bedell, Lisa; Dull, Peter

    2012-01-01

    In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.

  6. Safety and tolerability of regadenoson CMR.

    Science.gov (United States)

    Nguyen, Kim-Lien; Bandettini, W Patricia; Shanbhag, Sujata; Leung, Steve W; Wilson, Joel R; Arai, Andrew E

    2014-07-01

    Knowledge of adverse events associated with regadenoson perfusion cardiac magnetic resonance (CMR) and patient tolerability has implications for patient safety and staff training. We sought to assess the safety and tolerability of regadenoson stress CMR. A group of 728 consecutive patients (median age 58, 44% female) and 25 normal volunteers (median age 21, 24% female) were recruited from August 2009 to March 2012 using a prospective, cross-sectional study design. Subjects were stressed using fixed-dose regadenoson and imaged using a 1.5T MRI scanner. Symptoms and adverse events including death, myocardial infarction (MI), ventricular tachycardia (VT)/ventricular fibrillation (VF), hospitalization, arrhythmias, and haemodynamic stability were assessed. There were no occurrences of death, MI, VT/VF, high-grade atrioventricular block, or stress-induced atrial fibrillation. Notable adverse events included one case of bronchospasm and one case of heart failure exacerbation resulting in hospitalization. The most common symptoms in patients were dyspnoea (30%, n = 217), chest discomfort (27%, n = 200), and headache (15%, n = 111). There was minimal change between baseline and peak systolic and diastolic blood pressure in both patients and volunteers (P > 0.05). A blunted heart rate response to regadenoson was noted in patients with body mass index (BMI) ≥ 30 kg/m(2) (P Regadenoson CMR is well tolerated and can be performed safely with few adverse events. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

  7. Tolerability and safety of antifungal drugs

    Directory of Open Access Journals (Sweden)

    Francesco Scaglione

    2013-08-01

    Full Text Available When treating critically ill patients, as those with fungal infections, attention should be focused on the appropriate use of drugs, especially in terms of dose, safety, and tolerability. The fungal infection itself and the concomitant physiological disorders concur to increase the risk of mortality in these patients, therefore the use of any antifungal agent should be carefully evaluated, considering both the direct action on the target fungus and the adverse effects eventually caused. Among antifungal drugs, echinocandins have the greatest tolerability. In fact, unlike amphotericin B, showing nephrotoxicity, and azoles, which are hepatotoxic, the use of echinocandins doesn’t result in major adverse events.http://dx.doi.org/10.7175/rhc.v4i2s.873

  8. Immunogenicity, effectiveness and safety of combined hepatitis A and B vaccine: a systematic literature review.

    Science.gov (United States)

    Bakker, Marina; Bunge, Eveline M; Marano, Cinzia; de Ridder, Marc; De Moerlooze, Laurence

    2016-07-01

    Hepatitis A and B are two of the most common vaccine-preventable diseases and vaccination for Hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for those at risk of contracting HAV and/or HBV through their occupation, travel or lifestyle. To describe the vaccine efficacy, immunogenicity, effectiveness and safety of the combined vaccine against hepatitis A and hepatitis B. A systematic review of the literature published between 1990 and 2015. Anti-HAV seropositivity rates ranged from 96.2% to 100% and anti-HBs seroprotection rates from 82% to 100%. Antibodies persisted up to 15 years and geometric mean concentration (GMC) remained above the seropositivity cut-off value for both. Anti-HAV and anti-HBs immune responses were lower in less immunocompetent individuals one month after completion of the immunization schedule. The safety profiles of Twinrix(TM) and monovalent hepatitis A and B vaccines were similar. The vaccine offers satisfactory long-term immunogenicity rates, expected duration of protection and safety profile similar to the monovalent hepatitis A or B vaccines.

  9. Immunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV-IPV/Hib in Indian infants

    Science.gov (United States)

    Lalwani, Sanjay K.; Agarkhedkar, Sharad; Sundaram, Balasubramanian; Mahantashetti, Niranjana S.; Malshe, Nandini; Agarkhedkar, Shalaka; Van Der Meeren, Olivier; Mehta, Shailesh; Karkada, Naveen; Han, Htay Htay; Mesaros, Narcisa

    2017-01-01

    ABSTRACT Multivalent combination vaccines have reduced the number of injections and therefore improved vaccine acceptance, timeliness of administration and global coverage. The hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b (DTPa-HBV-IPV/Hib; Infanrix hexa™) vaccine, administered according to various schedules, is widely used for the primary vaccination of infants worldwide. In the current publication, we are presenting the immunogenicity and safety of 3 doses of DTPa-HBV-IPV/Hib vaccine when administered to Indian infants. 224 healthy infants (mean age 6.8 weeks) were vaccinated at 6–10–14 weeks (W) of age (n = 112) or 2–4–6 months (M) of age (n = 112). One month after the third vaccine dose, the seroprotection/seropositivity status against diphtheria, pertussis, tetanus, polio, hepatitis B and Hib antigens ranged from 98.6% to 100% in both groups. The vaccine response rate to the pertussis antigens ranged from 97% to 100%. Pain (6–10–14W group: 25.2%; 2–4–6M group: 13.4%) and fever (15.3% and; 15.2%, respectively) were the most frequently reported solicited local and general symptoms. Unsolicited adverse events were reported for 35.7% (6–10–14W group) and 22.3% (2–4–6M group) of subjects. No vaccine related serious adverse events were reported. In conclusion, the hexavalent DTPa-HBV-IPV/Hib vaccine was immunogenic and well tolerated, irrespective of the dosing schedule. PMID:27629913

  10. Immunogenicity and safety of 3-dose primary vaccination with combined DTPa-HBV-IPV/Hib in Indian infants.

    Science.gov (United States)

    Lalwani, Sanjay K; Agarkhedkar, Sharad; Sundaram, Balasubramanian; Mahantashetti, Niranjana S; Malshe, Nandini; Agarkhedkar, Shalaka; Van Der Meeren, Olivier; Mehta, Shailesh; Karkada, Naveen; Han, Htay Htay; Mesaros, Narcisa

    2017-01-02

    Multivalent combination vaccines have reduced the number of injections and therefore improved vaccine acceptance, timeliness of administration and global coverage. The hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type b (DTPa-HBV-IPV/Hib; Infanrix hexa™) vaccine, administered according to various schedules, is widely used for the primary vaccination of infants worldwide. In the current publication, we are presenting the immunogenicity and safety of 3 doses of DTPa-HBV-IPV/Hib vaccine when administered to Indian infants. 224 healthy infants (mean age 6.8 weeks) were vaccinated at 6-10-14 weeks (W) of age (n = 112) or 2-4-6 months (M) of age (n = 112). One month after the third vaccine dose, the seroprotection/seropositivity status against diphtheria, pertussis, tetanus, polio, hepatitis B and Hib antigens ranged from 98.6% to 100% in both groups. The vaccine response rate to the pertussis antigens ranged from 97% to 100%. Pain (6-10-14W group: 25.2%; 2-4-6M group: 13.4%) and fever (15.3% and; 15.2%, respectively) were the most frequently reported solicited local and general symptoms. Unsolicited adverse events were reported for 35.7% (6-10-14W group) and 22.3% (2-4-6M group) of subjects. No vaccine related serious adverse events were reported. In conclusion, the hexavalent DTPa-HBV-IPV/Hib vaccine was immunogenic and well tolerated, irrespective of the dosing schedule.

  11. Immunogenicity and safety of a cell culture-derived inactivated trivalent influenza vaccine (NBP607): A randomized, double-blind, multi-center, phase 3 clinical trial.

    Science.gov (United States)

    Song, Joon Young; Cheong, Hee Jin; Lee, Jacob; Woo, Heung Jeong; Wie, Seong-Heon; Lee, Jin-Soo; Kim, Shin Woo; Noh, Ji Yun; Choi, Won Suk; Kim, Hun; Kim, Kyung-Ho; Kim, Woo Joo

    2015-10-05

    Cell culture-derived influenza vaccines (CCIVs) have several important advantages over egg-based influenza vaccines, including shorter production time, better preservation of wild-type virus antigenicity and large-scale production capacity. A randomized, double-blind, phase 3 trial was undertaken to evaluate the immunogenicity and safety of a novel cell culture-derived inactivated, subunit, trivalent influenza vaccine (NBP607, SK Chemicals, Seongnam, Korea) compared to the control vaccine (AgrippalS1, Novartis Vaccines and Diagnostics Srl, Siena, Italy) among healthy adults aged 19 years or older (Clinical trial Number-NCT02344134). Immunogenicity was determined at pre-vaccination, 1 month and 6 month post-vaccination by the hemagglutination inhibition assay. Solicited and unsolicited adverse events were assessed after vaccination. A total of 1156 healthy subjects were recruited. NBP607 met all of the criteria of Committee for Medicinal Products for Human Use (CHMP) at 21 days post-vaccination. Contrary to NBP607, the control vaccine did not satisfy the seroconversion criteria for influenza B irrespective of age. Although the geometric mean titer for each influenza subtype declined gradually, seroprotection rate still remained ≥80% for all subtypes up to six month after NBP607 administration. NBP607 recipients met the seroprotection criteria for all three influenza subtypes up to 6 month post-vaccination. There was no significant difference in the occurrence of adverse events between the NBP607 and control groups. NBP607, a novel CCIV, showed excellent immunogenicity that lasted ≥6 months after vaccination and had tolerable safety profiles. In particular, NBP607 was more immunogenic against influenza B compared to the control, an egg-based subunit vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. CLINICAL STUDIES OF REACTOGENICITY, SAFETY AND IMMUNOGENICITY OF LIVE MONOVALENT INFLUENZA VACCINE (STRAIN А/17/CALIFORNIA/2009/38 — H1N1 IN CHILDREN

    Directory of Open Access Journals (Sweden)

    D.S. Bushmenkov

    2010-01-01

    Full Text Available Results of performed pre-clinical and clinical studies with volunteers 18-60 years old allowed registration of vaccine «INFLUVIR» (live monovalent vaccine for the prophylaxis of influenza A/H1N1, strain A/17/California/2009/38 (H1N1, developed by NPO «Microgen» in Russian Federation so timely vaccination campaign was performed. As a result, the level of morbidity with influenza A/H1N1 in Russia was decreased, and development of complication was prevented. Clinical studies in different groups of children were performed for the purpose of widening indications for vaccine «INFLUVIR» administration. According to the results of studies vaccine «INFLUVIR» has good tolerability and safety, low reactogenicity, and significant immunogenicity. This fact will allow changing of present normative documentation and administration of «INFLUVIR» in children of different age for prophylaxis of influenza A/H1N1.Key words: children, influenza, virus A/H1N1, live influenza vaccine, tolerability, safety, immunogenicity.(Voprosy sovremennoi pediatrii — Current Pediatrics. – 2010;9(4:101-105

  13. Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate.

    Science.gov (United States)

    Batzloff, Michael R; Fane, Anne; Gorton, Davina; Pandey, Manisha; Rivera-Hernandez, Tania; Calcutt, Ainslie; Yeung, Grace; Hartas, Jon; Johnson, Linda; Rush, Catherine M; McCarthy, James; Ketheesan, Natkunam; Good, Michael F

    2016-12-01

    Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer.

  14. Safety and Immunogenicity of an Inactivated Whole Cell Plus Recombinant B Subunit (WC/RBS) Cholera Vaccine in Healthy Adult Peruvian Military Volunteers.

    Science.gov (United States)

    1992-11-30

    AD-A260 586 IFB0 919931 MIPR NO: 92MM2532W TITLE: SAFETY AND IMMUNOGENICITY OF AN INACTIVATED WHOLE CELL PLUS RECOMBINANT B SUBUNIT (WCIRBS) COLERA ...NUMBERS Safety and Immunogenicity of an Inactivated Whole MIPR No. Cell Plus Recombinant B Subunit (WC/RBS) Colera 92MM2532 Vaccine in Healthy Adult

  15. The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations.

    Science.gov (United States)

    Kirkpatrick, Beth D; Tenney, Katherine M; Larsson, Catherine J; O'Neill, J Patrick; Ventrone, Cassandra; Bentley, Matthew; Upton, Anthony; Hindle, Zoe; Fidler, Christine; Kutzko, Deborah; Holdridge, Regan; Lapointe, Casey; Hamlet, Sandra; Chatfield, Steven N

    2005-08-01

    M01ZH09 (Salmonella enterica serovar Typhi [Ty2 aroC(-) ssaV(-)] ZH9) is a live oral-dose typhoid vaccine candidate. M01ZH09 was rationally modified with 2 independently attenuating mutations, including a novel mutation in Salmonella pathogenicity island (SPI)-2. We demonstrate that M01ZH09, in a single oral dose, is well tolerated and prompts broad immune responses, regardless of whether prevaccination with a bicarbonate buffer is given. Thirty-two healthy adult subjects were randomized and given 5x109 cfu of M01ZH09, with (presentation 1) or without (presentation 2) prevaccination with a bicarbonate buffer. Immunogenicity data included Salmonella Typhi lipopolysaccharide (LPS)-specific immunoglobulin (Ig) A antibody-secreting cells (enzyme-linked immunospot [ELISPOT] assay), IgG serologic responses to Salmonella Typhi LPS, lymphocyte proliferation, and interferon (IFN)- gamma production. The vaccine was well tolerated; adverse events after vaccination were mild. No fever or prolonged vaccine shedding occurred. Immunogenicity data demonstrated that 88% and 93% of subjects who received presentation 1 and presentation 2, respectively, had a positive response by ELISPOT assay; 81% of subjects in both groups underwent IgG seroconversion on day 14. Both groups had similar cellular immune responses to presentation 1 and presentation 2; lymphocyte proliferation to Salmonella Typhi flagellin occurred in 63% and 67% of subjects, respectively, and 69% and 73% of subjects, respectively, had an increase in IFN- gamma production. The oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in a single oral dose, with and without prevaccination with a bicarbonate buffer. Field studies to demonstrate protective efficacy are planned.

  16. Efficacy, Immunogenicity and Safety of a Human Rotavirus Vaccine RIX4414 in Singaporean Infants.

    Science.gov (United States)

    Phua, Kong Boo; Lim, Fong Seng; Quak, Seng Hock; Lee, Bee Wah; Teoh, Yee Leong; Suryakiran, Pemmaraju V; Han, Htay Htay; Bock, Hans L

    2016-02-01

    This was the first study conducted to evaluate the efficacy of 2 oral doses of the human rotavirus vaccine, RIX4414 in Singaporean infants during the first 3 years of life. Healthy infants, 11 to 17 weeks of age were enrolled in this randomised (1:1), double-blinded, placebo-controlled study to receive 2 oral doses of RIX4414 vaccine/placebo following a 0-, 1-month schedule. Vaccine efficacy against severe rotavirus (RV) gastroenteritis (Vesikari score ≥11) caused by wild-type RV strains from a period starting from 2 weeks post-Dose 2 until 2 and 3 years of age was calculated with 95% confidence interval (CI). Immunogenicity and safety of the vaccine were also assessed. Of 6542 infants enrolled, 6466 were included in the efficacy analysis and a subset of 100 infants was included in the immunogenicity analysis. Fewer severe RV gastroenteritis episodes were reported in the RIX4414 group when compared to placebo at both 2 and 3 year follow-up periods. Vaccine efficacy against severe RV gastroenteritis at the respective time points were 93.8% (95% CI, 59.9 to 99.9) and 95.2% (95% CI, 70.5 to 99.9). One to 2 months post-Dose 2 of RIX4414, 97.5% (95% CI, 86.8 to 99.9) of infants seroconverted for anti-RV IgA antibodies. The number of serious adverse events recorded from Dose 1 until 3 years of age was similar in both groups. Two oral doses of RIX4414 vaccine was immunogenic and provided high level of protection against severe RV gastroenteritis in Singaporean children, during the first 3 years of life when the disease burden is highest.

  17. Safety and Immunogenicity of a Mycoplasma ovipneumoniae bacterin for domestic sheep (Ovis aries).

    Science.gov (United States)

    Ziegler, Jessie C; Lahmers, Kevin K; Barrington, George M; Parish, Steven M; Kilzer, Katherine; Baker, Katherine; Besser, Thomas E

    2014-01-01

    Mortality from epizootic pneumonia is hindering re-establishment of bighorn sheep populations in western North America. Mycoplasma ovipneumoniae, a primary agent of this disease, is frequently carried asymptomatically by the domestic sheep and goats that constitute the reservoir of this agent for transmission to bighorn sheep. Our long-term objective is to reduce the risk of M. ovipneumoniae infection of bighorn sheep; one approach to this objective is to control the pathogen in its reservoir hosts. The safety and immunogenicity of M. ovipneumoniae for domestic sheep was evaluated in three experimental immunization protocols: 1) live M. ovipneumoniae (50 ug protein); 2) killed M. ovipneumoniae (50 ug whole cell protein) in oil adjuvant; and 3) killed M. ovipneumoniae (250 ug whole cell protein) in oil adjuvant. Immunogenicity was assessed by two serum antibody measures: competitive enzyme-linked immunosorbent assay (cELISA) (experiments 1-3) and serum growth inhibition (Experiment 3). Passive immunogenicity was also assessed in the third experiment using the same assays applied to blood samples obtained from the lambs of immunized ewes. Adverse reactions to immunization were generally minor, but local reactions were regularly observed at immunization sites with bacterins in oil adjuvants. No evidence of M. ovipneumoniae specific antibody responses were observed in the first or second experiments and no resistance to colonization was observed in the first experiment. However, the ewes in the third experiment developed strong cELISA serum antibody responses and significant serum M. ovipneumoniae inhibition activity, and these responses were passively transferred to their lambs. The results of these trials indicate that immunization with relatively large antigenic mass combined with an adjuvant is capable of inducing strong active antibody responses in ewes and passively immunizing lambs.

  18. Assessing safety and immunogenicity of post-exposure prophylaxis following interchangeability of rabies vaccines in humans.

    Science.gov (United States)

    Ravish, Hardanahalli S; Sudarshan, Mysore K; Madhusudana, Shampur N; Annadani, Rachana R; Narayana, Doddabele H Ashwath; Belludi, Ashwin Y; Anandaiah, Gangaboraiah; Vijayashankar, Veena

    2014-01-01

    Rabies post exposure prophylaxis with cell culture vaccines by either intramuscular route or intradermal route spans over a period of one month. World Health Organization recommends completing post exposure prophylaxis against rabies with the same cell culture or embryonated egg rabies vaccine and with same route of administration and any deviation from this shall be an exception. In the present study, the safety and immunogenicity of rabies post-exposure prophylaxis was studied prospectively in 90 animal bite cases that had interchangeability of rabies vaccines either by route of administration or brand/type and such changes had occurred due to logistical/financial problems. Among them, 47 had change in route of administration from intramuscular to intradermal or vice versa and 43 had change in the brand/type of cell culture rabies vaccine. All of them had category III rabies exposure and received equine rabies immunoglobulin along with the rabies vaccine. None of the study subjects had any adverse reactions. The rabies virus neutralizing antibody titers was assessed by rapid fluorescent focus inhibition test and all the vaccinees had titers ≥0.5 IU per mL on day 14 which is considered as adequate for protection against rabies. Thus, the present study showed that, rabies post-exposure prophylaxis was safe and immunogenic despite changes in the route of administration and brand/type of rabies vaccine.

  19. Immunogenicity and safety of human papillomavirus (HPV) vaccination in Asian populations from six countries : a meta-analysis

    NARCIS (Netherlands)

    Setiawan, Didik; Luttjeboer, Jos; Pouwels, Koen B.; Wilschut, Jan C.; Postma, Maarten J.

    Cervical cancer is a serious public-health problem in Asian countries. Since human papillomavirus (HPV) infection is the main risk factor for cervical cancer, HPV vaccination is considered a promising strategy to prevent cervical cancer. However, comprehensive immunogenicity and safety information

  20. Immunogenicity and safety of human papillomavirus (HPV) vaccination in Asian populations from six countries : a meta-analysis

    NARCIS (Netherlands)

    Setiawan, Didik; Luttjeboer, Jos; Pouwels, Koen B; Wilschut, Jan C; Postma, Maarten J

    2017-01-01

    Cervical cancer is a serious public-health problem in Asian countries. Since human papillomavirus (HPV) infection is the main risk factor for cervical cancer, HPV vaccination is considered a promising strategy to prevent cervical cancer. However, comprehensive immunogenicity and safety information

  1. Safety and immunogenicity of an AMA-1 malaria vaccine in Malian adults: results of a phase 1 randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Mahamadou A Thera

    2008-01-01

    Full Text Available The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria.A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1 based on apical membrane antigen-1 (AMA-1 from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert. Sixty healthy, malaria-experienced adults aged 18-55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 microg/AS02A 0.25 mL or FMP2.1 50 microg/AS02A 0.5 mL or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively.The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site.

  2. Preclinical evaluation of the immunogenicity and safety of an inactivated enterovirus 71 candidate vaccine.

    Directory of Open Access Journals (Sweden)

    Shi-Hsia Hwa

    2013-11-01

    Full Text Available Human enterovirus 71 (EV71 is a significant cause of morbidity and mortality from Hand, Foot and Mouth Disease (HFMD and neurological complications, particularly in young children in the Asia-Pacific region. There are no vaccines or antiviral therapies currently available for prevention or treatment of HFMD caused by EV71. Therefore, the development of therapeutic and preventive strategies against HFMD is of growing importance. We report the immunogenic and safety profile of inactivated, purified EV71 preparations formulated with aluminum hydroxide adjuvant in preclinical studies in mice and rabbits. In mice, the candidate vaccine formulations elicited high neutralizing antibody responses. A toxicology study of the vaccine formulations planned for human use performed in rabbits showed no vaccine-related pathological changes and all animals remained healthy. Based on these preclinical studies, Phase 1 clinical testing of the EV71 inactivated vaccine was initiated.

  3. Evaluating the safety and immunogenicity of yellow fever vaccines: a systematic review

    Directory of Open Access Journals (Sweden)

    Thomas RE

    2015-04-01

    Full Text Available Roger E Thomas Department of Family Medicine, G012 Health Sciences Center, University of Calgary Medical School, Calgary, AB, Canada Purpose: To review the safety and immunogenicity of yellow fever vaccines. Literature search: The Cochrane Library (including the Cochrane CENTRAL Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the NHS Database of Abstracts of Reviews of Effects; MEDLINE; EMBASE; BIOSIS Previews; Global Health; CAB Abstracts; and the Lilacs Database of Latin American and Caribbean literature were searched for individual studies and systematic reviews through January 1, 2015. Results: Six yellow fever vaccines are currently produced, and they are effective against all seven yellow fever virus strains. There is a 99.2% homology of the genome sequences of the six current vaccines. Four systematic reviews identified very small numbers of serious adverse events. A systematic review (updated of all published cases identified 133 serious adverse events that met the Brighton Collaboration criteria: 32 anaphylactic, 42 neurologic (one death, 57 viscerotropic (25 deaths, and two of both neurologic and viscerotropic SAEs. The Sanofi Pasteur Global Pharmacovigilance database reported 276 million doses of Stamaril™ distributed worldwide and identified 12 reports of yellow fever vaccine-associated viscerotropic disease (YEL-AVD, 24 of yellow fever vaccine-associated neurologic disease (YEL-AND, and 33 reports of anaphylaxis (many already published. The Biomanguinhos manufacturer's database reported 110 million doses distributed worldwide between 1999 and 2009, and the rate of YEL-AND was estimated at 0.084/100,000 doses distributed and YEL-AVD at 0.02/100,000 doses distributed. Conclusion: Reports of serious adverse events are mostly from travelers from developed countries, and there is likely serious underreporting for developing countries. On the basis of the published reports, the yellow fever vaccines are

  4. The Safety and Immunogenicity of Rotavirus Vaccination in Infants With Intestinal Failure.

    Science.gov (United States)

    Javid, Patrick J; Sanchez, Sabrina E; Jacob, Susan; McNeal, Monica M; Horslen, Simon P; Englund, Janet A

    2014-03-01

    Young children with intestinal failure are at risk for complications from rotavirus gastroenteritis. To date, the safety and immunogenicity of rotavirus vaccines in these children are not known. We hypothesized that rotavirus vaccination would be safe and confer immunity to infants with intestinal failure and a history of abdominal surgery. The study population consisted of infants with early intestinal failure who required abdominal surgery and parenteral nutrition for necrotizing enterocolitis, gastroschisis, jejunoileal atresia, or meconium peritonitis. Subjects received a rotavirus vaccine series at the appropriate age. Safety assessments were performed for the first 5 days after each vaccine dose. Viral stool shedding and serum rotavirus antigen were measured at multiple time points after each dose of the vaccine. A 3-fold increase in rotavirus immunoglobulin A titer at study completion defined seroconversion. Fifteen infants were enrolled and 14 infants completed the study protocol. Mild diarrhea, emesis, and fever were noted after vaccination in 33%, 40%, and 7% of subjects, respectively. No subject experienced postvaccine intussusception, viremia, dehydration, or required alterations in nutritional care. Viral stool shedding was noted in 47%, but only 1 child shed virus beyond 2 weeks postvaccination. All subjects who were not considered immune at baseline developed seroconversion to rotavirus after vaccination. In infants with intestinal failure, rotavirus vaccination appears to be safe and immunogenic. We found no evidence for altered viral shedding in this population. Given the profound consequences associated with rotavirus infection and potential benefits of rotavirus vaccine in this cohort, multicenter studies focusing on vaccine efficacy are warranted. © The Author 2013. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Comparison of the safety and immunogenicity of a refrigerator-stable versus a frozen formulation of ProQuad (measles, mumps, rubella, and varicella virus vaccine live).

    Science.gov (United States)

    Bernstein, Henry H; Eves, Karen; Campbell, Kristy; Black, Steven B; Twiggs, Jerry D; Reisinger, Keith S; Conti, Ralph M; Flodmark, Carl-Erik; Rombo, Lars; Klopfer, Stephanie; Schödel, Florian; Hartzel, Jonathan; Kuter, Barbara J

    2007-06-01

    A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (-15 degrees C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation. In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination. The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was > or = 97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of > or = 5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was > or = 88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation. The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.

  6. [Immunogenicity and safety of the influenza vaccine, in a population older than 55-years in Mexico].

    Science.gov (United States)

    Ayala-Montiel, Octavio; Mascareñas, César; García-Hernández, Delfino; Rendón-Muñiz, Jorge; López, Irma; Felipe Montaño, Luis; Zenteno, I; Franco-Paredes, C

    2005-01-01

    To confirm the immunogenicity and tolerance of the inactivated, fractionated, and purified influenza vaccine, in a Mexican adult population aged 55 and older, medically served at a Petróleos Mexicanos Hospital (Pemex, Mexican Oil Company). The study was conducted between November and December, 2000, among ninety adult subjects aged 55 years and older who were seen at the Hospital Central Sur Pemex. The primary endpoints regarding immunogenicity were the percentage of individuals with protective antibodies targeting hemagglutinins higher than or equal to 1:40, and the percentage of subjects who seroconverted as measured by a four-fold increase in protective antibody production. Secondary endpoints included the frequency of local and systemic reactions to the vaccine. An additional criterion that was evaluated included antigen-antibody affinity assays to measure the polyclonal antibody response to the vaccine and the specific generation of high-affinity antibodies to viral proteins, before and after vaccination. The antibody protection rate was 95.6% against the HINI strain, 98.9% against the H3N2 strain, and a 100% against the B/Yamanashi strain. Seroconversion to the HINI strain was elicited in 74.4% of subjects, to the H3N2 strain in 88.9%, and to the B/Yamanashi strain in 82.2%. Eighteen (20%) subjects developed local reactions; 17 (18.8%) developed a systemic reaction post vaccination at day 5 and nine subjects (10%) at day 28. Local reactions consisted of pain in 10 (11.1%) subjects, redness in 8 (8.8%), and induration in 6 (6.6%). General malaise, headache, and fever were identified in 10, 8.8, and 0% of subjects, respectively, at day 5, and in 4.4, 6.6, and 0%, respectively, at day 28. Influenza vaccine was highly immunogenic in a healthy Mexican adult population aged 55 years and older. The generation of high-affinity antibodies to the virus after vaccination was also demonstrated. Local and systemic adverse reactions to the vaccine identified in our study

  7. Immunogenicity and safety of a novel quadrivalent meningococcal conjugate vaccine (MenACWY-CRM in healthy Korean adolescents and adults

    Directory of Open Access Journals (Sweden)

    Hoan Jong Lee

    2014-11-01

    Conclusions: Findings of this first study of a quadrivalent meningococcal polysaccharide conjugate vaccine in Korean adults and adolescents demonstrated that a single dose of MenACWY-CRM was well tolerated and immunogenic, as indicated by the percentages of subjects with hSBA titers ≥8 (79%, 99%, 98%, and 94% of subjects and geometric mean titers (48, 231, 147, and 107 against serogroups A, C, W, and Y, respectively, at 1 month post-vaccination.

  8. Safety, efficacy and immunogenicity evaluation of the SAG2 oral rabies vaccine in Formosan ferret badgers.

    Science.gov (United States)

    Hsu, Ai-Ping; Tseng, Chun-Hsien; Barrat, Jacques; Lee, Shu-Hwae; Shih, Yu-Hua; Wasniewski, Marine; Mähl, Philippe; Chang, Chia-Chia; Lin, Chun-Ta; Chen, Re-Shang; Tu, Wen-Jane; Cliquet, Florence; Tsai, Hsiang-Jung

    2017-01-01

    Since 2013, rabies cases have been reported among Formosan ferret badgers in Taiwan, and they have been shown to be the major reservoirs for Taiwanese enzootics. To control and eradicate rabies, the authorities plan to implement a vaccination programme. Before distributing live vaccines in the field, this study assessed the safety, efficacy, and immunogenicity of SAG2 vaccine on ferret badgers by direct oral instillation. After application of 109 TCID50/dose, no virus was excreted into the oral cavity 1-7 days post-application, and safety was also satisfactorily verified over a 266-day period. Moreover, despite the low level of rabies virus neutralising antibodies induced after vaccination of a 108 TCID50/dose, the efficacy assessment revealed a 100% survival rate (15/15) of vaccinees and an 87.5% fatality rate (7/8) in control animals after a challenge on the 198th day post-vaccination. The immunisation and protection rates obtained more than 6 months after a single vaccination dose demonstrated that SAG2 is an ideal vaccine candidate to protect Formosan ferret badgers against rabies in Taiwan.

  9. Safety and immunogenicity of a combined Tetanus, Diphtheria, recombinant acellular Pertussis vaccine (TdaP) in healthy Thai adults.

    Science.gov (United States)

    Sirivichayakul, Chukiat; Chanthavanich, Pornthep; Limkittikul, Kriengsak; Siegrist, Claire-Anne; Wijagkanalan, Wassana; Chinwangso, Pailinrut; Petre, Jean; Hong Thai, Pham; Chauhan, Mukesh; Viviani, Simonetta

    2017-01-02

    An acellular Pertussis (aP) vaccine containing recombinant genetically detoxified Pertussis Toxin (PTgen), Filamentous Hemagglutinin (FHA) and Pertactin (PRN) has been developed by BioNet-Asia (BioNet). We present here the results of the first clinical study of this recombinant aP vaccine formulated alone or in combination with tetanus and diphtheria toxoids (TdaP). A phase I/II, observer-blind, randomized controlled trial was conducted at Mahidol University in Bangkok, Thailand in healthy adult volunteers aged 18-35 y. The eligible volunteers were randomized to receive one dose of either BioNet's aP or Tetanus toxoid-reduced Diphtheria toxoid-acellular Pertussis (TdaP) vaccine, or the Tdap Adacel® vaccine in a 1:1:1 ratio. Safety follow-up was performed for one month. Immunogenicity was assessed at baseline, at 7 and 28 d after vaccination. Anti-PT, anti-FHA, anti-PRN, anti-tetanus and anti-diphtheria IgG antibodies were assessed by ELISA. Anti-PT neutralizing antibodies were assessed also by CHO cell assay. A total of 60 subjects (20 per each vaccine group) were enrolled and included in the safety analysis. Safety laboratory parameters, incidence of local and systemic post-immunization reactions during 7 d after vaccination and incidence of adverse events during one month after vaccination were similar in the 3 vaccine groups. One month after vaccination, seroresponse rates of anti-PT, anti-FHA and anti-PRN IgG antibodies exceeded 78% in all vaccine groups. The anti-PT IgG, anti-FHA IgG, and anti-PT neutralizing antibody geometric mean titers (GMTs) were significantly higher following immunization with BioNet's aP and BioNet's TdaP than Adacel® (Pdiphtheria GMTs at one month after immunization were comparable in all vaccine groups. All subjects had seroprotective titers of anti-tetanus and anti-diphtheria antibodies at baseline. In this first clinical study, PTgen-based BioNet's aP and TdaP vaccines showed a similar tolerability and safety profile to Adacel

  10. Immunogenicity and safety of Gardasil among mid-adult aged men (27-45 years)--The MAM Study.

    Science.gov (United States)

    Giuliano, Anna R; Isaacs-Soriano, Kimberly; Torres, B Nelson; Abrahamsen, Martha; Ingles, Donna J; Sirak, Bradley A; Quiterio, Manuel; Lazcano-Ponce, Eduardo

    2015-10-13

    The quadrivalent (types 6/11/16/18) human papillomavirus (HPV) vaccine, Gardasil, has demonstrated efficacy against persistent HPV infection and associated anogenital disease in males. The goal of this Phase II trial was to establish the immunogenicity and safety of Gardasil among mid-adult men ages 27-45 years. One hundred and fifty men from Tampa, FL, US, and Cuernavaca, Mexico who met eligibility criteria (male, 27-45 years old, completed four years of follow-up in the HPV Infection in Men (HIM) natural history study) were enrolled. Subjects completed four visits over seven months, with Gardasil administered at Day 1 and Months 2 and 6. Sera were collected at Day 1 (pre-vaccination) and Month 7 (one month post-dose three). Anti-HPV6, 11, 16, and 18 IgG levels were determined by competitive Luminex immunoassay. 100% of men seroconverted to each of the four HPV vaccine components, and the vaccine was generally well-tolerated. Antibody responses to vaccine did not differ by age group or sexual orientation, regardless of HPV type, and were significantly higher at Month 7 among men who entered the trial seropositive for HPV 6 or 11. The immune response to HPV vaccination in men ages 27-45 was comparable to that observed in younger men, in whom clinical efficacy was demonstrated. Further trials to assess the efficacy of HPV vaccines to prevent persistent HPV infections in mid-adult men are needed. Merck & Co. Inc. was the main sponsor of this trial (IISP39256) and provided the study product. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Safety and Immunogenicity of Typhoid Fever and Yellow Fever Vaccines When Administered Concomitantly With Quadrivalent Meningococcal ACWY Glycoconjugate Vaccine in Healthy Adults

    National Research Council Canada - National Science Library

    Alberer, Martin; Burchard, Gerd; Jelinek, Tomas; Reisinger, Emil; Beran, Jiri; Hlavata, Lucie Cerna; Forleo‐Neto, Eduardo; Dagnew, Alemnew F; Arora, Ashwani K

    2015-01-01

    .... This article discusses the immunogenicity and safety of travel vaccines for typhoid fever (TF) and yellow fever (YF), when administered with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine...

  12. Safety and immunogenicity of a new purified vero cell rabies vaccine (PVRV) administered by intramuscular and intradermal routes in healthy volunteers.

    Science.gov (United States)

    Kulkarni, Prasad S; Sapru, Amita; D'costa, Pradeep M; Pandit, Anand; Madhusudana, Shampur N; Yajaman, Ashwin Belludi; Mangrule, Somnath; Gunale, Bhagwat; Bavdekar, Ashish R

    2013-05-31

    Rabies is 100% fatal but preventable with modern vaccines and immunoglobulins. There is a huge demand for rabies vaccines in developing countries of Asia and Africa. We have developed a new purified vero cell rabies vaccine (PVRV) and evaluated its safety and immunogenicity in healthy volunteers by intramuscular (IM) and intradermal (ID) routes of vaccination. Sixty adults aged between 18 and 50 years were recruited in this actively controlled Phase I clinical study and were randomized to receive three 1 ml or 0.1 ml doses of new PVRV intramuscularly or intradermally on days 0, 7 and 21. The control group received commercially available PVRV (Verorab) by intramuscular route. Adverse events (AEs) were recorded with diary cards till day 28 post-vaccination. Immunogenicity was assessed on day 0, 7, 21 and 42 by rapid fluorescence focus inhibition test (RFFIT). In all, 116 solicited local and systemic events were reported across the three groups. Most were mild and resolved without sequelae. Also the few unsolicited events, deemed unrelated to the study vaccines, caused no problems. No significant changes in the routine laboratory parameters were found. Two doses of a vaccine elicited protective titres (≥ 0.5 IU/ml) in all subjects, the GMTs varying between 0.57 and 0.69 IU/ml on day 7, 3.07 and 3.97 IU/ml on day 21, and 6.12 and 8.52 IU/ml on day 42 post-vaccination. PVRV was well tolerated and showed good immunogenicity regardless of whether administered intramuscularly or, using a tenth of that volume, intradermally. Further studies with this new vaccine are warranted. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Immunogenicity and safety of a CRM-conjugated meningococcal ACWY vaccine administered concomitantly with routine vaccines starting at 2 months of age.

    Science.gov (United States)

    Nolan, Terry M; Nissen, Michael D; Naz, Aftab; Shepard, Julie; Bedell, Lisa; Hohenboken, Matthew; Odrljin, Tatjana; Dull, Peter M

    2014-01-01

    Infants are at the highest risk for meningococcal disease and a broadly protective and safe vaccine is an unmet need in this youngest population. We evaluated the immunogenicity and safety of a 4-dose infant/toddler regimen of MenACWY-CRM given at 2, 4, 6, and 12 months of age concomitantly with pentavalent diphtheria-tetanus-acellular pertussis-Hemophilus influenzae type b-inactivated poliovirus-combination vaccine (DTaP-IPV/Hib), hepatitis B vaccine (HBV), 7- or 13-valent conjugate pneumococcal vaccine (PCV), and measles, mumps, and rubella vaccine (MMR). Four doses of MenACWY-CRM induced hSBA titers ≥8 in 89%, 95%, 97%, and 96% of participants against serogroups A, C, W-135, and Y, respectively. hSBA titers ≥8 were present in 76-98% of participants after the first 3 doses. A categorical linear analysis incorporating vaccine group and study center showed responses to routine vaccines administered with MenACWY-CRM were non-inferior to routine vaccines alone, except for seroresponse to the pertussis antigen fimbriae. The reactogenicity profile was not affected when MenACWY-CRM was administered concomitantly with routine vaccines. MenACWY-CRM administered with routine concomitant vaccinations in young infants was well tolerated and induced highly immunogenic responses against each of the serogroups without significant interference with the immune responses to routine infant vaccinations. Healthy 2 month old infants were randomized to receive MenACWY-CRM with routine vaccines (n = 258) or routine vaccines alone (n = 271). Immunogenicity was assessed by serum bactericidal assay using human complement (hSBA). Medically attended adverse events (AEs), serious AEs (SAEs) and AEs leading to study withdrawal were collected throughout the study period.

  14. Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in Mexico

    Directory of Open Access Journals (Sweden)

    Maricruz Gutiérrez Brito

    2013-06-01

    Full Text Available OBJECTIVE: To assess the safety and immune responses induced by a 13-valent pneumococcal conjugate vaccine (PCV13 after immunization of infants in Mexico. METHODS: PCV13 was given with other routine childhood vaccinations to 225 infants in Mexico at ages 2, 4, 6, and 12 months. RESULTS: The proportions of subjects achieving immunoglobulin G (IgG concentrations ≥0.35 µg/mL after the infant series and toddler dose were ≥93.1% and ≥96.7%, respectively, for all 13 serotypes. The serotype-specific pneumococcal IgG geometric mean concentrations after the infant series and toddler dose ranged from 1.18 to 9.13 µg/mL and from 1.62 to 15.41 µg/mL, respectively. The most common local reaction and systemic event after each dose were tenderness and irritability, respectively. Most fever was mild; no fever >40.0°C (i.e., severe was reported. One subject withdrew because of Kawasaki disease 5 days after the first dose of vaccines, but this condition was not considered related to PCV13. CONCLUSIONS: Overall, PCV13 administered with routine pediatric vaccines was immunogenic and safe in healthy infants in Mexico.

  15. Immunogenicity and safety of currently available Japanese encephalitis vaccines: A systematic review

    Science.gov (United States)

    Li, Xing; Ma, Shu-Juan; Liu, Xie; Jiang, Li-Na; Zhou, Jun-Hua; Xiong, Yi-Quan; Ding, Hong; Chen, Qing

    2015-01-01

    A number of Japanese encephalitis (JE) vaccines have been used for preventing Japanese encephalitis around the world. We here reviewed the immunogenicity and safety of the currently available Japanese encephalitis vaccines. We searched Pubmed, Embase, Web of Science, the Cochrane Library and other online databases up to March 25, 2014 for studies focusing on currently used JE vaccines in any language. The primary outcomes were the seroconversion rate against JEV and adverse events. Meta-analysis was performed for the primary outcome when available. A total of 51 articles were included. Studies were grouped on the basic types of vaccines. This systematic review led to 2 aspects of the conclusions. On one hand, all the currently available JE vaccines are safe and effective. On the other hand, the overall of JE vaccine evaluation is disorganized, the large variation in study designs, vaccine types, schedules, doses, population and few hand-to-hand trails, make direct comparisons difficult. In order to make a more evidence-based decision on optimizing the JE vaccine, it is warranted to standardize the JE vaccine evaluation research. PMID:25668666

  16. Clinical Safety and Immunogenicity of Tumor-Targeted, Plant-Made Id-KLH Conjugate Vaccines for Follicular Lymphoma

    Directory of Open Access Journals (Sweden)

    Daniel Tusé

    2015-01-01

    Full Text Available We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ≥6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF. The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ≥4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11 displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies.

  17. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine administered to older infants and children naïve to pneumococcal vaccination.

    Science.gov (United States)

    Wysocki, Jacek; Brzostek, Jerzy; Szymański, Henryk; Tetiurka, Bogusław; Toporowska-Kowalska, Ewa; Wasowska-Królikowska, Krystyna; Sarkozy, Denise A; Giardina, Peter C; Gruber, William C; Emini, Emilio A; Scott, Daniel A

    2015-03-30

    Streptococcus pneumoniae infections are a major cause of morbidity and mortality in children vaccine (PCV13) has been developed and approved in many countries worldwide. Assess the safety and immunogenicity of PCV13 in healthy older infants and children naïve to previous pneumococcal vaccination. This was a phase 3, open-label, multicenter study conducted in Polish children (N=354) who were vaccinated according to 3 age-appropriate catch-up schedules: Group 1 (aged 7 to vaccine doses only; and Group 3 (aged 24 to vaccine, was determined for each vaccine serotype. In addition, antipolysaccharide immunoglobulin (Ig) G geometric mean concentrations (GMCs) were calculated. Safety assessments included systemic and local reactions, and adverse events. The proportion of immunological responders was ≥88% across groups for all serotypes. Antipolysaccharide IgG GMCs were generally similar across groups. Each schedule elicited immune response levels against all 13 serotypes comparable to or greater than levels previously reported in infants after a 3-dose series. The 3 catch-up schedules had similar tolerability and safety profiles; a trend was present towards greater local tenderness with increasing age and subsequent dose administration. Immunological responses and safety results support the use of PCV13 for catch-up schedules in older infants and children naïve to pneumococcal vaccination. Copyright © 2015. Published by Elsevier Ltd.

  18. Safety and immunogenicity of multi-antigen AMA1-based vaccines formulated with CoVaccine HT™ and Montanide ISA 51 in rhesus macaques

    Directory of Open Access Journals (Sweden)

    Walraven Vanessa

    2011-07-01

    Full Text Available Abstract Background Increasing the breadth of the functional antibody response through immunization with Plasmodium falciparum apical membrane antigen 1 (PfAMA1 multi-allele vaccine formulations has been demonstrated in several rodent and rabbit studies. This study assesses the safety and immunogenicity of three PfAMA1 Diversity-Covering (DiCo vaccine candidates formulated as an equimolar mixture (DiCo mix in CoVaccine HT™ or Montanide ISA 51, as well as that of a PfAMA1-MSP119 fusion protein formulated in Montanide ISA 51. Methods Vaccine safety in rhesus macaques was monitored by animal behaviour observation and assessment of organ and systemic functions through clinical chemistry and haematology measurements. The immunogenicity of vaccine formulations was assessed by enzyme-linked immunosorbent assays and in vitro parasite growth inhibition assays with three culture-adapted P. falciparum strains. Results These data show that both adjuvants were well tolerated with only transient changes in a few of the chemical and haematological parameters measured. DiCo mix formulated in CoVaccine HT™ proved immunologically and functionally superior to the same candidate formulated in Montanide ISA 51. Immunological data from the fusion protein candidate was however difficult to interpret as four out of six immunized animals were non-responsive for unknown reasons. Conclusions The study highlights the safety and immunological benefits of DiCo mix as a potential human vaccine against blood stage malaria, especially when formulated in CoVaccine HT™, and adds to the accumulating data on the specificity broadening effects of DiCo mix.

  19. Immunogenicity and Safety of the HZ/su Adjuvanted Herpes Zoster Subunit Vaccine in Adults Previously Vaccinated With a Live Attenuated Herpes Zoster Vaccine.

    Science.gov (United States)

    Grupping, Katrijn; Campora, Laura; Douha, Martine; Heineman, Thomas C; Klein, Nicola P; Lal, Himal; Peterson, James; Vastiau, Ilse; Oostvogels, Lidia

    2017-12-12

    Protection against herpes zoster (HZ) induced by the live attenuated zoster vaccine Zostavax (ZVL) wanes within 3-7 years. Revaccination may renew protection. We assessed whether (re)vaccination with the adjuvanted HZ subunit vaccine candidate (HZ/su) induced comparable immune responses in previous ZVL recipients and ZVL-naive individuals (HZ-NonVac). In an open-label, multicenter study, adults ≥65 years of age, vaccinated with ZVL ≥5 years previously (HZ-PreVac), were matched to ZVL-naive adults (HZ-NonVac). Participants received 2 doses of HZ/su 2 months apart. The primary objective of noninferiority of the humoral immune response 1 month post-dose 2 was considered demonstrated if the upper limit of the 95% confidence interval (CI) of the adjusted anti-glycoprotein E geometric mean concentration (GMC) ratio of HZ-NonVac over HZ-PreVac was <1.5. HZ/su cellular immunogenicity, reactogenicity, and safety were also assessed. In 430 participants, humoral immune response to HZ/su was noninferior in HZ-PreVac compared with HZ-NonVac (adjusted GMC ratio, 1.04 [95% CI, .92-1.17]). Cellular immunogenicity, reactogenicity, and safety appeared to be comparable between groups. HZ/su was well-tolerated, with no safety concerns raised within 1 month post-dose 2. HZ/su induces a strong immune response irrespective of prior vaccination with ZVL, and may be an attractive option to revaccinate prior ZVL recipients. NCT02581410.

  20. Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Raburn M Mallory

    Full Text Available BACKGROUND: The safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 live attenuated influenza vaccine (LAIV were evaluated in children and adults. METHODS/PRINCIPAL FINDINGS: Two randomized, double-blind, placebo-controlled studies were completed in children (2-17 y and adults (18-49 y. Subjects were assigned 4:1 to receive 2 doses of H1N1 LAIV or placebo 28 days apart. The primary safety endpoint was fever ≥38.3°C during days 1-8 after the first dose; the primary immunogenicity endpoint was the proportion of subjects experiencing a postdose seroresponse. Solicited symptoms and adverse events were recorded for 14 days after each dose and safety data were collected for 180 days post-final dose. In total, 326 children (H1N1 LAIV, n = 261; placebo, n = 65 and 300 adults (H1N1 LAIV, n = 240; placebo, n = 60 were enrolled. After dose 1, fever ≥38.3°C occurred in 4 (1.5% pediatric vaccine recipients and 1 (1.5% placebo recipient (rate difference, 0%; 95% CI: -6.4%, 3.1%. No adults experienced fever following dose 1. Seroresponse rates in children (H1N1 LAIV vs. placebo were 11.1% vs. 6.3% after dose 1 (rate difference, 4.8%; 95% CI: -9.6%, 13.8% and 32.0% vs. 14.5% after dose 2 (rate difference, 17.5%; 95% CI: 5.5%, 27.1%. Seroresponse rates in adults were 6.1% vs. 0% (rate difference, 6.1%; 95% CI: -5.6%, 12.6% and 14.9% vs. 5.6% (rate difference, 9.3%; 95% CI: -0.8%, 16.3% after dose 1 and dose 2, respectively. Solicited symptoms after dose 1 (H1N1 LAIV vs. placebo occurred in 37.5% vs. 32.3% of children and 41.7% vs. 31.7% of adults. Solicited symptoms occurred less frequently after dose 2 in adults and children. No vaccine-related serious adverse events occurred. CONCLUSIONS/SIGNIFICANCE: In subjects aged 2 to 49 years, two doses of H1N1 LAIV have a safety and immunogenicity profile similar to other previously studied and efficacious formulations of seasonal trivalent LAIV. TRIAL REGISTRATION

  1. Safety and immunogenicity of an investigational meningococcal ACWY conjugate vaccine (MenACWY-CRM) in healthy Indian subjects aged 2 to 75 years.

    Science.gov (United States)

    Lalwani, Sanjay; Agarkhedkar, Sharad; Gogtay, Nithya; Palkar, Sonali; Agarkhedkar, Shalaka; Thatte, Urmila; Vakil, Hoshang; Jonnalagedda, Rekha; Pedotti, Paola; Hoyle, Margaret; Bhusal, Chiranjiwi; Arora, Ashwani

    2015-09-01

    This phase 3, multi-center, open-label study evaluated the immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM, Menveo(®); Novartis Vaccines and Diagnostics S.r.l., Siena, Italy) in healthy Indian subjects aged 2-75 years, to provide data for licensure in India. A total of 180 subjects were enrolled (60 subjects 2-10 years, 60 subjects 11-18 years, and 60 subjects 19-75 years) and received one dose of MenACWY-CRM. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination. Adverse events were collected throughout the 29-day study period. Percentages of subjects with post-vaccination hSBA ≥8 were 72%, 95%, 94%, and 90% for serogroups A, C, W, and Y, respectively. Geometric mean titers rose 7-fold to 42-fold against the four serogroups. Similar immune responses were observed for the age subgroups 2-10 years, 11-18 years, and 19-75 years. Seroresponse rates at 1 month following vaccination were 72%, 88%, 55%, and 71% for serogroups A, C, W, and Y, respectively. The vaccine was well tolerated with no safety concerns. A single dose of MenACWY-CRM induced a robust immune response against all four meningococcal serogroups and was well tolerated in an Indian population 2-75 years of age. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis.

    Science.gov (United States)

    Riveau, Gilles; Deplanque, Dominique; Remoué, Franck; Schacht, Anne-Marie; Vodougnon, Hubert; Capron, Monique; Thiry, Michel; Martial, Joseph; Libersa, Christian; Capron, André

    2012-01-01

    Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST) in healthy volunteers, and to determine its immunogenicity. Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum) as adjuvant (n = 8), or Alum alone as a comparator (n = 8), twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8) received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production. Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST. rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that clinical

  3. Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis.

    Directory of Open Access Journals (Sweden)

    Gilles Riveau

    Full Text Available Treatment of urinary schistosomiasis by chemotherapy remains challenging due to rapid re-infection and possibly to limited susceptibility to praziquantel treatment. Therefore, therapeutic vaccines represent an attractive alternative control strategy. The objectives of this study were to assess the safety and tolerability profile of the recombinant 28 kDa glutathione S-transferase of Schistosoma haematobium (rSh28GST in healthy volunteers, and to determine its immunogenicity.Volunteers randomly received 100 µg rSh28GST together with aluminium hydroxide (Alum as adjuvant (n = 8, or Alum alone as a comparator (n = 8, twice with a 28-day interval between doses. A third dose of rSh28GST or Alum alone was administered to this group at day 150. In view of the results obtained, another group of healthy volunteers (n = 8 received two doses of 300 µg of rSh28GST, again with a 28-day interval. A six-month follow-up was performed with both clinical and biological evaluations. Immunogenicity of the vaccine candidate was evaluated in terms of specific antibody production, the capacity of sera to inhibit enzymatic activity of the antigen, and in vitro cytokine production.Among the 24 healthy male participants no serious adverse events were reported in the days or weeks after administration. Four subjects under rSh28GST reported mild reactions at the injection site while a clinically insignificant increase in bilirubin was observed in 8/24 subjects. No hematological nor biochemical evidence of toxicity was detected. Immunological analysis showed that rSh28GST was immunogenic. The induced Th2-type response was characterized by antibodies capable of inhibiting the enzymatic activity of rSh28GST.rSh28GST in Alum did not induce any significant toxicity in healthy adults and generated a Th2-type immune response. Together with previous preclinical results, the data of safety, tolerability and quality of the specific immune response provide evidence that

  4. Safety and immunogenicity of a 9-valent HPV vaccine in females 12-26 years of age who previously received the quadrivalent HPV vaccine.

    Science.gov (United States)

    Garland, Suzanne M; Cheung, Tak-Hong; McNeill, Shelly; Petersen, Lone Kjeld; Romaguera, Josefina; Vazquez-Narvaez, Jorge; Bautista, Oliver; Shields, Christine; Vuocolo, Scott; Luxembourg, Alain

    2015-11-27

    To assess the safety and immunogenicity of the investigational 9-valent (6/11/16/18/31/33/45/52/58) HPV (9vHPV) vaccine in prior recipients of a 3-dose regimen of quadrivalent (6/11/16/18) HPV (qHPV) vaccine. V503-006 was a randomized, double-blinded, safety/tolerability and immunogenicity study of the 9vHPV vaccine in females 12-26 years of age who were previously vaccinated with qHPV vaccine. Subjects were randomized in a 2:1 ratio to receive 3 doses of 9vHPV vaccine (n=618) or saline placebo (n=306) at day 1, month 2, and month 6. Systemic, injection-site and serious adverse experiences (AEs) were monitored. Serum samples were collected at day 1, month 2, and month 7. Anti-HPV 6/11/16/18/31/33/45/52/58 titers were measured using the 9-valent HPV competitive Luminex Immunoassay (cLIA). The frequency of injection-site AEs (days 1-5 following any vaccination) was higher in the 9vHPV vaccine group than in the placebo group (91.1% and 43.9%, respectively). The frequencies of vaccine-related systemic AEs (days 1-15 following any vaccination) were generally comparable between the 2 groups (30.6% in the 9vHPV vaccine group, and 25.9% in the placebo group). One vaccine-related serious AE was reported in each of the 9vHPV vaccine and placebo groups. Few subjects (9vHPV=0.5%; placebo=0%) discontinued due to an AE. At 4 weeks post-dose 3, over 98% of subjects in the 9vHPV vaccine group were seropositive for HPV types 31/33/45/52/58, with marked elevations in cLIA geometric mean titers (GMTs) to these HPV types. Anti-HPV 31/33/45/52/58 GMTs were lower than in subjects administered 9vHPV vaccine who had not previously received qHPV vaccine (based on cross-study analyses); the clinical significance of this difference is unknown. Administration of a 3-dose regimen of 9vHPV vaccine to adolescent girls and young women 12-26 years of age who are prior qHPV vaccine recipients is highly immunogenic with respect to HPV types 31/33/45/52/58 and generally well tolerated. Copyright

  5. Immunogenicity and safety of a new inactivated hepatitis A vaccine in a comparative study.

    Science.gov (United States)

    Goilav, C; Zuckerman, J; Lafrenz, M; Vidor, E; Lauwers, S; Ratheau, C; Benichou, G; Zuckerman, A

    1995-07-01

    A multicentre, controlled, randomised, open, comparative trial including 839 healthy adult volunteers was carried out in order to compare the immunogenicity and reactogenicity of two vaccines against hepatitis A virus (HAV) during primary immunization and after booster injection. The first vaccine was produced by Pasteur Mérieux (PM), and the second vaccine by Smith-Kline Beecham (SKB). The vaccination schedule consisted of 2 doses (months 0, 6) for PM and 3 doses (months 0, 1, and 6) for SKB. Two weeks after the first dose, the seroconversion rates among initially HAV seronegative subjects (n = 608) were 93.4% and 76.1% for the PM and SKB vaccines, respectively, the corresponding geometric mean titres (GMTs) were 59.0 mIU/ml versus 30.8 mlU/ml (modified RIA HAVAB assay, Abbott Laboratories). Two months after the beginning of immunization (one dose versus two doses) the GMTs were 138.4 and 161.6 mlU/ml, respectively. At month 7, the seroconversion rates were 100% for both vaccines, and the GMTs were 4,189 and 3,163 mlU/ml, respectively. After the first dose of vaccine, 24.6% and 19.6% of the PM and SKB vaccines reported local reactions. The rates for systemic reactions were 27.2% and 25.0%, respectively. Lower rates for local and systemic reactions were seen after booster injections and statistical differences were not observed between the two vaccines. The study also demonstrated that vaccination was as well tolerated in subjects with anti-HAV antibodies as in HAV seronegative subjects. Logistic regression analysis revealed a significant vaccine effect on seroconversion rates only at week 2 (P < 10(-4). The same conclusions were drawn from the analysis of GMT by multivariate regression.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Comparison of the safety and immunogenicity of live attenuated and inactivated hepatitis A vaccine in healthy Chinese children aged 18 months to 16 years: results from a randomized, parallel controlled, phase IV study.

    Science.gov (United States)

    Ma, F; Yang, J; Kang, G; Sun, Q; Lu, P; Zhao, Y; Wang, Z; Luo, J; Wang, Z

    2016-09-01

    For large-scale immunization of children with hepatitis A (HA) vaccines in China, accurately designed studies comparing the safety and immunogenicity of the live attenuated HA vaccine (HA-L) and inactivated HA vaccine (HA-I) are necessary. A randomized, parallel controlled, phase IV clinical trial was conducted with 6000 healthy children aged 18 months to 16 years. HA-L or HA-I was administered at a ratio of 1: 1 to randomized selected participants. The safety and immunogenicity were evaluated. Both HA-L and HA-I were well tolerated by all participants. The immunogenicity results showed that the seroconversion rates (HA-L versus HA-I: 98.0% versus 100%, respectively, p >0.05), and geometric mean concentrations in participants negative for antibodies against HA virus IgG (anti-HAV IgG) before vaccination did not differ significantly between the two types of vaccines (HA-L versus HA-I first dose: 898.9 versus 886.2 mIU/mL, respectively, p >0.05). After administration of the booster dose of HA-I, the geometric mean concentrations of anti-HAV IgG (HA-I booster dose: 2591.2 mIU/mL) was higher than that after the first dose (p <0.05) and that reported in participants administered HA-L (p <0.05). Additionally, 12 (25%) of the 48 randomized selected participants who received HA-L tested positive for HA antigen in stool samples. Hence, both HA-L and HA-I could provide acceptable immunogenicity in children. The effects of long-term immunogenicity after natural exposure to wild-type HA virus and the possibility of mutational shifts of the live vaccine virus in the field need to be studied in more detail. Copyright © 2016. Published by Elsevier Ltd.

  7. Critical factors and paths influencing construction workers' safety risk tolerances.

    Science.gov (United States)

    Wang, Jiayuan; Zou, Patrick X W; Li, Penny P

    2016-08-01

    While workers' safety risk tolerances have been regarded as a main reason for their unsafe behaviors, little is known about why different people have different risk tolerances even when confronting the same situation. The aim of this research is to identify the critical factors and paths that influence workers' safety risk tolerance and to explore how they contribute to accident causal model from a system thinking perceptive. A number of methods were carried out to analyze the data collected through interviews and questionnaire surveys. In the first and second steps of the research, factor identification, factor ranking and factor analysis were carried out, and the results show that workers' safety risk tolerance can be influenced by four groups of factors, namely: (1) personal subjective perception; (2) work knowledge and experiences; (3) work characteristics; and (4) safety management. In the third step of the research, hypothetical influencing path model was developed and tested by using structural equation modeling (SEM). It is found that the effects of external factors (safety management and work characteristics) on risk tolerance are larger than that of internal factors (personal subjective perception and work knowledge & experiences). Specifically, safety management contributes the most to workers' safety risk tolerance through its direct effect and indirect effect; while personal subjective perception comes the second and can act as an intermedia for work characteristics. This research provides an in-depth insight of workers' unsafe behaviors by depicting the contributing factors as shown in the accident causal model developed in this research. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Safety and immunogenicity of the malaria candidate vaccines FP9 CS and MVA CS in adult Gambian men.

    Science.gov (United States)

    Imoukhuede, E B; Berthoud, T; Milligan, P; Bojang, K; Ismaili, J; Keating, S; Nwakanma, D; Keita, S; Njie, F; Sowe, M; Todryk, S; Laidlaw, S M; Skinner, M A; Lang, T; Gilbert, S; Greenwood, B M; Hill, A V S

    2006-10-30

    We assessed the safety and immunogenicity of prime-boost vectors encoding the Plasmodium falciparum circumsporozoite (CS) protein expressed either in the attenuated fowl-pox virus (FP9) or modified vaccinia virus Ankara (MVA). Thirty-two adult Gambians in groups of four to eight received one, two or three doses of FP9 CS and/or MVA CS. No serious adverse event was observed following vaccination. The most immunogenic regimen was two doses of FP9 followed by a single dose of MVA 4 weeks later (an average of 1000 IFN-gamma spot forming units/million PBMCs). This level of effector T-cell responses appears higher than that seen in previously reported studies of CS-based candidate malaria vaccines.

  9. Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial.

    Science.gov (United States)

    Cadorna-Carlos, Josefina B; Nolan, Terry; Borja-Tabora, Charissa Fay; Santos, Jaime; Montalban, M Cecilia; de Looze, Ferdinandus J; Eizenberg, Peter; Hall, Stephen; Dupuy, Martin; Hutagalung, Yanee; Pépin, Stéphanie; Saville, Melanie

    2015-05-15

    Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains and one strain from each B lineage (Yamagata and Victoria) may offer broader protection against seasonal influenza than inactivated trivalent influenza vaccine (IIV3), containing a single B strain. This study examined the safety, immunogenicity, and lot consistency of an IIV4 candidate. This phase III, randomized, controlled, multicenter trial in children/adolescents (9 through 17 years) and adults (18 through 60 years) was conducted in Australia and in the Philippines in 2012. The study was double-blind for IIV4 lots and open-label for IIV4 vs IIV3. Children/adolescents were randomized 2:2:2:1 and adults 10:10:10:1 to receive one of three lots of IIV4 or licensed IIV3. Safety data were collected for up to 6 months post-vaccination. Hemagglutination inhibition and seroneutralization antibody titers were assessed pre-vaccination and 21 days post-vaccination. 1648 adults and 329 children/adolescents received IIV4, and 56 adults and 55 children/adolescents received IIV3. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for IIV3 and IIV4 recipients in both age groups. Injection-site pain, headache, malaise, and myalgia were the most frequently reported solicited reactions, most of which were mild and resolved within 3 days. No vaccine-related serious adverse events or deaths were reported. Post-vaccination antibody responses, seroconversion rates, and seroprotection rates for the 3 strains common to both vaccines were comparable for IIV3 and IIV4 in both age groups. Antibody responses to IIV4 were equivalent among vaccine lots and comparable between age groups for each of the 4 strains. IIV4 met all European Medicines Agency immunogenicity criteria for adults for all 4 strains. In both age groups, IIV4 was well tolerated and caused no safety concerns, induced robust antibody responses to all 4 influenza strains, and met all EMA immunogenicity

  10. Randomized, double-blind, multi-center, phase III clinical trial to evaluate the immunogenicity and safety of MG1109 (egg-based pre-pandemic influenza A/H5N1 vaccine) in healthy adults.

    Science.gov (United States)

    Song, Joon Young; Choi, Min Joo; Noh, Ji Yun; Choi, Won Suk; Cheong, Hee Jin; Wie, Seong-Heon; Lee, Jin-Soo; Woo, Gyu-Jin; Lee, Sang Ho; Kim, Woo Joo

    2017-05-04

    Considering the pandemic potential of avian influenza A/H5N1, development of an effective and well-tolerated vaccine is an essential part of pandemic preparedness plans. This phase III, randomized, double-blind study was conducted to assess the immunogenicity and safety profile of an alum-adjuvanted, whole virion, pre-pandemic influenza A/H5N1 vaccine (MG1109). Healthy individuals were randomly assigned, in a 3:1 ratio, to receive two doses of either MG1109 or placebo containing alum gel. Immunogenicity was determined by hemagglutination inhibition (HI) and microneutralization (MN) assays. Solicited and unsolicited adverse events were assessed after vaccination. Among 420 enrolled subjects, 418 were available for safety analysis, and 298 MG1109 recipients were available for per-protocol immunogenicity analyses. According to the HI assays, after two vaccine doses, all three of the Committee for Medicinal Products for Human Use (CHMP) criteria were met against the vaccine strain for all age groups: seroprotection rate = 74.8% (95% CI: 69.9 - 79.8), seroconversion rate = 67.8% (95% CI: 62.5-73.1), and geometric mean titer ratio (GMTR) = 5.9 (95% CI: 5.4 - 6.4). According to the MN assays, the GMTR was 2.4 (95% CI: 2.1 - 2.7) and 7.0 (95% CI: 6.3 - 7.9) three weeks after the first and second vaccine doses, respectively. Solicited local and systemic adverse events were mostly mild to moderate and were not significantly different between MG1109 and placebo recipients. In conclusion, two-dose administration of alum-adjuvanted H5N1 pre-pandemic influenza vaccine (MG1109) was highly immunogenic and tolerable in adults.

  11. ZIKA-001: Safety and Immunogenicity of an Engineered DNA Vaccine Against ZIKA virus infection

    Science.gov (United States)

    Tebas, Pablo; Roberts, Christine C; Muthumani, Kar; Reuschel, Emma; White, Scott; Khan, Amir S; Racine, Trina; Choi, Hyeree; Zaidi, Faraz; Boyer, Jean; Kudchodkar, Sagar; Park, Young K; Trottier, Sylvie; Remigio, Celine; Krieger, Diane; Kobinger, Gary P; Weiner, David; Maslow, Joel

    2017-01-01

    Abstract Background While Zika virus (ZIKV) infection is typically self-limited, congenital birth defects and Guillain-Barré syndrome are well-described. There are no therapies or vaccines against ZIKV infection. Methods ZIKA-001 is a phase I, open label, clinical trial designed to evaluate the safety, side effect profile, and immunogenicity of a synthetic, DNA vaccine (GLS-5700) targeting the pre-membrane+envelope proteins (prME) of the virus. Two groups of 20 participants received GLS-5700 at one of two dose levels: 1 mg or 2 mg DNA/dose at 0, 4, and 12 weeks. Vaccine was administered as 0.1 or 0.2 ml (1 or 2 mg) intradermal (ID) injection followed by electroporation (EP) with the CELLECTRA®-3P device Results The median age of the 40 participants was 38 (IQR 30–54) years; 60% were female 30% Latino and 78% white. No SAEs have been reported to date. Local minor AEs were injection site pain, redness, swelling and itching that occurred in half of the participants. Systemic adverse events were rare and included headache, myalgias, upper respiratory infections, fatigue/malaise and nausea. Four weeks after the first dose 25% vs. 60% of the participants in the 1 mg and 2 mg dose seroconverted. By week 6, 2 weeks after the second dose, the response was 65 and 84% respectively and 2 weeks after the third dose all participants in both dosing groups developed antibodies. At the end of the vaccination period over 60% of vaccinated person neutralized Zika virus in a vero cell assay and greater than 80% on neuronal cell targets. The protective efficacy of the antibodies generated by the vaccine was evaluated in the lethal IFNAR−/− mouse model. After the intraperitoneal administration of 0.1 ml of either baseline, week 14 serum or PBS the animals were challenged with 106 PFUs of ZIKV PR209 isolate. Whereas animals administered PBS (control) or baseline serum succumbed after a median of 5 days, those pretreated with week 14 serum from study participants survived

  12. Phase I study of safety and immunogenicity of an Escherichia coli-derived recombinant protective antigen (rPA vaccine to prevent anthrax in adults.

    Directory of Open Access Journals (Sweden)

    Bruce K Brown

    Full Text Available BACKGROUND: The fatal disease caused by Bacillus anthracis is preventable with a prophylactic vaccine. The currently available anthrax vaccine requires a lengthy immunization schedule, and simpler and more immunogenic options for protection against anthrax are a priority for development. In this report we describe a phase I clinical trial testing the safety and immunogenicity of an anthrax vaccine using recombinant Escherichia coli-derived, B. anthracis protective antigen (rPA. METHODOLOGY/PRINCIPAL FINDINGS: A total of 73 healthy adults ages 18-40 were enrolled and 67 received 2 injections separated by 4 weeks of either buffered saline placebo, or rPA formulated with or without 704 µg/ml Alhydrogel® adjuvant in increasing doses (5, 25, 50, 100 µg of rPA. Participants were followed for one year and safety and immunologic data were assessed. Tenderness and warmth were the most common post-injection site reactions. No serious adverse events related to the vaccine were observed. The most robust humoral immune responses were observed in subjects receiving 50 µg of rPA formulated with Alhydrogel® with a geometric mean concentration of anti-rPA IgG antibodies of 283 µg/ml and a toxin neutralizing geometric 50% reciprocal geometric mean titer of 1061. The highest lymphoproliferative peak cellular response (median Lymphocyte Stimulation Index of 29 was observed in the group receiving 25 µg Alhydrogel®-formulated rPA. CONCLUSIONS/SIGNIFICANCE: The vaccine was safe, well tolerated and stimulated a robust humoral and cellular response after two doses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00057525.

  13. REVIEW OF SAFETY AND TOLERANCE OF OMALIZUMAB

    Directory of Open Access Journals (Sweden)

    A.V. Emel'yanov

    2008-01-01

    Full Text Available The review of safety of monoclonal anti-ige-antibodies (xolair — a new medication for the treatment of severe allergic bronchial asthma is presented. Local and system adverse events, originating after injection of medicament in clinical studies and following administration in patients are discussed.Key words: children, bronchial asthma, monoclonal anti Ige antibodies.

  14. Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report.

    Science.gov (United States)

    Tebas, Pablo; Roberts, Christine C; Muthumani, Kar; Reuschel, Emma L; Kudchodkar, Sagar B; Zaidi, Faraz I; White, Scott; Khan, Amir S; Racine, Trina; Choi, Hyeree; Boyer, Jean; Park, Young K; Trottier, Sylvie; Remigio, Celine; Krieger, Diane; Spruill, Susan E; Bagarazzi, Mark; Kobinger, Gary P; Weiner, David B; Maslow, Joel N

    2017-10-04

    Background Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection. Methods In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks. Results The median age of the participants was 38 years, and 60% were women; 78% were white, and 22% black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-β receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer. Conclusions In this phase 1, open-label clinical

  15. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine

    Science.gov (United States)

    Naud, Paulo S; Roteli-Martins, Cecilia M; De Carvalho, Newton S; Teixeira, Julio C; de Borba, Paola C; Sanchez, Nervo; Zahaf, Toufik; Catteau, Gregory; Geeraerts, Brecht; Descamps, Dominique

    2014-01-01

    HPV-023 (NCT00518336; ClinicalTrial.gov) is a long-term follow-up of an initial double-blind, randomized (1:1), placebo-controlled study (HPV-001, NCT00689741) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities, persistence of immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine. Among the women, aged 15–25 years, enrolled in HPV-001 and who participated in the follow-up study HPV-007 (NCT00120848), a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up (HPV-023) for a total of 113 months (9.4 years). During HPV-023, anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay (ELISA) and pseudovirion-based neutralisation assay (PBNA). Cervical samples were tested for HPV DNA every 6 months, and cyto-pathological examinations were performed annually. During HPV-023, no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group. Vaccine efficacy (VE) against HPV-16/18 incident infection was 100% (95%CI: 66.1, 100). Over the 113 months (9.4 years), VE was 95.6% (86.2, 99.1; 3/50 cases in vaccine and placebo groups, respectively) against incident infection, 100% (84·1, 100; 0/21) against 6-month persistent infection (PI); 100% (61·4, 100; 0/10) against 12-month PI; 97·1% (82.5, 99.9; 1/30) against ≥ ASC-US; 95·0% (68.0, 99.9; 1/18) against ≥ LSIL; 100% (45.2, 100; 0/8) against CIN1+; and 100% (–128.1, 100; 0/3) against CIN2+ associated with HPV-16/18. All vaccinees remained seropositive to HPV-16/18, with antibody titers remaining several folds above natural infection levels, as measured by ELISA and PBNA. There were no safety concerns. To date, these data represent the longest follow-up reported for a licensed HPV vaccine. PMID:25424918

  16. Phase 1 safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1 B'/C candidate vaccine.

    Directory of Open Access Journals (Sweden)

    Sandhya Vasan

    Full Text Available BACKGROUND: We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B'/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers. METHODOLOGY/PRINCIPAL FINDINGS: ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1x10(7 (low, 5x10(7 (mid, or 2.5x10(8 pfu (high] volunteers were randomized in a 3:1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA. ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNgamma ELISpot response rate to any HIV antigen was 0/12 (0% in the placebo group, 3/12 (25% in the low dosage group, 6/12 (50% in the mid dosage group, and 8/13 (62% in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%, 8/13 (62%, 6/12 (50% and 10/13 (77% in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement

  17. Safety, reactogenicity and immunogenicity of the human rotavirus vaccine in preterm European Infants: a randomized phase IIIb study.

    Science.gov (United States)

    Omenaca, Felix; Sarlangue, Jean; Szenborn, Leszek; Nogueira, Marta; Suryakiran, Pemmaraju V; Smolenov, Igor V; Han, Htay H

    2012-05-01

    Rotavirus disease is more severe in preterm infants than in full-term infants. This study assessed the safety, reactogenicity and immunogenicity of a human rotavirus vaccine, RIX4414, in European preterm infants. A total of 1009 preterm infants were randomized (2:1, vaccine:placebo) and stratified into 2 groups: 20% of early (27-30 weeks, group 1) and 80% of late (31-36 weeks, group 2) gestational age preterm infants in each group. Two doses of RIX4414/placebo were administered to these preterm infants according to the recommended chronologic age for full-term infants with an interval of 30-83 days between doses. Serious adverse events were recorded throughout the study period. Solicited and unsolicited adverse events were recorded for 15 and 31 days post-each dose. Antirotavirus IgA concentrations (enzyme-linked immunosorbent assay cutoff = 20 U/mL) and geometric mean concentration were determined pre-dose 1 and 30-83 days post-dose 2 in a subset of 300 infants. This study is registered with ClinicalTrials.gov, number NCT00420745 (eTrack106481). Serious adverse events were reported at a similar frequency in both groups (P = 0.266). Fifty-seven infants reported at least 1 serious adverse event (5.1% [3.5-7.0] in the RIX4414 group and 6.8% [4.3-10.0] in the placebo group). During the 15-day postvaccination follow-up period, diarrhea, vomiting and fever occurred at a similar frequency in both groups; fever could have been due to concomitant vaccines. Five cases (RIX4414 = 3, Placebo = 2) of rotavirus gastroenteritis were reported. The onset of rotavirus gastroenteritis in the RIX4414 group was 1-5 days after vaccination (vaccine strain identified in all cases) and in the placebo group it was 3-4 days after receiving placebo (wild-type rotavirus identified from both cases). Antirotavirus IgA seroconversion rates at 30-83 days post-dose 2 were 85.7% (79.0-90.9) in the RIX4414 group and 16.0% (8.8-25.9) in the placebo group. Geometric mean concentrations were 202.2 U

  18. Safety and immunogenicity of the recombinant BCG vaccine VPM1002 in a phase 1 open-label randomized clinical trial.

    Science.gov (United States)

    Grode, Leander; Ganoza, Christian A; Brohm, Christiane; Weiner, January; Eisele, Bernd; Kaufmann, Stefan H E

    2013-02-18

    Current vaccination using Mycobacterium bovis bacillus Calmette-Guérin (BCG), fails to prevent pulmonary tuberculosis (TB). New vaccination strategies are essential for reducing the global incidence of TB. We assessed the safety and immunogenicity of VPM1002, a recombinant BCG vaccine candidate. EudraCT (2007-002789-37) and ClinicalTrials.gov (NCT00749034). Healthy volunteers were enrolled in a phase 1 open-label, dose escalation randomized clinical trial, and received one intradermal dose of VPM1002 (Mycobacterium bovis BCG ΔureC::hly Hm(R)) or BCG. Immunogenicity was assessed by interferon-gamma (IFN-γ) production, cellular immune response markers by flow cytometry and serum antibodies against mycobacterial antigens. Eighty volunteers were randomized into two groups according to previous BCG vaccination and mycobacterial exposure (BCG-naïve, n=40 and BCG-immune, n=40). In each group, 30 individuals were vaccinated with VPM1002 (randomized to three escalating doses) and 10 with BCG. VPM1002 was safe and stimulated IFN-γ-producing and multifunctional T cells, as well as antibody-producing B cells in BCG-naïve and BCG-immune individuals. VPM1002 was safe and immunogenic for B-cell and T-cell responses and hence will be brought forward through the clinical trial pipeline. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Immunogenicity and safety of cell-derived MF59®-adjuvanted A/H1N1 influenza vaccine for children

    Science.gov (United States)

    Knuf, Markus; Leroux-Roels, Geert; Rümke, Hans; Rivera, Luis; Pedotti, Paola; Arora, Ashwani Kumar; Lattanzi, Maria; Kieninger, Dorothee; Cioppa, Giovanni Della

    2015-01-01

    Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza. We evaluated the immunogenicity, safety, and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents. This was a randomized, single-blind, multicenter study with a total of 666 healthy subjects aged 6 months–17 y in one of 3 vaccination groups, each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59. A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations. Antibody titers were assessed by hemagglutination inhibition (HI) and microneutralization assays obtained on days 1, 22, 43, 366, and 387 (3 weeks post booster). Safety was monitored throughout the study. One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50% MF59 (3.75_halfMF59) or 7.5 μg of A/H1N1 antigen formulated with 100% MF59 (7.5_fullMF59) induced an HI titer ≥1:40 in >70% of children in the 1–vaccinations with nonadjuvanted 15 μg A/H1N1 antigen were needed to achieve this response in the 1–children aged 6–11 months, 1 dose of 7.5_fullMF59 resulted in an HI titer ≥1:40 in >70% while 2 doses of 3.75_halfMF59 were required to achieve this result. All vaccines were well tolerated. Our findings support the immunogenicity and safety of the 3.75_halfMF59 (2 doses for children vaccine formulations for use in children and adolescents aged 6 months to 17 y The use of the 3.75_halfMF59 could have the benefit of antigen and adjuvant sparing, increasing the available vaccine doses allowing vaccination of more people. PMID:25621884

  20. Safety and Immunogenicity of the Malaria Vaccine Candidate MSP3 Long Synthetic Peptide in 12–24 Months-Old Burkinabe Children

    Science.gov (United States)

    Sirima, Sodiomon B.; Tiono, Alfred B.; Ouédraogo, Alphonse; Diarra, Amidou; Ouédraogo, André Lin; Yaro, Jean Baptiste; Ouédraogo, Espérance; Gansané, Adama; Bougouma, Edith C.; Konaté, Amadou T.; Kaboré, Youssouf; Traoré, Abdoulaye; Roma, Chilengi; Soulama, Issiaka; Luty, Adrian J. F.; Cousens, Simon; Nébié, Issa

    2009-01-01

    Background A Phase Ia trial in European volunteers of the candidate vaccine merozoite surface protein 3 (MSP3), a Plasmodium falciparum blood stage membrane, showed that it induces biologically active antibodies able to achieve parasite killing in vitro, while a phase Ib trial in semi-immune adult volunteers in Burkina Faso confirmed that the vaccine was safe. The aim of this study was to assess the safety and immunogenicity of this vaccine candidate in children aged 12–24 months living in malaria endemic area of Burkina Faso. Methods The study was a double-blind, randomized, controlled, dose escalation phase Ib trial, designed to assess the safety, reactogenicity and immunogenicity of three doses of either 15 or 30 µg of MSP3-LSP adsorbed on aluminum hydroxide in 45 children 12 to 24 months of age randomized into three equal groups. Each group received 3 vaccine doses (on days 0, 28 and 56) of either 15 µg of MSP3-LSP, 30 µg of MSP3-LSP or of the Engerix B hepatitis B vaccine. Children were visited at home daily for the 6 days following each vaccination to solicit symptoms which might be related to vaccination. Serious adverse events occurring during the study period (1 year) were recorded. Antibody responses to MSP3-LSP were measured on days 0, 28, 56 and 84. Results All 45 enrolled children received three MSP3 vaccine doses. No serious adverse events were reported. Most of the adverse events reported were mild to moderate in severity. The only reported local symptoms with grade 3 severity were swelling and induration, with an apparently dose related response. All grade 3 adverse events resolved without any sequelae. Both MSP3 doses regimens were able to elicit high levels of anti-MSP3 specific IgG1 and IgG3 antibodies in the volunteers with very little or no increase in IgG2, IgG4 and IgM classes: i.e. vaccination induced predominantly the isotypes involved in the monocyte-dependent mechanism of P. falciparum parasite-killing. Conclusion Our results support

  1. Safety and immunogenicity of Ontario Rabies Vaccine Bait (ONRAB) in the first us field trial in raccoons (Procyon lotor).

    Science.gov (United States)

    Slate, Dennis; Chipman, Richard B; Algeo, Timothy P; Mills, Samuel A; Nelson, Kathleen M; Croson, Christopher K; Dubovi, Edward J; Vercauteren, Kurt; Renshaw, Randall W; Atwood, Todd; Johnson, Shylo; Rupprecht, Charles E

    2014-07-01

    In 2011, we conducted a field trial in rural West Virginia, USA to evaluate the safety and immunogenicity of a live, recombinant human adenovirus (AdRG1.3) rabies virus glycoprotein vaccine (Ontario Rabies Vaccine Bait; ONRAB) in wild raccoons (Procyon lotor) and striped skunks (Mephitis mephitis). We selected ONRAB for evaluation because of its effectiveness in raccoon rabies management in Ontario and Quebec, Canada, and significantly higher antibody prevalence rates in raccoons compared with a recombinant vaccinia-rabies glycoprotein (V-RG) vaccine, Raboral V-RG®, in US-Canada border studies. Raccoon rabies was enzootic and oral rabies vaccination (ORV) had never been used in the study area. We distributed 79,027 ONRAB baits at 75 baits/km(2) mostly by fixed-wing aircraft along parallel flight lines at 750-m intervals. Antibody prevalence was significantly higher at 49.2% (n=262) in raccoons after ONRAB was distributed than the 9.6% (n=395) before ORV. This was the highest antibody prevalence observed in raccoons by US Department of Agriculture Wildlife Services for areas with similar management histories evaluated before and after an initial ORV campaign at 75 baits/km(2) with Raboral V-RG. Tetracycline biomarker (TTCC) was significantly higher among antibody-positive raccoons after ONRAB baiting and was similar among raccoons before ORV had been conducted, an indication of vaccine-induced rabies virus-neutralizing antibody production following consumption of bait containing TTCC. Skunk sample size was inadequate to assess ONRAB effects. Safety and immunogenicity results supported replication of this field trial and led to a recommendation for expanded field trials in 2012 to evaluate safety and immunogenicity of ground-distributed ONRAB at 150 baits/km(2) in residential and commercial habitats in Ohio, USA and aerially distributed ONRAB at 75 baits/km(2) in rural habitats along US-Quebec border.

  2. Safety, efficacy and tolerability of meprasilm in the treatment of ...

    African Journals Online (AJOL)

    A clinical trial was carried out to establish the tolerability, safety and efficacy of Meprasil brand of omeprazole among Nigerians with acid peptic disease using 20mg daily or 20mg bid of Meprasil. Forty patients were enrolled for the study and were asked to rate their abdominal pains pre-commencement of therapy using a ...

  3. Oral ganciclovir in children : Pharmacokinetics, safety, tolerance, and antiviral effects

    NARCIS (Netherlands)

    Frenkel, LM; Capparelli, EV; Dankner, WM; Smith, IL; Ballow, A; Culnane, M; Read, JS; Thompson, M; Mohan, KM; Shaver, A; Robinson, CA; Stempien, MJ; Burchett, SK; Melvin, AJ; Borkowsky, W; Petru, A; Kovacs, A; Yogev, R; Goldsmith, J; McFarland, EJ; Spector, SA

    2000-01-01

    The pharmacokinetics, safety, tolerance, and antiviral effects of ganciclovir (Gcv) administered orally were evaluated in 36 children infected with cytomegalovirus (CMV) who were severely immunocompromised by infection with human immunodeficiency virus type 1, In this dose-escalation study, 30 mg/kg

  4. Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

    NARCIS (Netherlands)

    van Meer, P.J.K.; Kooijman, M.; Brinks, V.; Gispen-de Wied, C.C.; Silva-Lima, B.; Moors, E.H.M.; Schellekens, H.

    2013-01-01

    The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not

  5. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults.

    Science.gov (United States)

    Greenberg, David P; Robertson, Corwin A; Noss, Michael J; Blatter, Mark M; Biedenbender, Rex; Decker, Michael D

    2013-01-21

    To evaluate the safety and immunogenicity of a prototype quadrivalent inactivated influenza vaccine (QIV) containing two influenza B strains, one of each lineage, compared with licensed trivalent inactivated influenza vaccines (TIVs) containing either a Victoria B-lineage strain (2009-2010 TIV) or a Yamagata B-lineage strain (2008-2009 TIV). Healthy adults ≥18 years of age were eligible to participate in this phase II, open-label, randomized, controlled, multicenter study conducted in the US. Participants received a single dose of 2009-2010 TIV, 2008-2009 TIV, or QIV. Sera were collected before and 21 days after vaccine administration to test for hemagglutination inhibition (HAI) antibodies to each of the four influenza strains. Immunogenicity endpoints included geometric mean HAI antibody titers (GMTs) and rates of seroprotection (titer ≥1:40) and seroconversion (4-fold rise pre- to post-vaccination). Safety endpoints included frequency of solicited injection-site and systemic reactions occurring within 3 days of vaccination, and unsolicited non-serious adverse events (AEs) and serious AEs (SAEs) within 21 days of vaccination. One hundred and ninety participants were enrolled to each vaccine group. QIV induced GMTs to each A and B strain that were noninferior to those induced by the 2009-2010 and 2008-2009 TIVs (i.e., lower limit of the two-sided 95% confidence interval of the ratio of GMT(QIV)/GMT(TIV)>0.66 for each strain). Rates of seroprotection and seroconversion were similar in all groups. Incidence and severity of solicited injection-site and systemic reactions, AEs, and SAEs were similar among groups. QIV, containing two B strains (one from each B lineage), was as safe and immunogenic as licensed TIV. QIV has the potential to be a useful alternative to TIV and offer protection against both B lineages. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Enhanced Maritime Safety through Diagnosis and Fault Tolerant Control

    DEFF Research Database (Denmark)

    Blanke, Mogens

    2001-01-01

    -tolerant control is a methodology to help prevent that faults develop into failure. The means include on-line fault diagnosis, automatic condition assessment and calculation of remedial action to avoid hazards. This paper gives an overview of methods to obtain fault-tolerance: fault diagnosis; analysis......Faults in steering, navigation instruments or propulsion machinery are serious on a marine vessel since the consequence could be loss of maneuvering ability, and imply risk of damage to vessel personnel or environment. Early diagnosis and accomodation of faults could enhance safety. Fault...

  7. Safety and immunogenicity of a candidate bioconjugate vaccine against Shigella dysenteriae type 1 administered to healthy adults: A single blind, partially randomized Phase I study.

    Science.gov (United States)

    Hatz, Christoph F R; Bally, Bettina; Rohrer, Susanne; Steffen, Robert; Kramme, Stefanie; Siegrist, Claire-Anne; Wacker, Michael; Alaimo, Cristina; Fonck, Veronica Gambillara

    2015-08-26

    Shigellae cause severe disease in endemic countries, especially in children. Several efficacy trials have been conducted with candidate vaccines against Shigellae, but the lack of protection, the safety concerns, or manufacturing challenges hindered successful market approval. Conjugated vaccines have been shown to be safe and effective for different pathogens (i.e., Neisseria meningitidis, Shigella pneumonia, Haemophilus influenzae). The bio-conjugation technology, exploited here for the Shigella dysenteriae candidate vaccine, offers a novel and potentially simpler way to develop and produce vaccines against one of the major causes of morbidity and mortality in developing countries. A novel S. dysenteriae bioconjugate vaccine (GVXN SD133) made of the polysaccharide component of the Shigella O1 lipopolysaccharide, conjugated to the exotoxin protein A of Pseudomonas aeruginosa (EPA), was evaluated for immunogenicity and safety in healthy adults in a single blind, partially randomized Phase I study. Forty subjects (10 in each dose group; 2 μg or 10 μg with or without aluminium adjuvant) received two injections 60 days apart and were followed-up for 150 days. Both doses and formulations were well tolerated; the safety and reactogenicity profiles were consistent with that of other conjugated vaccines, adjuvanted or not, independent of the dose and the number of injections. The GVXN SD133 vaccine elicited statistically significant O1 specific humoral responses at all time points in all vaccination groups. Between-group comparisons did not show statistically significant differences in geometric mean titers of immunoglobulin G and A at any post-vaccination time point. This study demonstrated that the GVXN SD133 vaccine has a satisfactory safety profile. It elicited a significant humoral response to Shigella O1 polysaccharides at all doses tested. The protein carrier also elicited functional antibodies, showing the technology's advantages in preserving both sugar and

  8. A dose-escalation safety and immunogenicity study of a new live attenuated human rotavirus vaccine (Rotavin-M1) in Vietnamese children.

    Science.gov (United States)

    Dang, Duc Anh; Nguyen, Van Trang; Vu, Dinh Thiem; Nguyen, Thi Hien Anh; Nguyen, Duc Mao; Yuhuan, Wang; Baoming, Jiang; Nguyen, Dang Hien; Le, Thi Luan

    2012-04-27

    We tested a candidate live, oral, rotavirus vaccine (Rotavin-M1™) derived from an attenuated G1P [8] strain (KH0118-2003) isolated from a child in Vietnam. The vaccine was tested first for safety in 29 healthy adults. When deemed safe, it was further tested for safety and immunogenicity in 160 infants (4 groups) aged 6-12 weeks in a dose and schedule ranging study. The vaccine was administered in low titer (10(6.0)FFU/dose) on a 2-dose schedule given 2 months apart (Group 2L) and on a 3-dose schedule given 1 month apart (Group 3L) and in high titer (10(6.3)FFU/dose) in 2 doses 2 months apart (Group 2H) and in 3 doses 1 month apart (Group 3H). For comparison, 40 children (group Rotarix™) were given 2 doses of the lyophilized Rotarix™ vaccine (10(6.5)CCID(50)/dose) 1 month apart. All infants were followed for 30 days after each dose for clinical adverse events including diarrhea, vomiting, fever, abdominal pain, irritability and intussusception. Immunogenicity was assessed by IgA seroconversion and viral shedding was monitored for 7 days after administration of each dose. Two doses of Rotavin-M1 (10(6.3)FFU/dose) were well tolerated in adults. Among infants (average 8 weeks of age at enrollment), administration of Rotavin-M1 was safe and did not lead to an increased rate of fever, diarrhea, vomiting or irritability compared to Rotarix™, indicating that the candidate vaccine virus had been fully attenuated by serial passages. No elevation of levels of serum transaminase, blood urea, or blood cell counts were observed. The highest rotavirus IgA seroconversion rate (73%, 95%CI (58-88%)) was achieved in group 2H (2 doses--10(6.3)FFU/dose, 2 months apart). The 2 dose schedules performed slightly better than the 3 dose schedules and the higher titer doses performed slightly better than the lower titer doses. These rates of seroconversion were similar to that of the Rotarix™ group (58%, 95%CI (42-73%)). However more infants who received Rotarix™ (65%) shed virus

  9. Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Bines, Julie E; Danchin, Margaret; Jackson, Pamela; Handley, Amanda; Watts, Emma; Lee, Katherine J; West, Amanda; Cowley, Daniel; Chen, Mee-Yew; Barnes, Graeme L; Justice, Frances; Buttery, Jim P; Carlin, John B; Bishop, Ruth F; Taylor, Barry; Kirkwood, Carl D

    2015-12-01

    Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55-0·88; pvaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44-0·81; pvaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. RV3-BB vaccine was

  10. Immunogenicity and safety of Southern Hemisphere inactivated quadrivalent influenza vaccine: a Phase III, open-label study of adults in Brazil.

    Science.gov (United States)

    Zerbini, Cristiano A F; Ribeiro Dos Santos, Rodrigo; Jose Nunes, Maria; Soni, Jyoti; Li, Ping; Jain, Varsha K; Ofori-Anyinam, Opokua

    The World Health Organization influenza forecast now includes an influenza B strain from each of the influenza B lineages (B/Yamagata and B/Victoria) for inclusion in seasonal influenza vaccines. Traditional trivalent influenza vaccines include an influenza B strain from one lineage, but because two influenza B lineages frequently co-circulate, the effectiveness of trivalent vaccines may be reduced in seasons of influenza B vaccine-mismatch. Thus, quadrivalent vaccines may potentially reduce the burden of influenza compared with trivalent vaccines. In this Phase III, open-label study, we assessed the immunogenicity and safety of Southern Hemisphere inactivated quadrivalent influenza vaccine (Fluarix™ Tetra) in Brazilian adults (NCT02369341). The primary objective was to assess hemagglutination-inhibition antibody responses against each vaccine strain 21 days after vaccination in adults (aged ≥18-60 years) and older adults (aged >60 years). Solicited adverse events for four days post-vaccination, and unsolicited adverse events and serious adverse events for 21 days post-vaccination were also assessed. A total of 63 adults and 57 older adults received one dose of inactivated quadrivalent influenza vaccine at the beginning of the 2015 Southern Hemisphere influenza season. After vaccination, in adults and older adults, the hemagglutination-inhibition titers fulfilled the European licensure criteria for immunogenicity. In adults, the seroprotection rates with HI titer ≥1:40 were 100% (A/H1N1), 98.4% (A/H3N2), 100% (B/Yamagata), and 100% (B/Victoria); in older adults were 94.7% (A/H1N1), 96.5% (A/H3N2), 100% (B/Yamagata), and 100% (B/Victoria). Pain was the most common solicited local adverse events in adults (27/62) and in older adults (13/57), and the most common solicited general adverse events in adults was myalgia (9/62), and in older adults were myalgia and arthralgia (both 2/57). Unsolicited adverse events were reported by 11/63 adults and 10/57 older adults

  11. Safety and immunogenicity of Brucella abortus strain RB51 vaccine in cross bred cattle calves in India.

    Science.gov (United States)

    Singh, Rashmi; Basera, Sanjay Singh; Tewari, Kamal; Yadav, Shweta; Joshi, Sumit; Singh, Brajesh; Mukherjee, Falguni

    2012-03-01

    Safety and immunogenicity of Brucella abortus RB51 vaccine has been evaluated in an organised dairy farm in India. All the cattle (r = 29) vaccinated with strain RB51 'responded' to the vaccine as demonstrated by iELISA using acetone killed strain RB51 antigen. The percentage responders at day 35, 60 and 90 post vaccination were 100%, 95% and 20%, respectively. Strain RB51 was able to elicit a good IFN-gamma response from vaccinated animals. The post-vaccination time point analysis indicated that the cumulative IFN-gamma response of whole blood from vaccinates stimulated with heat killed RB51 antigen was elicited in 80% of calves at 60 days post vaccination. Absence of strain RB51 in the secretions and excretion and lack of local or systemic reaction indicated the safety of the vaccine.

  12. Fall Protection Characteristics of Safety Belts and Human Impact Tolerance.

    Science.gov (United States)

    Hino, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

    2014-08-23

    Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt1), which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness2, 3), which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference4-9) to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model10) was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls.

  13. Fall protection characteristics of safety belts and human impact tolerance.

    Science.gov (United States)

    Hino, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

    2014-01-01

    Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt, which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness, which has been used in many other countries. To determine human tolerance for impact trauma, this study discusses features of safety belts with reference to relevant studies in the medical science, automobile crash safety, and aircrew safety. For this purpose, simple drop tests were carried out in a virtual workplace to measure impact load, head acceleration, and posture in the experiments, the Hybrid-III pedestrian model was used as a human dummy. Hybrid-III is typically employed in official automobile crash tests (New Car Assessment Program: NCAP) and is currently recognized as a model that faithfully reproduces dynamic responses. Experimental results shows that safety performance strongly depends on both the variety of safety belts used and the shock absorbers attached onto lanyards. These findings indicate that fall prevention equipment, such as safety belts, lanyards, and shock absorbers, must be improved to reduce impact injuries to the human head and body during falls.

  14. Fall Protection Characteristics of Safety Belts and Human Impact Tolerance

    OpenAIRE

    HINO, Yasumichi; Ohdo, Katsutoshi; Takahashi, Hiroki

    2014-01-01

    Abstract: Many fatal accidents due to falls from heights have occurred at construction sites not only in Japan but also in other countries. This study aims to determine the fall prevention performance of two types of safety belts: a body belt1 ), which has been used for more than 40 yr in the Japanese construction industry as a general type of safety equipment for fall accident prevention, and a full harness2, 3 ), which has been used in many other countries. To determine human tolerance for ...

  15. Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.

    Science.gov (United States)

    Norrby, Maria; Vesikari, Timo; Lindqvist, Lars; Maeurer, Markus; Ahmed, Raija; Mahdavifar, Shahnaz; Bennett, Sean; McClain, J Bruce; Shepherd, Barbara M; Li, Daner; Hokey, David A; Kromann, Ingrid; Hoff, Søren T; Andersen, Peter; de Visser, Adriëtte W; Joosten, Simone A; Ottenhoff, Tom H M; Andersson, Jan; Brighenti, Susanna

    2017-03-14

    Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150μg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50μg of H4 in combination with the 500nmol IC31 adjuvant dose. The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50μg of H4 and 500nmol of IC31. ClinicalTrials.gov, NCT02066428 and NCT02074956. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study.

    Science.gov (United States)

    Togashi, Takehiro; Mitsuya, Nodoka; Kogawara, Osamu; Sumino, Shuji; Takanami, Yohei; Sugizaki, Kayoko

    2016-08-31

    Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0μg/mL, after the primary series. Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (pvaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns. Registered on ClinicalTrials.gov: NCT01379846. Copyright © 2016 The Authors

  17. In a randomized trial, the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination

    Science.gov (United States)

    Whitehead, Stephen S.; Durbin, Anna P.; Pierce, Kristen K.; Elwood, Dan; McElvany, Benjamin D.; Fraser, Ellen A.; Carmolli, Marya P.; Tibery, Cecilia M.; Hynes, Noreen A.; Jo, Matthew; Lovchik, Janece M.; Larsson, Catherine J.; Doty, Elena A.; Dickson, Dorothy M.; Luke, Catherine J.; Subbarao, Kanta; Kirkpatrick, Beth D.

    2017-01-01

    Infection caused by the four serotypes of dengue virus (DENV-1-4) is a leading cause of mosquito-borne disease. Clinically-severe dengue disease is more common when secondary dengue infection occurs following prior infection with a heterologous dengue serotype. Other flaviviruses such as yellow fever virus, Japanese encephalitis virus, and Zika virus, can also elicit antibodies which are cross-reactive to DENV. As candidate dengue vaccines become available in endemic settings and for individuals who have received other flavivirus vaccines, it is important to examine vaccine safety and immunogenicity in these flavivirus-experienced populations. We performed a randomized, controlled trial of the National Institutes of Health live attenuated tetravalent dengue vaccine candidate (TV003) in fifty-eight individuals with prior exposure to flavivirus infection or vaccine. As in prior studies of this vaccine in flavivirus-naive volunteers, flavivirus-experienced subjects received two doses of vaccine six months apart and were followed closely for clinical events, laboratory changes, viremia, and neutralizing antibody titers. TV003 was well tolerated with few adverse events other than rash, which was predominately mild. Following one dose, 87% of vaccinees had an antibody response to all four serotypes (tetravalent response), suggesting a robust immune response. In addition, 76% of vaccinees were viremic; mean peak titers ranged from 0.68–1.1 log10 PFU/mL and did not differ by serotype. The second dose of TV003 was not associated with viremia, rash, or a sustained boost in antibody titers indicating that a single dose of the vaccine is likely sufficient to prevent viral replication and thus protect against disease. In comparison to the viremia and neutralizing antibody response elicited by TV003 in flavivirus-naïve subjects from prior studies, we found that subjects who were flavivirus-exposed prior to vaccination exhibited slightly higher DENV-3 viremia, higher

  18. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033.

    Science.gov (United States)

    Tran, Jonathan Q; Rana, Jitesh; Barkhof, Frederik; Melamed, Isaac; Gevorkyan, Hakop; Wattjes, Mike P; de Jong, Remko; Brosofsky, Kristin; Ray, Soma; Xu, Lei; Zhao, Jim; Parr, Edward; Cadavid, Diego

    2014-08-01

    To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS). In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1-100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3-100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated. All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low. The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders. This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0-7.6%).

  19. Assessment of Tolerability and Safety of Monocomponent Complementary Food Products in the Diet of Infants With Risk for Allergic Diseases

    Directory of Open Access Journals (Sweden)

    L. S. Namazova-Baranova

    2016-01-01

    Full Text Available Background: Children with burdened allergological history and/or having preliminary allergy manifestations need the effective prevention of allergy from the first months of life.Objective: Our aim was to assess the tolerability, safety, and efficacy of monocomponent complementary food products in the diet of infants with high risk for allergic diseases.Methods: Tolerability, safety, and efficacy of monocomponent complementary food products (vegetable puree, fruit juices, and after 6 months — meat sauce were studied in a singlecentre, prospective, comparative study. The symptoms of indigestion, skin allergy symptoms were registered, the results of coprological research and immunogenicity of complementary food products were assessed.Results: The study included 200 children in the age from 5 months from the risk group of allergy developing. Children were divided into 4 groups of 50 people. It was found that complementary food products were well tolerated and assimilated by children, did not cause skin and gastrointestinal allergic reactions in healthy children with risk of allergy developing. Food antigens of complementary food components (pumpkin, rabbit meat, turkey meat, apples, pears, plums were characterized by low immunogenicity: the level of specific IgE to the specified products did not change in blood serum and remained at a low level at the beginning and at the end of the study (ranging from 0.01 to 0.03 kE/l.Conclusion: Studied complementary food products (vegetable-, fruit- and meat-based can be used in the diet of children with high risk for allergy.

  20. Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age.

    Science.gov (United States)

    Knuf, Markus; Leroux-Roels, Geert; Rümke, Hans C; Abarca, Katia; Rivera, Luis; Lattanzi, Maria; Pedotti, Paola; Arora, Ashwani; Kieninger-Baum, Dorothee; Della Cioppa, Giovanni

    2015-01-01

    This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects. Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months). A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event. An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the

  1. Safety and immunogenicity of measles-mumps-rubella vaccine in children with congenital immunodeficiency (DiGeorge syndrome).

    Science.gov (United States)

    Azzari, Chiara; Gambineri, Eleonora; Resti, Massimo; Moriondo, Maria; Betti, Letizia; Saldias, Lucien Rojas; G Gelli, Anna M; Vierucci, Alberto

    2005-02-25

    Live attenuated vaccines are usually contraindicated in patients with congenital or acquired immunodeficiency. On the other hand, infections due to wild type virus may be particularly severe in patients with low levels of T cells. The aim of the present study was to evaluate safety and immunogenicity of measles-mumps-rubella (MMR) vaccine in children with congenital T cell defect (DiGeorge anomaly). Fourteen patients were included in the study. No severe adverse reaction was reported. No difference between patients and controls was found in frequency of seroconversion for both measles (92.9% versus 96.3%) and rubella (92.9% versus 100%). No difference in mean titres of anti-measles (1.62+/-0.54 versus 1.89+/-0.49 index) (p=0.13) or anti-rubella (78.1+/-48.0 versus 72.0+/-41.0 UI/ml, p=0.68) antibodies was found between patients and controls. No decrease in CD4 cells was detected after immunization. MMR vaccine is immunogenic and can be safely used in patients with DiGeorge anomaly, so preventing severe complication due to wild virus infection.

  2. Immunogenicity and safety of a single dose of a CRM-conjugated meningococcal ACWY vaccine in children and adolescents aged 2-18 years in Taiwan: results of an open label study.

    Science.gov (United States)

    Huang, Li-Min; Chiu, Nan-Chang; Yeh, Shu-Jen; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

    2014-09-08

    MenACWY-CRM (Menveo®, Novartis Vaccines, Siena, Italy) is a quadrivalent meningococcal conjugate vaccine developed to help prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W, and Y. It is approved within the European Union in persons >2 years of age and in persons from 2 months to 55 years of age in the United States, among other countries. Little is known about the immunogenicity and safety of this vaccine in Taiwanese children >2 years and adolescents. This study assessed the immunogenicity and safety of a single injection of MenACWY-CRM vaccine in Taiwanese subjects aged 2-18 years old. In this phase III, multicentre, open-label study 341 subjects received one dose of MenACWY-CRM. Immunogenicity measures were rates of seroresponse (defined as the proportion of subjects with a postvaccination hSBA ≥1:8 if the prevaccination (baseline) titre was CRM vaccination at Day 29 for the serogroups A, C, W, and Y were 83%, 93%, 50%, and 65%, respectively. At Day 29 the percentages of subjects with hSBA ≥1:8 against all four serogroups A, C, W and Y were: 83%, 96%, 96% and 82%, respectively. GMTs against all serogroups rose by ≥7-fold from baseline to Day 29. The vaccine was well tolerated. A single dose of MenACWY-CRM demonstrated a robust immune response, and an acceptable safety profile in Taiwanese children and adolescents. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Safety, immunogenicity, and lot-to-lot consistency of a split-virion quadrivalent influenza vaccine in younger and older adults: a phase III randomized, double-blind clinical trial.

    Science.gov (United States)

    Sesay, Sanie; Brzostek, Jerzy; Meyer, Ingo; Donazzolo, Yves; Leroux-Roels, Geert; Rouzier, Régine; Astruc, Béatrice; Szymanski, Henryk; Toursarkissian, Nicole; Vandermeulen, Corinne; Kowalska, Edyta; Van Damme, Pierre; Salamand, Camille; Pepin, Stephanie

    2017-10-02

    Here, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014-2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18-60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

  4. Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: A randomized, controlled trial of DAR-901.

    Directory of Open Access Journals (Sweden)

    C Fordham von Reyn

    Full Text Available Development of a tuberculosis vaccine to boost BCG is a major international health priority. SRL172, an inactivated whole cell booster derived from a non-tuberculous mycobacterium, is the only new vaccine against tuberculosis to have demonstrated efficacy in a Phase 3 trial. In the present study we sought to determine if a three-dose series of DAR-901 manufactured from the SRL172 master cell bank by a new, scalable method was safe and immunogenic.We performed a single site, randomized, double-blind, controlled, Phase 1 dose escalation trial of DAR-901 at Dartmouth-Hitchcock Medical Center in the United States. Healthy adult subjects age 18-65 with prior BCG immunization and a negative interferon-gamma release assay (IGRA were enrolled in cohorts of 16 subjects and randomized to three injections of DAR-901 (n = 10 per cohort, or saline placebo (n = 3 per cohort, or two injections of saline followed by an injection of BCG (n = 3 per cohort; 1-8 x 106 CFU. Three successive cohorts were enrolled representing DAR-901 at 0.1, 0.3, and 1 mg per dose. Randomization was performed centrally and treatments were masked from staff and volunteers. Subsequent open label cohorts of HIV-negative/IGRA-positive subjects (n = 5 and HIV-positive subjects (n = 6 received three doses of 1 mg DAR-901. All subjects received three immunizations at 0, 2 and 4 months administered as 0.1 mL injections over the deltoid muscle alternating between right and left arms. The primary outcomes were safety and immunogenicity. Subjects were followed for 6 months after dose 3 for safety and had phlebotomy performed for safety studies and immune assays before and after each injection. Immune assays using peripheral blood mononuclear cells included cell-mediated IFN-γ responses to DAR-901 lysate and to Mycobacterium tuberculosis (MTB lysate; serum antibody to M. tuberculosis lipoarabinomannan was assayed by ELISA.DAR-901 had an acceptable safety profile and was well-tolerated at all

  5. Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: A randomized, controlled trial of DAR-901.

    Science.gov (United States)

    von Reyn, C Fordham; Lahey, Timothy; Arbeit, Robert D; Landry, Bernard; Kailani, Leway; Adams, Lisa V; Haynes, Brenda C; Mackenzie, Todd; Wieland-Alter, Wendy; Connor, Ruth I; Tvaroha, Sue; Hokey, David A; Ginsberg, Ann M; Waddell, Richard

    2017-01-01

    Development of a tuberculosis vaccine to boost BCG is a major international health priority. SRL172, an inactivated whole cell booster derived from a non-tuberculous mycobacterium, is the only new vaccine against tuberculosis to have demonstrated efficacy in a Phase 3 trial. In the present study we sought to determine if a three-dose series of DAR-901 manufactured from the SRL172 master cell bank by a new, scalable method was safe and immunogenic. We performed a single site, randomized, double-blind, controlled, Phase 1 dose escalation trial of DAR-901 at Dartmouth-Hitchcock Medical Center in the United States. Healthy adult subjects age 18-65 with prior BCG immunization and a negative interferon-gamma release assay (IGRA) were enrolled in cohorts of 16 subjects and randomized to three injections of DAR-901 (n = 10 per cohort), or saline placebo (n = 3 per cohort), or two injections of saline followed by an injection of BCG (n = 3 per cohort; 1-8 x 106 CFU). Three successive cohorts were enrolled representing DAR-901 at 0.1, 0.3, and 1 mg per dose. Randomization was performed centrally and treatments were masked from staff and volunteers. Subsequent open label cohorts of HIV-negative/IGRA-positive subjects (n = 5) and HIV-positive subjects (n = 6) received three doses of 1 mg DAR-901. All subjects received three immunizations at 0, 2 and 4 months administered as 0.1 mL injections over the deltoid muscle alternating between right and left arms. The primary outcomes were safety and immunogenicity. Subjects were followed for 6 months after dose 3 for safety and had phlebotomy performed for safety studies and immune assays before and after each injection. Immune assays using peripheral blood mononuclear cells included cell-mediated IFN-γ responses to DAR-901 lysate and to Mycobacterium tuberculosis (MTB) lysate; serum antibody to M. tuberculosis lipoarabinomannan was assayed by ELISA. DAR-901 had an acceptable safety profile and was well-tolerated at all dose levels

  6. Immunogenicity of two oat varieties, in relation to their safety for celiac patients.

    Science.gov (United States)

    Maglio, Mariantonia; Mazzarella, Giuseppe; Barone, Maria Vittoria; Gianfrani, Carmen; Pogna, Norberto; Gazza, Laura; Stefanile, Rosita; Camarca, Alessandra; Colicchio, Barbara; Nanayakkara, Merlin; Miele, Erasmo; Iaquinto, Gaetano; Giardullo, Nicola; Maurano, Francesco; Santoro, Pasquale; Troncone, Riccardo; Auricchio, Salvatore

    2011-10-01

    Most of the recent studies suggest that oats are well tolerated by celiac disease (CD) patients. However, it is still possible that different oat cultivars may display different biological properties relevant for CD pathogenesis. We aimed to investigate biological and immunological properties of two oat varieties, Avena genziana and Avena potenza, in relation to their safety for CD patients. Phosphorylation of extracellular signal-regulated kinase (ERK) and trans-epithelial electrical resistance (TEER) were evaluated in CaCo-2 cells treated with peptic-tryptic (PT) digests from the two oats and from gliadin (PTG). With the same PT-digests, duodenal biopsies from 22 CD patients were treated in vitro for 24 h and density of CD25+ cells in lamina propria and of intraepithelial CD3+ T cells was measured, as well as crypt cell proliferation and epithelial expression of interleukin 15. Finally, interferon γ (IFN-γ) production was measured as evidence of gliadin-specific T-cell activation by PT-digests. In contrast to PTG, oats PT-digests were not able to induce significant increase in ERK phosphorylation and decrease in TEER in CaCo-2 cells. In the organ culture system, oats PT-digests, unlike PTG, did not induce significant increase in crypt enterocyte proliferation, increase in interleukin 15 expression or in lamina propria CD25+ cells. Nevertheless Avena potenza increased intraepithelial T-cell density, while Avena genziana-induced IFN-γ production in 3/8 CD intestinal T cell lines. Our data show that Avena genziana and Avena potenza do not display in vitro activities related to CD pathogenesis. Some T-cell reactivity could be below the threshold for clinical relevance.

  7. Safety and immunogenicity of GMZ2 - a MSP3-GLURP fusion protein malaria vaccine candidate

    DEFF Research Database (Denmark)

    Esen, Meral; Kremsner, Peter G; Schleucher, Regina

    2009-01-01

    Malaria is a major public health problem in Sub-Saharan Africa. In highly endemic regions infants, children and pregnant women are mostly affected. An effective malaria vaccine would complement existing malaria control strategies because it can be integrated in existing immunization programs easily....... Here we present the results of the first phase Ia clinical trial of GMZ2 adjuvanted in aluminium hydroxide. GMZ2 is a malaria vaccine candidate, designed upon the rationale to induce immune responses against asexual blood stages of Plasmodium falciparum similar to those encountered in semi...... is a safe and immunogenic malaria vaccine candidate suitable for further clinical development....

  8. Immunogenicity and safety of heat-inactivated hepatitis B vaccine (CLB) in low risk human volunteers and in patients treated with chronic haemodialysis in the Netherlands

    NARCIS (Netherlands)

    Reerink-Brongers, E. E.; Lelie, P. N.; Reesink, H. W.; Dees, P. J.; Brummelhuis, H. G.; van Aken, W. G.

    1983-01-01

    The immunogenicity and safety of a heat-inactivated hepatitis B vaccine (HB-vaccine) were studied in healthy human volunteers (n = 471) at a low risk to be infected with hepatitis B virus (HBV) and in patients on chronic haemodialysis (n = 227), who were treated in hepatitis B free centres. After

  9. Immunogenicity and safety of a plasma-derived heat-inactivated hepatitis B vaccine (CLB). Studies in volunteers at a low risk of infection with hepatitis B virus

    NARCIS (Netherlands)

    Lelie, P. N.; Reesink, H. W.; de Jong-van Manen, S. T.; Dees, P. J.; Reerink-Brongers, E. E.

    1984-01-01

    The safety and immunogenicity of a plasma-derived heat-inactivated hepatitis B vaccine (CLB) were evaluated in 471 healthy human volunteers, who, both in their occupations and in their private lives, had been at minimal risk of being infected with hepatitis B virus. The first 202 individuals

  10. Safety and immunogenicity of the RIVM hexavalent meningococcal B vesicle vaccine for Rotterdam children aged 2-3 and 7-8

    NARCIS (Netherlands)

    Labadie J; Kleijn ED de; Lafeber AB; Mees MMM; Booy K; Groot R de; Omme GW van; Dijken H van; Kuipers AJ; Dobbelsteen G van den; Juttmann RE; Wala M; Alphen AJW van; Rumke HC; Sophia Kinderziekenhuis /; LVO

    2000-01-01

    This report documents the results of a randomised controlled phase-II clinical study into the safety and immunogenicity of the RIVM hexavalent MenB vesicle vaccine among 189 children aged 2-3 and 168 children aged 7-8 in the city of Rotterdam, the Netherlands. Two concentrations of the MenB vesicle

  11. Safety and immunogenicity of subcutaneous or intramuscular administration of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae in healthy volunteers

    NARCIS (Netherlands)

    Laurichesse, H.; Gourdon, F.; Smits, H. L.; Abdoe, T. H.; Estavoyer, J. M.; Rebika, H.; Pouliquen, P.; Catalina, P.; Dubray, C.; Beytout, J.

    2007-01-01

    The safety and immunogenicity of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae was evaluated in 84 volunteers according to the route of administration, i.e., subcutaneous (SC) or intramuscular (IM), in a double-blind randomised trial. The volunteers

  12. The immunogenicity and safety of the new, Indonesian DTwP-HB-Hib vaccine compared to the DTwP/HB vaccine given with the Hib vaccine

    Directory of Open Access Journals (Sweden)

    Novilia Sjafri Bachtiar

    2017-06-01

    Full Text Available Background Haemophilus influenzae type b (Hib causes infection with predominant manifestations of pneumonia, meningitis, and other invasive diseases, occurring primarily in children aged under 2 years, particularly in infants.  The World Health Organization (WHO and Indonesian Technical Advisory Group for Immunization recommend to include the Hib vaccine into the national immunization program. The newly developed DTwP-HB-Hib combination vaccine is anticipated to be the preferred choice for Hib vaccine introduction; it is efficient, simple, and has higher coverage. Objective To evaluate the immunogenicity and safety of a new, combined Bio Farma DTwP-HB-Hib vaccine, compared to the registered Hib monovalent vaccine given simultaneously with the local DTwP-HB vaccine, when used as the primary vaccination of Indonesian infants. Methods A prospective, randomized, open-label, phase II study was conducted on the DTwP-HB-Hib vaccine compared to the Hib (registered vaccine given simultaneously with the DTwP-HB vaccine, in Bandung from July 2011 to January 2012. Infants were serially vaccinated at 6-11, 10-15, and 14-19 weeks. Serological assessments were done prior to the first vaccine dose and 28 days after the third dose. Safety was assessed from the time of first injection until 1 month after the last injection. Results Of 220 healthy infants enrolled, 211 completed the study, with 105 receiving the combined vaccine and 106 the two separate vaccines. All vaccines were well tolerated. No differences in rates of local and systemic reactions were seen between the two methods of administration. No serious adverse events were considered to be related to the vaccines. In the DTwP-HB-Hib primary-vaccination group, at least 98% of the infants reached protective levels of antibodies (seropositivity against the antigens employed in the vaccines while 96% in the control group. Conclusion The DTwP-HB-Hib combined vaccine is immunogenic and safe, as well as

  13. A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in children in Gabon.

    Directory of Open Access Journals (Sweden)

    Bertrand Lell

    2009-10-01

    Full Text Available The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion--based formulation (AS02 and a formulation based on liposomes (AS01.In this Phase II, double-blind study (NCT00307021, 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01(E or RTS,S/AS02(D, on a 0-1-2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02(D/AS01(E of 0.88 (95% CI: 0.68-1.15 post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated.RTS,S/AS01(E proved similarly as well tolerated and immunogenic as RTS,S/AS02(D, completing an essential step in the age de-escalation process within the RTS,S clinical development plan.ClinicalTrials.gov. NCT00307021.

  14. Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial.

    Science.gov (United States)

    Agnandji, Selidji T; Fernandes, José F; Bache, Emmanuel B; Obiang Mba, Régis M; Brosnahan, Jessica S; Kabwende, Lumeka; Pitzinger, Paul; Staarink, Pieter; Massinga-Loembe, Marguerite; Krähling, Verena; Biedenkopf, Nadine; Fehling, Sarah Katharina; Strecker, Thomas; Clark, David J; Staines, Henry M; Hooper, Jay W; Silvera, Peter; Moorthy, Vasee; Kieny, Marie-Paule; Adegnika, Akim A; Grobusch, Martin P; Becker, Stephan; Ramharter, Michael; Mordmüller, Benjamin; Lell, Bertrand; Krishna, Sanjeev; Kremsner, Peter G

    2017-10-01

    The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)-glycoprotein (GP)-specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%-100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264-908), 556 (95% CI: 280-1,101), 1,245 (95% CI: 899-1,724), and 1,503 (95% CI: 931-2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647-1,591), 1,887 (1,154-3,085), 1,445 (1,013-2,062), and 3,958 (2,249-6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine

  15. Randomized Phase I: Safety, Immunogenicity and Mucosal Antiviral Activity in Young Healthy Women Vaccinated with HIV-1 Gp41 P1 Peptide on Virosomes.

    Science.gov (United States)

    Leroux-Roels, Geert; Maes, Cathy; Clement, Frédéric; van Engelenburg, Frank; van den Dobbelsteen, Marieke; Adler, Michael; Amacker, Mario; Lopalco, Lucia; Bomsel, Morgane; Chalifour, Anick; Fleury, Sylvain

    2013-01-01

    Mucosal antibodies harboring various antiviral activities may best protect mucosal surfaces against early HIV-1 entry at mucosal sites and they should be ideally induced by prophylactic HIV-1 vaccines for optimal prevention of sexually transmitted HIV-1. A phase I, double-blind, randomized, placebo-controlled trial was conducted in twenty-four healthy HIV-uninfected young women. The study objectives were to assess the safety, tolerability and immunogenicity of virosomes harboring surface HIV-1 gp41-derived P1 lipidated peptides (MYM-V101). Participants received placebo or MYM-V101 vaccine at 10 μg/dose or 50 μg/dose intramuscularly at week 0 and 8, and intranasally at week 16 and 24. MYM-V101 was safe and well-tolerated at both doses administered by the intramuscular and intranasal routes, with the majority of subjects remaining free of local and general symptoms. P1-specific serum IgGs and IgAs were induced in all high dose recipients after the first injection. After the last vaccination, vaginal and rectal P1-specific IgGs could be detected in all high dose recipients. Approximately 63% and 43% of the low and high dose recipients were respectively tested positive for vaginal P1-IgAs, while 29% of the subjects from the high dose group tested positive for rectal IgAs. Serum samples had total specific IgG and IgA antibody concentrations ≥ 0.4 μg/mL, while mucosal samples were usually below 0.01 μg/mL. Vaginal secretions from MYM-V101 vaccinated subjects were inhibiting HIV-1 transcytosis but had no detectable neutralizing activity. P1-specific Th1 responses could not be detected on PBMC. This study demonstrates the excellent safety and tolerability of MYM-V101, eliciting systemic and mucosal antibodies in the majority of subjects. Vaccine-induced mucosal anti-gp41 antibodies toward conserved gp41 motifs were harboring HIV-1 transcytosis inhibition activity and may contribute to reduce sexually-transmitted HIV-1. ClinicalTrials.gov NCT01084343.

  16. Randomized Phase I: Safety, Immunogenicity and Mucosal Antiviral Activity in Young Healthy Women Vaccinated with HIV-1 Gp41 P1 Peptide on Virosomes.

    Directory of Open Access Journals (Sweden)

    Geert Leroux-Roels

    Full Text Available Mucosal antibodies harboring various antiviral activities may best protect mucosal surfaces against early HIV-1 entry at mucosal sites and they should be ideally induced by prophylactic HIV-1 vaccines for optimal prevention of sexually transmitted HIV-1. A phase I, double-blind, randomized, placebo-controlled trial was conducted in twenty-four healthy HIV-uninfected young women. The study objectives were to assess the safety, tolerability and immunogenicity of virosomes harboring surface HIV-1 gp41-derived P1 lipidated peptides (MYM-V101. Participants received placebo or MYM-V101 vaccine at 10 μg/dose or 50 μg/dose intramuscularly at week 0 and 8, and intranasally at week 16 and 24. MYM-V101 was safe and well-tolerated at both doses administered by the intramuscular and intranasal routes, with the majority of subjects remaining free of local and general symptoms. P1-specific serum IgGs and IgAs were induced in all high dose recipients after the first injection. After the last vaccination, vaginal and rectal P1-specific IgGs could be detected in all high dose recipients. Approximately 63% and 43% of the low and high dose recipients were respectively tested positive for vaginal P1-IgAs, while 29% of the subjects from the high dose group tested positive for rectal IgAs. Serum samples had total specific IgG and IgA antibody concentrations ≥ 0.4 μg/mL, while mucosal samples were usually below 0.01 μg/mL. Vaginal secretions from MYM-V101 vaccinated subjects were inhibiting HIV-1 transcytosis but had no detectable neutralizing activity. P1-specific Th1 responses could not be detected on PBMC. This study demonstrates the excellent safety and tolerability of MYM-V101, eliciting systemic and mucosal antibodies in the majority of subjects. Vaccine-induced mucosal anti-gp41 antibodies toward conserved gp41 motifs were harboring HIV-1 transcytosis inhibition activity and may contribute to reduce sexually-transmitted HIV-1.ClinicalTrials.gov NCT01084343.

  17. Immunogenicity and safety of an inactivated hepatitis A vaccine when coadministered with Diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines in children 15 months of age.

    Science.gov (United States)

    Trofa, Andrew F; Klein, Nicola P; Paul, Ian M; Michaels, Marian G; Goessler, Mary; Chandrasekaran, Vijayalakshmi; Blatter, Mark

    2011-09-01

    This study (NCT00197236) evaluated the safety and immunogenicity of a hepatitis A virus (HAV) vaccine when coadministered with diphtheria-tetanus-acellular pertussis (DTaP) and Haemophilus influenzae type b (Hib) vaccines in children 15 months of age. This was an open-labeled, multicenter study with healthy subjects enrolled and randomized (1:1:1) into 3 treatment groups. A total of 394 subjects received the first study vaccinations at 15 months of age. Group HAV (N = 135) received 2 doses of HAV vaccine 6 to 9 months apart. Group HAV+DTaP+Hib (N = 127) received HAV vaccine coadministered with DTaP and Hib vaccines and the second dose of HAV vaccine, 6 to 9 months later. Group DTaP+Hib→HAV (N = 132) received the DTaP and Hib vaccines at 15 months of age, followed by HAV vaccine 30 days later and the second dose of HAV vaccine 7 to 10 months after the DTaP+Hib vaccines. Immune responses were evaluated before the first study vaccination and 30 days after each vaccine dose. Solicited, unsolicited, and serious adverse events were collected. After 2 doses of the HAV vaccine, all subjects in the 3 groups were seropositive. The geometric mean concentration of anti-HAV antibodies ranged between 1625.1 and 1904.4 mIU/mL. Coadministration of the 3 vaccines did not impact immunogenicity of the HAV, DTaP, or Hib vaccines. Vaccines were well tolerated in all groups. A 2-dose schedule of HAV vaccine was well tolerated and immunogenic when administered to children starting at 15 months of age. Immune responses to the DTaP or Hib vaccines were similar whether they were administered alone or were coadministered with the HAV vaccine.

  18. Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women.

    Science.gov (United States)

    Kahn, Jessica A; Xu, Jiahong; Kapogiannis, Bill G; Rudy, Bret; Gonin, René; Liu, Nancy; Wilson, Craig M; Worrell, Carol; Squires, Kathleen E

    2013-09-01

    The objective of this study was to determine whether the 3-dose quadrivalent human papillomavirus (HPV) vaccine series (HPV-6, -11, -16, -18) is immunogenic and safe in young women infected with human immunodeficiency virus (HIV). We enrolled 99 women aged 16-23 years in a phase 2, open-label, multicenter trial, conducted from 2008 to 2011 by the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Outcome measures were immunogenicity 4 weeks after dose 3, measured by (1) geometric mean titers (GMTs) and (2) seroconversion rates for HPV-6, -11, -16, and -18, among those seronegative and HPV DNA negative for each type. Immune responses were compared to those of a historical comparison group of HIV-negative women (n = 267) using univariate methods. Clinical and laboratory adverse events were assessed after each dose. The mean age of subjects was 21.4 years; 80% were non-Hispanic black, 69 were not taking antiretroviral therapy (ART), and 30 were taking ART. No differences in GMTs were noted among participants taking ART vs the comparison group, but GMTs were lower in participants not taking ART vs the comparison group for HPV-16 (2393 vs 3892 milli-Merck units per milliliter [mMU/mL], P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003). Seroconversion rates were 100% for HPV-6, -11, -16, and -18 among participants taking ART. Rates ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) among participants not taking ART. One severe adverse event (fatigue) was noted. In a sample of HIV-infected women who were HPV DNA and HPV seronegative, immune responses to HPV vaccination were generally robust and the vaccine was well tolerated.

  19. Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario.

    Science.gov (United States)

    Frey, Sharon E; Winokur, Patricia L; Salata, Robert A; El-Kamary, Samer S; Turley, Christine B; Walter, Emmanuel B; Hay, Christine Mhorag; Newman, Frances K; Hill, Heather R; Zhang, Ying; Chaplin, Paul; Tary-Lehmann, Magdalena; Belshe, Robert B

    2013-06-24

    Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic's (BN) IMVAMUNE(®) (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses. Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination. The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group: 0+7, Group: 0+28 and Group: 0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group: 0+7, Group: 0+28, and Group: 0, respectively (Chi-square test, P=0.77). Based on BN's Plaque Reduction Assay GMTs, Group: 0+7 was non-inferior to Group: 0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group: 0+7 and Group: 0+28 GMT were 10.8 (CI: 9.0, 12.9) and 30.2 (CI: 22.1, 41.1), respectively. Based on BN's Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group: 0+28 was significantly greater than that for Group: 0+7 after second vaccination at Days 4 and 180. By Day 14 after the second dose, the IFN-γ enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group: 0+28 and Group: 0+7. Overall, a standard dose of IMVAMUNE (0.5 mL of 1 x 10(8) TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-γ ELISPOT responses were similar for Group: 0+28 and Group: 0

  20. Safety and immunogenicity of Onderstepoort Biological Products’ Rift Valley fever Clone 13 vaccine in sheep and goats under field conditions in Senegal

    Directory of Open Access Journals (Sweden)

    Modou M. Lo

    2015-02-01

    Full Text Available This blinded field safety study was conducted in Senegal to assess safety and immunogenicity of administration of the registered dose of Rift Valley fever virus (RVFV Clone 13 vaccine (Onderstepoort Biological Products to sheep and goats of West African breeds under natural conditions. A total of 267 small ruminants (220 sheep, 47 goats were included; half received RVFV Clone 13 vaccine at the recommended dose and half received the diluent (as placebo only. The study was performed on three commercial farms in the northern and eastern region of Senegal in accordance with veterinary good clinical practices. The animals were observed daily for 3 days after vaccination, and then weekly for 1 year. In both sheep and goats vaccinated against RVFV seroconversion rates above 70% were recorded. No seroconversion related to RVFV was observed in placebo-treated animals. No statistically significant differences were determined between placebo and vaccinated groups for mean rectal temperatures for the first 3 days after administration (p > 0.05. No abnormal clinical signs related to treatment were noted, and only one slight injection site reaction was observed in one vaccinated animal for 2 days after vaccination. Out of 176 births assessed over 1 year (93 from the vaccinated group, 83 from the placebo group, 9 were abnormal in the placebo group and 3 in the vaccinated group (p > 0.05. The frequency of adverse events was similar in the placebo and vaccinated groups. RVFV Clone 13 vaccine administered according to the manufacturer’s instructions was safe and well tolerated in West African breeds of sheep and goats, including animals of approximately 6 months of age and pregnant females, under field conditions in Senegal. Antibody levels persisted up to 1 year after vaccination.

  1. Safety and immunogenicity of live attenuated human-bovine (UK) reassortant rotavirus vaccines with VP7-specificity for serotypes 1, 2, 3 or 4 in adults, children and infants.

    Science.gov (United States)

    Clements-Mann, M L; Makhene, M K; Mrukowicz, J; Wright, P F; Hoshino, Y; Midthun, K; Sperber, E; Karron, R; Kapikian, A Z

    1999-06-04

    Live rotavirus vaccine candidates representing VP7 serotypes 1, 2, 3 or 4 derived by reassortment between bovine UK rotavirus and human rotavirus strains D, DS-1, P or ST3 were evaluated for safety and immunogenicity in adults, children and infants. Infection was defined by evidence of rotavirus shed in stools or a 4-fold or greater increase in serum rotavirus-specific IgA or IgG ELISA or plaque reduction neutralization antibody. A single oral dose (10(5.3) or 10(5.8) pfu) of reassortant virus was well tolerated and infected most infants: 10/20 (50%) by D x UK; 9/11 (82%) by DS-1 x UK; 8/10 (80%) by P x UK and 13/14 (93%) by ST3 x UK. All 14 infants given two doses of D x UK were infected. These findings demonstrating satisfactory levels of attenuation, safety, infectivity and immunogenicity of each reassortant in infants warrant additional studies of a candidate vaccine containing these four strains.

  2. Sero-Surveillance to assess immunity to rubella and assessment of immunogenicity and safety of a single dose of rubella vaccine in school girls

    Directory of Open Access Journals (Sweden)

    Sharma Hitt

    2010-01-01

    Full Text Available Background: Rubella vaccination is not yet included in National Immunization Schedule in India. Serosurvey is frequently used to assess epidemiologic pattern of Rubella in a community. Serosurveys in different parts of India have found that 6-47% of women are susceptible for Rubella infection. The present serosurveillance was conducted in Jammu, India, in two public schools. Objective: To determine serological status of Rubella antibodies of school girls and assessment of immunogenicity and reactogenicity of Rubella immunization in seronegative girls. Materials and Methods: The current study was conducted to determine Rubella serostatus in peripubertal schoolgirls aged 11-18 years and also to assess immunogenicity and safety of Rubella vaccine (R-Vac of Serum Institute of India Ltd., Pune, in seronegative girls. For screening, pre-vaccination serum Rubella IgG antibodies were determined and to assess immunogenicity of the vaccine, post-vaccination IgG antibodies were compared with pre-vaccination levels. Safety assessment was done for a period of 8 weeks, post-vaccination. Results: A total of 90 (32.7% seronegative girls were vaccinated. All girls (100% became seropositive, post-vaccination. Clinically relevant and statistically significant increase in anti-Rubella IgG titres was observed. The adverse events were mild and self-limiting. Conclusions: R-Vac vaccine used in the study demonstrated an excellent safety and immunogenicity profile.

  3. Comparison of safety and immunogenicity of purified chick embryo cell vaccine using Zagreb and Essen regimens in patients with category II exposure in China.

    Science.gov (United States)

    Hu, Quan; Liu, Man-Qing; Zhu, Zheng-Gang; Zhu, Ze-Rong; Lu, Sha

    2014-01-01

    The aim was to compare the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) with Zagreb 2-1-1 and Essen 1-1-1-1-1 regimens in patients with WHO category II exposure in China. Side effects including systemic and local symptoms were recorded for all patients during vaccination with purified chick embryo cell vaccine (PCECV) under Zagreb 2-1-1 or Essen 1-1-1-1-1 regimens, and the rabies neutralization antibody titers in patients' serum at days 0, 7, 14, 45, 365 post-immunization were measured to determine the immunogenicity. Fever and pain were the most common events for systemic and local symptoms respectively, and most side effects (86.78%, 105/121) occurred after the first dose of vaccination. Safety analysis showed differences in side effects inEssen regimens, especially after the first dose of vaccination (P = 0.043). Immunogenicity analysis indicated that Zagreb can achieve higher neutralization antibody titers and a greater seroconversion rate in a shorter time but had less persistence than Essen. When compared with the Essen regimen, the Zagreb regimen had a different immunogenicity in all study subjects, and different safety profile in young children, and a further study with a larger population and longer surveillance is warranted.

  4. Immunogenicity of therapeutic proteins: influence of aggregation.

    Science.gov (United States)

    Ratanji, Kirsty D; Derrick, Jeremy P; Dearman, Rebecca J; Kimber, Ian

    2014-01-01

    The elicitation of anti-drug antibodies (ADA) against biotherapeutics can have detrimental effects on drug safety, efficacy, and pharmacokinetics. The immunogenicity of biotherapeutics is, therefore, an important issue. There is evidence that protein aggregation can result in enhanced immunogenicity; however, the precise immunological and biochemical mechanisms responsible are poorly defined. In the context of biotherapeutic drug development and safety assessment, understanding the mechanisms underlying aggregate immunogenicity is of considerable interest. This review provides an overview of the phenomenon of protein aggregation, the production of unwanted aggregates during bioprocessing, and how the immune response to aggregated protein differs from that provoked by non-aggregated protein. Of particular interest is the nature of the interaction of aggregates with the immune system and how subsequent ADA responses are induced. Pathways considered here include 'classical' activation of the immune system involving antigen presenting cells and, alternatively, the breakdown of B-cell tolerance. Additionally, methods available to screen for aggregation and immunogenicity will be described. With an increased understanding of aggregation-enhanced immune responses, it may be possible to develop improved manufacturing and screening processes to avoid, or at least reduce, the problems associated with ADA.

  5. Assessing the Immunogenicity of Biopharmaceuticals.

    Science.gov (United States)

    Pineda, Carlos; Castañeda Hernández, Gilberto; Jacobs, Ira A; Alvarez, Daniel F; Carini, Claudio

    2016-06-01

    Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.

  6. Evaluation of the safety, immunogenicity and efficacy of three capripoxvirus vaccine strains against lumpy skin disease virus.

    Science.gov (United States)

    Gari, Getachew; Abie, Getnet; Gizaw, Daniel; Wubete, Alehegn; Kidane, Membere; Asgedom, Hagos; Bayissa, Berecha; Ayelet, Gelagay; Oura, Christopher A L; Roger, Francois; Tuppurainen, Eeva S M

    2015-06-22

    The safety, immunogenicity and efficacy of three commercially available vaccines against lumpy skin disease (LSD) in cattle have been evaluated using a combination of vaccine challenge experiments and the monitoring of immune responses in vaccinated animals in the field. The three vaccines evaluated in the study included two locally produced (Ethiopian) vaccines (lumpy skin disease virus (LSDV) Neethling and Kenyan sheep and goat pox (KSGP) O-180 strain vaccines) and a Gorgan goat pox (GTP) vaccine manufactured by Jordan Bio-Industries Centre (JOVAC). The latter vaccine was evaluated for the first time in cattle against LSDV. The Ethiopian Neethling and KSGPO-180 vaccines failed to provide protection in cattle against LSDV, whereas the Gorgan GTP vaccine protected all the vaccinated calves from clinical signs of LSD. There was no significant difference in protective efficacy detected between two dosage levels (P=0.2, P=0.25, and P=0.1 for KSGP, Neethling and Gorgan vaccines, respectively). Additionally, the Gorgan GTP vaccinated cattle showed stronger levels of cellular immune responses measured using Delayed-Type Hypersensitivity (DTH) reactions at the vaccination site indicating higher levels of immunogenicity produced by the GTPV vaccine in cattle, as opposed to the other two vaccines. This study indicated, for the first time, that the Gorgan GTP vaccine can effectively protect cattle against LSDV and that the Neethling and KSGP O-180 vaccine were not protective. The results emphasise the need for molecular characterization of the Neethling and KSGP O-180 vaccine seed viruses used for vaccine production in Ethiopia. In addition, the potency and efficacy testing process of the Ethiopian LSD Neethling and KSGP O-180 vaccines should be re-evaluated. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Immunogenicity and safety of a quadrivalent influenza vaccine in children and adolescents in Taiwan: A phase III open-label trial

    Directory of Open Access Journals (Sweden)

    Chun-Yi Lu

    2016-01-01

    Full Text Available Until recently, all seasonal influenza vaccines have been trivalent, containing strains A(H1N1, A(H3N2, and one of the two B strain lineages (Yamagata or Victoria, resulting in frequent mismatches between the circulating B strain lineage and that included in the vaccine. A quadrivalent, inactivated, split-virion influenza vaccine (IIV4 containing strains from both B lineages has been developed to address this. We performed an open-label phase III study to assess the immunogenicity and safety of the 2013–2014 Northern Hemisphere formulation of IIV4 in children and adolescents 9–17 years of age in Taiwan. Participants were vaccinated with one dose of IIV4 by intramuscular or deep subcutaneous injection. Hemagglutinin inhibition (HAI titers were measured before and 21 days after vaccination. Solicited injection-site and systemic reactions were assessed for up to 7 days after vaccination, and adverse events (AEs were recorded until day 21. One hundred participants were included. Despite relatively high pre-vaccination titers, post-vaccination HAI titers increased for all four strains, with geometric mean ratios (day 21/day 0 of 2.29 for A(H1N1, 2.05 for A(H3N2, 3.33 for B/Massachusetts (Yamagata lineage, and 4.59 for B/Brisbane (Victoria lineage. Post-vaccination seroprotection rates were 99% for A(H3N2 and 100% for A(H1N1, B/Massachusetts, and B/Brisbane. Due to high pre-vaccination titers, rates of seroconversion/significant increase of HAI titer were relatively low at 24% for A(H1N1, 20% for A(H3N2, 39% for B/Massachusetts, and 48% for B/Brisbane. Injection-site pain (56%, myalgia (45%, and malaise (15% were the most frequently reported solicited reactions, and most solicited reactions were mild or moderate. No treatment-related AEs, immediate unsolicited AEs, unsolicited non-serious injection-site AEs, grade 3 unsolicited AEs, or serious AEs were reported. In conclusion, this study showed that the 2013–2014 Northern Hemisphere

  8. Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults.

    Science.gov (United States)

    Landrum, Michael L; Lalani, Tahaniyat; Niknian, Minoo; Maguire, Jason D; Hospenthal, Duane R; Fattom, Ali; Taylor, Kimberly; Fraser, Jamie; Wilkins, Kenneth; Ellis, Michael W; Kessler, Paul D; Fahim, Rafaat E F; Tribble, David R

    2017-04-03

    We conducted a randomized, double-blind, placebo-controlled dose-escalation study in healthy adults to evaluate the safety and immunogenicity of recombinant Staphylococcus aureus candidate vaccine antigens, recombinant α-toxoid (rAT) and a sub-unit of Panton-Valentine leukocidin (rLukS-PV). 176 subjects were enrolled and randomized within 1 of 11 treatment cohorts: monovalent rAT or rLukS-PV dosages of 10, 25, 50, and 100 μg; bivalent rAT:rLukS dosages of 10:10, 25:25, and 50:50 μg; and alum or saline placebo. All subjects were assessed at Days 0, 7, 14, 28, and 84. Subjects in the 50:50 μg bivalent cohort received a second injection on Day 84 and were assessed on Days 98 and 112. Incidence and severity of reactogenicity and adverse events (AEs) were compared. Geometric mean serum concentrations (GMC) and neutralizing activity of anti-rAT and anti-rLukS-PV IgG were assessed. Reactogenicity incidence was significantly higher in vaccine than placebo recipients (77% versus 55%, respectively; p = 0.006). However, 77% of reactogenicity events were mild and 19% were moderate in severity. The AE incidence and severity were similar between the cohorts. All monovalent and bivalent rAT dosages resulted in a significant increase in the anti-rAT IgG and anti- rLukS-PV GMCs between day 0 and 28 compared with placebo, and persisted through Day 84. Exploratory subgroup analyses suggested a higher GMC and neutralizing antibody titers for the 50 μg monovalent or bivalent rAT and rLukS-PV dose as compared to the other doses. No booster effect was observed after administration of the second dose. We conclude that the rAT and rLukS-PV vaccine formulations were well-tolerated and had a favorable immunogenicity profile, producing antibody with neutralizing activity through day 84. There was no benefit observed with a booster dose of the vaccine.

  9. Immunogenicity and safety of a respiratory syncytial virus fusion protein (RSV F) nanoparticle vaccine in older adults.

    Science.gov (United States)

    Fries, Louis; Shinde, Vivek; Stoddard, Jeffrey J; Thomas, D Nigel; Kpamegan, Eloi; Lu, Hanxin; Smith, Gale; Hickman, Somia P; Piedra, Pedro; Glenn, Gregory M

    2017-01-01

    A preventative strategy for Respiratory Syncytial Virus (RSV) infection constitutes an under-recognized unmet medical need among older adults. Four formulations of a novel recombinant RSV F nanoparticle vaccine (60 or 90 μg RSV F protein, with or without aluminum phosphate adjuvant) administered concurrently with a licensed inactivated trivalent influenza vaccine (TIV) in older adult subjects were evaluated for safety and immunogenicity in this randomized, observer-blinded study. A total of 220 healthy males and females ≥ 60 years of age, without symptomatic cardiopulmonary disease, were vaccinated concurrently with TIV and RSV F vaccine or placebo. All vaccine formulations produced an acceptable safety profile, with no vaccine-related serious adverse events or evidence of systemic toxicity. Vaccine-induced immune responses were rapid, rising as early as 7 days post-vaccination; and were comparable in all formulations in terms of magnitude, with maximal levels attained within 28 (unadjuvanted) or 56 (adjuvanted) days post-vaccination. Peak anti-F protein IgG antibody levels rose 3.6- to 5.6-fold, with an adjuvant effect observed at the 60 μg dose, and a dose-effect observed between the unadjuvanted 60 and 90 μg regimens. The anti-F response persisted through 12 months post-vaccination. Palivizumab-competitive antibodies were below quantifiable levels (F protein, closely paralleled the anti-F response. However, a larger proportion of antibodies in adjuvanted vaccine recipients bound to the Site II peptide at high avidity. Day 0 neutralizing antibodies were high in all subjects and rose 1.3- to 1.7-fold in response to vaccination. Importantly, the RSV F vaccine co-administered with TIV did not impact the serum hemagglutination inhibition antibody responses to a standard-dose TIV, and TIV did not impact the immune response to the RSV F vaccine. RSV F protein nanoparticle vaccine induced increases in measures of functional immunity to RSV in older adults

  10. Comparative safety of vaccine adjuvants: a summary of current evidence and future needs

    OpenAIRE

    Petrovsky, Nikolai

    2015-01-01

    Improved use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety or posing undue risk. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on alum...

  11. Immunogenicity and safety of a quadrivalent inactivated influenza vaccine compared with two trivalent inactivated influenza vaccines containing alternate B strains in adults: A phase 3, randomized noninferiority study.

    Science.gov (United States)

    Treanor, John T; Albano, Frank R; Sawlwin, Daphne C; Graves Jones, Alison; Airey, Jolanta; Formica, Neil; Matassa, Vince; Leong, Jane

    2017-04-04

    Vaccination is the most effective means of influenza prevention. Efficacy of trivalent vaccines may be enhanced by including both B strain lineages. This phase 3, double-blind study assessed the immunogenicity and safety/tolerability of a quadrivalent inactivated influenza vaccine (IIV4) versus the United States (US)-licensed 2014-2015 trivalent inactivated influenza vaccine (IIV3-Yamagata [IIV3-YAM]; Afluria) and IIV3 containing the alternate Victoria B strain (IIV3-VIC) in adults ≥18years. Participants (n=3484) were randomized 2:1:1 and stratified by age to receive IIV4 (n=1741), IIV3-YAM (n=871), or IIV3-VIC (n=872). The primary objective was to demonstrate noninferiority of the immunological response to IIV4 versus IIV3-YAM and IIV3-VIC. Noninferiority was assessed by hemagglutination inhibition geometric mean titer (GMT) ratio (IIV3/IIV4; upper bound of two-sided 95% confidence interval [CI]≤1.5) and seroconversion rate (SCR) difference (IIV3 - IIV4; upper bound of two-sided 95% CI≤10%) for vaccine strains. Solicited local and systemic adverse events (AEs) were assessed for 7days postvaccination, AEs recorded for 28days postvaccination, and serious AEs for 6months postvaccination. IIV4 elicited a noninferior immune response for matched strains, and superior response for unmatched B strains not contained in IIV3 comparators. Adjusted GMT ratios (95% CI) for A/H1N1, A/H3N2, B/YAM, and B/VIC strains were 0.93 (0.88, 0.99), 0.93 (0.88, 0.98), 0.87 (IIV3-YAM; 0.82, 0.93), and 0.95 (IIV3-VIC; 0.88, 1.03), respectively. Corresponding values for SCR differences (95% CI) were -1.1 (-4.5, 2.3), -1.7 (-5.0, 1.7), -3.2 (IIV3-YAM; -7.4, 0.9), and -1.6 (IIV3-VIC; -5.8, 2.5). AEs were generally mild and experienced by 52.9% of participants. Serious AEs were reported with a slightly higher frequency with IIV4 (2.3%) versus IIV3-YAM (1.6%) and IIV3-VIC (1.5%). IIV4 demonstrated immunological noninferiority to the US-licensed IIV3, and superiority for unmatched B strains

  12. Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults.

    Science.gov (United States)

    Keitel, Wendy A; Dekker, Cornelia L; Mink, ChrisAnna; Campbell, James D; Edwards, Kathryn M; Patel, Shital M; Ho, Dora Y; Talbot, Helen K; Guo, Kuo; Noah, Diana L; Hill, Heather

    2009-11-05

    Dosage-sparing strategies, adjuvants and alternative substrates for vaccine production are being explored for influenza vaccine development. We assessed the safety and immunogenicity of a Vero cell culture-grown inactivated whole virus influenza A/H5N1 vaccine with or without aluminum hydroxide adjuvant [Al(OH)(3)] in healthy young adults. Vaccines were well tolerated, but injection site discomfort was more frequent in groups receiving Al(OH)(3). Dose-related increases in serum antibody levels were observed. Neutralizing antibody titers varied significantly when tested by two different laboratories. Al(OH)(3) did not enhance HAI or neutralizing antibody responses, and contributed to increased injection site pain. Because influenza antibody titers vary significantly between different laboratories, international standardization of assays is warranted.

  13. Short-Term Immunogenicity and Safety of an Accelerated Pre-Exposure Prophylaxis Regimen With Japanese Encephalitis Vaccine in Combination With a Rabies Vaccine: A Phase III, Multicenter, Observer-Blind Study.

    Science.gov (United States)

    Jelinek, Tomas; Burchard, Gerd D; Dieckmann, Sebastian; Bühler, Silja; Paulke-Korinek, Maria; Nothdurft, Hans D; Reisinger, Emil; Ahmed, Khaleel; Bosse, Dietrich; Meyer, Seetha; Costantini, Marco; Pellegrini, Michele

    2015-01-01

    The current Japanese encephalitis (JE) vaccination regimen requires two doses and 4 weeks to complete, which may not always be feasible for travelers on short notice. One of the primary endpoints of this phase III study was to demonstrate noninferiority of immune responses to a JE vaccine following an accelerated 1-week JE vaccination regimen administered concomitantly with a rabies vaccine as compared to a standard 4-week JE regimen alone. In addition, the immunogenicity of concomitant administration of JE and rabies vaccines following standard regimens was evaluated, as well as the tolerability and safety profile of each regimen under study. Healthy adults aged 18 to ≤65 years were randomized to regimens with an accelerated or standard schedule: JE+rabies-standard (n = 167), JE+rabies-accelerated (n = 217) or JE-standard (n = 56). Immunogenicity against JE antigen was assessed by a 50% plaque reduction neutralization test (PRNT50 ) titer of ≥1 : 10, measured 28 days after last active vaccine (LAV) administration. Solicited reactions were collected 7 days after each vaccination; spontaneously reported adverse events (AEs) and serious AEs were monitored up to day 57. This paper reports results until day 57. Noninferiority of immune responses was established for JE+rabies-accelerated compared to the JE-standard regimen 28 days after LAV administration. Overall, 99% and 100% of subjects in the JE+rabies-accelerated and JE-standard groups, respectively, achieved PRNT50 titers of ≥1 : 10 at 28 days after LAV administration. No impact of concomitant rabies vaccination was observed either on immune responses or on the safety profile of the JE vaccine. This was the first randomized, controlled trial that demonstrated the strong short-term immunogenicity of a new, accelerated, 1-week JE-regimen, which was noninferior to that of the standard regimen, with a satisfactory tolerability and safety profile and no impact of concomitant rabies vaccination. This accelerated

  14. Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

    Science.gov (United States)

    van Damme, Pierre; Kafeja, Froukje; Anemona, Alessandra; Basile, Venere; Hilbert, Anne Katrin; De Coster, Ilse; Rondini, Simona; Micoli, Francesca; Qasim Khan, Rana M; Marchetti, Elisa; Di Cioccio, Vito; Saul, Allan; Martin, Laura B; Podda, Audino

    2011-01-01

    Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults. Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine. All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship. Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia. ClinicalTrials.gov NCT01123941 NCT01193907.

  15. Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials.

    Science.gov (United States)

    Modjarrad, Kayvon; Lin, Leyi; George, Sarah L; Stephenson, Kathryn E; Eckels, Kenneth H; De La Barrera, Rafael A; Jarman, Richard G; Sondergaard, Erica; Tennant, Janice; Ansel, Jessica L; Mills, Kristin; Koren, Michael; Robb, Merlin L; Barrett, Jill; Thompson, Jason; Kosel, Alison E; Dawson, Peter; Hale, Andrew; Tan, C Sabrina; Walsh, Stephen R; Meyer, Keith E; Brien, James; Crowell, Trevor A; Blazevic, Azra; Mosby, Karla; Larocca, Rafael A; Abbink, Peter; Boyd, Michael; Bricault, Christine A; Seaman, Michael S; Basil, Anne; Walsh, Melissa; Tonwe, Veronica; Hoft, Daniel F; Thomas, Stephen J; Barouch, Dan H; Michael, Nelson L

    2017-12-04

    A safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings. We did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233. We enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies. The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults. Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

    Directory of Open Access Journals (Sweden)

    Pierre van Damme

    Full Text Available Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇ for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults.Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen, a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen with the polysaccharide vaccine.All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.ClinicalTrials.gov NCT01123941 NCT01193907.

  17. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN® in 56-80-Year-Old Subjects.

    Directory of Open Access Journals (Sweden)

    Richard N Greenberg

    Full Text Available Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA was assessed in a 56-80 years old population.MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56-80 year old vaccinia-experienced subjects (N = 120. Subjects received either two injections of MVA (MM group or one injection of Placebo and one injection of MVA (PM group four weeks apart. Safety was evaluated by assessment of adverse events (AE, focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA and a plaque reduction neutralization test (PRNT before and at different time points after vaccination.Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4 were as follows: Seroconversion (SC rates (doubling of titers from baseline in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%], and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]. Geometric mean titers (GMT measured by ELISA two weeks after the final vaccination for

  18. Safety and immunogenicity of an investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM, compared with licensed vaccines in adults in Latin America.

    Science.gov (United States)

    Stamboulian, D; Lopardo, G; Lopez, P; Cortes-Barbosa, C; Valencia, A; Bedell, L; Karsten, A; Dull, P M

    2010-10-01

    This study compared the investigational quadrivalent meningococcal CRM₁₉₇ conjugate vaccine, MenACWY-CRM, with licensed quadrivalent polysaccharide (MPSV4) and conjugate (MenACWY-D) meningococcal vaccines. In this phase III multicenter study, 2505 adults (aged 19-55 years) were randomized to receive either MenACWY-CRM or MenACWY-D, and 326 adults (aged 56-65 years) were randomized to receive either MenACWY-CRM or MPSV4. Sera obtained pre-vaccination and at 1-month post-vaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA) for immunogenicity non-inferiority and superiority analyses. The vaccines in all groups were well tolerated. In the 19-55 years age group, post-vaccination geometric mean titers (GMTs) were consistently higher for MenACWY-CRM than for MenACWY-D for all four serogroups. MenACWY-CRM was non-inferior to MenACWY-D for all serogroups, and superior for serogroup Y. In the 56-65 years age group, post-vaccination GMTs were 1.2- to 5.4-fold higher for MenACWY-CRM than for MPSV4 for the four serogroups. MenACWY-CRM is well tolerated and immunogenic in adults aged 19-65 years, with at least non-inferior immunogenicity compared with the currently licensed meningococcal vaccines. Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  19. Assessing the Immunogenicity of Biopharmaceuticals

    OpenAIRE

    Pineda, Carlos; Casta?eda Hern?ndez, Gilberto; Jacobs, Ira A.; Alvarez, Daniel F.; Carini, Claudio

    2016-01-01

    Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, qua...

  20. IMMUNOGENICITY AND SAFETY OF QUINVAXEM® (DIPHTHERIA, TETANUS, WHOLE-CELL PERTUSSIS, HEPATITIS B AND HAEMOPHILUS INFLUENZAE TYPE B VACCINE) GIVEN TO VIETNAMESE INFANTS AT 2 TO 4 MONTHS OF AGE.

    Science.gov (United States)

    Huu, Tran Ngoc; Phuong, Nguyen Thi Minh; Toan, Nguyen Trong; Thang, Ho Vinh

    2015-07-01

    Vietnam plans to replace the routine childhood diphtheria, pertussis and tetanus combination (DPT) vaccine with a pentavalent vaccine. The present study was performed to assess the immunogenicity and safety of the combined diphtheria, tetanus, whole-cell pertussis, hepatitis B (HepB), and Haemophilus influenzae type b (Hib) (DTwP-HepB-Hib) Quinvaxem® vaccine in children. A total of 131 infants received the Quinvaxem® vaccine at 2, 3 and 4 months. Antibody levels were measured at baseline, at one month after the third injection and one year after the first injection. Seroprotection rates were high for each vaccine antigen at one month after the third dose: 93.1% for diphtheria, 98.5% for tetanus, 99.2% for pertussis (seroconversion rate), 93.1% for HepB, and 100% for Hib (anti-PRP ≥ 0.15 µg/ml). The rate of children with protective antibodies persisting at one year after the first dose was 88.4% for diphtheria, 49.6% for pertussis, 82.2% for tetanus, 76.7% for HepB and 97.7% for Hib (anti-PRP ≥ 0.15 µg/ml). The Quinvaxem® vaccine was well tolerated and has a low rate of adverse events. Quinvaxem® given at 2, 3 and 4 months of age was immunogenic and safe for primary immunization among infants in Vietnam.

  1. Safety and immunogenicity of 13-valent pneumococcal conjugate vaccine formulations with and without aluminum phosphate and comparison of the formulation of choice with 23-valent pneumococcal polysaccharide vaccine in elderly adults: a randomized open-label trial.

    Science.gov (United States)

    Juergens, Christine; de Villiers, Pierre J T; Moodley, Keymanthri; Jayawardene, Deepthi; Jansen, Kathrin U; Scott, Daniel A; Emini, Emilio A; Gruber, William C; Schmoele-Thoma, Beate

    2014-01-01

    This randomized open-label trial was designed to provide preliminary immunogenicity and safety data to support development of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) for adults. The aims were to: identify an age-appropriate PCV13 formulation, i.e., with (n = 309) or without (n = 304) aluminum phosphate (AlPO 4); compare the selected PCV13 formulation (n = 309) with 23-valent pneumococcal polysaccharide vaccine (PPSV23; n = 301); and, together with an extension study, assess sequential use of pneumococcal vaccines at 1-year intervals in adults aged ≥65 years (n = 105) not pre-vaccinated with PPSV23. Immune responses were measured by ELISA and opsonophagocytic activity assays 1 month postvaccination. Immunoglobulin G responses elicited by PCV13 with AlPO 4 and PCV13 without AlPO 4 were similar for the majority, and noninferior for all PCV13 serotypes. PCV13 with AlPO 4 was generally more reactogenic, with reactions mainly mild or moderate. Thus, PCV13 with AlPO 4 (hereafter PCV13) became the selected formulation. Immune responses to PCV13 were noninferior for all but one serotype and for most PCV13 serotypes superior to PPSV23. Vaccine sequence assessments showed that for PCV13/PPSV23, the initial PCV13 dose generally enhanced responses to a subsequent PPSV23 dose, compared with PPSV23 alone. For PCV13/PCV13, a second dose did not enhance the first dose response when given after 1 year. For PCV13/PPSV23/PCV13, priming with PCV13 (vaccination 1) did not protect against lower responses induced by PPSV23 to subsequent PCV13 (vaccination 3). In conclusion, the pediatric PCV13 formulation with AlPO 4 is well tolerated and immunogenic in adults, is generally more immunogenic than PPSV23, and subsequent vaccination with PPSV23 is possible if required.

  2. Safety and immunogenicity of LC16m8, an attenuated smallpox vaccine in vaccinia-naive adults.

    Science.gov (United States)

    Kennedy, Jeffrey S; Gurwith, Marc; Dekker, Cornelia L; Frey, Sharon E; Edwards, Kathryn M; Kenner, Julie; Lock, Michael; Empig, Cyril; Morikawa, Shigeru; Saijo, Masayuki; Yokote, Hiroyuki; Karem, Kevin; Damon, Inger; Perlroth, Mark; Greenberg, Richard N

    2011-11-01

    LC16m8 is an attenuated cell culture-adapted Lister vaccinia smallpox vaccine missing the B5R protein and licensed for use in Japan. We conducted a phase I/II clinical trial that compared the safety and immunogenicity of LC16m8 with Dryvax in vaccinia-naive participants. Adverse events were assessed, as were electrocardiography and laboratory testing for cardiotoxicity and viral culturing of the vaccination sites. Neutralization titers to vaccinia, monkeypox, and variola major were assessed and cell-mediated immune responses were measured by interferon (IFN)-γ enzyme-linked immunosorbent spot and lymphoproliferation assays. Local and systemic reactions after vaccination with LC16m8 were similar to those reported after Dryvax. No clinically significant abnormalities consistent with cardiac toxicity were seen for either vaccine. Both vaccines achieved antivaccinia, antivariola, and antimonkeypox neutralizing antibody titers >1:40, although the mean plaque reduction neutralization titer of LC16m8 at day 30 after vaccination was significantly lower than Dryvax for anti-NYCBH vaccinia (P smallpox. Clinical Trials Registration. NCT00103584.

  3. Safety and Immunogenicity of purified chick embryo cell rabies vaccine (VaxiRab N) administered intradermally as post exposure prophylaxis.

    Science.gov (United States)

    Ravish, Hardanahalli S; Vijayashankar, Veena; Madhusudana, Shampur N; Sudarshan, Mysore K; Narayana, Doddabele Ha; Andanaiah, Gangaboraiah; Ashwin, Belludi Y; Rachana, Annadani R; Shamanna, Manjula

    2014-01-01

    The affordability to rabies vaccine for intramuscular administration in post exposure prophylaxis is a major constraint. Therefore, in countries, where there are financial constraints, World Health Organization recommends intradermal rabies vaccination that reduces the quantity and cost of vaccination. This study was done to evaluate the safety and immunogenicity of indigenously developed rabies vaccine (VaxiRab N) in comparison to a WHO recommended rabies vaccine (Rabipur) with demonstrated efficacy when administered by intradermal route using updated Thai Red Cross regimen. Eighty-six dog bite cases were randomly given either VaxiRab N (n = 43) or Rabipur (n = 43) as post exposure prophylaxis. The rabies virus neutralizing antibody concentrations on days 14, 28, 90, and 180 were tested by modified rapid fluorescent focus inhibition test. The geometric mean RVNA concentration of both the groups were compared using t- test and was found that, P value > 0.05 on all days, thus showing no significant difference between the 2 groups. The adverse drug events were also compared using Z-test and was found to be not statistically significant (Z = 1.476, P = 0.139). In conclusion, VaxiRab N was found to be safe and effective in post exposure prophylaxis by intradermal route and was similar to the WHO recommended rabies vaccine (Rabipur) of demonstrated efficacy.

  4. Meta-analysis of the immunogenicity and tolerability of pandemic influenza A 2009 (H1N1 vaccines.

    Directory of Open Access Journals (Sweden)

    Lamberto Manzoli

    Full Text Available BACKGROUND: Although the 2009 (H1N1 influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation. METHODS: We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI; secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis. RESULTS: Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects. After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70% in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines. Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 µg (even with as little as 1.875 µg of hemagglutinin antigen was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects. However, mild to moderate adverse reactions were more (and very frequent for oil-in-water adjuvanted vaccines. CONCLUSIONS: Several one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is

  5. Safety and tolerability review of lorcaserin in clinical trials.

    Science.gov (United States)

    Greenway, F L; Shanahan, W; Fain, R; Ma, T; Rubino, D

    2016-10-01

    Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations. © 2016 World Obesity.

  6. Safety and immunogenicity of a parenterally administered rotavirus VP8 subunit vaccine in healthy adults.

    Science.gov (United States)

    Fix, Alan D; Harro, Clayton; McNeal, Monica; Dally, Len; Flores, Jorge; Robertson, George; Boslego, John W; Cryz, Stanley

    2015-07-17

    The P2-VP8 subunit vaccine for the prevention of rotavirus gastroenteritis is comprised of a truncated VP8 subunit protein from the rotavirus Wa strain (G1[P8]) fused to the tetanus toxin P2 epitope, and adsorbed on aluminum hydroxide for intramuscular administration. Three groups of 16 adults were randomized to receive three injections of P2-VP8 (12) or placebo (4) at doses of 10, 30 or 60 μg of vaccine. IgG and IgA antibodies to P2-VP8 were assessed by ELISA in serum and lymphocyte supernatant (ALS). Serum samples were tested for neutralizing antibodies to homologous and heterologous strains of rotavirus. The vaccine was well-tolerated. All vaccine recipients demonstrated significant IgA responses and all but one demonstrated IgG responses; in the 60 μg cohort, geometric mean titers (GMTs) rose 70- and 80-fold for IgA and IgG, respectively. Homologous neutralizing antibody responses were observed in about half of participants in all three dose cohorts; in the 60 μg cohort, GMTs against Wa rose from 128 to 992. Neutralizing antibody responses were robust to P[8] strains, moderate to P[4] strains and negligible to P[6] strains. ALS IgA responses were dose dependent. The P2-VP8 subunit vaccine was well tolerated and evoked promising immune responses. NCT01764256. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Tolerability and safety of the new anti-obesity medications.

    Science.gov (United States)

    Hainer, Vojtech; Aldhoon-Hainerová, Irena

    2014-09-01

    Worldwide obesity prevalence has nearly doubled since 1980. Due to numerous co-morbidities, obesity represents a serious health and socioeconomic problem worldwide. Pharmacotherapy should be an integral part of comprehensive obesity management. Drug therapy can assist in weight loss and its maintenance in those individuals who do not achieve appropriate weight loss through lifestyle interventions alone. After the withdrawal of sibutramine from the market in 2010, orlistat, a lipase inhibitor, was the only remaining prescription drug approved for the long-term treatment of obesity. In 2012, phentermine/topiramate extended-release (PHEN/TPM ER) combination and lorcaserin were approved by the US FDA as novel medications for long-term weight management. Three major phase III trials conducted with each drug confirmed their efficacy in terms of weight loss/maintenance and improvement of cardiometabolic risks. No head-to-head studies between the two new anti-obesity drugs have been carried out. However, in the existing studies PHEN/TPM ER had a superior weight loss profile to lorcaserin but the incidence of adverse effects was lower with lorcaserin. Both drugs were well-tolerated, and adverse events were modest in intensity, dose dependent, rather rare, and tended to decrease with the duration of treatment. Major safety concerns regarding PHEN/TPM ER include elevations in resting pulse rate, teratogenicity, mild metabolic acidosis, and psychiatric and cognitive adverse events. Valvulopathy, cognitive impairment, psychiatric disorders, and hypoglycemia represent major safety concerns for lorcaserin. Although existing trials have not demonstrated any significant issues with PHEN/TPM ER-induced heart rate elevation and lorcaserin-induced valvulopathy, all safety concerns should be seriously taken into account in patients treated with either of these novel anti-obesity medications.

  8. Safety, tolerability and efficacy of intradermal rabies immunization with DebioJect™.

    Science.gov (United States)

    Vescovo, Paul; Rettby, Nils; Ramaniraka, Nirinarilala; Liberman, Julie; Hart, Karen; Cachemaille, Astrid; Piveteau, Laurent-Dominique; Zanoni, Reto; Bart, Pierre-Alexandre; Pantaleo, Giuseppe

    2017-03-27

    In a single-center study, 66 healthy volunteers aged between 18 and 50years were randomized to be immunized against rabies with three different injection routes: intradermal with DebioJect™ (IDJ), standard intradermal with classical needle (IDS), also called Mantoux method, and intramuscular with classical needle (IM). "Vaccin rabique Pasteur®" and saline solution (NaCl 0.9%) were administered at D0, D7 and D28. Antigen doses for both intradermal routes were 1/5 of the dose for IM. Tolerability, safety and induced immunogenicity of IDJ were compared to IDS and IM routes. Pain was evaluated at needle insertion and at product injection for all vaccination visits. Solicited Adverse Event (SolAE) and local reactogenicity symptoms including pain, redness and pruritus were recorded daily following each vaccination visit. Adverse events (AE) were recorded over the whole duration of the study. Humoral immune response was measured by assessing the rabies virus neutralizing antibody (VNA) titers using Rapid Fluorescent Focus Inhibition Test (RFFIT). Results demonstrated that the DebioJect™ is a safe, reliable and efficient device. Significant decreases of pain at needle insertion and at vaccine injection were reported with IDJ compared to IDS and IM. All local reactogenicity symptoms (pain, redness and pruritus) after injection with either vaccine or saline solution, were similar for IDJ and IDS, except that IDJ injection induced more redness 30min after saline solution. No systemic SolAE was deemed related to DebioJect™ and classical needles. No AE was deemed related to DebioJect™. No Serious Adverse Event (SAE) was reported during the study. At the end of the study all participants were considered immunized against rabies and no significant difference in humoral response was observed between the 3 studied routes. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Immunogenicity and safety of an AS03-adjuvanted H5N1 pandemic influenza vaccine in Korean adults: a phase IV, randomized, open-label, controlled study.

    Science.gov (United States)

    Izurieta, Patricia; Kim, Woo Joo; Wie, Seong-Heon; Lee, Jacob; Lee, Jin-Soo; Dramé, Mamadou; Vaughn, David W; Schuind, Anne

    2015-06-04

    AS03-adjuvanted H5N1 pandemic influenza vaccines have been assessed in an extensive clinical development program conducted in North America, Europe, and Asia including children from 6 months of age, adults, and elderly adults. We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age. This Phase IV, randomized, study was conducted to assess the immunogenicity, reactogenicity, and safety of two doses (3.75μg of hemagglutinin antigen) of A/Indonesia/5/2005 (H5N1) adjuvanted with AS03 given 21 days apart in Korean adults. Antibody responses were assessed using hemagglutination-inhibition (HI) assays against the vaccine strain and a vaccine-heterologous strain (A/Vietnam/1194/2004) 21 days after the second dose. A control group (safety) received a licensed seasonal inactivated trivalent influenza vaccine (TIV). Reactogenicity was assessed for 7 days after each vaccination, and unsolicited adverse events were assessed for 182 days following vaccination in both study groups (NCT01730378). AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100% for the vaccine strain and 69.1% for the heterologous strain (N=81). HI antibody responses fulfilled the European licensure criteria for immunogenicity (primary endpoint). The incidence of local and systemic solicited adverse events (reactogenicity) was higher with AS03-H5N1 than TIV. There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups. The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.

    Science.gov (United States)

    Huttner, Angela; Dayer, Julie-Anne; Yerly, Sabine; Combescure, Christophe; Auderset, Floriane; Desmeules, Jules; Eickmann, Markus; Finckh, Axel; Goncalves, Ana Rita; Hooper, Jay W; Kaya, Gürkan; Krähling, Verena; Kwilas, Steve; Lemaître, Barbara; Matthey, Alain; Silvera, Peter; Becker, Stephan; Fast, Patricia E; Moorthy, Vasee; Kieny, Marie Paule; Kaiser, Laurent; Siegrist, Claire-Anne

    2015-10-01

    Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a

  11. Immunogenicity and safety of the candidate RTS,S/AS01 vaccine in young Nigerian children: a randomized, double-blind, lot-to-lot consistency trial.

    Science.gov (United States)

    Umeh, Rich; Oguche, Stephen; Oguonu, Tagbo; Pitmang, Simon; Shu, Elvis; Onyia, Jude-Tony; Daniyam, Comfort A; Shwe, David; Ahmad, Abdullahi; Jongert, Erik; Catteau, Grégory; Lievens, Marc; Ofori-Anyinam, Opokua; Leach, Amanda

    2014-11-12

    For regulatory approval, consistency in manufacturing of vaccine lots is expected to be demonstrated in confirmatory immunogenicity studies using two-sided equivalence trials. This randomized, double-blind study (NCT01323972) assessed consistency of three RTS,S/AS01 malaria vaccine batches formulated from commercial-scale purified antigen bulk lots in terms of anti-CS-responses induced. Healthy children aged 5-17 months were randomized (1:1:1:1) to receive RTS,S/AS01 at 0-1-2 months from one of three commercial-scale purified antigen bulk lots (1600 litres-fermentation scale; commercial-scale lots), or a comparator vaccine batch made from pilot-scale purified antigen bulk lot (20 litres-fermentation scale; pilot-scale lot). The co-primary objectives were to first demonstrate consistency of antibody responses against circumsporozoite (CS) protein at one month post-dose 3 for the three commercial-scale lots and second demonstrate non-inferiority of anti-CS antibody responses at one month post-dose 3 for the commercial-scale lots compared to the pilot-scale lot. Safety and reactogenicity were evaluated as secondary endpoints. One month post-dose-3, anti-CS antibody geometric mean titres (GMT) for the 3 commercial scale lots were 319.6 EU/ml (95% confidence interval (CI): 268.9-379.8), 241.4 EU/ml (207.6-280.7), and 302.3 EU/ml (259.4-352.3). Consistency for the RTS,S/AS01 commercial-scale lots was demonstrated as the two-sided 95% CI of the anti-CS antibody GMT ratio between each pair of lots was within the range of 0.5-2.0. GMT of the pooled commercial-scale lots (285.8 EU/ml (260.7-313.3)) was non-inferior to the pilot-scale lot (271.7 EU/ml (228.5-323.1)). Each RTS,S/AS01 lot had an acceptable tolerability profile, with infrequent reports of grade 3 solicited symptoms. No safety signals were identified and no serious adverse events were considered related to vaccination. RTS,S/AS01 lots formulated from commercial-scale purified antigen bulk batches induced a

  12. Safety and immunogenicity of the Na-GST-1 hookworm vaccine in Brazilian and American adults.

    Directory of Open Access Journals (Sweden)

    David J Diemert

    2017-05-01

    Full Text Available Necator americanus Glutathione-S-Transferase-1 (Na-GST-1 plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 μg adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF, or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies.ClinicalTrials.gov (NCT01261130 for the Brazil trial

  13. Safety and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (IMOJEV®) in children.

    Science.gov (United States)

    Chokephaibulkit, K; Houillon, G; Feroldi, E; Bouckenooghe, A

    2016-01-01

    JE-CV (IMOJEV®, Sanofi Pasteur, France) is a live attenuated virus vaccine constructed by inserting coding sequences of the prM and E structural proteins of the Japanese encephalitis SA14-14-2 virus into the genome of yellow fever 17D virus. Primary immunization with JE-CV requires a single dose of the vaccine. This article reviews clinical trials of JE-CV in children aged up to 6 years conducted in countries across South-East Asia. Strong and persistent antibody responses were observed after single primary and booster doses, with 97% of children seroprotected up to five years after booster vaccination. Models of long-term antibody persistence predict a median duration of protection of approximately 30 years after a booster dose. The safety and reactogenicity profiles of JE-CV primary and booster doses are comparable to other widely used childhood vaccines.

  14. A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico.

    Science.gov (United States)

    Bauer, Kristen; Esquilin, Ines O; Cornier, Alberto Santiago; Thomas, Stephen J; Quintero Del Rio, Ana I; Bertran-Pasarell, Jorge; Morales Ramirez, Javier O; Diaz, Clemente; Carlo, Simon; Eckels, Kenneth H; Tournay, Elodie; Toussaint, Jean-Francois; De La Barrera, Rafael; Fernandez, Stefan; Lyons, Arthur; Sun, Wellington; Innis, Bruce L

    2015-09-01

    This was a double-blind, randomized, controlled, phase II clinical trial, two dose study of re-derived, live-attenuated, tetravalent dengue virus (TDEN) vaccine (two formulations) or placebo in subjects 1-50 years of age. Among the 636 subjects enrolled, 331 (52%) were primed, that is, baseline seropositive to at least one dengue virus (DENV) type. Baseline seropositivity prevalence increased with age (10% [vaccines were similar to placebo regardless of priming status. No vaccine-related serious adverse events (SAEs) were reported. Among unprimed subjects, immunogenicity (geometric mean antibody titers [GMT] and seropositivity rates) for each DENV increased substantially in both TDEN vaccine groups with at least 74.6% seropositive for four DENV types. The TDEN vaccine candidate showed an acceptable safety and immunogenicity profile in children and adults ranging from 1 to 50 years of age, regardless of priming status. ClinicalTrials.gov: NCT00468858. © The American Society of Tropical Medicine and Hygiene.

  15. Safety and immunogenicity of two live attenuated human rotavirus vaccine candidates, 116E and I321, in infants: results of a randomised controlled trial.

    Science.gov (United States)

    Bhandari, Nita; Sharma, Pooja; Glass, Roger I; Ray, Pratima; Greenberg, Harry; Taneja, Sunita; Saksena, Manju; Rao, C Durga; Gentsch, Jon R; Parashar, Umesh; Maldonado, Yvonne; Ward, Richard L; Bhan, M K

    2006-07-26

    We evaluated safety and immunogenicity of two orally administered human rotavirus vaccine candidates 116E and I321. Ninety healthy infants aged 8 weeks received a single dose of 116E (10(5)FFu (florescence focus units)), I321 (10(5)FFu) or placebo. There were no significant differences in the number of adverse events. Fever was reported by 6/30, 1/30 and 5/30 in the 116E, I321 and placebo groups; the corresponding figures for diarrhoea were 5/30, 8/29 and 3/30. Serum IgA seroconversion rates were 73%, 39% and 20% in the 116E, I321 and placebo groups, respectively. Vaccine virus was shed on days 3, 7 or 28 in 11/30 infants of the 116E and none in the other two groups. The 116E strain is attenuated, clinically safe and highly immunogenic with a single dose.

  16. Immune tolerance induction to factor IX through B cell gene transfer: TLR9 signaling delineates between tolerogenic and immunogenic B cells.

    Science.gov (United States)

    Wang, Xiaomei; Moghimi, Babak; Zolotukhin, Irene; Morel, Laurence M; Cao, Ou; Herzog, Roland W

    2014-06-01

    A subset of patients with severe hemophilia B, the X-linked bleeding disorder resulting from absence of coagulation factor IX (FIX), develop pathogenic antibody responses during replacement therapy. These inhibitors block standard therapy and are often associated with anaphylactic reactions to FIX. Established clinical immune tolerance induction protocols often fail for FIX inhibitors. In a murine model of this immune complication, retrovirally transduced primary B cells expressing FIX antigen fused with immunoglobulin-G heavy chain prevented antibody formation to FIX and was also highly effective in desensitizing animals with preexisting response. In contrast, transplant of B cells that received the identical expression cassette via nucleofection of plasmid vector substantially heightened antibody formation against FIX, a response that could be blocked by toll-like receptor 9 (TLR9) inhibition. While innate responses to TLR4 activation or to retrovirus were minimal in B cells, plasmid DNA activated TLR9, resulting in CpG-dependent NF-κB activation/IL-6 expression and adaptor protein 3 dependent, CpG-independent induction of IFN-I. Neither response was seen in TLR9-deficient B cells. Therefore, TLR9 signaling in B cells, in particular in response to plasmid vector, is highly immunogenic and has to be avoided in design of tolerance protocols.

  17. Lithium safety and tolerability in mood disorders: a critical review

    Directory of Open Access Journals (Sweden)

    Ivan Aprahamian

    2014-04-01

    Full Text Available Background : Lithium is a first-line treatment for bipolar disorder in all phases, also indicated as add-on drug for unipolar depression and suicide prevention. This study encompasses a broad critical review on the safety and tolerability of lithium for mood disorders. Methods : A computerized search for English written human studies was made in MEDLINE, using the keywords “lithium” and “mood disorders”, starting from July 1993 through July 2013 (n = 416. This initial search aimed to select clinical trials, prospective data, and controlled design studies of lithium treatment for mood disorders reporting adverse effects (n = 36. The final selection yielded 91 studies. Results : The most common general side effects in patients on lithium treatment were thirst, frequent urination, dry mouth, weight gain, fatigue and cognitive complaints. Lithium users showed a high prevalence of hypothyroidism, hyperparathyroidism, and decrease in urinary concentration ability. Reduction of glomerular filtration rate in patients using lithium was also observed, but in a lesser extent. The evidence of teratogenicity associated with lithium use is not well established. Anti-inflammatory non-steroidal drugs, thiazide diuretics, angiotensin-converting enzyme inhibitors, and alprazolam may increase serum lithium and the consequent risk for intoxication. Discussion : Short-term lithium treatment is associated with mild side effects. Medium and long-term lithium treatment, however, might have effects on target organs which may be prevented by periodical monitoring. Overall, lithium is still a safe option for the treatment of mood disorders.

  18. Immunogenicity, safety, and lot consistency of a novel inactivated enterovirus 71 vaccine in Chinese children aged 6 to 59 months.

    Science.gov (United States)

    Hu, Yue-Mei; Wang, Xu; Wang, Jun-Zhi; Wang, Ling; Zhang, Yong-Jie; Chang, Lin; Liang, Zheng-Lun; Xia, Jie-Lai; Dai, Qi-Gang; Hu, Ya-Ling; Mao, Qun-Ying; Zhu, Feng-Cai; Song, Yu-Fei; Gao, Fan; Chen, Jiang-Ting

    2013-12-01

    The determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children (n = 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between -0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered at ClinicalTrials.gov under registration no. NCT01636245.).

  19. Immunogenicity and safety of a meningococcal quadrivalent conjugate vaccine in Saudi Arabian adolescents previously vaccinated with one dose of bivalent and quadrivalent meningococcal polysaccharide vaccines: a phase III, controlled, randomized, and modified blind-observer study.

    Science.gov (United States)

    Al-Mazrou, Yagob; Khalil, Mohamed; Findlow, Helen; Chadha, Helen; Bosch Castells, Valerie; Johnson, David R; Borrow, Ray

    2012-07-01

    Reduced immune responses to repeated polysaccharide vaccination have been previously reported, but there are limited immunogenicity data on the use of meningococcal polysaccharide vaccine (PSV) followed by meningococcal conjugate vaccine. Saudi Arabian adolescents (aged 16 to 19 years) who had previously been vaccinated with ≥1 dose of bivalent meningococcal polysaccharide vaccine and 1 dose of quadrivalent meningococcal polysaccharide (MPSV4) were enrolled in a controlled, randomized, and modified observer-blind study (collectively termed the PSV-exposed group). The PSV-exposed group was randomized to receive either quadrivalent meningococcal conjugate vaccine (MCV4) (n = 145 PSV-exposed/MCV4 group) or MPSV4 (n = 142 PSV-exposed/MPSV4 group), and a PSV-naïve group received MCV4 (n = 163). Serum samples collected prevaccination and 28 days postvaccination were measured by baby rabbit serum bactericidal antibody (rSBA) assay, and vaccine tolerability and safety were also evaluated. For each serogroup, the postvaccination geometric mean titers (GMTs) were significantly higher in the PSV-naïve group than in either group comprised of the PSV-exposed participants. The postvaccination serogroup C rSBA GMT was significantly higher in the PSV-MCV4 group than in the PSV-MPSV4 group after adjusting for prevaccination GMTs. Although not statistically significant, similar differences were observed for serogroups A, Y, and W-135. No worrisome safety signals were detected. This study demonstrated MCV4 to be safe and immunogenic in those who had previously received polysaccharide vaccination, and it suggests that conjugate vaccine can partially compensate for the hyporesponsiveness seen with repeated doses of polysaccharide vaccine.

  20. StrataGraft skin substitute is well-tolerated and is not acutely immunogenic in patients with traumatic wounds: results from a prospective, randomized, controlled dose escalation trial

    Science.gov (United States)

    Centanni, John M.; Straseski, Joely A.; Wicks, April; Hank, Jacquelyn A.; Rasmussen, Cathy A.; Lokuta, Mary A.; Schurr, Michael J.; Foster, Kevin N.; Faucher, Lee D.; Caruso, Daniel M.; Comer, Allen R.; Allen-Hoffmann, B. Lynn

    2012-01-01

    Objective The goal of this study was to assess the immunogenicity and antigenicity of StrataGraft skin tissue in a randomized phase I/II clinical trial for the temporary management of full-thickness skin loss. Summary Background Data StrataGraft skin tissue consists of a dermal equivalent containing human dermal fibroblasts and a fully-stratified, biologically active epidermis derived from NIKS cells, a pathogen-free, long-lived, consistent, human keratinocyte progenitor. Methods Traumatic skin wounds often require temporary allograft coverage to stabilize the wound bed until autografting is possible. StrataGraft and cadaveric allograft were placed side-by-side on 15 patients with full-thickness skin defects for one week prior to autografting. Allografts were removed from the wound bed and examined for allogeneic immune responses. Immunohistochemistry and indirect immunofluorescence were used to assess tissue structure and cellular composition of allografts. In vitro lymphocyte proliferation assays, chromium-release assays, and development of antibodies were used to examine allogeneic responses. Results One week after patient exposure to allografts, there were no differences in the numbers of T or B lymphocytes or Langerhans cells present in StrataGraft skin substitute compared to cadaver allograft, the standard of care. Importantly, exposure to StrataGraft skin substitute did not induce the proliferation of patient peripheral blood mononuclear cells to NIKS keratinocytes or enhance cell-mediated lysis of NIKS keratinocytes in vitro. Similarly, no evidence of antibody generation targeted to the NIKS keratinocytes was seen. Conclusions These findings indicate that StrataGraft tissue is well-tolerated and not acutely immunogenic in patients with traumatic skin wounds. Notably, exposure to StrataGraft did not increase patient sensitivity toward or elicit immune responses against the NIKS keratinocytes. We envision this novel skin tissue technology will be widely used

  1. Hepatitis B virus vaccination in children with steroid sensitive nephrotic syndrome: immunogenicity and safety?

    Science.gov (United States)

    Yıldız, N; Sever, Lale; Kasapçopur, Ö; Çullu, F; Arısoy, Nil; Çalışkan, S

    2013-07-18

    We investigated the efficacy and safety of Hepatitis B vaccine (HBVac) in steroid sensitive nephrotic syndrome (SSNS) children. 41 patients with SSNS and 30 controls were vaccinated with HBVac(Engerix B(®)). Patients were divided into 3 subgroups:full dose steroid users, alternate-day steroid users and steroid non-users. Seroconversion rate was lower in steroid users than non-users at the 6th(p=0.015) and 12th(p=0.036) months. Antibody to Hepatitis B surface antigen(HBsAb) titers were significantly different between subgroups and controls at the 15th month. However, HBsAb and response rates were not different between subgroups at the 12th and 15th months (p>0.05). Five patients were unresponsive to HBVac. Relapse rates after the vaccination were higher than those in the prevaccination period (p=0.002). HBVac is less effective in producing immune response in SSNS children with steroid therapy. HBVac may trigger relapse in some patients. We recommend HBVac to SSNS children with low dose steroid therapy or after steroids are discontinued. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Evaluation of immunogenicity and safety of Genevac B: A new recombinant hepatitis b vaccine in comparison with Engerix B and Shanvac B in healthy adults

    Directory of Open Access Journals (Sweden)

    Vijayakumar V

    2004-01-01

    Full Text Available PURPOSE: Genevac B, a new indigenous recombinant hepatitis B vaccine was evaluated for its immunogenicity and safety in comparison with Engerix B (Smithkline Beecham Biologicals, Belgium and Shanvac B (Shantha Biotechnics, India in healthy adult volunteers. METHODS: While 240 study subjects were included in the Genevac B group, 80 each were the subjects for Engerix B and Shanvac B. A three dose regimen of 0,1,2 months was adopted with 20 gm dosage uniformly in all the three groups. Vaccinees were assessed during prevaccination, followup and post vaccination periods for clinical, haematological, biochemical and immunological parameters for safety and immunogenicity. RESULTS: Successful follow-up in all parameters for four months could be achieved in 92.5% (222/240 for Genevac B study subjects and the same was 85% (68/80 and 80% (64/80 for Engerix B and Shanvac B respectively. While 100% seroconversion was observed in all the three groups, the rate of seroprotectivity was 99.5% by Genevac B, 98.5% by Engerix B and 98.4% for Shanvac B. However the difference was not statistically significant (p>0.05. The GMT values of anti HBs after one month of completion of the vaccination were 735.50, 718.23 and 662.20 mIU/mL respectively. No systemic reaction was either seen or reported by the volunteers during the vaccination process of Genevac B and other two vaccines. Clinical, haematological and biochemical safety parameters remained within normal limits throughout the study period. CONCLUSION: The study confirms that Genevac B, the new recombinant Hepatitis B vaccine has the acceptable international standards of safety and immunogenicity.

  3. Immunogenicity and safety of an inactivated hepatitis A vaccine administered concomitantly with diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines to children less than 2 years of age.

    Science.gov (United States)

    Nolan, Terry; Bernstein, Henry; Blatter, Mark M; Bromberg, Kenneth; Guerra, Fernando; Kennedy, William; Pichichero, Michael; Senders, Shelly D; Trofa, Andrew; Collard, Alix; Sullivan, Diane C; Descamps, Dominique

    2006-09-01

    The availability of a hepatitis A virus vaccine for infant and early childhood immunization could reduce the transmission of hepatitis A virus in the United States. This study evaluated the immunogenicity and safety of a hepatitis A virus vaccine (Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) administered concomitantly with diphtheria-tetanus-acellular pertussis and Haemophilus influenzae type b vaccines to children vaccination history. Subjects 11 to 13 months of age received 2 doses of hepatitis A virus vaccine 6 months apart (N = 243). Subjects aged 15 to 18 months received 2 doses of hepatitis A virus vaccine 6 months apart (N = 241); or hepatitis A virus vaccine, diphtheria-tetanus-acellular pertussis, and H influenzae type b at month 0 and the second dose of hepatitis A virus vaccine 6 months later (N = 183); or diphtheria-tetanus-acellular pertussis and H influenzae type b at month 0 and hepatitis A virus vaccine at months 1 and 7 (N = 175). Subjects 23 to 25 months of age received hepatitis A virus vaccine at months 0 and 6 (N = 242). Immune responses were measured at baseline and 30 days after vaccine doses, and solicited and unsolicited adverse events were collected. After 2 doses of hepatitis A virus vaccine, all of the subjects in all of the groups were seropositive. Coadministration of hepatitis A virus vaccine with diphtheria-tetanus-acellular pertussis and H influenzae type b vaccines did not impact the immunogenicity of the 3 vaccines, except for the antipertussis toxoid vaccine response, which was slightly decreased. Hepatitis A virus vaccine was well tolerated in children 11 to 25 months of age. The administration of 2 doses of hepatitis A virus vaccine on a 0- and 6-month schedule starting at 11 to 13 months of age or at 15 to 18 months of age was as immunogenic and well tolerated as the administration of 2 doses in children 2 years of age. Immune responses to diphtheria-tetanus-acellular pertussis and H influenzae type b either given

  4. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine

    Science.gov (United States)

    Baron, Mira; Levin, Myron J; Chatterjee, Archana; Fox, Bradley; Scholar, Sofia; Rosen, Jeffrey; Chakhtoura, Nahida; Meric, Dorothée; Dessy, Francis J; Datta, Sanjoy K; Descamps, Dominique; Dubin, Gary

    2011-01-01

    In this observer-blind study (NCT00423046), women (N = 1,106), stratified by age (18–26, 27–35, 36–45 y), were randomized (1:1) to receive the HPV-16/18 vaccine (Cervarix®, GlaxoSmithKline Biologicals, Months 0, 1, 6) or the HPV-6/11/16/18 vaccine (Gardasil® Merck and Co., Inc., Months 0, 2, 6). Month 7 results were previously reported; we now report Month 24 results. In the according-to-protocol cohort for immunogenicity (seronegative and DNA-negative at baseline for HPV type analyzed), seropositivity rates of neutralizing antibodies (nAbs) [pseudovirion-based neutralization assay] were, across all age strata, 100% (HPV-16/18 vaccine) and 97.5–100% (HPV-6/11/16/18 vaccine) for HPV-16, and 99.0–100% (HPV-16/18 vaccine) and 72.3–84.4% (HPV-6/11/16/18 vaccine) for HPV-18. Corresponding geometric mean titers (GMTs) were 2.4–5.8-fold higher for HPV-16 and 7.7–9.4-fold higher for HPV-18 with the HPV-16/18 vaccine vs. the HPV-6/11/16/18 vaccine; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (p vaccinated cohort (received ≥1 vaccine dose, irrespective of baseline sero/DNA-status). Similar results were obtained using enzyme-linked immunosorbent assay (ELISA ). Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions (ELISA) were not significantly different between vaccines. At Month 24, CD4+ T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16. Both vaccines were generally well tolerated. Although an immunological correlate of protection has not been defined, differences in the magnitude of immune response between vaccines may represent determinants of duration of protection. PMID:22048173

  5. Immunogenicity and safety of the inactivated hepatitis A vaccine in children with juvenile idiopathic arthritis on methotrexate treatment: a matched case-control study.

    Science.gov (United States)

    Maritsi, Despoina N; Coffin, Susan E; Argyri, Ioanna; Vartzelis, George; Spyridis, Nick; Tsolia, Maria N

    2017-01-01

    To describe the immunogenicity and side effects of immunisation against hepatitis A virus (HAV) in JIA patients on methotrexate treatment, who have not been previously exposed to HAV. Case-control study performed in JIA patients and healthy controls matched on age and gender. The subjects received two doses of inactivated anti-HAV vaccine (720 mIU/ml) intramuscularly at 0 and 6 months. Seroconversion, seroprotection rates and anti-HAV-IgG titres were measured at 1, 7 and 18 months. Children were monitored for adverse events. 83 JIA patients and 76 controls were enrolled in the study. At one month, seroprotection rates were lower in children with, as compared to those without JIA (48.2% vs. 65%; p=0.05). At 7 and 18 months, rates of seroprotection rose significantly and were similar in both groups. The titre of anti-HAV-IgG was lower in children with JIA than healthy children at all time points (p<0.001). Vaccines were well tolerated. Two doses of inactivated HAV vaccine were well tolerated and immunogenic in most immunosuppressed children with JIA; however, a single dose of HAV vaccine was insufficient to induce seroprotection in half of the patients. Further studies are required to analyse the long-term immunity against HAV in this population and optimal HAV immunisation regimen.

  6. Safety and immunogenicity of inactivated varicella-zoster virus vaccine in adults with hematologic malignancies receiving treatment with anti-CD20 monoclonal antibodies.

    Science.gov (United States)

    Parrino, Janie; McNeil, Shelly A; Lawrence, Steven J; Kimby, Eva; Pagnoni, Marco F; Stek, Jon E; Zhao, Yanli; Chan, Ivan S F; Kaplan, Susan S

    2017-03-27

    Immunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZVIN) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZVIN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80). This was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZVIN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4. ZVIN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion. Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZVIN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain. In adults with HM receiving anti-CD20

  7. Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants.

    Science.gov (United States)

    Klein, Nicola P; Abu-Elyazeed, Remon; Cornish, Matthew; Leonardi, Michael L; Weiner, Leonard B; Silas, Peter E; Grogg, Stanley E; Varman, Meera; Frenck, Robert W; Cheuvart, Brigitte; Baine, Yaela; Miller, Jacqueline M; Leyssen, Maarten; Mesaros, Narcisa; Roy-Ghanta, Sumita

    2017-06-16

    Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines' antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. Hib

  8. Extended Safety, Immunogenicity and Efficacy of a Blood-Stage Malaria Vaccine in Malian Children: 24-Month Follow-Up of a Randomized, Double-Blinded Phase 2 Trial

    Science.gov (United States)

    Laurens, Matthew B.; Thera, Mahamadou A.; Coulibaly, Drissa; Ouattara, Amed; Kone, Abdoulaye K.; Guindo, Ando B.; Traore, Karim; Traore, Idrissa; Kouriba, Bourema; Diallo, Dapa A.; Diarra, Issa; Daou, Modibo; Dolo, Amagana; Tolo, Youssouf; Sissoko, Mahamadou S.; Niangaly, Amadou; Sissoko, Mady; Takala-Harrison, Shannon; Lyke, Kirsten E.; Wu, Yukun; Blackwelder, William C.; Godeaux, Olivier; Vekemans, Johan; Dubois, Marie-Claude; Ballou, W. Ripley; Cohen, Joe; Dube, Tina; Soisson, Lorraine; Diggs, Carter L.; House, Brent; Bennett, Jason W.; Lanar, David E.; Dutta, Sheetij; Heppner, D. Gray; Plowe, Christopher V.; Doumbo, Ogobara K.

    2013-01-01

    Background The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali. Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic. It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy. Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy. Methods A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1) vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali. Children aged 1–6 years were randomized in a 1∶1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60. Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons. Findings 400 children were enrolled. Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination. After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group. For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p = 0.51) against first clinical malaria episodes and 9.9% (p = 0.19) against all malaria episodes. For the final 16-month follow-up period, vaccine efficacy was 0.9% (p = 0.98) against all malaria episodes. Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up. Interpretation Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies. This study presents an opportunity to evaluate correlates of partial protection against

  9. Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial.

    Directory of Open Access Journals (Sweden)

    Matthew B Laurens

    Full Text Available The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali. Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic. It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy. Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy.A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1 vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali. Children aged 1-6 years were randomized in a 1∶1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60. Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons.400 children were enrolled. Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination. After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group. For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p = 0.51 against first clinical malaria episodes and 9.9% (p = 0.19 against all malaria episodes. For the final 16-month follow-up period, vaccine efficacy was 0.9% (p = 0.98 against all malaria episodes. Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up.Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies. This study presents an opportunity to evaluate correlates of partial protection against clinical malaria that waned during

  10. A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults.

    Science.gov (United States)

    Minhinnick, Alice; Satti, Iman; Harris, Stephanie; Wilkie, Morven; Sheehan, Sharon; Stockdale, Lisa; Manjaly Thomas, Zita-Rose; Lopez-Ramon, Raquel; Poulton, Ian; Lawrie, Alison; Vermaak, Samantha; Le Vert, Alexandre; Del Campo, Judith; Hill, Fergal; Moss, Paul; McShane, Helen

    2016-03-08

    There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited. This trial was registered on clinicatrials.gov ref. NCT01879163. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Evaluation of rabies immunogenicity and tolerability following a purified chick embryo cell rabies vaccine administered concomitantly with a Japanese encephalitis vaccine.

    Science.gov (United States)

    Jelinek, Tomas; Cramer, Jakob P; Dieckmann, Sebastian; Hatz, Christoph; Paulke-Korinek, Maria; Alberer, Martin; Reisinger, Emil C; Costantini, Marco; Gniel, Dieter; Bosse, Dietrich; Lattanzi, Maria

    2015-01-01

    For individuals traveling at short notice to rabies and Japanese encephalitis (JE) endemic countries, concomitant administration of travel vaccines within a short period is often required. The aim of this study was to determine whether an accelerated (one-week: Days 1-8) pre-exposure rabies (Rabipur(®), Novartis Vaccines) vaccination regimen administered concomitantly with a Japanese encephalitis (JE) vaccination (Ixiaro(®), Valneva) regimen, is non-inferior to the standard (four-week: Days 1, 8, 29) rabies regimen administered alone or concomitantly with the JE vaccine. Healthy adults (18 to ≤ 65 years) were randomized into Rabies + JE-Standard, Rabies + JE-Accelerated, Rabies-Standard and JE-Standard groups. Relative immunogenicity for rabies in each regimen was assessed using the rapid fluorescent focus inhibition test. Safety was evaluated up to and including Day 57. Non-inferior immunogenicity for rabies was established between the Rabies + JE-Accelerated group compared to both the Rabies-Standard and Rabies + JE-Standard groups; as well as between the Rabies + JE-Standard regimen and the Rabies-Standard regimen. By Day 57, adequate neutralizing levels were achieved by 97-100% of subjects across all groups. Adverse events (AEs) were comparable for all groups. An accelerated pre-exposure rabies and JE vaccination regimen is non-inferior to the standard four-week rabies regimen and may thus provide a more convenient regimen for individuals traveling to endemic countries at short notice. NCT01662440. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. A phase I safety and immunogenicity trial of rVSVG ZEBOV GP vaccine in adults and children in Lambarn, Gabon.

    Science.gov (United States)

    2017-05-10

    between adults, adolescents and children receiving 2x107 PFU *Already reported in the New England Journal of Medicine, DOI: 10.1056/NEJMoa1502924...Page 1 of 41 A phase I safety and immunogenicity trial of rVSV∆G-ZEBOV-GP vaccine in adults and children in Lambaréné, Gabon. Selidji T...forming units (PFU), n = 20 each; 3x106 PFU (n = 39) and 2x107 PFU (n = 16)). A single dose of 2x107 PFU was studied in adolescents and children (n

  13. Immunogenicity, safety and reactogenicity of a booster dose of the 10-valent pneumococcal Nontypeable H. influenzae Protein D conjugate vaccine coadministered with DTPa-IPV-Hib in Dutch children

    NARCIS (Netherlands)

    Van Den Bergh, Menno R.; Spijkerman, Judith; François, Nancy; Swinnen, Kristien; Borys, Dorota; Schuerman, Lode; Veenhoven, Reinier H.; Sanders, Elisabeth A M

    2016-01-01

    Background: Immune responses and safety profiles may be affected when vaccines are coadministered. We evaluated the immunogenicity, safety and reactogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate (PHiD-CV; Synflorix GSK Vaccines) and

  14. Safety and tolerability of grass pollen tablets in sublingual immunotherapy--a phase-1 study

    DEFF Research Database (Denmark)

    Larsen, T H; Poulsen, Lars K.; Melac, M

    2006-01-01

    A single-centre, randomized, double-blind, placebo-controlled study. Aims: To compare the safety and tolerability of four different sublingual immunotherapy (SLIT) regimes in grass pollen allergic rhinitis....

  15. Safety aspects of genetically modified crops with abiotic stress tolerance

    NARCIS (Netherlands)

    Liang, C.; Prins, T.W.; Wiel, van de C.C.M.; Kok, E.J.

    2014-01-01

    Abiotic stress, such as drought, salinity, and temperature extremes, significantly reduce crop yields. Hence, development of abiotic stress-tolerant crops by modern biotechnology may contribute to global food security. Prior to introducing genetically modified crops with abiotic stress tolerance to

  16. HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia.

    Science.gov (United States)

    Samuels, Sanne; Marijne Heeren, A; Zijlmans, Henry J M A A; Welters, Marij J P; van den Berg, Joost H; Philips, Daisy; Kvistborg, Pia; Ehsan, Ilina; Scholl, Suzy M E; Nuijen, Bastiaan; Schumacher, Ton N M; van Beurden, Marc; Jordanova, Ekaterina S; Haanen, John B A G; van der Burg, Sjoerd H; Kenter, Gemma G

    2017-09-01

    Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH). The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16 + uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry. Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4 + and/or CD8 + T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1β (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients. DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.

  17. Safety and immunogenicity of an FP9-vectored candidate tuberculosis vaccine (FP85A), alone and with candidate vaccine MVA85A in BCG-vaccinated healthy adults: a phase I clinical trial.

    Science.gov (United States)

    Rowland, Rosalind; Pathan, Ansar A; Satti, Iman; Poulton, Ian D; Matsumiya, Magali M L; Whittaker, Megan; Minassian, Angela M; O'Hara, Geraldine A; Hamill, Matthew; Scott, Janet T; Harris, Stephanie A; Poyntz, Hazel C; Bateman, Cynthia; Meyer, Joel; Williams, Nicola; Gilbert, Sarah C; Lawrie, Alison M; Hill, Adrian V S; McShane, Helen

    2013-01-01

    The safety and immunogenicity of a new candidate tuberculosis (TB) vaccine, FP85A was evaluated alone and in heterologous prime-boost regimes with another candidate TB vaccine, MVA85A. This was an open label, non-controlled, non-randomized Phase I clinical trial. Healthy previously BCG-vaccinated adult subjects were enrolled sequentially into three groups and vaccinated with FP85A alone, or both FP85A and MVA85A, with a four week interval between vaccinations. Passive and active data on adverse events were collected. Immunogenicity was evaluated by Enzyme Linked Immunospot (ELISpot), flow cytometry and Enzyme Linked Immunosorbent assay (ELISA). Most adverse events were mild and there were no vaccine-related serious adverse events. FP85A vaccination did not enhance antigen 85A-specific cellular immunity. When MVA85A vaccination was preceded by FP85A vaccination, cellular immune responses were lower compared with when MVA85A vaccination was the first immunisation. MVA85A vaccination, but not FP85A vaccination, induced anti-MVA IgG antibodies. Both MVA85A and FP85A vaccinations induced anti-FP9 IgG antibodies. In conclusion, FP85A vaccination was well tolerated but did not induce antigen-specific cellular immune responses. We hypothesize that FP85A induced anti-FP9 IgG antibodies with cross-reactivity for MVA85A, which may have mediated inhibition of the immune response to subsequent MVA85A. ClinicalTrials.gov identification number: NCT00653770.

  18. Safety and immunogenicity of an investigational fully liquid hexavalent DTaP-IPV-Hep B-PRP-T vaccine at two, four and six months of age compared with licensed vaccines in Latin America.

    Science.gov (United States)

    Macías, Mercedes; Lanata, Claudio F; Zambrano, Betzana; Gil, Ana I; Amemiya, Isabel; Mispireta, Monica; Ecker, Lucie; Santos-Lima, Eduardo

    2012-08-01

    This trial assessed the safety of a fully liquid investigational hexavalent DTaP-IPV-Hep B-PRP-T vaccine containing 10 μg Hansenula polymorpha-derived recombinant hepatitis B (hep B) antigen for primary vaccination of infants at 2, 4 and 6 months of age compared with licensed comparators. Participants received the DTaP-IPV-Hep B-PRP-T vaccine (group 1, N = 1422) or licensed DTwP-Hep B//Hib (Tritanrix-Hep B/Hib) and oral poliovirus vaccines (group 2, N = 711). The incidence of severe fever (≥ 39.6°C rectal equivalent) in the 2 groups was compared statistically; reactogenicity was evaluated from parental reports. Anti-Hep B antibody titers were measured in a subset of participants (no hepatitis B vaccination at birth) 1 month after dose 3. The investigational vaccine was well tolerated. After any dose, fever (rectal equivalent temperature ≥ 38°C) was observed in 74.8% and 92.7% of participants in groups 1 and 2; severe fever was observed in 4.0% and 5.5% of participants. Solicited injection site and systemic reactions were numerically less frequent in group 1 than group 2, although this difference was not assessed statistically. In both groups, all participants included in the immunogenicity analysis achieved anti-Hep B ≥ 10 mIU/mL and ≥ 96.2% of participants achieved anti-Hep B ≥ 100 mIU/mL, although geometric mean titer was approximately 3-fold lower for the investigational vaccine. This new, fully liquid acellular pertussis hexavalent vaccine demonstrated less reactogenicity than the licensed comparator whole cell pertussis vaccine and was highly immunogenic for the new Hep B valence.

  19. Evaluation of safety and immunogenicity of a live attenuated tetravalent (G1-G4) Bovine-Human Reassortant Rotavirus vaccine (BRV-TV) in healthy Indian adults and infants.

    Science.gov (United States)

    Dhingra, M S; Kundu, R; Gupta, M; Kanungo, S; Ganguly, N; Singh, M P; Bhattacharya, M K; Ghosh, R; Kumar, R; Sur, D; Chadha, S M; Saluja, T

    2014-08-11

    arm (RotaTeq), 28 days post each vaccine dose. The safety profile was comparable across the treatment groups. Overall, the results showed that all three doses of BRV-TV vaccine were safe, well tolerated and displayed good immunogenicity (dose-response) in healthy Indian infants. Copyright © 2014. Published by Elsevier Ltd.

  20. Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults.

    Science.gov (United States)

    Hopkins, Robert J; Kalsi, Gurdyal; Montalvo-Lugo, Victor M; Sharma, Mona; Wu, Yukun; Muse, Derek D; Sheldon, Eric A; Hampel, Frank C; Lemiale, Laurence

    2016-04-19

    AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax(®) (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1-2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2-4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (≥0.56) to be ≥40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects.

    Science.gov (United States)

    Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

    2017-06-03

    To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China.

  2. Combination Measles-Mumps-Rubella-Varicella Vaccine in Healthy Children: A Systematic Review and Meta-analysis of Immunogenicity and Safety.

    Science.gov (United States)

    Ma, Shu-Juan; Li, Xing; Xiong, Yi-Quan; Yao, A-Ling; Chen, Qing

    2015-11-01

    A combined measles-mumps-rubella-varicella (MMRV) vaccine is expected to facilitate universal immunization against these 4 diseases. This study was undertaken to synthesize current research findings of the immunogenicity and safety of MMRV in healthy children.We searched PubMed, Embase, BIOSIS Previews, Web of Science, Cochrane Library, and other databases through September 9, 2014. Eligible randomized controlled trials (RCTs) were selected and collected independently by 2 reviewers. Meta-analysis was conducted using Stata 12.0 and RevMan 5.3.Twenty-four RCTs were included in qualitative synthesis. Nineteen RCTs compared single MMRV dose with measles-mumps-rubella vaccine with or without varicella vaccine (MMR + V/MMR). Similar seroconversion rates of these 4 viruses were found between comparison groups. There were comparable geometric mean titers (GMTs) against mumps and varicella viruses between MMRV group and MMR + V/MMR group. MMRV group achieved enhanced immune response to measles component, with GMT ratio of 1.66 (95% confidence interval [CI] 1.48, 1.86; P rubella component in MMRV group was slightly reduced, GMT ratios were 0.81 (95% CI 0.78, 0.85; P rubella-like rash (relative risks 1.44-1.45) in MMRV groups.MMRV had comparable immunogenicity and overall safety profiles to MMR + V/MMR in healthy children based on current evidence.

  3. A randomized, controlled, blinded study of the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine made in China in Chinese people.

    Science.gov (United States)

    Li, Shuming; Li, Li; Ai, Xing; Yang, Liqing; Bai, Yunhua; Wang, Zhaoyun; Han, Huixia; Lu, Qiang; Luo, Fengji; Zhang, Zheng; Liu, Chunyu; Xiao, Jun; Shi, Nianmin

    2014-01-01

    To evaluate the safety, immunogenicity and batch consistency of Aleph inactivated split influenza vaccine, 3308 healthy Chinese people more than 3 years old were enrolled in a randomized, controlled, blinded study and divided into four age groups: 3-10 years, 11-17 years, 18-54 years, and more than 55 years. Each age group was then randomized (2:1) to receive either influenza vaccine or control vaccine (recombinant hepatitis B) for one dose. Also each influenza vaccine group was randomized (1:1:1) to receive three different batches of influenza vaccine. Systematic and local adverse reactions for 28 days after vaccination were recorded, and influenza antibody titer was determined by hemagglutination inhibition (HI) assay at 28 days after vaccination. There were significant differences in seroconversion and seroprotection rates achieved post-immunization of three strains of influenza antibody (H1N1, H3N2, B) between experimental group and control group in all age groups (P0.05), except for the systematic reaction rates in the 18-54 years and ≥ 55 years age groups (PAleph inactivated split influenza vaccine has good safety and immunogenicity.

  4. Phase 2 Assessment of the Safety and Immunogenicity of Two Inactivated Pandemic Monovalent H1N1 Vaccines in Adults as a Component of the U.S. Pandemic Preparedness Plan in 2009

    Science.gov (United States)

    Chen, Wilbur H.; Winokur, Patricia L.; Edwards, Kathryn M.; Jackson, Lisa A.; Wald, Anna; Walter, Emmanuel B.; Noah, Diana L.; Wolff, Mark; Kotloff, Karen L.

    2012-01-01

    Background The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. Methods Healthy adults, stratified by age (18 to 64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 μg or 30 μg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). Results Both vaccines were well-tolerated. A single 15 μg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82%-95%) and 81% of elderly (95% CI 71%–88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 μg HA in the standard potency assay), and in 80% of younger adults (95% CI 71%–88%) and 60% of elderly (95% CI 50%–70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 μg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. Conclusion These trials provided evidence for policymakers that a single 15 μg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30

  5. Immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine and DTPa-IPV-Hib when coadministered as a 3-dose primary vaccination schedule in The Netherlands: a randomized controlled trial.

    Science.gov (United States)

    van den Bergh, Menno R; Spijkerman, Judith; François, Nancy; Swinnen, Kristien; Borys, Dorota; Schuerman, Lode; Veenhoven, Reinier H; Sanders, Elisabeth A M

    2011-09-01

    Recent reviews have highlighted the unpredictability of immunologic interference when multivalent conjugated vaccines are coadministered with other pediatric vaccines. To evaluate immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix, GlaxoSmithKline Biologicals) and DTPa-IPV-Hib (Pediacel, Sanofi Pasteur MSD) when coadministered as a 3-dose primary vaccination course. In a single-blind, single-center, randomized controlled trial in the Netherlands, healthy infants (n = 780) were randomly assigned (1:1:1) to receive either (1) PHiD-CV + DTPa-HBV-IPV/Hib (Infanrix Hexa, GlaxoSmithKline Biologicals), (2) PHiD-CV + DTPa-IPV-Hib, or (3) 7-valent pneumococcal conjugate vaccine (Prevenar/Prevnar, Pfizer Inc.) + DTPa-IPV-Hib at 2, 3, and 4 months of age. Blood samples were collected 1 month after dose 3. Diary cards were used to record safety and reactogenicity. Antibody concentrations elicited by PHiD-CV coadministered with DTPa-IPV-Hib were noninferior to those following DTPa-HBV-IPV/Hib coadministration for 9 of 10 vaccines pneumococcal serotypes and protein D. For serotype 18C (conjugated to tetanus toxoid), the antibody concentration was higher with DTPa-HBV-IPV/Hib coadministration (1.73 vs. 1.07 μg/mL). The percentages of infants with antibody concentrations ≥0.2 μg/mL (68.9%-100% in the PHiD-CV + DTPa-HBV-IPV/Hib group vs. 64.9%-100% in the PHiD-CV + DTPa-IPV-Hib group) and with measurable opsonophagocytic activity (56.1%-100% in the PHiD-CV + DTPa-HBV-IPV/Hib group vs. 61.1%-100% in the PHiD-CV + DTPa-IPV-Hib group) were comparable for all serotypes in both PHiD-CV groups. Group differences in antibody responses to the DTPa-IPV-Hib antigens remained within the predefined limit for noninferiority. Safety and reactogenicity profiles were comparable across groups. : PHiD-CV and DTPa-IPV-Hib were immunogenic and well tolerated when coadministered as a 3-dose

  6. Immunogenicity and safety of a trivalent inactivated 2010-2011 influenza vaccine in Taiwan infants aged 6-12 months.

    Science.gov (United States)

    Hwang, Kao-Pin; Hsu, Yu-Lung; Hsieh, Tsung-Hsueh; Lin, Hsiao-Chuan; Yen, Ting-Yu; Wei, Hsiu-Mei; Lin, Hung-Chih; Chen, An-Chyi; Chow, Julie Chi; Huang, Li-Min

    2014-05-01

    This prospective study aimed to investigate the immune responses and safety of an influenza vaccine in vaccine-naïve infants aged 6-12 months, and was conducted from November 2010 to May 2011. Fifty-nine infants aged 6-12 months received two doses of trivalent inactivated influenza vaccine 4 weeks apart. Hemagglutination inhibition titers were measured 4 weeks after the two doses of study vaccine. Based on the assumption that a hemagglutination inhibition titer of 1:40 or greater against the antigen would be protective in adults, two doses of the study vaccine generated a protective immune response of 63.2% against influenza A(H1N1), 82.5% against influenza A(H3N2) and 38.6% against influenza B viruses in infants aged 6-12 months. The geometric mean fold rises against influenza type A and B viruses also met the European Medicines Agency criteria for flu vaccines. The solicited events within 7 days after vaccination were mild in intensity. No deaths or adverse events such as optic neuritis, cranial neuropathy, and brachial neuropathy or Guillain-Barre syndrome were reported. Two doses of inactivated influenza vaccine were well tolerated and induced a protective immune response against influenza in infants aged 6-12 months. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Safety and immunogenicity of high-dose trivalent inactivated influenza vaccine in adults 50-64 years of age.

    Science.gov (United States)

    DiazGranados, Carlos A; Saway, William; Gouaux, James; Baron, Mira; Baker, Jeffrey; Denis, Martine; Jordanov, Emilia; Landolfi, Victoria; Yau, Eddy

    2015-12-16

    Individuals 50-64 years of age have reduced immune responses to influenza vaccines. The current study examined whether a high-dose inactivated trivalent influenza vaccine (IIV3-HD) might improve immune responses over a standard-dose inactivated influenza vaccine (IIV3-SD) in this age group. This was a multicenter, observer-blinded, randomized, active-controlled phase II trial. Adults 50-64 years of age were randomized 1:1 to receive IIV3-HD or IIV3-SD. Hemagglutination inhibition titers were measured before and 28 days after vaccination. Reactogenicity was recorded for 7 days after vaccination and adverse events for 28 days. 148 participants received IIV3-HD and 152 received IIV3-SD. For all vaccine strains, day 28 geometric mean hemagglutination inhibition titers were significantly higher in the IIV3-HD group than in the IIV3-SD group (geometric mean titer ratio [95% confidence interval (CI)]=1.43 [1.04-1.97] for A/H1N1, 1.65 [1.21-2.25] for A/H3N2, and 1.60 [1.23-2.08] for B). Seroconversion rates were significantly higher in the IIV3-HD group than in the IIV3-SD group for strains A/H3N2 and B but not A/H1N1 (difference [95% CI]=13.5% [4.76-22.0] for A/H3N2, 23.1% [11.7-33.6] for B, and -0.2% [-9.66 to 9.18] for A/H1N1). The post-vaccination seroprotection rate was significantly higher in the IIV3-HD group than in the IIV3-SD group for strain B but not for strains A/H1N1 or A/H3N2 (difference=9.1% [2.95-15.7] for B, 2.0% [-0.907 to 5.68] for A/H1N1, and 0.6% [-3.14 to 4.43] for A/H3N2). Reactogenicity was higher in the IIV3-HD group than in the IIV3-SD group, but reactions were mostly of low intensity, transient, and self-limited. Rates of unsolicited adverse events were similar between groups. No serious AEs, AEs leading to early withdrawal, or deaths were reported. The study suggests that in adults 50-64 years of age, IIV3-HD may improve immunogenicity compared to IIV3-SD while maintaining an acceptable safety profile. Copyright © 2015 The Authors. Published

  8. The Immunogenicity and Safety of a Combined DTaP-IPV//Hib Vaccine Compared with Individual DTaP-IPV and Hib (PRP~T) Vaccines: a Randomized Clinical Trial in South Korean Infants.

    Science.gov (United States)

    Kang, Jin Han; Lee, Hoan Jong; Kim, Kyung Hyo; Oh, Sung Hee; Cha, Sung Ho; Lee, Jin; Kim, Nam Hee; Eun, Byung Wook; Kim, Chang Hwi; Hong, Young Jin; Kim, Hyun Hee; Lee, Kyung Yil; Kim, Yae Jean; Cho, Eun Young; Kim, Hee Soo; Guitton, Fabrice; Ortiz, Esteban

    2016-09-01

    Recommended infant vaccination in Korea includes DTaP-IPV and Hib vaccines administered as separate injections. In this randomized, open, controlled study we assessed the non-inferiority of immunogenicity of DTaP-IPV//Hib pentavalent combination vaccine (Pentaxim™) compared with licensed DTaP-IPV and Hib (PRP~T) vaccines. We enrolled 418 healthy Korean infants to receive either separate DTaP-IPV and Hib vaccines (n = 206) or the pentavalent DTaP-IPV//Hib (n = 208) vaccine at 2, 4, 6 months of age. Antibodies to all components were measured before the first vaccination and one month after the third, and safety was assessed after each vaccination including recording of reactions by parents. We confirmed the non-inferiority of DTaP-IPV//Hib compared with DTaP-IPV and Hib vaccines; 100% of both groups achieved seroprotection against D, T, IPV and PRP~T, and 97.5%-99.0% demonstrated seroresponses to pertussis antigens. Antibody levels were similar in both groups, except for those to the Hib component, PRP~T. In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 μg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 μg/mL, indicative of long-term protection. All vaccines were well tolerated, with no vaccine-related serious adverse event. Both groups had similar safety profiles, but the combined vaccine group had fewer injection site reactions. The immunological non-inferiority and similar safety profile of DTaP-IPV//Hib vaccine to separate DTaP-IPV and Hib vaccines, with the advantage of fewer injections and injection site reactions, supports the licensure and incorporation of DTaP-IPV//Hib into the Korean national vaccination schedule (Clinical trial registry, NCT01214889).

  9. A randomized study of the immunogenicity and safety of Japanese encephalitis chimeric virus vaccine (JE-CV) in comparison with SA14-14-2 vaccine in children in the Republic of Korea.

    Science.gov (United States)

    Kim, Dong Soo; Houillon, Guy; Jang, Gwang Cheon; Cha, Sung-Ho; Choi, Soo-Han; Lee, Jin; Kim, Hwang Min; Kim, Ji Hong; Kang, Jin Han; Kim, Jong-Hyun; Kim, Ki Hwan; Kim, Hee Soo; Bang, Joon; Naimi, Zulaikha; Bosch-Castells, Valérie; Boaz, Mark; Bouckenooghe, Alain

    2014-01-01

    A new live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) has been developed based on innovative technology to give protection against JE with an improved immunogenicity and safety profile. In this phase 3, observer-blind study, 274 children aged 12-24 months were randomized 1:1 to receive one dose of JE-CV (Group JE-CV) or the SA14-14-2 vaccine currently used to vaccinate against JE in the Republic of Korea (Group SA14-14-2). JE neutralizing antibody titers were assessed using PRNT50 before and 28 days after vaccination. The primary endpoint of non-inferiority of seroconversion rates on D28 was demonstrated in the Per Protocol analysis set as the difference between Group JE-CV and Group SA14-14-2 was 0.9 percentage points (95% confidence interval [CI]: -2.35; 4.68), which was above the required -10%. Seroconversion and seroprotection rates 28 days after administration of a single vaccine dose were 100% in Group JE-CV and 99.1% in Group SA14-14-2; all children except one (Group SA14-14-2) were seroprotected. Geometric mean titers (GMTs) increased in both groups from D0 to D28; GM of titer ratios were slightly higher in Group JE-CV (182 [95% CI: 131; 251]) than Group SA14-14-2 (116 [95% CI: 85.5, 157]). A single dose of JE-CV was well tolerated and no safety concerns were identified. In conclusion, a single dose of JE-CV or SA14-14-2 vaccine elicited a comparable immune response with a good safety profile. Results obtained in healthy Korean children aged 12-24 months vaccinated with JE-CV are consistent with those obtained in previous studies conducted with JE-CV in toddlers.

  10. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine when used in combination with sodium stibogluconate for the treatment of mucosal leishmaniasis.

    Science.gov (United States)

    Llanos-Cuentas, Alejandro; Calderón, Wessmark; Cruz, María; Ashman, Jill A; Alves, Fabiana P; Coler, Rhea N; Bogatzki, Lisa Y; Bertholet, Sylvie; Laughlin, Elsa M; Kahn, Stuart J; Beckmann, Anna Marie; Cowgill, Karen D; Reed, Steven G; Piazza, Franco M

    2010-10-28

    Adult patients with mucosal leishmaniasis (ML) were enrolled in a randomized, double-blind, placebo-controlled, dose-escalating clinical trial and were randomly assigned to receive three injections of either the LEISH-F1+MPL-SE vaccine (consisting of 5, 10, or 20 μg recombinant Leishmania polyprotein LEISH-F1 antigen+25 μg MPL(®)-SE adjuvant) (n=36) or saline placebo (n=12). The study injections were given subcutaneously on Days 0, 28, and 56, and the patients were followed through Day 336 for safety, immunological, and clinical evolution endpoints. All patients received standard chemotherapy with sodium stibogluconate starting on Day 0. The vaccine was safe and well tolerated, and induced both humoral and cell-mediated immune responses. Furthermore, intracellular cytokine staining showed an increase in the proportion of memory LEISH-F1-specific IL-2(+) CD4 T-cells after vaccination, which was associated with clinical cure. This clinical trial shows that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in patients with ML. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. Safety and Tolerability of Conserved Region Vaccines Vectored by Plasmid DNA, Simian Adenovirus and Modified Vaccinia Virus Ankara Administered to Human Immunodeficiency Virus Type 1-Uninfected Adults in a Randomized, Single-Blind Phase I Trial: e101591

    National Research Council Canada - National Science Library

    Emma-Jo Hayton; Annie Rose; Umar Ibrahimsa; Mariarosaria Del Sorbo; Stefania Capone; Alison Crook; Antony P Black; Lucy Dorrell; Tomás Hanke

    2014-01-01

      Trial Design HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors...

  12. Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine Coadministered With Seasonal Influenza Vaccine in Adults Aged 50 Years or Older.

    Science.gov (United States)

    Schwarz, Tino F; Aggarwal, Naresh; Moeckesch, Beate; Schenkenberger, Isabelle; Claeys, Carine; Douha, Martine; Godeaux, Olivier; Grupping, Katrijn; Heineman, Thomas C; Fauqued, Marta Lopez; Oostvogels, Lidia; Van den Steen, Peter; Lal, Himal

    2017-12-12

    The immunogenicity and safety of an adjuvanted herpes zoster subunit (HZ/su) vaccine when coadministered with a quadrivalent seasonal inactivated influenza vaccine (IIV4) was investigated in a phase 3, open-label, randomized clinical trial in adults aged ≥50 years. Subjects were randomized 1:1 to receive either HZ/su (varicella zoster virus glycoprotein E; AS01B Adjuvant System) and IIV4 at day 0 followed by a second HZ/su dose at month 2 (coadministration group), or IIV4 at month 0 and HZ/su at months 2 and 4 (control group). The primary objectives were the HZ/su vaccine response rate in the coadministration group and the noninferiority of the antibody responses to HZ/su and IIV4 in the coadministration compared with the control group. Safety information was collected throughout the duration of the study. A total of 413 subjects were vaccinated in the coadministration group and 415 in the control group. The HZ/su vaccine response rate in the coadministration group was 95.8% (95% confidence interval, 93.3%-97.6%) and the anti-glycoprotein E GMCControl/Coadmin ratio was 1.08 (.97-1.20). The primary noninferiority objectives were met. No safety concerns were observed. No interference in the immune responses to either vaccine was observed when the vaccines were coadministered, and no safety concerns were identified. NCT01954251.

  13. A clinical trial to assess the immunogenicity and safety of Inactivated Influenza Vaccine (Whole Virion IP (Pandemic Influenza (H1N1 2009 Monovalent Vaccine; VaxiFlu-S ™ in healthy Indian adult population

    Directory of Open Access Journals (Sweden)

    A H Kubavat

    2011-01-01

    Full Text Available Background : The pandemic of H1N1 2009 influenza has spread world over and low degree of virus transmission has continued in several regions of India. Aims : To assess the immunogenicity and safety of Pandemic Influenza (H1N1 2009 Monovalent Vaccine in healthy adult Indian population. Settings and Design : Prospective, open label, multicentric, phase 2/3 clinical trial. Materials and Methods : Healthy adult Indian subjects belonging to either 18-59 years or ≥60 years age groups were enrolled and administered a single 0.5 ml (≥15 mcg of hemagglutinin antigen dose of vaccine in the deltoid muscle. Anti-hemagglutinin antibody titer was assessed at baseline and 21 (±2 days after vaccination by Hemagglutination Inhibition (HI test. Safety assessments were done for a period of 42 days. Statistical Analysis Used : Percentages of appropriate population with 95% confidence intervals calculated, log transformation of the data to calculate Geometric Mean Titers (GMTs and chi-square test and student′s t-test applied for significance testing. Results : 182/198 and 53/63 volunteers in age groups of 18-59 years and ≥60 years, respectively, achieved an HI titer ≥1 : 40 at Day 21 (91.9% [95% confidence interval: 88.1-95.7%] and 84.1% [75.1-93.2%]; P=0.072. Further, 171/198 and 50/63 volunteers in the respective age groups achieved seroconversion/four-fold increase in titer at Day 21 (86.4% [81.6-91.1%] and 79.4% [69.4-89.4%]; P=0.179. A significant rise of 22.6-fold [18.0-28.4] and 10.5-fold [7.4-15.0] was noted in GMT in the respective age groups (P<0.001 for both groups as compared to baseline. Nine vaccine-related adverse events were reported (3.4% incidence [1.2-5.6%], which were of low severity only. Conclusions : Pandemic Influenza (H1N1 2009 Monovalent Vaccine produces excellent immunogenic response with a good tolerability profile in adult Indian population.

  14. One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series.

    Science.gov (United States)

    Cramer, Jakob P; Jelinek, Tomas; Paulke-Korinek, Maria; Reisinger, Emil C; Dieckmann, Sebastian; Alberer, Martin; Bühler, Silja; Bosse, Dietrich; Meyer, Seetha; Fragapane, Elena; Costantini, Marco; Pellegrini, Michele; Lattanzi, Maria; Dovali, Claudia

    2016-03-01

    Conventional rabies pre-exposure prophylaxis (PrEP) and Japanese encephalitis (JE) primary series vaccination regimens each require up to 4 weeks to complete and, thus, may not be feasible for individuals who need these immunizations on short notice. This Phase 3b, randomized, controlled, observer-blind study evaluated the immunogenicity and safety of concomitant administration of a purified chick embryo cell culture rabies vaccine and an inactivated, adsorbed JE vaccine according to an accelerated (1 week) regimen when compared with the conventional regimens (4 weeks). This report describes the kinetics of immune responses up to 1 year after vaccination. A total of 661 healthy adults (18 to ≤65 years) were randomized into the following accelerated or conventional vaccine regimens: Rabies + JE-Conventional, Rabies + JE-Accelerated, Rabies-Conventional and JE-Conventional. Immunogenicity was assessed by virus neutralization tests. Safety and tolerability were also evaluated. Irrespective of rabies vaccination regimen, ≥97% of subjects had adequate levels of rabies virus neutralizing antibody (RVNA) concentrations (≥0.5 IU/ml) up to Day 57, with percentages of subjects with RVNA concentrations ≥0.5 IU/ml at Day 366 ranging between 68% in the Rabies + JE-Accelerated group and 80% of subjects in the Rabies-Conventional group. The Rabies + JE-Accelerated group revealed high JE neutralizing antibody titers at all-time points. At Day 366, the percentage of subjects with antibody titers indicative of seroprotection (PRNT50 titers ≥1:10) remained high across JE vaccine groups (86-94%). The accelerated PrEP rabies and JE vaccination regimens, once licensed, could represent a valid alternative in the short-term to currently recommended conventional regimens. The concomitant administration of these two vaccines does not compromise immune responses to any of the vaccine antigens particularly when aiming for short-term protection. Further evidence

  15. Live-attenuated Tetravalent Dengue Vaccine in Dengue-naïve Children, Adolescents, and Adults in Mexico City: Randomized Controlled Phase 1 Trial of Safety and Immunogenicity.

    Science.gov (United States)

    Poo, Jorge; Galan, Francisco; Forrat, Remi; Zambrano, Betzana; Lang, Jean; Dayan, Gustavo

    2011-01-01

    Preliminary results in healthy, young US adults showed that a tetravalent, live-attenuated dengue vaccine (TDV) was safe and immunogenic, but no data are available in children. In a multicenter, randomized, controlled, observer-blinded study in the city of Mexico, children aged 2 to 5, 6 to 11, and 12 to 17 years (36 children per age group), and adults (n = 18) aged dengue serotype was in the range 77% to 92%, compared with 85% to 94% after completion of the YF-TDV-TDV regimen. Of the 2- to 11-year-old participants, 95% were seropositive against ≥3 serotypes after 3 vaccinations. A 3-dose TDV regimen had a favorable safety profile in children and adults and elicited neutralizing antibody responses against all 4 serotypes. These findings support the continued development of this vaccine.

  16. Safety and immunogenicity of chromatographically purified Vero cell rabies vaccine for intradermal pre- and post-exposure rabies prophylaxis.

    Science.gov (United States)

    Tantawichien, Terapong; Sibunruang, Suda; Tantawichien, Thanphet; Angsanakul, Jaruboot; Benjavongkulchai, Maneerat; Limsuwan, Kornvika; Udomchaisakul, Piyada; Khomvilai, Sumana; Sitprija, Visith

    2014-12-01

    Improved rabies pre- and post-exposure prophylaxis (PrEP and PEP) in developing countries uses an economic multi-site intradermal vaccination. To evaluate immunogenicity of chromatographically purified Vero cell vaccine (CPRV) for intradermal PrEP and PEP. The subjects received conventional PrEP with CPRV or PVRV in PrEP study or received intradermal PEP with CPRV or PVRV and rabies immunoglobulin in PEP study. All subjects who received PrEP with CPRV had protective neutralizing antibody (Nab) titers (≥0.5 IU/ml) 14 days after completing vaccination. In PEP study, Nab titers in the CPRV groups reached ≥ 0.5 IU/ml in all subjects by day 14 through day 90 after vaccination. The geometric mean titers of Nab in the CPRV groups had significantly higher titers than the PVRV group on day 14 through day 365 (p < 0.05). No serious adverse reactions were observed. CPRV is safe and immunogenic when given for intradermal PrEP and PEP.

  17. [Safety and immunogenicity of combined hepatitis A and hepatitis B vaccine according to 0 and 6 months schedule in healthy children].

    Science.gov (United States)

    Wang, Ya-Long; Chen, Wen-Yu; Xu, Wen-Guo; Wang, Xu; Liu, Yan; Wu, Jian-Fang; Chen, Jiang-Ting

    2010-02-01

    To evaluate the safety and immunogenicity of the Bilive(TM) combined hepatitis A and hepatitis B vaccine in healthy children. A total of 116 healthy children aged 1 - 10 years, who, without history of hepatitis A vaccine vaccination and anti-HAV negative, had completed the full immunization of hepatitis B vaccine were recruited in city of Changzhou in Jiangsu province. The Bilive(TM) combined hepatitis A and hepatitis B vaccine was administered according to a two-dose schedule (0, 6 months). The dosage was 250 U for hepatitis A antigen and 5 microg for hepatitis B surface antigen. The potential adverse effects were observed within 72 hours after vaccination. The serum samples were collected for the testing of anti-HAV and anti-HBs at month 1, 6 and 7 after initial dose. The local and systemic adverse reactions after immunization were slight and temporary. The rates of local and systemic adverse reactions were 12.1% (14/116) and 6.0% (7/116). The sero-conversion rates of HAV were from 92.9% (92/99) to 100.0% (101/101) and the geometric mean titers (GMT) ranged from 47.0 mIU/ml to 2762.3 mIU/ml 1, 6, 7 months after initial dose. The sero-protection rate of HBV was 86.1% (87/101) before vaccination and came up to 100.0% (101/101) one month after initial dose, and the GMTs of HBV were from 894.3 mIU/ml to 3314.3 mIU/ml 1, 6, 7 months after initial dose. The Bilive(TM) combined hepatitis A and hepatitis B vaccine has good safety and immunogenicity in healthy children who had preexisting immunity to hepatitis B virus.

  18. Comparing the immunogenicity and safety of 3 Japanese encephalitis vaccines in Asia-Pacific area: A systematic review and meta-analysis.

    Science.gov (United States)

    Wang, Shi-Yuan; Cheng, Xiao-Hua; Li, Jing-Xin; Li, Xi-Yan; Zhu, Feng-Cai; Liu, Pei

    2015-01-01

    Japanese encephalitis virus (JEV), a leading cause of Japanese encephalitis (JE) in children and adults, is a major public health problem in Asian countries. This study reports a meta-analysis of the immunogenicity and safety of vaccines used to protect infants or children from JE. Three types of JE vaccine were examined, namely, Japanese encephalitis live-attenuated vaccine (JEV-L), Japanese encephalitis inactivated vaccine (Vero cell) (JEV-I(Vero)), and Japanese encephalitis inactivated vaccine (primary hamster kidney cell) (JEV-I(PHK)). These vaccines are used to induce fundamental immunity against JE; however, few studies have compared their immunogenicity and safety in infants and young children less than 2 years of age. Data were obtained by searching 5 databases: Web of Science, PubMed, China National Knowledge Infrastructure, the China Wanfang database, and the Cochrane database. Fifteen articles were identified and scored using the Jadad score for inclusion in the meta-analysis. Random effect models were used to calculate the pooled seroconversion rate and adverse reaction rate when tests for heterogeneity were significant. The results showed that the pooled seroconversion rate for JEV-I(PHK) (62.23%) was lower than that for JEV-I(Vero) (86.49%) and JEV-L (83.52%), and that the pooled adverse reaction rate for JEV-L (18.09%) was higher than that for JEV-I(PHK) (10.08%) and JEV-I(Vero) (12.49%). The pooled relative risk was then calculated to compare the seroconversion and adverse reaction rates. The results showed that JEV-I(Vero) and JEV-L were more suitable than JEV-I(PHK) for inducing fundamental immunity to JE in infants and children less than 2 years of age.

  19. Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine when given as a booster to BCG in Gambian infants: an open-label randomized controlled trial.

    Science.gov (United States)

    Idoko, Olubukola T; Owolabi, Olumuyiwa A; Owiafe, Patrick K; Moris, Philippe; Odutola, Aderonke; Bollaerts, Anne; Ogundare, Ezra; Jongert, Erik; Demoitié, Marie-Ange; Ofori-Anyinam, Opokua; Ota, Martin O

    2014-12-01

    We evaluated the candidate tuberculosis vaccine M72/AS01 in Bacille-Calmette-Guérin (BCG)-vaccinated infants after or concomitantly with Expanded-Programme-on-Immunization (EPI) vaccines. In a Phase-II study in The Gambia (NCT01098474), 2 cohorts of 150 BCG-vaccinated infants each were randomized 1:1:1. The 'Outside-EPI' cohort received one or two M72/AS01 doses, or meningitis vaccine, 1-2 months after primary EPI vaccination. The 'Within-EPI' cohort received one or two M72/AS01 doses concomitantly with the third or last two doses of their primary EPI-regimen, respectively, or EPI vaccines alone. Safety, M72-specific humoral (ELISA) and cell-mediated (whole-blood ICS) responses, and humoral responses to EPI vaccines were assessed. M72/AS01 was acceptably tolerated with no vaccine-related serious adverse events reported. Seropositivity/seroprotection rates against EPI antigens in the Within-EPI cohort were comparable between groups, irrespective of M72/AS01 co-administration. Up to one year post M72/AS01 vaccination, M72-specific humoral and CD4(+) T-cell responses were higher after 2 doses versus 1 dose in both cohorts (p 0.05). M72/AS01 given to infants after or concomitantly with EPI vaccines had an acceptable safety profile. Our results suggest no interference of immunogenicity profiles occurred following co-administration of M72/AS01 and EPI vaccines. Two M72/AS01 doses elicited higher immune responses than one dose. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Safety and immunogenicity of tetanus-diphtheria-acellular pertussis vaccine administered to children 10 or 11 years of age.

    Science.gov (United States)

    Marshall, Gary S; Pool, Vitali; Greenberg, David P; Johnson, David R; Sheng, Xiaohua; Decker, Michael D

    2014-11-01

    Boosting immunity to tetanus, diphtheria, and pertussis through the use of Tdap vaccines is routinely recommended at 11 to 12 years of age; some states, however, require Tdap for entry into middle school, which may begin at 10 years of age. This study was conducted to determine whether Tdap5 (Adacel), which is licensed for use in children beginning at 11 years of age, is as safe and immunogenic in 10-year-olds as it is in 11-year-olds. Children who had received 5 previous doses of any diphtheria-tetanus-acellular pertussis (DTaP) vaccine were enrolled in a phase IV clinical trial; 646 10-year-olds and 645 11-year-olds completed the study, which involved a single intramuscular dose of Tdap5 along with pre- and postvaccination serologies. Postvaccination geometric mean concentrations (GMCs) of antibody to pertussis antigens (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbria types 2 and 3) of 10-year-olds were noninferior to those of 11-year-olds, as were booster response rates for all pertussis antibodies, except for those to fimbrial antigens (94% and 97%, respectively). Seroprotection rates among 10-year-olds for tetanus and diphtheria were noninferior to those in 11-year-olds. Rates of injection site reactions, solicited systemic reactions, and unsolicited adverse events, adverse reactions, and serious adverse events were similar in the two groups. These data support the conclusion that Tdap5 is safe and immunogenic in 10-year-olds. (This study has been registered at ClinicalTrials.gov under registration no. NCT01311557.). Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  1. Safety and immunogenicity of novel recombinant BCG and modified vaccinia virus Ankara vaccines in neonate rhesus macaques.

    Science.gov (United States)

    Rosario, Maximillian; Fulkerson, John; Soneji, Shamit; Parker, Joe; Im, Eung-Jun; Borthwick, Nicola; Bridgeman, Anne; Bourne, Charles; Joseph, Joan; Sadoff, Jerald C; Hanke, Tomás

    2010-08-01

    Although major inroads into making antiretroviral therapy available in resource-poor countries have been made, there is an urgent need for an effective vaccine administered shortly after birth, which would protect infants from acquiring human immunodeficiency virus type 1 (HIV-1) through breast-feeding. Bacillus Calmette-Guérin (BCG) is given to most infants at birth, and its recombinant form could be used to prime HIV-1-specific responses for a later boost by heterologous vectors delivering the same HIV-1-derived immunogen. Here, two groups of neonate Indian rhesus macaques were immunized with either novel candidate vaccine BCG.HIVA(401) or its parental strain AERAS-401, followed by two doses of recombinant modified vaccinia virus Ankara MVA.HIVA. The HIVA immunogen is derived from African clade A HIV-1. All vaccines were safe, giving local reactions consistent with the expected response at the injection site. No systemic adverse events or gross abnormality was seen at necropsy. Both AERAS-401 and BCG.HIVA(401) induced high frequencies of BCG-specific IFN-gamma-secreting lymphocytes that declined over 23 weeks, but the latter failed to induce detectable HIV-1-specific IFN-gamma responses. MVA.HIVA elicited HIV-1-specific IFN-gamma responses in all eight animals, but, except for one animal, these responses were weak. The HIV-1-specific responses induced in infants were lower compared to historic data generated by the two HIVA vaccines in adult animals but similar to other recombinant poxviruses tested in this model. This is the first time these vaccines were tested in newborn monkeys. These results inform further infant vaccine development and provide comparative data for two human infant vaccine trials of MVA.HIVA.

  2. The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure

    NARCIS (Netherlands)

    Klapholz, Marc; Abraham, William T.; Ghali, Jalal K.; Ponikowski, Piotr; Anker, Stefan D.; Knusel, Beat; Sun, Yan; Wasserman, Scott M.; van Veldhuisen, Dirk J.

    2009-01-01

    To assess the safety and tolerability of darbepoetin alfa (DA) in the treatment of anaemia in heart failure (HF). In this pooled analysis of three randomized, double-blind, placebo-controlled studies of anaemic [haemoglobin (Hb) <12.0 g/dL or <12.5 g/dL] symptomatic HF subjects, DA was administered

  3. Safety and tolerability of prolonged-release nicotinic acid in statin-treated patients

    NARCIS (Netherlands)

    Birjmohun, R. S.; Kastelein, J. J. P.; Poldermans, D.; Stroes, E. S. G.; Hostalek, U.; Assmann, G.

    2007-01-01

    Objective: To evaluate the safety and tolerability of prolonged -release nicotinic acid (Niaspan*) added to statin therapy in patients at increased cardiovascular risk. Methods: This was a 6-month, prospective, observational, multicentre, open-label evaluation of prolonged-release nicotinic acid

  4. Safety and Tolerability of Atomoxetine over 3 to 4 Years in Children with ADHD

    Science.gov (United States)

    Donnelly, Craig; Bangs, Mark; Trzepacz, Paula; Jin, Ling; Zhang, Shuyu; Witte, Michael M.; Ball, Susan G.; Spencer, Thomas J.

    2009-01-01

    Data from 13 double-blind, placebo-controlled trials and three open-label extension studies were pooled to examine the safety of atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents for less than or equal to three or four years. Results show that atomoxetine is safe and well tolerated in the subjects.

  5. [Diuretics in the treatment of hypertension. Efficacy, safety and tolerability].

    Science.gov (United States)

    Düsing, R

    2011-12-01

    In the treatment of hypertension, both the thiazide diuretics hydrochlorothiazide and bendroflumethiazide and the "thiazide-like" diuretics chlorthalidone and indapamide are used. Guidelines refer to these as the class of thiazide diuretics suggesting their interchangeability. However, bendroflumethiazide and hydrochlorothiazide, at least in the commonly used low dose range, are less potent with respect to blood pressure lowering and may also be less effective in preventing morbidity and mortality events. This is of great clinical relevance since hydrochlorothiazide is by far the most widely prescribed diuretic. Increasing the dose of hydrochlorothiazide would further reduce tolerability of treatment due to an increase in dose-dependent side effects. The underlying mechanisms of the suggested superiority of chlorthalidone on cardiovascular morbidity and mortality remain unclear. The half-life of chlorthalidone has been estimated at >50 h thus exceeding the half-life of hydrochlorothiazide by about 5-fold. Given the documented irregular intake of antihypertensive drugs, the prolonged efficacy of chlorthalidone makes this agent a "forgiving drug" with a definite advantage over hydrochlorothiazide. On the basis of the available evidence, whenever diuretic treatment is indicated in a hypertensive patient, a thiazide-like agent, preferably chlorthalidone should be employed.

  6. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  7. [Safety and tolerability of GLP-1 receptor agonists].

    Science.gov (United States)

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  8. Immunogenicity and safety of high-dose hepatitis B vaccine among drug users: A randomized, open-labeled, blank-controlled trial.

    Science.gov (United States)

    Feng, Yongliang; Shi, Jing; Gao, Linying; Yao, Tian; Feng, Dan; Luo, Dan; Li, Zhansheng; Zhang, Yawei; Wang, Fuzhen; Cui, Fuqiang; Li, Li; Liang, Xiaofeng; Wang, Suping

    2017-06-03

    Due to the low uptake, adherence, and completion of vaccination among drug users, and their compromised immune responses to hepatitis B vaccination, the current practice of hepatitis B vaccination may not provide optimal protection. The aim of this study was to evaluate the immunogenicity and safety of 60 µg and 20 µg hepatitis B vaccines among drug users. A randomized, open-labeled, blank-controlled trial was conducted among drug users at 2 drug rehabilitation centers in China. The eligible participants were drug users who were serologically negative for the hepatitis B surface antigen (HBsAg) and the hepatitis B surface antibody (anti-HBs). Participants were randomized in a ratio of 1:1:1 to receive 20 µg (IM20 group) or 60 µg (IM60 group) of hepatitis B vaccine or blank control at months 0, 1, and 6, and followed at months 6, 7, and 12. Seroconversion rates of 94.7% and 92.6% were observed in IM20 and IM60 groups at month 7, and correspondingly decreased to 89.5% and 91.7% respectively at month 12. The IM60 group showed significantly higher geometric mean concentrations (GMCs) of anti-HBs (2022.5 and 676.7 mIU mL-1) than the IM20 group did (909.6 and 470.5 mIU mL-1) at months 7 and 12 (P B vaccines showed good immunogenicity among the drug users.

  9. Immunogenicity and safety after booster vaccination of diphtheria, tetanus, and acellular pertussis in young adults: an open randomized controlled trial in Japan.

    Science.gov (United States)

    Hara, Megumi; Okada, Kenji; Yamaguchi, Yuko; Uno, Shingo; Otsuka, Yasuko; Shimanoe, Chisato; Nanri, Hinako; Horita, Mikako; Ozaki, Iwata; Nishida, Yuichiro; Tanaka, Keitaro

    2013-12-01

    The recent increase of pertussis in young adults in Japan is hypothesized to be due in part to waning protection from the acellular pertussis vaccine. While a booster immunization may prevent an epidemic of pertussis among these young adults, little is known about the safety and immunogenicity of such a booster with the diphtheria, tetanus, and acellular pertussis vaccine (DTaP), which is currently available in Japan. One hundred and eleven medical students with a mean age of 19.4 years were randomly divided into 2 groups of 55 and 56 subjects and received, respectively, 0.2 or 0.5 ml of DTaP. Immunogenicity was assessed by performing the immunoassay using serum, and the geometric mean concentration (GMC), GMC ratio (GMCR), seropositive rate, and booster response rate were calculated. Adverse reactions and adverse events were monitored for 7 days after vaccination. After booster vaccination in the two groups, significant increases were found in the antibodies against pertussis toxin, filamentous hemagglutinin, diphtheria toxoid, and tetanus toxoid, and the booster response rates for all subjects reached 100%. The GMCs and GMCRs against all antigens were significantly higher in the 0.5-ml group than in the 0.2-ml group. No serious adverse events were observed. Frequencies of local reactions were similar in the 2 groups, although the frequency of severe local swelling was significantly higher in the 0.5-ml group. These data support the acceptability of booster immunization using both 0.2 and 0.5 ml of DTaP for young adults for controlling pertussis. (This study was registered at UMIN-CTR under registration number UMIN000010672.).

  10. Safety and Immunogenicity of Full-Dose Trivalent Inactivated Influenza Vaccine (TIV) Compared With Half-Dose TIV Administered to Children 6 Through 35 Months of Age.

    Science.gov (United States)

    Halasa, Natasha B; Gerber, Michael A; Berry, Andrea A; Anderson, Edwin L; Winokur, Patricia; Keyserling, Harry; Eckard, Allison Ross; Hill, Heather; Wolff, Mark C; McNeal, Monica M; Edwards, Kathryn M; Bernstein, David I

    2015-09-01

    Children 6 through 35 months of age are recommended to receive half the dose of influenza vaccine compared with older children and adults. This was a 6-site, randomized 2:1, double-blind study comparing full-dose (0.5 mL) trivalent inactivated influenza vaccine (TIV) with half-dose (0.25 mL) TIV in children 6 through 35 months of age. Children previously immunized with influenza vaccine (primed cohort) received 1 dose, and those with no previous influenza immunizations (naive cohort) received 2 doses of TIV. Local and systemic adverse events were recorded. Sera were collected before immunization and 1 month after last dose of TIV. Hemagglutination inhibition antibody testing was performed. Of the 243 subjects enrolled (32 primed, 211 naive), data for 232 were available for complete analysis. No significant differences in local or systemic reactions were observed. Few significant differences in immunogenicity to the 3 vaccine antigens were noted. The immune response to H1N1 was significantly higher in the full-dose group among primed subjects. In the naive cohort, the geometric mean titer for all 3 antigens after 2 doses of TIV were significantly higher in the 12 through 35 months compared with the 6 through 11 months age group. Our study confirms the safety of full-dose TIV given to children 6 through 35 months of age. An increase in antibody responses after full- versus half-dose TIV was not observed, except for H1N1 in the primed group. Larger studies are needed to clarify the potential for improved immunogenicity with higher vaccine doses. Recommending the same dose could simplify the production, storage, and administration of influenza vaccines.

  11. Immunogenicity and safety of a new meningococcal A conjugate vaccine in Indian children aged 2-10 years: a phase II/III double-blind randomized controlled trial.

    Science.gov (United States)

    Hirve, Siddhivinayak; Bavdekar, Ashish; Pandit, Anand; Juvekar, Sanjay; Patil, Malini; Preziosi, Marie-Pierre; Tang, Yuxiao; Marchetti, Elisa; Martellet, Lionel; Findlow, Helen; Elie, Cheryl; Parulekar, Varsha; Plikaytis, Brian; Borrow, Ray; Carlone, George; Kulkarni, Prasad S; Goel, Akshay; Suresh, Karupothula; Beri, Suresh; Kapre, Subhash; Jadhav, Suresh; Preaud, Jean-Marie; Viviani, Simonetta; LaForce, F Marc

    2012-10-05

    This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac™, Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY(®), GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 μg/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 μg/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac™ is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. A Phase 2a Randomized Study to Evaluate the Safety and Immunogenicity of the 1790GAHB Generalized Modules for Membrane Antigen Vaccine against Shigella sonnei Administered Intramuscularly to Adults from a Shigellosis-Endemic Country

    Directory of Open Access Journals (Sweden)

    Christina W. Obiero

    2017-12-01

    Full Text Available Shigellosis is a mild-to-severe diarrheal infection, caused by the genus Shigella, and is responsible for significant morbidity and mortality worldwide. We evaluated the safety and immunogenicity of an investigational Shigella sonnei vaccine (1790GAHB based on generalized modules for membrane antigens (GMMA in Kenya, a Shigella-endemic country. This phase 2a, observer-blind, controlled randomized study (NCT02676895 enrolled 74 healthy adults aged 18–45 years, of whom 72 were vaccinated. Participants received, in a 1:1:1 ratio, two vaccinations with the 1790GAHB vaccine at doses of either 1.5/25 μg of O antigen (OAg/protein (group 1.5/25 μg or 5.9/100 μg (group 5.9/100 μg at day (D 1 and D29, or vaccination with a quadrivalent meningococcal vaccine at D1 and tetanus, diphtheria, and acellular pertussis vaccine at D29 (control group. Solicited and unsolicited adverse events (AEs, serious AEs (SAEs, and AEs of special interest (neutropenia and reactive arthritis were collected. Anti-S. sonnei lipopolysaccharide (LPS serum immunoglobulin G (IgG geometric mean concentrations (GMC were evaluated at D1, D29, and D57 and compared to anti-S. sonnei LPS antibody levels in convalescent patients naturally exposed to S. sonnei. The percentages of participants with seroresponse were also calculated. The most frequently reported solicited local and systemic AEs across all groups were pain and headache, respectively. Only one case of severe systemic reaction was reported (severe headache after first vaccination in group 5.9/100 μg. Seven and three episodes of neutropenia, assessed as probably or possibly related to vaccination respectively, were reported in the investigational and control groups, respectively. No other SAEs were reported. Despite very high baseline anti-S. sonnei LPS serum IgG levels, the 1790GAHB vaccine induced robust antibody responses. At D29, GMC increased 2.10- and 4.43-fold from baseline in groups 1.5/25 and 5.9/100

  13. Immunogenicity and safety of a quadrivalent inactivated influenza virus vaccine compared with a comparator quadrivalent inactivated influenza vaccine in a pediatric population: A phase 3, randomized noninferiority study.

    Science.gov (United States)

    Airey, Jolanta; Albano, Frank R; Sawlwin, Daphne C; Jones, Alison Graves; Formica, Neil; Matassa, Vince; Leong, Jane

    2017-05-09

    Seqirus 2010 Southern Hemisphere split-virion trivalent inactivated influenza vaccine (IIV3) was associated with increased febrile reactions in children. Studies in vitro concluded that increasing concentrations of splitting agent decreased residual lipids and attenuated proinflammatory cytokine signals associated with fever. We assessed immunogenicity and safety of a quadrivalent inactivated influenza vaccine (IIV4; produced using higher concentration of splitting agent) versus a United States-licensed comparator IIV4 in healthy children aged 5-17years. Participants (N=2278) were randomized 3:1 and stratified by age (5-8years; 9-17years) to receive IIV4 (n=1709) or comparator IIV4 (n=569). Primary objective was to demonstrate noninferiority of IIV4 versus comparator IIV4 as assessed by hemagglutination inhibition (HI) geometric mean titer (GMT) ratio (upper bound of two-sided 95% confidence interval [CI]≤1.5) and difference in seroconversion rate (upper bound of two-sided 95% CI≤10%) for all four vaccine strains. HI antibody titers were assessed at baseline and 28days postvaccination. Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period, respectively. IIV4 met immunogenicity criteria for noninferiority. Adjusted GMT ratios (comparator IIV4/IIV4) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.01 (95% CI; 0.93, 1.09), 1.05 (0.96, 1.15), 0.89 (0.81, 0.98), and 0.92 (0.83, 1.02), respectively. Corresponding values for differences (95% CI) in seroconversion rates (comparator IIV4 minus IIV4) were -3.1 (-8.0, 1.8), 0.4 (-4.5, 5.3), -3.4 (-8.3, 1.5), and -2.0 (-6.9, 2.9). Fever rates were numerically higher, but not statistically different, with IIV4 versus comparator IIV4. No new safety signals were reported. IIV4 demonstrated immunological noninferiority to the comparator IIV4 with a clinically acceptable safety profile in children aged 5-17years. Increased levels of virus splitting agent seem to

  14. Safety and tolerability of medications approved for chronic weight management.

    Science.gov (United States)

    Fujioka, Ken

    2015-04-01

    In 2014 we have 4 new weight loss medications and one older medication with very different mechanisms of action – all approved for chronic weight management. Each medication has its own unique risk profile that makes patient selection important. Knowledge of the contraindications and safety issues can guide physicians to the most appropriate choice for a particular patient. Obesity medicine is entering a new era where our available options for prescribing have been very well studied. There should be no surprises, because bupropion, naltrexone, phentermine, topiramate and liraglutide have been prescribed for many years in millions of patients and lorcaserin has high specificity for a single receptor subtype. The FDA demanded very detailed risk-oriented studies to have these medications approved. In addition, the FDA has established REMS programs or risk management strategies to help ensure that the patients do not receive inappropriate medications. These medications were approved by the US FDA after very thorough testing. The decision to approve these medications was based on the benefits out-weighing the risks. Thus, if following the appropriate guidelines according to package labels, the practitioner can feel safe in prescribing these medications.

  15. An Albumin-Free Formulation for Escherichia coli-Derived Interferon Beta-1b with Decreased Immunogenicity in Immune Tolerant Mice

    NARCIS (Netherlands)

    Haji Abdolvahab, Mohadeseh; Fazeli, Ahmad; Radmalekshahi, Mazda; Nejadnik, M Reza; Fazeli, Mohammad Reza; Schellekens, Huub

    2016-01-01

    Human serum albumin (HSA)-free formulation of Escherichia coli-derived human interferon beta (IFNβ-1b) with a high percentage of monomeric protein and low immunogenicity is developed and characterized in the current study. UV spectroscopy, fluorescence spectroscopy, dynamic light scattering, sodium

  16. Safety and immunogenicity of heterologous prime-boost immunisation with Plasmodium falciparum malaria candidate vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in healthy Gambian and Kenyan adults.

    Directory of Open Access Journals (Sweden)

    Caroline Ogwang

    Full Text Available Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63 and Modified vaccinia Virus Ankara (MVA vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI.We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns.ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC.ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted.Pactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430.

  17. Salmonella typhi vaccine strain CVD 908 expressing the circumsporozoite protein of Plasmodium falciparum: strain construction and safety and immunogenicity in humans.

    Science.gov (United States)

    Gonzalez, C; Hone, D; Noriega, F R; Tacket, C O; Davis, J R; Losonsky, G; Nataro, J P; Hoffman, S; Malik, A; Nardin, E; Sztein, M B; Heppner, D G; Fouts, T R; Isibasi, A; Levine, M M

    1994-04-01

    rcsp, encoding amino acids 21-398 of Plasmodium falciparum circumsporozoite protein (CSP), under control of tacP was integrated into the chromosomal delta aroC locus of attenuated delta aroC, delta aroD Salmonella typhi CVD 908. By immunoblot and ELISA, rCSP expression was greater from a multicopy plasmid than from the single chromosomal gene. CVD 908 omega (delta aroC1019::tacP-rcsp) was well tolerated by 10 volunteers who were fed two doses of 5 x 10(7) organisms 8 days apart. Seven subjects excreted the vaccine strain for 1-3 days. All subjects developed serologic responses to O and H antigens of the live vector, whereas 3 vaccinees responded to the foreign antigen: 1 developed an 80-fold rise in serum anti-sporozoite antibody, another had a 4-fold rise in antibody to a recombinant portion of CSP (residues 309-345), while a third vaccinee developed CSP-specific CD8+ cytotoxic T lymphocyte activity. This is the first report of attenuated S. typhi eliciting a human serologic or a cytotoxic T lymphocyte response to a foreign protein. Improved foreign gene expression should enhance immunogenicity.

  18. Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults.

    Science.gov (United States)

    Creech, C Buddy; Dekker, Cornelia L; Ho, Dora; Phillips, Shanda; Mackey, Sally; Murray-Krezan, Cristina; Grazia Pau, Maria; Hendriks, Jenny; Brown, Valerie; Dally, Leonard G; Versteege, Isabella; Edwards, Kathryn M

    2013-12-01

    Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

  19. Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

    Directory of Open Access Journals (Sweden)

    Mpimbaza Arthur

    2008-06-01

    Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of

  20. Safety and immunogenicity of 4 intramuscular double doses and 4 intradermal low doses vs standard hepatitis B vaccine regimen in adults with HIV-1: a randomized controlled trial.

    Science.gov (United States)

    Launay, Odile; van der Vliet, Diane; Rosenberg, Arielle R; Michel, Marie-Louise; Piroth, Lionel; Rey, David; Colin de Verdière, Nathalie; Slama, Laurence; Martin, Karine; Lortholary, Olivier; Carrat, Fabrice

    2011-04-13

    Alternative schedules more immunogenic than the standard hepatitis B vaccine regimen are needed in patients with human immunodeficiency virus 1 (HIV-1) infection. To compare the safety and immunogenicity of 4 intramuscular double-dose and 4 intradermal low-dose regimens vs the standard hepatitis B vaccine regimen. An open-label, multicenter, 1:1:1 parallel-group, randomized trial conducted between June 28, 2007, and October 23, 2008 (date of last patient visit, July 3, 2009) at 33 centers in France with patients enrolled in French National Agency for Research on AIDS and Viral Hepatitis trials in adults with HIV-1 infection who were hepatitis B virus (HBV) seronegative and having CD4 cell counts of more than 200 cells/μL. Patients were randomly assigned to receive 3 intramuscular injections of the standard dose (20 μg) of recombinant HBV vaccine at weeks 0, 4, and 24 (IM20 × 3 group, n = 145); 4 intramuscular double doses (40 μg [2 injections of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (IM40 × 4 group, n = 148); or 4 intradermal injections of low doses (4 μg [1/5 of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (ID4 × 4 group, n = 144). Percentage of responders at week 28, defined as patients with hepatitis B surface antibody (anti-HBs) of at least 10 mIU/mL in patients who received at least 1 dose of vaccine. Patients with missing anti-HBs titer measurement at the final follow-up visit at week 28 were considered as nonresponders in the primary (efficacy) analysis. A total of 437 patients were randomized to the 3 study groups, of whom 11 did not receive any vaccine. Of these, 396 had available anti-HBs titers at week 28. The percentage of responders at week 28 was 65% (95% confidence interval [CI], 56%-72%) in the IM20 × 3 group (n = 91), 82% (95% CI, 77%-88%) in the IM40 × 4 group (n = 119) (P < .001 vs IM20 × 3 group), and 77% (95% CI, 69%-84%) in the ID4 × 4 group (n = 108) (P = .02 vs IM20 × 3 group). No safety

  1. Immunogenicity and safety results from a randomized multicenter trial comparing a Tdap-IPV vaccine (REPEVAX®) and a tetanus monovalent vaccine in healthy adults: new considerations for the management of patients with tetanus-prone injuries.

    Science.gov (United States)

    Laurichesse, Henri; Zimmermann, Ulrich; Galtier, Florence; Launay, Odile; Duval, Xavier; Richard, Patrick; Sadorge, Christine; Soubeyrand, Benoit

    2012-12-01

    In adults with a tetanus-prone injury, combined vaccines such as Tdap-IPV (REPEVAX®) can boost immunity against several diseases simultaneously. This Phase IIIb, parallel-group, open-label trial compared antibody responses to Tdap-IPV and tetanus monovalent vaccine (TMV; Vaccin Tétanique Pasteur® or Tetavax®) against tetanus toxoid 10 and 28 d post-vaccination. Between July and December 2009, four centers in France and five in Germany recruited healthy adults who had received a tetanus-containing vaccine 5-10 y previously. Participants were randomized 1:1 to receive at the first visit a single dose (0.5 mL) of Tdap-IPV or TMV, with follow-up visits at Day 10 and Day 28. per protocol (PP) population immunogenicity at Day 10 (primary) and at Day 28 (secondary); safety throughout the study. Of 456 adults randomized, 223 received Tdap-IPV and 233 received TMV (PP population: 183 and 199 participants, respectively). All participants receiving Tdap-IPV and 99.0% receiving TMV had an anti-tetanus antibody concentration ≥ 0.1 IU/mL, confirming non-inferiority of Tdap-IPV to TMV (95% confidence interval of the difference: -1.2, 3.6). Number of adverse events reported was comparable in each group. Injection-site reactions were reported by 76.6% participants receiving Tdap-IPV and 74.6% receiving TMV. Systemic events (e.g., malaise, myalgia and headache) were reported in 47.7% and 39.7% of the Tdap-IPV and the TMV groups, respectively. Tdap-IPV is effective and well-tolerated for use in the management of tetanus-prone injuries in emergency settings in persons for whom a booster against diphtheria, pertussis and poliomyelitis is also needed.

  2. Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS®) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio®) given as a booster dose at 6 years of age

    Science.gov (United States)

    Gajdos, Vincent; Soubeyrand, Benoit; Vidor, Emmanuel; Richard, Patrick; Boyer, Julie; Sadorge, Christine

    2011-01-01

    This randomized, comparative, phase-IIIb study conducted in France aimed to demonstrate whether seroprotection against diphtheria, tetanus and poliomyelitis 1 month after a single dose of REVAXIS (low-dose diphtheria) is non-inferior to seroprotection 1 month after a single dose of DT Polio (standard-dose diphtheria), both vaccines being given as a second booster to healthy children at 6 years of age. Children were randomly assigned to receive a single intramuscular dose of REVAXIS or DT Polio. Primary endpoints were the 1-month post-booster seroprotection rates for diphtheria, tetanus and poliovirus type-1, -2 and -3 antigens. Secondary endpoints were immunogenicity and safety observations. Of 788 children screened, 760 were randomized: REVAXIS group, 384 children; DT Polio group, 376 children. No relevant difference in demographic characteristics at baseline was observed between REVAXIS and DT Polio groups. Noninferiority of REVAXIS compared with DT Polio for seroprotection was demonstrated against diphtheria (respectively 98.6% and 99.3%), tetanus (respectively 99.6% and 100%) and poliovirus antigens (100% for each types in both groups). No allergic reactions to REVAXIS were reported. A benefit/risk ratio in favor of REVAXIS was suggested by the trend towards a better tolerability of REVAXIS compared with DT Polio regarding the rate of severe solicited injection-site reactions. The results support the use of REVAXIS as a booster at 6 years of age in infants who previously received a three-dose primary series within the first 6 months of life and a first booster including diphtheria, tetanus and poliovirus vaccine(s) given before 2 years of age. PMID:21441781

  3. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated...... by the desire to experiment and to become otherwise. The objective is to discuss what gets lost, conceptually as well as politically, when we neglect the subsistence of active tolerance within other practices of tolerance, and to develop a theory of active tolerance in which tolerance's mobilizing character...... the current models of restraint and benevolence, other ways of understanding the politics of democratic pluralism might be developed, which will enable us to conceive of tolerance's future in terms different than those currently on offer. Tolerance: A Sensorial Orientation to Politics develops...

  4. Immunogenicity and safety of single-dose, 13-valent pneumococcal conjugate vaccine in pediatric and adolescent oncology patients.

    Science.gov (United States)

    Hung, Te-Yu; Kotecha, Rishi S; Blyth, Christopher C; Steed, Sarah K; Thornton, Ruth B; Ryan, Anne L; Cole, Catherine H; Richmond, Peter C

    2017-11-01

    Children receiving immunosuppressive treatment for cancer are at high risk for invasive pneumococcal disease. The 13-valent pneumococcal conjugate vaccine (PCV13) can prevent pneumococcal disease in healthy children; however, there is an absence of literature regarding the benefit of PCV13 in immunocompromised children with cancer. A prospective, open-label cohort study recruited children between ages 1 and 18 years who were receiving active immunosuppressive therapy (AIT) or were within 12 months after completing immunosuppressive therapy (CIT). Blood samples were taken before and 4 weeks after the administration of single-dose PCV13. Serotype-specific immunoglobulin G antibody titers were measured, and titers ≥0.35 μg/mL were considered protective. Solicited side effects were recorded in a 7-day diary after vaccination. Eighty-five children were recruited. At baseline, ≤50% had protective antibody titers against Streptococcus pneumoniae for 10 serotypes in the AIT group and for 8 serotypes in the CIT group. Postvaccination, ≥70% had protective antibody titers for 9 and 11 serotypes in the AIT and CIT groups, respectively. Both groups had comparable responses to PCV7 serotypes, whereas a significantly higher proportion in the CIT group achieved protective antibody titers to PCV13 serotypes. There was a low rate of serious adverse events (3.5%). A single-dose of PCV13 is safe and immunogenic in children diagnosed with cancer. All children who are receiving therapy for cancer should receive a single dose of PCV13 as soon as possible after diagnosis, regardless of prior PCV exposure. The current data support the recommendation for an additional dose of PCV13 after the completion of immunosuppressive therapy to provide additional protection against invasive pneumococcal disease. Cancer 2017;123:4215-4223. © 2017 American Cancer Society. © 2017 American Cancer Society.

  5. Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls.

    Science.gov (United States)

    Pedersen, Court; Breindahl, Morten; Aggarwal, Naresh; Berglund, Johan; Oroszlán, György; Silfverdal, Sven Arne; Szüts, Péter; O'Mahony, Michael; David, Marie-Pierre; Dobbelaere, Kurt; Dubin, Gary; Descamps, Dominique

    2012-01-01

    This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone. Healthy girls (9-15 years) were age-stratified (9, 10-12, and 13-15 years) and randomized to receive HPV (n = 270), HAB (n = 271), or HPV + HAB (n = 272). Vaccines were administered at months 0, 1, and 6. Immunogenicity was evaluated at months 0 and 7. The hepatitis A immune response was noninferior for HPV + HAB, versus HAB, for seroconversion rates (100% in each group) and geometric mean antibody titers (GMTs) (95% CI) (4,504.2 [3,993.0-5,080.8] and 5,288.4 [4,713.3-5,933.7] mIU/mL, respectively). The hepatitis B immune response was noninferior for HPV + HAB, versus HAB, for anti-HBs seroprotection rates (98.3% and 100%); GMTs were 3,136.5 [2,436.0-4,038.4] and 5,646.5 [4,481.3-7,114.6] mIU/mL, respectively. The HPV-16/18 immune response was noninferior for HPV + HAB, versus HPV, for seroconversion rates (99.6% and 100% for both antigens) and GMTs (22,993.5 [20,093.4-26,312.0] and 26,981.9 [23,909.5-30,449.1] EL.U/mL for HPV-16; 8,671.2 [7,651.7-9,826.6] and 11,182.7 [9,924.8-12,600.1] EL.U/mL for HPV-18, respectively). No subject withdrew because of adverse events. No vaccine-related serious adverse events were reported. Immune responses and reactogenicity were similar in girls aged 9 years compared with the entire study population. Results support coadministration of HPV-16/18 vaccine with HAB vaccine in girls aged 9-15 years. The HPV-16/18 vaccine was immunogenic and generally well tolerated in 9-year-old girls. Copyright © 2012 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  6. Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Groome, Michelle J; Koen, Anthonet; Fix, Alan; Page, Nicola; Jose, Lisa; Madhi, Shabir A; McNeal, Monica; Dally, Len; Cho, Iksung; Power, Maureen; Flores, Jorge; Cryz, Stanley

    2017-08-01

    Efficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines. We assessed the safety and immunogenicity of the P2-VP8-P[8] subunit rotavirus vaccine at different doses in South African toddlers and infants. This double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P[8] vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P[8] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov, number NCT02109484. Between March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67-91) of 47 infants in the 30 μg group

  7. Immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV) compared to separate administration of standalone DTaP and IPV vaccines: a randomized, controlled study in infants in the Republic of Korea.

    Science.gov (United States)

    Lee, Soo Young; Hwang, Hui Sung; Kim, Jong Hyun; Kim, Hyun Hee; Lee, Hyun Seung; Chung, Eun Hee; Park, Su Eun; Ma, Sang Hyuk; Chang, Jin Keun; Guitton, Fabrice; Ortiz, Esteban; Kang, Jin Han

    2011-02-11

    This randomized trial enrolled 442 infants in the Republic of Korea to assess the immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV; Tetraxim™) for primary vaccination at 2, 4 and 6 months of age compared with DTaP and IPV vaccines given separately. Immunogenicity was high in both groups; seroprotection and seroconversion rates of the combined vaccine (Group A) were non-inferior to the control vaccines (Group B). All subjects were seroprotected against poliovirus types 1, 2 and 3 (≥ 81/dil) and anti-diphtheria (≥ 0.01 IU/mL); 99.0% were seroprotected against tetanus (≥ 0.1 IU/mL). At least 93.6% had anti-diphtheria antibody titers ≥ 0.1 IU/mL. Anti-pertussis toxoid (PT) and anti-filamentous haemagglutinin (FHA) seroconversion (≥ 4-fold increase in antibody titer) rates were 96.6% and 94.4% for Group A, 92.2% and 78.4% for Group B. Most solicited reactions occurred within 4 days of vaccination, resolved within 3 days and were mild. Severe solicited reactions occurred after ≤ 0.5% of doses in Group A and ≤ 0.9% in Group B. No withdrawals occurred because of adverse events. The DTaP-IPV combined vaccine given at 2, 4, and 6 months of age was well tolerated; immunogenicity was similar to the control vaccines. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years

    DEFF Research Database (Denmark)

    Huh, Warner K; Joura, Elmar A; Giuliano, Anna R

    2017-01-01

    BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18...... antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity......, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central...

  9. Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children.

    Science.gov (United States)

    Brady, Rebecca C; Hu, Wilson; Houchin, Vonda G; Eder, Frank S; Jackson, Kenneth C; Hartel, Gunter F; Sawlwin, Daphne C; Albano, Frank R; Greenberg, Michael

    2014-12-12

    A trivalent inactivated influenza vaccine (CSL's TIV, CSL Limited) was licensed under USA accelerated approval regulations for use in persons≥18 years. We performed a randomized, observer-blind study to assess the safety and immunogenicity of CSL's TIV versus an established US-licensed vaccine in a population≥6 months to vaccination history determined the dosing regimen (one or two vaccinations). Subjects received CSL's TIV (n=739) or the established vaccine (n=735) in the autumn of 2009. Serum hemagglutination-inhibition titers were determined pre-vaccination and 30 days after the last vaccination. No febrile seizures or other vaccine-related SAEs were reported. After the first vaccination for Cohorts A and B, respectively, the relative risks of fever were 2.73 and 2.32 times higher for CSL's TIV compared to the established vaccine. Irritability and loss of appetite (for Cohort A) and malaise (for Cohort B) were also significantly higher for CSL's TIV compared to the established vaccine. Post-vaccination geometric mean titers (GMTs) for CSL's TIV versus the established vaccine were 385.49 vs. 382.45 for H1N1; 669.13 vs. 705.61 for H3N2; and 100.65 vs. 93.72 for B. CSL's TIV demonstrated immunological non-inferiority to the established vaccine in all cohorts. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. The safety and tolerability of nintedanib in the treatment of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Cottin, Vincent

    2017-07-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that primarily affects older individuals. Nintedanib, a tyrosine kinase inhibitor, has been approved for the treatment of IPF in several countries. The safety and tolerability of nintedanib have been investigated in clinical trials and in real-world studies (compassionate use programs and post-marketing surveillance). Areas covered: Most frequent adverse events reported in patients treated with nintedanib (gastrointestinal); additional adverse events of special interest (elevations in liver enzymes, bleeding, cardiovascular adverse events); recommendations for managing adverse events. Expert opinion: Experience with nintedanib in real-world clinical practice suggests that it has a safety and tolerability profile consistent with that observed in clinical trials. Upon initiation of nintedanib, patient education, regular monitoring and proactive management of adverse events such as diarrhea are needed to minimize the risk of permanent treatment discontinuation. Algorithms are available to help manage diarrhea and liver enzyme elevations. Further investigation of the safety and tolerability profile of nintedanib when used in combination with pirfenidone is warranted.

  11. Safety and immunogenicity study of a new purified chick embryo cell rabies vaccine Vaxirab-N (Pitman-Moore strain) manufactured in India.

    Science.gov (United States)

    Ashwath Narayana, Doddabele Hanumanthaiah; Madhusudana, Shampur Narayana; Sampath, Gadey; Tripathy, Radhe Madhab; Sudarshan, Mysore Kalappa; Gangaboraiah; Ravish, Haradanahalli Shankaraiah; Satapathy, Durga Madhab; Gowda, Giriyanna; Holla, Ramesh; Ashwin, Belludi Yajman; Padhi, Asutosh; Manjula, Shamanna; Patel, Pradip Maganlal

    2014-01-01

    Zydus Cadila Health care, India developed a new purified chick embryo cell rabies vaccine (PCECV, Vaxirab-N; 1 mL) by adapting Pitman-Moore strain of virus on to the chick embryo fibroblast cell line in 2006. During 2007-10, a series of safety and immunogenicity studies were conducted as per ICH-GCP guidelines after obtaining permission from Drug Controller General of India. In the first study, Vaxirab-N was administered to 35 healthy adult volunteers by intramuscular (IM) route using pre exposure regimen. The geometric mean concentration (GMC) of rabies virus neutralizing antibody (RvnAb) of 7.5 IU/mL on day 35. In the second study, Vaxirab-N was administered to 35 healthy adult volunteers using simulated post- exposure prophylaxis regimen by IM route. A GMC of 6.3 IU/mL on day 14, 13.2 IU/mL on day 28 and 8.6 IU/mL on day 90 was obtained. In the third study, Vaxirab-N administered by intradermal (ID) route using Updated Thai Red Cross (TRC) regimen in 36 healthy adult volunteers showed GMC of 7.8 IU/mL on day 14, 11.5 IU/mL on day 28 and 6.0 IU/mL on day 90. The 4th study was multi centric and Vaxirab-N was administered to 129 animal bite cases by IM route using post-exposure Essen regimen. The GMC following this schedule was 8.2 IU/mL on day 14, 13.01 IU/mL on day 28, 7.92 IU/mL on day 90 and 3.72 IU/mL on day 180. Mild to moderate adverse events were reported to Vaxirab-N but no serious adverse events were reported in any of these studies. In conclusion, Vaxirab-N developed by Zydus Cadila was found to be safe and immunogenic by both intramuscular and intradermal route and is recommended for rabies prophylaxis (CTRI No. 2010/091/000055 and 2010/091/000509).

  12. Immunogenicity and safety of two doses of catch-up immunization with Haemophilus influenzae type b conjugate vaccine in Indian children living with HIV.

    Science.gov (United States)

    Arya, Bikas K; Bhattacharya, Sangeeta Das; Sutcliffe, Catherine G; Saha, Malay K; Bhattacharyya, Subhasish; Niyogi, Swapan Kumar; Moss, William J; Panda, Samiran; Das, Ranjan Saurav; Mallick, Mausom; Mandal, Sutapa

    2016-04-27

    Children living with HIV are at increased risk of disease from Haemophilus influenzae type b (Hib). Data are limited on the immunogenicity of a two-dose, catch-up schedule for Hib conjugate vaccine (HibCV) among HIV-infected children accessing antiretroviral therapy (ART) late. The objectives of the study were to: (1) evaluate baseline immunity to Hib and the immunogenicity and safety of two doses of HibCV among HIV-infected Indian children; and (2) document the threshold antibody level required to prevent Hib colonization among HIV-infected children following immunization. We conducted a prospective cohort study among HIV-infected children 2-15 years of age and HIV-uninfected children 2-5 years of age. HIV-infected children received two doses of HibCV and uninfected children received one. Serum anti-Hib PRP IgG antibodies were measured at baseline and two months after immunization in the HIV-infected children. Nasopharyngeal (NP) swabs were collected at baseline and follow-up. 125 HIV-infected and 44 uninfected children participated. 40% of HIV-infected children were receiving ART and 26% had a viral load >100,000 copies/mL. The geometric mean concentration of serum anti-Hib PRP antibody increased from 0.25 μg/mL at baseline to 2.65 μg/mL after two doses of HibCV, representing a 10.6-fold increase (pchildren mounted an immune response. Moderate or severe immune suppression, trimethoprim/sulfamethoxazole prophylaxis, and lower baseline antibody levels were associated with lower post-vaccine serum anti-Hib PRP IgG antibodies. A serum anti-Hib PRP IgG antibody level ≥ 3.3 μg/mL was protective against Hib NP colonization. There were no differences in adverse events between HIV-infected and uninfected children. Including a catch-up immunization schedule for older HIV infected children in countries introducing Hib vaccines is important. Older HIV-infected children with delayed access to ART and without suppressed viral loads mounted an adequate immune response

  13. Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study

    Science.gov (United States)

    Sampath, Gadey; Banzhoff, Angelika; Deshpande, Alaka; Malerczyk, Claudius; Arora, Ashwani Kumar; Vakil, Hoshang; Preiss, Scott

    2017-01-01

    ABSTRACT This phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule. PMID:28406752

  14. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated by the d...... these alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech....

  15. Safety and immunogenicity of a live attenuated RSV vaccine in healthy RSV-seronegative children 5 to 24 months of age.

    Directory of Open Access Journals (Sweden)

    Elissa Malkin

    Full Text Available Despite substantial morbidity associated with respiratory syncytial virus (RSV infection, there is no licensed vaccine. MEDI-559 is a live attenuated intranasal vaccine candidate being developed for prevention of lower respiratory illness due to RSV in young children. This randomized, placebo-controlled study evaluated safety of MEDI-559 in healthy, RSV-seronegative children. MEDI-559 or placebo was administered on 3 occasions, 2 months apart. Primary safety was based on solicited symptoms (SSs and adverse events (AEs collected for 28 days after each dose. Nasal wash samples were collected 3 times after each dose (days 7-10, 12-18, 28-34 and at sick visits. Serum was collected for measuring antibody immune responses to RSV prior to first vaccination and 28 days post final dose. Long-term safety was monitored for 365 days from first dose. SSs were mild and frequent (MEDI-559 84%; placebo 91%; most common SSs were runny/stuffy nose, cough, and irritability/fussiness. AEs occurred in 67% MEDI-559 and 57% placebo recipients: most common AE was upper respiratory tract infection (MEDI-559 35%; placebo 23%. Higher incidence of medically attended lower respiratory illness within 28 days after dosing occurred in the MEDI-559 arm compared to placebo (none associated with vaccine virus shedding. There was no evidence of enhanced RSV disease. Vaccine virus was detected only in MEDI-559 recipients; shedding occurred in 56%subjects, primarily post dose 1. A functional immune response was observed in 59% and 9% MEDI-559 and placebo recipients, respectively, by an RSV microneutralization assay. Vaccine take, assessed by proportion that shed vaccine-type virus or had a seroresponse against RSV, was seen in 95% MEDI-559 subjects. MEDI-559 is therefore biologically active and immunogenic in this seronegative pediatric population. Although the frequency of SSs and AEs was not considered clinically significant, the increase in medically attended lower respiratory

  16. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated by the d...... these alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech.......Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated...... by the desire to experiment and to become otherwise. The objective is to discuss what gets lost, conceptually as well as politically, when we neglect the subsistence of active tolerance within other practices of tolerance, and to develop a theory of active tolerance in which tolerance's mobilizing character...

  17. Immunogenicity and safety of CRM₁₉₇ conjugated 9-valent pneumococcal and meningococcal C combination vaccine in healthy infants.

    Science.gov (United States)

    Mallet, Eric; Brachet, Elisabeth; Fernsten, Philip; Laudat, France; Razmpour, Ahmad; Gruber, William C

    2011-08-05

    Streptococcus pneumoniae and Neisseria meningitidis cause invasive disease in children aged <2 years. While individual conjugate vaccines are available to protect this age group against these pathogens, availability of a vaccine combining these antigens into a single injection is desirable. This study randomized 467 healthy infants to receive 4 doses of combination 9-valent pneumococcal and meningococcal serogroup C conjugate vaccine (9vPnC-MnCC) or 9-valent pneumococcal conjugate vaccine (9vPnC). Percentages of subjects achieving immunoglobulin G (IgG) antibody concentrations ≥0.35μg/mL and geometric mean IgG concentrations for each pneumococcal serotype in the 9vPnC-MnCC group were noninferior compared to the 9vPnC group. Both vaccines were well-tolerated. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Immunogenicity and safety of high-dose trivalent inactivated influenza vaccine compared to standard-dose vaccine in children and young adults with cancer or HIV infection.

    Science.gov (United States)

    Hakim, Hana; Allison, Kim J; Van de Velde, Lee-Ann; Tang, Li; Sun, Yilun; Flynn, Patricia M; McCullers, Jonathan A

    2016-06-08

    Approaches to improve the immune response of immunocompromised patients to influenza vaccination are needed. Children and young adults (3-21 years) with cancer or HIV infection were randomized to receive 2 doses of high-dose (HD) trivalent influenza vaccine (TIV) or of standard-dose (SD) TIV. Hemagglutination inhibition (HAI) antibody titers were measured against H1, H3, and B antigens after each dose and 9 months later. Seroconversion was defined as ≥4-fold rise in HAI titer comparing pre- and post-vaccine sera. Seroprotection was defined as a post-vaccine HAI titer ≥1:40. Reactogenicity events (RE) were solicited using a structured questionnaire 7 and 14 days after each dose of vaccine, and adverse events by medical record review for 21 days after each dose of vaccine. Eighty-five participants were enrolled in the study; 27 with leukemia, 17 with solid tumor (ST), and 41 with HIV. Recipients of HD TIV had significantly greater fold increase in HAI titers to B antigen in leukemia group and to H1 antigen in ST group compared to SD TIV recipients. This increase was not documented in HIV group. There were no differences in seroconversion or seroprotection between HD TIV and SD TIV in all groups. There was no difference in the percentage of solicited RE in recipients of HD TIV (54% after dose 1 and 38% after dose 2) compared to SD TIV (40% after dose 1 and 20% after dose 2, p=0.27 and 0.09 after dose 1 and 2, respectively). HD TIV was more immunogenic than SD TIV in children and young adults with leukemia or ST, but not with HIV. HD TIV was safe and well-tolerated in children and young adults with leukemia, ST, or HIV. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. [Study on the immunogenicity and safety of recombinant B-subunit/whole cell cholera vaccine infused with antacids in healthy population at ages of 2-6 years].

    Science.gov (United States)

    Huang, T; Li, R C; Liu, D P

    2017-09-06

    Objective: To assess the immunogenicity and safety of recombinant B-subunit/whole cell cholera vaccine (rBS/WC) oral cholera vaccine (Ora Vacs) infused with antacids in healthy population at ages of 2-6 years. Methods: Between December 2009 and January 2010, we recruited 900 volunteers aged 2-6 years od through giving out recruitment notice for the eligible children's parents from different vaccination clinics of Chongzuo city in Guangxi Zhuang Autonomous Region. This study was a randomized, double-blind, placebo-controlled trial, and subjects were randomly (2∶1) assigned to receive Cholera vaccine infused with antacids or placebo, and observed for safety. Serum samples of 300 subjects in immunogenicity subgroups (200 for vaccine groups, 100 for control groups) before the 1st dose and 49 d (±3 d) after immunization were collected, and determined for antibody levels against the cholera toxin (anti-CT) and cholera vibriocidal (anti-Vab) with Enzyme-linked immunosorbent assays (ELISA), based on which the GMT was calculated. There were 266 cases paired with the serum samples before and after immunization (177 for vaccine groups, 89 for control groups). The comparison of subjects' age at enrollment and the level of GMT before and after immunization between groups were analyzed by t test. The superiority test for the difference between seroconversion rates of vaccine groups and control groups were analyzed by χ(2) test. Results: Of 900 subjects enrolled, the number of males and females were 503 and 397 respectively (vaccine groups 335 vs. 265, control groups 168 vs. 132), the average ages of vaccine groups and control groups at enrollment were (4.8±1.2) years and (4.9±1.2) years respectively. There were no significant differences between groups in terms of gender and age (χ(2)=0.00, P=1.000; t=0.55, P=0.585). The 2 times increase rates of anti-CT and anti-Vab in vaccine groups after inoculation were 90.96% and 57.63% respectively, which were superiority to those

  20. Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein.

    Science.gov (United States)

    Lundgren, A; Leach, S; Tobias, J; Carlin, N; Gustafsson, B; Jertborn, M; Bourgeois, L; Walker, R; Holmgren, J; Svennerholm, A-M

    2013-02-06

    We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhea containing killed recombinant E. coli bacteria expressing increased levels of ETEC colonization factors (CFs) and a recombinant protein (LCTBA), i.e. a hybrid between the binding subunits of E. coli heat labile toxin (LTB) and cholera toxin (CTB). We describe a randomized, comparator controlled, double-blind phase I trial in 60 adult Swedish volunteers of a prototype of this vaccine. The safety and immunogenicity of the prototype vaccine, containing LCTBA and an E. coli strain overexpressing the colonization factor CFA/I, was compared to a previously developed oral ETEC vaccine, consisting of CTB and inactivated wild type ETEC bacteria expressing CFA/I (reference vaccine). Groups of volunteers were given two oral doses of either the prototype or the reference vaccine; the prototype vaccine was administered at the same or a fourfold higher dosage than the reference vaccine. The prototype vaccine was found to be safe and equally well-tolerated as the reference vaccine at either dosage tested. The prototype vaccine induced mucosal IgA (fecal secretory IgA and intestine-derived IgA antibody secreting cell) responses to both LTB and CFA/I, as well as serum IgA and IgG antibody responses to LTB. Immunization with LCTBA resulted in about twofold higher mucosal and systemic IgA responses against LTB than a comparable dose of CTB. The higher dose of the prototype vaccine induced significantly higher fecal and systemic IgA responses to LTB and fecal IgA responses to CFA/I than the reference vaccine. These results demonstrate that CF over-expression and inclusion of the LCTBA hybrid protein in an oral inactivated ETEC vaccine does not change the safety profile when compared to a previous generation of such a vaccine and that the prototype vaccine induces significant dose dependent mucosal immune responses against CFA/I and LTB. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomised, observer-blind, age de-escalation, phase 2 trials.

    Science.gov (United States)

    Bhutta, Zulfiqar A; Capeding, Maria Rosario; Bavdekar, Ashish; Marchetti, Elisa; Ariff, Shabina; Soofi, Sajid B; Anemona, Alessandra; Habib, Muhammad A; Alberto, Edison; Juvekar, Sanjay; Khan, Rana M Qasim; Marhaba, Rachid; Ali, Noshad; Malubay, Nelia; Kawade, Anand; Saul, Allan; Martin, Laura B; Podda, Audino

    2014-02-01

    Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia. We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18-45 years, children aged 24-59 months, older infants aged 9-12 months, and infants aged 6-8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267. 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67-190] to 208 U/mL [117

  2. Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial.

    Directory of Open Access Journals (Sweden)

    Emma-Jo Hayton

    Full Text Available HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported.Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination.Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1 and predominantly transient (<48 hours. Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range of 633 (231-1533 post-vaccination, which is of no safety concern.These data demonstrate safety and good tolerability of the pSG2

  3. Immunogenicity and safety of concomitant administration of a combined hepatitis A/B vaccine and a quadrivalent meningococcal conjugate vaccine in healthy adults.

    Science.gov (United States)

    Alberer, Martin; Burchard, Gerd; Jelinek, Tomas; Reisinger, Emil C; Meyer, Seetha; Forleo-Neto, Eduardo; Dagnew, Alemnew F; Arora, Ashwani Kumar

    2015-01-01

    This phase 3b randomized, open-label study evaluated the immunogenicity and safety of coadministration of a hepatitis A and/or B vaccine with a quadrivalent oligosaccharide meningococcal CRM197 -conjugate vaccine (MenACWY-CRM), in the context of an accelerated hepatitis A and/or B immunization schedule. A total of 252 healthy adult subjects were randomized to three groups to receive hepatitis A/B only (HepA/B), hepatitis A/B coadministered with MenACWY-CRM (HepA/B+MenACWY-CRM), or MenACWY-CRM only (MenACWY-CRM). Hepatitis A and/or B vaccination was administered in the form of a single booster dose or a primary three-dose series, depending on the hepatitis A and/or B vaccination history of subjects. Antibody responses to hepatitis A/B vaccination were assessed 1 month following the last hepatitis A and/or B dose. Serum bactericidal activity with human complement (hSBA) against meningococcal serogroups A, C, W-135, and Y was assessed 1 month post-MenACWY-CRM vaccination. Safety was monitored throughout the study. At 1 month following the final hepatitis A and/or B vaccination, concomitant administration of hepatitis A/B and MenACWY-CRM was non-inferior to administration of hepatitis A/B alone in terms of geometric mean concentrations of antibodies against the hepatitis A and B antigens. One month post-MenACWY-CRM vaccination, the percentages of subjects achieving hSBA titers ≥8 for serogroups A, C, W-135, and Y in the HepA/B+MenACWY-CRM group (76, 87, 99, and 94%, respectively) were comparable to those in the MenACWY-CRM group (67, 82, 96, and 88%, respectively). The percentages of subjects reporting adverse events (AEs) were similar across study groups and a majority of the reported AEs were mild to moderate in nature. There were no study vaccine-related serious AEs. MenACWY-CRM can be administered concomitantly with a hepatitis A and/or B vaccine in the context of an accelerated hepatitis A and/or B immunization schedule without increasing safety concerns

  4. Safety and immunogenicity of H5N1 influenza vaccine based on baculovirus surface display system of Bombyx mori.

    Directory of Open Access Journals (Sweden)

    Rongzhong Jin

    Full Text Available Avian influenza virus (H5N1 has caused serious infections in human beings. This virus has the potential to emerge as a pandemic threat in humans. Effective vaccines against H5N1 virus are needed. A recombinant Bombyx mori baculovirus, Bmg64HA, was constructed for the expression of HA protein of H5N1 influenza virus displaying on the viral envelope surface. The HA protein accounted for approximately 3% of the total viral proteins in silkworm pupae infected with the recombinant virus. Using a series of separation and purification methods, pure Bmgp64HA virus was isolated from these silkworm pupae bioreactors. Aluminum hydroxide adjuvant was used for an H5N1 influenza vaccine. Immunization with this vaccine at doses of 2 mg/kg and 0.67 mg/kg was carried out to induce the production of neutralizing antibodies, which protected monkeys against influenza virus infection. At these doses, the vaccine induced 1:40 antibody titers in 50% and 67% of the monkeys, respectively. The results of safety evaluation indicated that the vaccine did not cause any toxicity at the dosage as large as 3.2 mg/kg in cynomolgus monkeys and 1.6 mg/kg in mice. The results of dose safety evaluation of vaccine indicated that the safe dose of the vaccine were higher than 0.375 mg/kg in rats and 3.2 mg/kg in cynomolgus monkeys. Our work showed the vaccine may be a candidate for a highly effective, cheap, and safe influenza vaccine for use in humans.

  5. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions.

    Science.gov (United States)

    Comi, Giancarlo; Freedman, Mark S; Kappos, Ludwig; Olsson, Tomas P; Miller, Aaron E; Wolinsky, Jerry S; O'Connor, Paul W; Benamor, Myriam; Dukovic, Deborah; Truffinet, Philippe; Leist, Thomas P

    2016-01-01

    Teriflunomide, a once-daily oral immunomodulator for the treatment of relapsing-remitting multiple sclerosis, has demonstrated consistent efficacy on clinical and MRI parameters in clinical trials. To summarize the safety and tolerability profile of teriflunomide based on data from four placebo-controlled trials. Safety and tolerability were assessed using two teriflunomide clinical program data pools. Pool 1 contained 3044 patients randomized to teriflunomide (14 mg or 7 mg) or placebo in the core studies of one phase 2 trial and three phase 3 trials, with cumulative treatment exposure >1500 patient-years per group. Pool 2 comprised 2338 patients who received teriflunomide treatment in the above trials, including those continuing in extension studies, with a duration of treatment up to 12 years, representing >6800 patient-years. Safety assessments included adverse events, laboratory parameters, and physical examinations. In Pool 1, the number of patients experiencing adverse events and serious adverse events was similar in the three treatment groups. Common events occurring in ≥ 10% of patients in either teriflunomide group, and with an incidence ≥ 2% compared with placebo, were alanine aminotransferase (ALT) increase, headache, diarrhea, hair thinning, and nausea. Overall, the nature of events observed in Pool 2 was similar to Pool 1. The majority of events in both pools were of mild-to-moderate intensity, were self-limiting, and infrequently resulted in discontinuation of therapy. The most common reason for treatment discontinuation in all treatment groups was ALT elevation, reflecting the protocol requirement to discontinue treatment on confirmation of ALT > 3 × the upper limit of normal. No new or unexpected safety signals beyond those detected in individual trials were identified in this pooled analysis with treatment duration exceeding 12 years and a cumulative exposure to teriflunomide exceeding 6800 patient-years. Overall, both doses of teriflunomide

  6. Immunogenicity and safety of an adjuvanted herpes zoster subunit candidate vaccine in adults ≥ 50 years of age with a prior history of herpes zoster: A phase III, non-randomized, open-label clinical trial.

    Science.gov (United States)

    Godeaux, Olivier; Kovac, Martina; Shu, Daniel; Grupping, Katrijn; Campora, Laura; Douha, Martine; Heineman, Thomas C; Lal, Himal

    2017-05-04

    This phase III, non-randomized, open-label, multi-center study (NCT01827839) evaluated the immunogenicity and safety of an adjuvanted recombinant subunit herpes zoster (HZ) vaccine (HZ/su) in adults aged ≥ 50 y with prior physician-documented history of HZ. Participants (stratified by age: 50-59, 60-69 and ≥ 70 y) received 2 doses of HZ/su 2 months apart and were followed-up for another 12 months. Anti-glycoprotein E (gE) antibodies were measured by enzyme-linked immunosorbent assay before vaccination and 1 month after the second dose (Month 3). Solicited local and general adverse events (AEs) were recorded for 7 d and unsolicited AEs for 30 d after each vaccination. Serious AEs were recorded until study end. The primary immunogenicity objective was met if the lower limit of the 95% confidence interval (CI) of the vaccine response rate (VRR), defined as a 4-fold increase in anti-gE over baseline, at Month 3 was ≥ 60%. 96 participants (32/age group) were enrolled. The primary immunogenicity objective was met, as the VRR at Month 3 was 90.2% (95% CI: 81.7-95.7). Geometric mean anti-gE antibody concentrations at Month 3 were similar across age groups. 77.9% and 71.6% of participants reported local and general solicited AEs, respectively. The most frequent solicited AEs were pain at injection site, fatigue, headache, myalgia and shivering. The HZ/su vaccine was immunogenic in adults aged ≥ 50 y with a physician-documented history of HZ, and no safety concerns were identified.

  7. Immunogenicity and safety of measles-mumps-rubella vaccine delivered by disposable-syringe jet injector in healthy Brazilian infants: a randomized non-inferiority study.

    Science.gov (United States)

    de Menezes Martins, Reinaldo; Curran, Birute; Maia, Maria de Lourdes Sousa; Ribeiro, Maria das Graças Tavares; Camacho, Luiz Antonio Bastos; da Silva Freire, Marcos; Yamamura, Anna Maya Yoshida; Siqueira, Marilda Mendonça; Lemos, Maria Cristina F; de Albuquerque, Elizabeth Maciel; von Doellinger, Vanessa dos Reis; Homma, Akira; Saganic, Laura; Jarrahian, Courtney; Royals, Michael; Zehrung, Darin

    2015-03-01

    This study aimed to determine if immunogenicity to measles-mumps-rubella vaccine delivered to infants via a disposable-syringe jet injector (DSJI) was non-inferior to that administered by needle and syringe (NS). Vaccination safety was evaluated, as were the use, performance, and acceptability of each delivery method. The DSJI was the PharmaJet 2009 generation-1 device (G1) and the vaccine was measles-mumps-rubella vaccine from Bio-Manguinhos. Five hundred eighty-two healthy Brazilian infants were randomized to receive vaccine via G1 or NS. Seroconversion rates against measles and mumps viruses in the G1 treatment group did not meet non-inferiority criteria when compared with the NS group; however, responses in the G1 group to rubella virus were non-inferior to those of NS vaccinees. Most adverse events were mild or moderate. Crying after injection was more frequent in the NS group, and local skin reactions were more common in the G1 group. Five serious adverse events were judged causally unrelated to treatment and all resolved. Parents/guardians expressed a strong preference for G1 over NS for their children. Vaccinators found the G1 easy to use but noted incomplete vaccine delivery in some cases. Although the G1 has been superseded by an updated device, our results are important for the continued improvement and evaluation of DSJIs, which have the potential to overcome many of the challenges and risks associated with needle-based injections worldwide. Recommendations for future DSJI clinical studies include rigorous training of vaccinators, quantitative measurement of wetness on the skin following injection, and regular monitoring of device and vaccinator performance. Copyright © 2014. Published by Elsevier Inc.

  8. Improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design: the Phacilitate Vaccine Forum, Washington D.C. 2011.

    Science.gov (United States)

    Moldovan, Ioana R; Tary-Lehmann, Magdalena

    2011-06-01

    The 9th Annual Vaccine Forum organized by Phacilitate in Washington D.C. 2011 brought together 50+ senior level speakers and over 400 participants representing all the key stakeholders concerning vaccines. The main focus of the meeting was to define priorities in the global vaccines sector from funding to manufacturing and evaluation of vaccine efficacy. A special session was devoted to improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design. The current regulatory approach to clinical assay specification, validation and standardization that enable more direct comparisons of efficacy between trials was illustrated by the success in meningococcal vaccine development. The industry approach to validation strategies was exemplified by a new serologic test used on the diagnostic of pneumococcal pneumonia. The application of the Animal Rule to bridge clinical and non-clinical studies in botulism has allowed significant progress in developing one of the first vaccines to seek approval under the FDA Animal Efficacy Rule. An example of pushing the boundaries in the correlation of immunological responses and efficacy points was represented by a recent cell-based influenza vaccine for which the same correlates of protection apply as for the traditional, egg-based flue vaccine. In the field of HIV phase 2b studies are underway, based on promising results obtained with some vaccine candidates. The conclusion of this session was that creativity in vaccine design and evaluation is beneficial and can lead to innovative new vaccine designs as well as to validated assays to assess vaccine efficacy.

  9. Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety?

    Science.gov (United States)

    Murdaca, Giuseppe; Spanò, Francesca; Contatore, Miriam; Guastalla, Andrea; Penza, Elena; Magnani, Ottavia; Puppo, Francesco

    2016-01-01

    TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, and may be administered off-label to treat disseminated granuloma annulare systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. infliximab and adalimumab can induce the development of anti-infliximab (anti-IFX) and anti-adalimumab (anti-ADA) monoclonal antibodies (mAbs). In this review, we discuss the impact of anti-IFX and anti-ADA mAbs upon efficacy and safety of these biological agents. IgG/IgE neutralizing antibodies against infliximab and adalimumab decrease the possibility of achieving a minimal disease activity state or clinical remission, decrease drug survival, increase the need for doctors to prescribe a higher drug dosage and, finally, favor the occurrence of adverse events. Concomitant administration of DMARDs such as methotrexate or leflunomide prevents the development of neutralizing Abs against infliximab and adalimumab.

  10. Tolerance and safety of nifurtimox in patients with chronic chagas disease.

    Science.gov (United States)

    Jackson, Yves; Alirol, Emilie; Getaz, Laurent; Wolff, Hans; Combescure, Christophe; Chappuis, François

    2010-11-15

    Nifurtimox has been used to treat Chagas disease for 40 years, but tolerance and safety data in adults are scarce. We aimed to evaluate nifurtimox tolerance and safety in a cohort of Trypanosoma cruzi-infected adult patients in a country of nonendemicity. This observational study included all consecutive adults patients who were given a diagnosis of T. cruzi infection from June through December 2008. Eligible patients received nifurtimox at 10 mg/kg/day for 60 days, with regular medical and biological follow-up. Adverse events (AEs) were recorded according to Common Terminology Criteria for Adverse Events, version 3.0. Eighty-one patients received nifurtimox. Eight were lost to follow-up during treatment, and 41 (56.2%) completed the 60-day course. All premature treatment terminations were caused by AEs; 97.5% of patients suffered from AEs, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction: drug reaction with eosinophilia and systemic symptoms (n = 3), Quincke edema (n = 1), acute myocarditis (n = 1), and anaphylaxis (n = 1). Patients with 3 or more AEs had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% confidence interval, 1.6-45.5). Nifurtimox is poorly tolerated among adults with chronic Chagas disease, resulting in a low treatment completion rate. Considering the significant risk of serious AEs, close monitoring is required, which may be difficult to implement in poor rural areas of countries of endemicity. The safety and efficacy of nifurtimox and benznidazole should be compared to improve current therapeutic recommendations, and pharmacovigilance systems should be enhanced.

  11. Phase I safety, tolerability and pharmacokinetic study of recombinant human mannan-binding lectin

    DEFF Research Database (Denmark)

    Petersen, K.A.; Matthiesen, F.; Agger, T.

    2006-01-01

    Mannan-binding lectin (MBL), a human plasma protein, plays an important role in the innate immune defence. MBL recognizes microorganisms through surface carbohydrate structures. Due to genetic polymorphisms, MBL plasma concentrations range from 5 to 10,000 ng/mL. Approximately 30% of the human...... (rhMBL) is in development as a novel therapeutic approach. To assess the safety, tolerability, and pharmacokinetics of rhMBL, a placebo-controlled double-blinded study was performed in MBL-deficient healthy male subjects. rhMBL was administered as both single intravenous (i.v.) infusions (0.01, 0...

  12. A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis.

    Directory of Open Access Journals (Sweden)

    Richard N Greenberg

    Full Text Available Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD. Prior studies evaluating Modified Vaccinia Ankara virus (MVA, a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers.This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD ≤ 30 and 282 healthy subjects.Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored.The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects.The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%.MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD.ClinicalTrials.gov NCT00316602.

  13. Reactor Safety Gap Evaluation of Accident Tolerant Components and Severe Accident Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Farmer, Mitchell T. [Argonne National Lab. (ANL), Argonne, IL (United States); Bunt, R. [Southern Nuclear, Atlanta, GA (United States); Corradini, M. [Univ. of Wisconsin, Madison, WI (United States); Ellison, Paul B. [GE Power and Water, Duluth, GA (United States); Francis, M. [Argonne National Lab. (ANL), Argonne, IL (United States); Gabor, John D. [Erin Engineering, Walnut Creek, CA (United States); Gauntt, R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Henry, C. [Fauske and Associates, Burr Ridge, IL (United States); Linthicum, R. [Exelon Corp., Chicago, IL (United States); Luangdilok, W. [Fauske and Associates, Burr Ridge, IL (United States); Lutz, R. [PWR Owners Group (PWROG); Paik, C. [Fauske and Associates, Burr Ridge, IL (United States); Plys, M. [Fauske and Associates, Burr Ridge, IL (United States); Rabiti, Cristian [Idaho National Lab. (INL), Idaho Falls, ID (United States); Rempe, J. [Rempe and Associates LLC, Idaho Falls, ID (United States); Robb, K. [Argonne National Lab. (ANL), Argonne, IL (United States); Wachowiak, R. [Electric Power Research Inst. (EPRI), Knovville, TN (United States)

    2015-01-31

    The overall objective of this study was to conduct a technology gap evaluation on accident tolerant components and severe accident analysis methodologies with the goal of identifying any data and/or knowledge gaps that may exist, given the current state of light water reactor (LWR) severe accident research, and additionally augmented by insights obtained from the Fukushima accident. The ultimate benefit of this activity is that the results can be used to refine the Department of Energy’s (DOE) Reactor Safety Technology (RST) research and development (R&D) program plan to address key knowledge gaps in severe accident phenomena and analyses that affect reactor safety and that are not currently being addressed by the industry or the Nuclear Regulatory Commission (NRC).

  14. Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults.

    Directory of Open Access Journals (Sweden)

    Spyros A Kalams

    Full Text Available BACKGROUND: DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques. METHODOLOGY/PRINCIPAL FINDINGS: We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37 DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug IL-12 DNA. However, after three doses, 44.4% (4/9 of vaccinees receiving gag DNA and intermediate dose (500 ug of IL-12 DNA demonstrated a detectable cellular immune response. CONCLUSIONS/SIGNIFICANCE: This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity. TRIAL REGISTRATION: Clinicaltrials.gov NCT00115960 NCT00111605.

  15. A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).

    Science.gov (United States)

    Frey, Sharon E; Lottenbach, Kathleen; Graham, Irene; Anderson, Edwin; Bajwa, Kanwaldeep; May, Ryan C; Mizel, Steven B; Graff, Aaron; Belshe, Robert B

    2017-12-04

    Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10mcg. Subjects were observed for 4h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject's participation lasted 13months. Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10mcg doses of vaccine were 260.0 (102.6-659.0) and 983.6 (317.3-3048.8), respectively, against F1 and V antigens. The 6mcg dose group provided similar titers. Titers were low for the placebo, 1mcg and 3mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited. Copyright © 2017. Published by Elsevier Ltd.

  16. Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.

    Science.gov (United States)

    Bennett, Jason W; Yadava, Anjali; Tosh, Donna; Sattabongkot, Jetsumon; Komisar, Jack; Ware, Lisa A; McCarthy, William F; Cowden, Jessica J; Regules, Jason; Spring, Michele D; Paolino, Kristopher; Hartzell, Joshua D; Cummings, James F; Richie, Thomas L; Lumsden, Joanne; Kamau, Edwin; Murphy, Jittawadee; Lee, Cynthia; Parekh, Falgunee; Birkett, Ashley; Cohen, Joe; Ballou, W Ripley; Polhemus, Mark E; Vanloubbeeck, Yannick F; Vekemans, Johan; Ockenhouse, Christian F

    2016-02-01

    A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.

  17. Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.

    Directory of Open Access Journals (Sweden)

    Jason W Bennett

    2016-02-01

    Full Text Available A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001, a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP and a truncated repeat region that contains repeat sequences from both the VK210 (type 1 and the VK247 (type 2 parasites, was developed as a vaccine candidate for global use.We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.

  18. Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases.

    Science.gov (United States)

    Novák, Zoltán; Yáñez, Anahí; Kiss, Ildikó; Kuna, Piotr; Tortajada-Girbés, Miguel; Valiente, Román

    2016-08-01

    Regulations on medicinal products for paediatric use require that pharmacokinetics and safety be characterized specifically in the paediatric population. A previous study established that a 10-mg dose of bilastine in children aged 2 to bilastine 10 mg in children with allergic rhinoconjunctivitis and chronic urticaria. In this phase III, multicentre, double-blind study, children were randomized to once-daily treatment with bilastine 10-mg oral dispersible table (n = 260) or placebo (n = 249) for 12 weeks. Safety evaluations included treatment-emergent adverse events (TEAEs), laboratory tests, cardiac safety (ECG recordings) and somnolence/sedation using the Pediatric Sleep Questionnaire (PSQ). The primary hypothesis of non-inferiority between bilastine 10 mg and placebo was demonstrated on the basis of a near-equivalent proportion of children in each treatment arm without TEAEs during 12 weeks' treatment (31.5 vs. 32.5%). No clinically relevant differences between bilastine 10 mg and placebo were observed from baseline to study end for TEAEs or related TEAEs, ECG parameters and PSQ scores. The majority of TEAEs were mild or moderate in intensity. TEAEs led to discontinuation of two patients treated with bilastine 10 mg and one patient treated with placebo. Bilastine 10 mg had a safety and tolerability profile similar to that of placebo in children aged 2 to <12 years with allergic rhinoconjunctivitis or chronic urticaria. © 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.

  19. Tolerance and safety of superficial chemical peeling with salicylic acid in various facial dermatoses

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    Iqbal Zafar

    2005-03-01

    Full Text Available BACKGROUND: Chemical peeling is a skin-wounding procedure that may have some potentially undesirable side-effects. AIMS: The present study is directed towards safety concerns associated with superficial chemical peeling with salicylic acid in various facial dermatoses. METHODS: The study was a non-comparative and a prospective one. Two hundred and sixty-eight patients of either sex, aged between 10 to 60 years, undergoing superficial chemical peeling for various facial dermatoses (melasma, acne vulgaris, freckles, post-inflammatory scars/pigmentation, actinic keratoses, plane facial warts, etc. were included in the study. Eight weekly peeling sessions were carried out in each patient. Tolerance to the procedure and any undesirable effects noted during these sessions were recorded. RESULTS: Almost all the patients tolerated the procedure well. Mild discomfort, burning, irritation and erythema were quite common but the incidence of major side-effects was very low and these too, were easily manageable. There was no significant difference in the incidence of side-effects between facial dermatoses (melasma, acne and other pigmentary disorders. CONCLUSION: Chemical peeling with salicylic acid is a well tolerated and safe treatment modality in many superficial facial dermatoses.

  20. Immunogenicity and safety of a new hexavalent vaccine (DTaP5-IPV-HB-Hib) administered in a mixed primary series schedule with a pentavalent vaccine (DTaP5-IPV-Hib).

    Science.gov (United States)

    Martinón-Torres, Federico; Boisnard, Florence; Thomas, Stéphane; Sadorge, Christine; Borrow, Ray

    2017-06-27

    DTaP5-IPV-HB-Hib vaccine is a fully-liquid, combination hexavalent vaccine. This phase III, open-label, multicentre study conducted in Spain, evaluated the immune response to all DTaP5-IPV-HB-Hib antigens when the vaccine was used in a mixed hexa/penta/hexa primary series. Infants (who had received one dose of hepatitis B vaccine at birth) received a mixed schedule including DTaP5-IPV-HB-Hib (PRP-OMP conjugate) at 2 and 6months of age, DTaP5-IPV-Hib at 4months, meningococcal serogroup C conjugate (MCC) vaccine at 2 and 4months, and routine rotavirus and pneumococcal vaccination. One month post-dose 3 of the mixed schedule, response rates were considered acceptable if the lower bound of the two-sided 95% confidence interval around the post-vaccination response rate was >90% for hepatitis B and >80% for Haemophilus influenzae type b (Hib). Secondary immunogenicity objectives included description of the antibody response to all hexavalent antigens one month after completion of the mixed schedule, and to MCC antigen one month after the second MCC dose. The safety profile after each dose of study vaccine was described. Of 385 healthy infants enrolled, 384 completed the study. The primary objective was achieved for both hepatitis B and Hib; the lower bound of the 2-sided 95% CI of the response rates (97.2% and 99.0%, respectively) were greater than the pre-specified acceptability thresholds. One month post-dose 3 of the mixed schedule, all participants were seroprotected against diphtheria, tetanus and polio. The mixed schedule induced a robust immune response to all hexavalent antigens. The co-administration of the hexavalent vaccine in a mixed schedule with MCC vaccine did not reduce the immune response to vaccine antigens. Vaccines were well tolerated. In conclusion, the acceptability of response rates against Hib and hepatitis B were demonstrated one month post-dose 3 of the mixed schedule; robust immune responses against all other hexavalent antigens were observed

  1. Immunogenicity and safety of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with DTPa vaccine in Japanese children: A randomized, controlled study

    Science.gov (United States)

    Iwata, Satoshi; Kawamura, Naohisa; Kuroki, Haruo; Tokoeda, Yasunobu; Miyazu, Mitsunobu; Iwai, Asayuki; Oishi, Tomohiro; Sato, Tomohide; Suyama, Akari; François, Nancy; Shafi, Fakrudeen; Ruiz-Guiñazú, Javier; Borys, Dorota

    2015-01-01

    This phase III, randomized, open-label, multicenter study (NCT01027845) conducted in Japan assessed the immunogenicity, safety, and reactogenicity of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, given intramuscularly) co-administered with diphtheria-tetanus-acellular pertussis vaccine (DTPa, given subcutaneously). Infants (N=360 ) were randomized (2:1) to receive either PHiD-CV and DTPa (PHiD-CV group) or DTPa alone (control group) as 3-dose primary vaccination (3–4–5 months of age) and booster vaccination (17–19 months of age). Immune responses were measured before and one month after primary/booster vaccination and adverse events (AEs) were recorded. Post-primary immune responses were non-inferior to those in pivotal/efficacy European or Latin American pneumococcal protein D-conjugate vaccine studies. For each PHiD-CV serotype, at least 92.6% of infants post-primary vaccination and at least 97.7% of children post-booster had pneumococcal antibody concentrations ≥0.2 μg/ml, and at least 95.4% post-primary and at least 98.1% post-booster had opsonophagocytic activity (OPA) titers ≥8 . Geometric mean antibody concentrations and OPA titers (except OPA titer for 6B) were higher post-booster than post-priming for each serotype. All PHiD-CV-vaccinated children had anti-protein D antibody concentrations ≥100 EL.U/ml one month post-primary/booster vaccination and all were seroprotected/seropositive against each DTPa antigen. Redness and irritability were the most common solicited AEs in both groups. Incidences of unsolicited AEs were comparable between groups. Serious AEs were reported for 47 children (28 in PHiD-CV group); none were assessed as vaccine-related. In conclusion, PHiD-CV induced robust immune responses and was well tolerated when co-administered with DTPa in a 3-dose priming plus booster regimen to Japanese children. PMID:25830489

  2. The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV-infected, BCG-vaccinated adults with CD4(+) T cell counts >350 cells/mm(3).

    Science.gov (United States)

    Churchyard, Gavin John; Snowden, Margaret Ann; Hokey, David; Dheenadhayalan, Veerabadran; McClain, J Bruce; Douoguih, Macaya; Pau, Maria Grazia; Sadoff, Jerry; Landry, Bernard

    2015-04-08

    The safety and immunogenicity of a replication deficient adenovirus serotype 35 tuberculosis (TB) vaccine containing gene inserts for Antigens (Ag) 85A, Ag85B and TB10.4 (AERAS-402/AD35.TB-S) was evaluated in previously BCG vaccinated, HIV-infected South African adults with baseline CD4 counts >350 cells/mm(3). Subjects were randomized (1:1) to receive two doses of either intramuscular AERAS-402/AD35.TB-S or placebo at month 0 and at month 1. Participants were monitored for adverse events 28 days after each vaccination and for serious adverse events over 12 months. CD4(+) and CD8(+) T-cell and antibody responses to vaccine antigens were evaluated post first and second vaccination. 26 subjects were randomly assigned to receive AERAS-402/AD35.TB-S (N=13) or placebo (N=13). The mean age was 29.0 years, all were Black-African, 88.5% were female, 46.2% were QuantiFERON Test (QFT) positive at baseline, and the median CD4 count was 559.5 cells/mm(3), all similar by treatment group. All subjects received their first vaccination and 24 subjects received their second vaccination. Injection site reactions and some systemic reactions were reported more commonly in the AERAS-402/AD35.TB-S versus placebo recipients. AERAS-402/AD35.TB-S did not appear to influence CD4 counts and HIV-1 viral load over the course of study follow-up. AERAS-402/AD35.TB-S induced a mixed CD4(+) T-cell and CD8(+) T-cell responses to Ag85B. The CD4(+) T-cell responses peaked to Ag85A and Ag85B 14 days after the second vaccination and had declined by Day 182. AERAS-402/AD35.TB-S predominantly induced CD4(+) T-cells expressing three (IFN-γ, TNF, IL-2) or two (IL-2 and TNF) cytokines, two weeks after the last vaccination, which did not differ by baseline Quantiferon test status. AERAS-402/AD35.TB-S induced strong Ag85A and Ag85B specific antibody responses, particularly after the second vaccination. AERAS-402/AD35.TB-S was well tolerated, safe and induced predominantly polyfunctional CD4(+) and CD8(+) T

  3. First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus–Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

    Science.gov (United States)

    Nyombayire, Julien; Anzala, Omu; Gazzard, Brian; Karita, Etienne; Bergin, Philip; Hayes, Peter; Kopycinski, Jakub; Omosa-Manyonyi, Gloria; Jackson, Akil; Bizimana, Jean; Farah, Bashir; Sayeed, Eddy; Parks, Christopher L.; Inoue, Makoto; Hironaka, Takashi; Hara, Hiroto; Shu, Tsugumine; Matano, Tetsuro; Dally, Len; Barin, Burc; Park, Harriet; Gilmour, Jill; Lombardo, Angela; Excler, Jean-Louis; Fast, Patricia; Laufer, Dagna S.; Cox, Josephine H.

    2017-01-01

    Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)–vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. Methods. Sixty-five HIV-1–uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35–vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH). Results. All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot–determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic. Conclusions. SeV-Gag primed functional, durable HIV-specific T

  4. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Corte, Tamera; Bonella, Francesco; Crestani, Bruno; Demedts, Maurits G; Richeldi, Luca; Coeck, Carl; Pelling, Katy; Quaresma, Manuel; Lasky, Joseph A

    2015-09-24

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by dyspnea and loss of lung function. Using pooled data from the replicate, randomized, 52-week, placebo-controlled INPULSIS(®) trials, we characterized the safety and tolerability of nintedanib 150 mg twice daily in patients with IPF and described how adverse events were managed during these trials. One thousand and sixty- one patients were treated (nintedanib 638; placebo 423). Higher proportions of patients in the nintedanib group than the placebo group had ≥ 1 dose reduction to 100 mg bid (27.9% versus 3.8%) or treatment interruption (23.7% versus 9.9%). Adverse events led to permanent treatment discontinuation in 19.3% and 13.0% of patients in the nintedanib and placebo groups, respectively. Diarrhea was the most frequent adverse event, reported in 62.4% of patients in the nintedanib group versus 18.4% in the placebo group; however, only 4.4% of nintedanib-treated patients discontinued trial medication prematurely due to diarrhea. Monitoring of liver enzymes before and periodically during nintedanib treatment was recommended so that liver enzyme elevations could be managed through dose reduction or treatment interruption. Nintedanib had a manageable safety and tolerability profile in patients with IPF. Recommendations for adverse event management minimized permanent treatment discontinuations in the INPULSIS(®) trials. clinicaltrials.gov NCT01335464 and NCT01335477.

  5. Safety and immunogenicity of H1/IC31®, an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial.

    Directory of Open Access Journals (Sweden)

    Klaus Reither

    Full Text Available Novel tuberculosis vaccines should be safe, immunogenic, and effective in various population groups, including HIV-infected individuals. In this phase II multi-centre, double-blind, placebo-controlled trial, the safety and immunogenicity of the novel H1/IC31 vaccine, a fusion protein of Ag85B-ESAT-6 (H1 formulated with the adjuvant IC31, was evaluated in HIV-infected adults.HIV-infected adults with CD4+ T cell counts >350/mm3 and without evidence of active tuberculosis were enrolled and followed until day 182. H1/IC31 vaccine or placebo was randomly allocated in a 5:1 ratio. The vaccine was administered intramuscularly at day 0 and 56. Safety assessment was based on medical history, clinical examinations, and blood and urine testing. Immunogenicity was determined by a short-term whole blood intracellular cytokine staining assay.47 of the 48 randomised participants completed both vaccinations. In total, 459 mild or moderate and 2 severe adverse events were reported. There were three serious adverse events in two vaccinees classified as not related to the investigational product. Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p = 0.015. Solicited systemic and unsolicited adverse events were similar by study arm. The baseline CD4+ T cell count and HIV viral load were similar by study arm and remained constant over time. The H1/IC31 vaccine induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells, as well as polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells.H1/IC31 was well tolerated and safe in HIV-infected adults with a CD4+ Lymphocyte count greater than 350 cells/mm3. The vaccine did not have an effect on CD4+ T cell count or HIV-1 viral load. H1/IC31 induced a specific and durable Th1 immune response.Pan African Clinical Trials Registry (PACTR PACTR201105000289276.

  6. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Zou Heng

    2011-05-01

    Full Text Available Abstract Background Donepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD, was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d. Method Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434 included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed. Results The safety population comprised 1434 patients: donepezil 23 mg/d (n = 963; donepezil 10 mg/d (n = 471; completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively. AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group, nausea (1.9% and 0.4%, diarrhea (1.7% and 0.4%, and dizziness (1.1% and 0.0%. The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%. Discussion The 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs

  7. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease

    Science.gov (United States)

    2011-01-01

    Background Donepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d. Method Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed. Results The safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%). Discussion The 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those

  8. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

    Science.gov (United States)

    Paul, Gesine; Zachrisson, Olof; Varrone, Andrea; Almqvist, Per; Jerling, Markus; Lind, Göran; Rehncrona, Stig; Linderoth, Bengt; Bjartmarz, Hjalmar; Shafer, Lisa L; Coffey, Robert; Svensson, Mikael; Mercer, Katarina Jansson; Forsberg, Anton; Halldin, Christer; Svenningsson, Per; Widner, Håkan; Frisén, Jonas; Pålhagen, Sven; Haegerstrand, Anders

    2015-03-02

    BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

  9. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

    Science.gov (United States)

    Butler, Kathleen; Teng, Renli

    2010-01-01

    AIM To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y12 receptor antagonist, in healthy volunteers. METHODS This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day−1, or placebo for 14 days. RESULTS Ticagrelor was absorbed with median tmax 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean Cmax and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified. CONCLUSIONS Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with Cmax and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day−1 was well tolerated. PMID:20642549

  10. Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis

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    Davies Michael J

    2008-10-01

    Full Text Available Abstract Background Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415 or a comparator agent (placebo or an active comparator (N = 2724; non-exposed group. The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences. Results For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence

  11. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Ashwinikumar A Raut

    2012-01-01

    Full Text Available Ashwagandha (Withania somnifera (WS, a "rasayana" drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30 were enrolled. After baseline investigations, they received WS capsules (Rx (aqueous extract, 8:1 daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day x10 days, 1 000 mg/day x 10 days, 1 250 mg/day x 10 days. Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar′s test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia.

  12. Hypothesis Testing of Inclusion of the Tolerance Interval for the Assessment of Food Safety.

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    Hungyen Chen

    Full Text Available In the testing of food quality and safety, we contrast the contents of the newly proposed food (genetically modified food against those of conventional foods. Because the contents vary largely between crop varieties and production environments, we propose a two-sample test of substantial equivalence that examines the inclusion of the tolerance intervals of the two populations, the population of the contents of the proposed food, which we call the target population, and the population of the contents of the conventional food, which we call the reference population. Rejection of the test hypothesis guarantees that the contents of the proposed foods essentially do not include outliers in the population of the contents of the conventional food. The existing tolerance interval (TI0 is constructed to have at least a pre-specified level of the coverage probability. Here, we newly introduce the complementary tolerance interval (TI1 that is guaranteed to have at most a pre-specified level of the coverage probability. By applying TI0 and TI1 to the samples from the target population and the reference population respectively, we construct a test statistic for testing inclusion of the two tolerance intervals. To examine the performance of the testing procedure, we conducted a simulation that reflects the effects of gene and environment, and residual from a crop experiment. As a case study, we applied the hypothesis testing to test if the distribution of the protein content of rice in Kyushu area is included in the distribution of the protein content in the other areas in Japan.

  13. Exploratory study to evaluate tolerability, safety, and activity of Ashwagandha (Withania somnifera) in healthy volunteers.

    Science.gov (United States)

    Raut, Ashwinikumar A; Rege, Nirmala N; Tadvi, Firoz M; Solanki, Punita V; Kene, Kirti R; Shirolkar, Sudatta G; Pandey, Shefali N; Vaidya, Rama A; Vaidya, Ashok B

    2012-07-01

    Ashwagandha (Withania somnifera) (WS), a "rasayana" drug, is recommended for balavardhan and mamsavardhan. The study was intended to evaluate dose-related tolerability, safety, and activity of WS formulation in normal individuals. The design was prospective, open-labeled, variable doses in volunteers. Eighteen apparently healthy volunteers (12M:6F, age:18-30 years, and BMI: 19-30) were enrolled. After baseline investigations, they received WS capsules (Rx) (aqueous extract, 8:1) daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day ×10 days, 1 000 mg/day × 10 days, 1 250 mg/day × 10 days). Volunteers were assessed for symptoms/signs, vital functions, hematological and biochemical organ function tests. Muscle activity was measured by hand grip strength, quadriceps strength, and back extensor force. Exercise tolerance was determined using cycle ergometry. Lean body weight and fat% were computed from skin fold thickness measurement. Adverse events were recorded, as volunteered by the subjects. Repeated measures ANOVA, McNemar's test, and paired t test were employed. All but one volunteer tolerated WS without any adverse event. One volunteer showed increased appetite, libido, and hallucinogenic effects with vertigo at the lowest dose and was withdrawn from study. In six subjects, improvement in quality of sleep was found. Organ function tests were in normal range before and after the intervention. Reduction in total- and LDL- cholesterol and increase of strength in muscle activity was significant. Total body fat percentage showed a reduction trend. WS, in escalated dose, was tolerated well. The formulation appeared safe and strengthened muscle activity. In view of its traditional Rasayana use, further studies are planned to evaluate potential of this drug in patients of sarcopenia.

  14. Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications.

    Science.gov (United States)

    Kuriakose, Anshu; Chirmule, Narendra; Nair, Pradip

    2016-01-01

    Today, potential immunogenicity can be better evaluated during the drug development process, and we have rational approaches to manage the clinical consequences of immunogenicity. The focus of the scientific community should be on developing sensitive diagnostics that can predict immunogenicity-mediated adverse events in the small fraction of subjects that develop clinically relevant anti-drug antibodies. Here, we discuss the causes of immunogenicity which could be product-related (inherent property of the product or might be picked up during the manufacturing process), patient-related (genetic profile or eating habits), or linked to the route of administration. We describe various posttranslational modifications (PTMs) and how they may influence immunogenicity. Over the last three decades, we have significantly improved our understanding about the types of PTMs of biotherapeutic proteins and their association with immunogenicity. It is also now clear that all PTMs do not lead to clinical immunogenicity. We also discuss the mechanisms of immunogenicity (which include T cell-dependent and T cell-independent responses) and immunological tolerance. We further elaborate on the management of immunogenicity in preclinical and clinical setting and the unique challenges raised by biosimilars, which may have different immunogenic potential from their parent biotherapeutics.

  15. Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications

    Directory of Open Access Journals (Sweden)

    Anshu Kuriakose

    2016-01-01

    Full Text Available Today, potential immunogenicity can be better evaluated during the drug development process, and we have rational approaches to manage the clinical consequences of immunogenicity. The focus of the scientific community should be on developing sensitive diagnostics that can predict immunogenicity-mediated adverse events in the small fraction of subjects that develop clinically relevant anti-drug antibodies. Here, we discuss the causes of immunogenicity which could be product-related (inherent property of the product or might be picked up during the manufacturing process, patient-related (genetic profile or eating habits, or linked to the route of administration. We describe various posttranslational modifications (PTMs and how they may influence immunogenicity. Over the last three decades, we have significantly improved our understanding about the types of PTMs of biotherapeutic proteins and their association with immunogenicity. It is also now clear that all PTMs do not lead to clinical immunogenicity. We also discuss the mechanisms of immunogenicity (which include T cell-dependent and T cell-independent responses and immunological tolerance. We further elaborate on the management of immunogenicity in preclinical and clinical setting and the unique challenges raised by biosimilars, which may have different immunogenic potential from their parent biotherapeutics.

  16. Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke

    DEFF Research Database (Denmark)

    Mori, Etsuro; Minematsu, Kazuo; Nakagawara, Jyoji

    2015-01-01

    BACKGROUND AND PURPOSE: This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke. METHODS: Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 rat...... tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467....

  17. Immunogenicity and safety of monovalent RIVM meningococcal B OMP vesicle F91 vaccine administered to children that received hexavalent meningococcal B vaccine 2.5 years ago

    NARCIS (Netherlands)

    Lafeber AB; Limpt CJP van; Berbers GAM; Labadie J; Kleijn ED de; Groot R de; Rumke HC; Alphen AJW van; Sophia Kinderziekenhuis /; LVO

    2000-01-01

    This report describes the results with respect to immunogenicity as well as reactogenicity of a monovalent P1.7h,4 OMV vaccine (MonoMen) used as booster vaccination in children previously vaccinated with a hexavalent MenB vaccine. The participants in this study were immunised in 1995-1996 with

  18. Efficacy, safety, and tolerability of fentanyl pectin nasal spray in patients with breakthrough cancer pain.

    Science.gov (United States)

    Ueberall, Michael A; Lorenzl, Stefan; Lux, Eberhard A; Voltz, Raymond; Perelman, Michael

    2016-01-01

    Assessment of analgesic effectiveness, safety, and tolerability of fentanyl pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain (BTcP) in routine clinical practice. A prospective, open-label, noninterventional study (4-week observation period, 3 month follow-up) of opioid-tolerant adults with BTcP in 41 pain and palliative care centers in Germany. Standardized BTcP questionnaires and patient diaries were used. Evaluation was made of patient-reported outcomes with respect to "time to first effect", "time to maximum effect", BTcP relief, as well as changes in BTcP-related impairment of daily life activities, quality-of-life restrictions, and health care resource utilization. A total of 235 patients were recruited of whom 220 completed all questionnaires and reported on 1,569 BTcP episodes. Patients reported a significant reduction of maximum BTcP intensity (11-stage numerical rating scale [0= no pain, 10= worst pain conceivable]) with FPNS (mean ± standard deviation = 2.8±2.3) compared with either that reported at baseline (8.5±1.5), experienced immediately before FPNS application (7.4±1.7), or that achieved with previous BTcP medication (6.0±2.0; P<0.001 for each comparison). In 12.3% of BTcP episodes, onset of pain relief occurred ≤2 minutes and in 48.4% ≤5 minutes; maximum effects were reported within 10 minutes for 37.9% and within 15 minutes for 79.4%. By the end of the study, there had been significant improvements versus baseline in BTcP-related daily life activities (28.3±16.9 vs 53.1±11.9), physical (35.9±8.4 vs 26.8±6.5), and mental quality of life (38.7±8.5 vs 29.9±7.9) (P<0.001 for each comparison vs baseline); in addition, health care resource utilization requirements directly related to BTcP were reduced by 67.5%. FPNS was well tolerated; seven patients (3.2%) experienced eight treatment-emergent adverse events of which none was serious. There were no indicators of misuse or abuse. FPNS provided rapid and highly

  19. Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: a 6-month real-life observational study.

    Science.gov (United States)

    Benucci, Maurizio; Gobbi, Francesca Li; Bandinelli, Francesca; Damiani, Arianna; Infantino, Maria; Grossi, Valentina; Manfredi, Mariangela; Parisi, Simone; Fusaro, Enrico; Batticciotto, Alberto; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola; Meacci, Francesca

    2017-02-01

    Biosimilar infliximab (INX) was recently approved by the European Medicine Agency for the treatment of rheumatoid arthritis, ankylosing spondylitis (AS), Crohn's disease, ulcerative colitis, psoriatic arthritis (PsA), and psoriasis on the grounds that its pharmacokinetics, safety, and efficacy were comparable to those of innovator INX. The aim of this study was to investigate the real-life efficacy, safety, and immunogenicity of switching from innovator to biosimilar INX in patients with spondyloarthritis (SpA). Forty-one patients attending three Italian rheumatology centres with a previous diagnosis of SpA and clinically inactive or moderate disease activity (ASDAS-CRP Law No. 450 of 7 April 2015) and followed up for 6 months. A record was kept of their BASDAI, BASFI, ASDAS-CRP, DAS28-CRP (in the presence of peripheral disease), MASES, VAS pain scores, the duration of morning stiffness, and adverse events (AEs). At the time of the switch, the patients had a median age of 50.9 years (range 23-80), a median disease duration of 124.5 months (range 14-372), and a median duration of treatment with innovator INX of 73.7 months (range 6-144). After 6 months of biosimilar INX therapy, there were no statistical differences in their median BASDAI (2.73 ± 1.5 vs. 2.6 ± 1.3, p = .27), BASFI (2.34 ± 1.3 vs. 2.17 ± 1.2, p = 0.051), ASDAS-CRP (1.35 ± 0.3 vs. 1.28 ± 0.2, p = 0.24), DAS28-CRP (2.66 ± 0.67 vs. 2.67 ± 0.35, p = 0.92), MASES (0.35 ± 0.7 vs. 0.17 ± 0.4, p = 0.08), or VAS pain scores (18 ± 14.7 vs. 16.7 ± 11.3, p = 0.55), whereas the median duration of morning stiffness had significantly decreased (7.2 ± 6.9 vs. 5.8 ± 6, p = 0.02). Furthermore, there was no change in circulating INX (4.22 ± 2.89 vs 4.84 ± 2.86 μg/mL, p = 0.80) or anti-INX antibody levels (27.76 ± 17.13 vs 27.27 ± 17.28 ng/mL, p = 0.98). The switch from innovator to biosimilar INX in this Italian multicentre SpA cohort was

  20. Immunogenicity and tolerability of inactivated flu vaccine In high risk and healthy children Inmunogenicidad y tolerancia de la vacuna inactivada anti-influenza en niños en alto riesgo y en controles sanos

    Directory of Open Access Journals (Sweden)

    Maria Luisa Avila Aguero

    2007-08-01

    Full Text Available We conducted this open study to evaluate the immunogenicity and safety of the inactivated influenza vaccine, Imovax Gripe® in 154 children between 6 and 36 months of age at high risk of influenza- related complications, and in a reference group of 64 healthy children. The study was conducted over two flu seasons, in which the vaccine contained the same A strains but different B strains. The results for the A/H3N2 and A/H1N1 strains from the two flu seasons were pooled, but those for the B strains were not. Anti-hemagglutinin (HA antibody titers were determined before, and one month after each vaccination, and safety was evaluated based on diary card reporting any adverse event observed, either included or not in the list of "solicited events". Within each group of vaccines, the seroconversion rates, seroprotection rates, and ratio of post- to prevaccination geometric mean titers (GMTR for the A/H3N2 and the A/H1N1 strains fulfilled all requirements of the criteria of the European Union Committee for Proprietary Medicinal Products (CPMP. The immune responses in high-risk and in healthy children were similar, and consistent with those observed in previous studies conducted in healthy children. The vaccine was equally well tolerated by all study groups. Reactogenicity was low and similar in both high-risk and healthy children. Overall from 9.5% to 15.4% of at-risk children and 12% of healthy children reported a solicited local reaction; 23.0 to 28.8% of high-risk and 25.3% of healthy children reported a solicited systemic reaction. The study results provide support for vaccination of children at high-risk of influenza related complications.Se realizó un estudio clínico abierto para evaluar la inmunogenícidad y la seguridad de la vacuna inactivada anti-influenza, Imovax Gripe®, en 154 niños entre 6 y 36 meses de edad con alto riesgo de complicaciones ligadas a la influenza, y en un grupo de referencia de 64 niños sanos. El estudio fue

  1. Induction of Specific Immunotherapy with Hymenoptera Venoms Using Ultrarush Regimen in Children: Safety and Tolerance

    Directory of Open Access Journals (Sweden)

    Alice Köhli-Wiesner

    2012-01-01

    Full Text Available Background & Objective. Ultrarush induction for specific venom immunotherapy has been shown to be reliable and efficacious in adults. In this study its safety and tolerance in children was evaluated. Methods. Retrospective analysis of 102 ultrarush desensitizations carried out between 1997 and 2005 in 94 children, aged 4 to 15 years. Diagnosis and selection for immunotherapy were according to recommendations of the European Academy of Allergy and Clinical Immunology. Systemic adverse reactions (SARs were described using the classification of H. L. Mueller. Results. All patients reached the cumulative dose of 111.1 μg hymenoptera venom within 210 minutes. Six patients (6% had allergic reactions grade I; 2 patients (2% grade II and 5 patients (5% grade III. Three patients (3% showed unclassified reactions. SARs did not occur in the 15 patients aged 4 to 8 years and they were significantly more frequent in girls (29% compared with boys (12% (=0.034, multivariant analysis and in bee venom extract treated patients (20% compared to those treated with wasp venom extract (8% (OR 0.33, 95% Cl 0.07–1.25. Conclusion. Initiation of specific immunotherapy by ultrarush regimen is safe and well tolerated in children and should be considered for treating children with allergy to hymenoptera venom.

  2. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.

    Science.gov (United States)

    Clarke, Kieran; Tchabanenko, Kirill; Pawlosky, Robert; Carter, Emma; Todd King, M; Musa-Veloso, Kathy; Ho, Manki; Roberts, Ashley; Robertson, Jeremy; Vanitallie, Theodore B; Veech, Richard L

    2012-08-01

    Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Safety and Tolerability of Esomeprazole in Children With Gastroesophageal Reflux Disease.

    Science.gov (United States)

    Gilger, Mark A; Tolia, Vasundhara; Vandenplas, Yvan; Youssef, Nader N; Traxler, Barry; Illueca, Marta

    2015-07-01

    To evaluate safety, tolerability, and symptom improvement with once-daily esomeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). In this 8-week, multicenter, randomized, uncontrolled, double-blind study, children ages 1 to 11 years were stratified by weight to receive esomeprazole 5 or 10 mg (children esomeprazole 5 and 10 mg, respectively, and 83.9% and 82.8% of children ≥ 20 kg receiving esomeprazole 10 and 20 mg, respectively, regardless of causality. Overall, only 9.3% of patients reported 13 treatment-related AEs; the most common were diarrhea (2.8% [3/108]), headache (1.9% [2/108]), and somnolence (1.9% [2/108]). Vomiting, a serious AE in 2 patients, was not judged by the investigator to be related to treatment. At the final visit, PGA scores improved significantly from baseline (P esomeprazole (at daily doses of 5, 10, or 20 mg) was generally well tolerated. The frequency and severity of GERD-related symptoms were significantly reduced during the active treatment period.

  4. Safety and tolerability of once-daily tiotropium Respimat (R) as add-on to at least inhaled corticosteroids in adult patients with symptomatic asthma : A pooled safety analysis

    NARCIS (Netherlands)

    Dahl, Ronald; Engel, Michael; Dusser, Daniel; Halpin, David; Kerstjens, Huib A. M.; Zaremba-Pechmann, Liliana; Moroni-Zentgraf, Petra; Busse, William W.; Bateman, Eric D.

    Background: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma. Objective: To evaluate safety and tolerability of

  5. Randomized, controlled trial of the long term safety, immunogenicity and efficacy of RTS,S/AS02(D) malaria vaccine in infants living in a malaria-endemic region.

    Science.gov (United States)

    Abdulla, Salim; Salim, Nahya; Machera, Francisca; Kamata, Richard; Juma, Omar; Shomari, Mwanajaa; Kubhoja, Sulende; Mohammed, Ali; Mwangoka, Grace; Aebi, Thomas; Mshinda, Hassan; Schellenberg, David; Carter, Terrell; Villafana, Tonya; Dubois, Marie-Claude; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Cohen, Joe; Ballou, W Ripley; Tanner, Marcel

    2013-01-08

    The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02(D) vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up. This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02(D) or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20. From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02(D) (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02(D) and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02(D) and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02(D) group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine efficacy against

  6. Randomized, controlled trial of the long term safety, immunogenicity and efficacy of RTS,S/AS02D malaria vaccine in infants living in a malaria-endemic region

    Science.gov (United States)

    2013-01-01

    Background The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02D vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up. Methods This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02D or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20. Results From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02D (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02D and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02D and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02D group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine

  7. Scalp Cooling: A Literature Review of Efficacy, Safety, and Tolerability for Chemotherapy-Induced Alopecia
.

    Science.gov (United States)

    Ross, Mikel; Fischer-Cartlidge, Erica

    2017-04-01

    More than 75% of patients with cancer cite alopecia as the most feared side effect of treatment, with as many as 10% considering treatment refusal. Despite wide acceptance in other countries, scalp cooling to reduce chemotherapy-induced alopecia (CIA) has been uncommon in the United States because of longstanding concerns of scalp metastases and a lack of reliable efficacy data. 
. This article reviews 40 years of efficacy, safety, and tolerability literature on scalp cooling to prevent CIA. 
. A systematic review was performed in PubMed and CINAHL®. Forty articles were reviewed, with 12 articles demonstrating high levels of evidence and meeting inclusion criteria. Comparative trials, systematic reviews, and one large single-arm trial were included. 
. Scalp cooling efficacy is dependent on many factors but demonstrates better hair preservation than no cooling. No increase in scalp metastases or statistically significant difference in overall survival was seen in retrospective safety data when cooling was used. Few patients discontinue cooling early because of adverse experiences.

  8. Suspension tolerance in a full-body safety harness, and a prototype harness accessory.

    Science.gov (United States)

    Turner, Nina L; Wassell, James T; Whisler, Richard; Zwiener, Joyce

    2008-04-01

    Workers wearing full-body safety harnesses are at risk for suspension trauma if they are not rescued in 5 to 30 min after a successfully arrested fall. Suspension trauma, which may be fatal, occurs when a person's legs are immobile in a vertical posture, leading to the pooling of blood in the legs, pelvis, and abdomen, and the reduction of return blood flow to the heart and brain. To measure suspension tolerance time, 22 men and 18 women with construction experience were suspended from the chest D-ring (CHEST) and back D-ring (BACK) of full-body, fall-arrest harnesses. Fifteen men and 13 women from the original group of subjects were then suspended using a newly developed National Institute for Occupational Safety and Health harness accessory (ACCESS), which supports the upper legs. Midthigh circumference changes were 1.4 and 1.9 cm, changes in minute ventilation were 1.2 and 1.5 L/min, changes in heart rate (HR) were 15.1 and 21.6 bpm, and changes in mean arterial pressure were 5.1 and -2.6 mmHg (p harness accessory to delay or prevent suspension trauma.

  9. [Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety].

    Science.gov (United States)

    Mücke, M; Carter, C; Cuhls, H; Prüß, M; Radbruch, L; Häuser, W

    2016-02-01

    Cannabinoids have multiple medical indications in palliative care, such as relief of pain or nausea or increase of appetite and weight stabilisation. The value of cannabinoids for these indications is not resolved sufficiently for palliative patients. A systematic review with meta-analysis of the efficacy, tolerability and safety on the basis of randomised controlled studies (RCT) or randomised open label or crossover studies has not yet been conducted. An extensive search for RCTs, randomised open label or crossover studies dealing with the underlying question was performed in the databases of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus and Clinicaltrials.gov up to April 2015. Studies with a duration of ≥ 2 weeks and ≥ 10 participants per treatment group were included into analysis. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables and risk differences (RD) for dichotomous variables were calculated. Out of initially 108 studies 9, with a total of 1561 participants suffering from advanced or end stage diseases, were included. The median study duration of the cancer research was 8 weeks (16 days-11 weeks), of the HIV research 6 weeks (3-12 weeks) and of the study concentrating on Alzheimer's 2 × 6 weeks. The outcome results for cannabis/cannabinoids vs. placebo in patients with cancer were not significant for the 30 % decrease in pain (RD: 0.07; 95 % confidence interval (CI): - 0.01 to 0.16; p = 0.07), caloric intake (SMD: 0.2; 95 % CI: - 0.66 to 1.06; p = 0.65) or sleep problems (SMD: - 0.09; 95 % CI: - 0.62 to 0.43; p = 0.72). In the treatment of HIV cannabinoids were superior to placebo for the outcome of weight change (SMD: 0.57; 95 % CI: 0.22-0.92; p = 0.001). Change in appetite was significant for the treatment of HIV (SMD: 0.57; 95 % CI: 0.11-1.03; p = 0.02), but

  10. Efficacy, safety, and tolerability of fentanyl pectin nasal spray in patients with breakthrough cancer pain

    Directory of Open Access Journals (Sweden)

    Ueberall MA

    2016-08-01

    Full Text Available Michael A Ueberall,1 Stefan Lorenzl,2 Eberhard A Lux,3,4 Raymond Voltz,5 Michael Perelman6 1Institute of Neurological Sciences, Nuremberg, Germany; 2Institute of Nursing Science and Practice, Paracelsus Private Medical University of Salzburg, Salzburg, Austria; 3Faculty of Medicine, Witten/Herdecke University, Witten, Germany; 4Clinic for Pain and Palliative Care Medicine, St.- Marien-Hospital, Luenen, Germany; 5Department of Palliative Medicine, University Hospital Cologne, Cologne, Germany; 6Archimedes Development Ltd., Nottingham, United Kingdom Objective: Assessment of analgesic effectiveness, safety, and tolerability of fentanyl pectin nasal spray (FPNS in the treatment of breakthrough cancer pain (BTcP in routine clinical practice.Methods: A prospective, open-label, noninterventional study (4-week observation period, 3 month follow-up of opioid-tolerant adults with BTcP in 41 pain and palliative care centers in Germany. Standardized BTcP questionnaires and patient diaries were used. Evaluation was made of patient-reported outcomes with respect to “time to first effect”, “time to maximum effect”, BTcP relief, as well as changes in BTcP-related impairment of daily life activities, ­quality-of-life restrictions, and health care resource utilization.Results: A total of 235 patients were recruited of whom 220 completed all questionnaires and reported on 1,569 BTcP episodes. Patients reported a significant reduction of maximum BTcP intensity (11-stage numerical rating scale [0= no pain, 10= worst pain conceivable] with FPNS (mean ± standard deviation = 2.8±2.3 compared with either that reported at baseline (8.5±1.5, experienced immediately before FPNS application (7.4±1.7, or that achieved with previous BTcP medication (6.0±2.0; P<0.001 for each comparison. In 12.3% of BTcP episodes, onset of pain relief occurred ≤2 minutes and in 48.4% ≤5 minutes; maximum effects were reported within 10 minutes for 37.9% and within 15 minutes

  11. H7N9 T-cell epitopes that mimic human sequences are less immunogenic and may induce Treg-mediated tolerance.

    Science.gov (United States)

    Liu, Rui; Moise, Leonard; Tassone, Ryan; Gutierrez, Andres H; Terry, Frances E; Sangare, Kotou; Ardito, Matthew T; Martin, William D; De Groot, Anne S

    2015-01-01

    Avian-origin H7N9 influenza is a novel influenza A virus (IAV) that emerged in humans in China in 2013. Using immunoinformatics tools, we identified several H7N9 T cell epitopes with T cell receptor (TCR)-facing residues identical to those of multiple epitopes from human proteins. We hypothesized that host tolerance to these peptides may impair T helper response and contribute to the low titer, weak hemagglutination inhibiting (HI) antibody responses and diminished seroconversion rates that have been observed in human H7N9 infections and vaccine trials. We found that the magnitude of human T effector responses to individual H7N9 peptides was inversely correlated with the peptide's resemblance to self. Furthermore, a promiscuous T cell epitope from the hemagglutinin (HA) protein suppressed responses to other H7N9 peptides when co-administered in vitro. Along with other highly 'human-like' peptides from H7N9, this peptide was also shown to expand FoxP3(+) regulatory T cells (Tregs). Thus, H7N9 may be camouflaged from effective human immune response by T cell epitope sequences that avert or regulate effector T cell responses through host tolerance.

  12. Safety and Tolerability of Nebulized Amoxicillin-Clavulanic Acid in Patients with COPD (STONAC 1 and STONAC 2)

    NARCIS (Netherlands)

    Nijdam, L.C.; Assink, M.D.M.; Kuijvenhoven, J.C.; de Saegher, M.E.A.; van der Valk, P.D.L.P.M.; van der Palen, Jacobus Adrianus Maria; Brusse-Keizer, M.G.J.; Movig, K.L.L.

    2016-01-01

    The safety and tolerability of nebulized amoxicillin clavulanic acid were determined in patients with stable COPD and during severe exacerbations of COPD. Nine stable COPD patients received doses ranging from 50:10 mg up to 300:60 mg amoxicillin clavulanic acid and eight patients hospitalised for a

  13. Clinical safety and efficacy of first indigenous recombinant hepatitis B vaccine.

    Science.gov (United States)

    Kumar, A; Joshi, N; Sreenivas, D V; Palan, S; Nagarjuna Kumar, Y R

    1998-07-01

    A pilot study was conducted to assess the clinical safety and immunogenicity of an indigenously developed recombinant hepatitis B vaccine (Shanvac B) in 18 healthy adults. 20 microg of vaccine was administered at 0, 1 and 2 months. Protective anti HBs titres developed in 22%, 77% and 100% one month after 1st, 2nd and 3rd dose of vaccination, respectively. The geometric mean titre after the 3rd dose was 1015.29 mIu/ml. The vaccine was well tolerated with minor local and systemic side effects in 28% and 22%, respectively. The indigenously developed recombinant hepatitis B vaccine is safe, well tolerated and highly immunogenic.

  14. Immunogenicity and safety of the new reduced-dose tetanus-diphtheria vaccine in healthy Korean adolescents: A comparative active control, double-blind, randomized, multicenter phase III study.

    Science.gov (United States)

    Han, Seung Beom; Rhim, Jung-Woo; Shin, Hye Jo; Kim, Sang Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Lee, Kyung-Yil; Kim, Hwang Min; Choi, Young Youn; Ma, Sang Hyuk; Kim, Chun Soo; Kim, Dong Ho; Ahn, Dong Ho; Kang, Jin Han

    2017-04-01

    A new reduced-dose tetanus-diphtheria (Td) vaccine was developed in Korea, and phase I and II clinical trials were successfully undertaken. We conducted this double-blind, randomized, multicenter phase III clinical trial to assess the immunogenicity and safety of the new Td vaccine. Healthy adolescents 11-12 years of age were enrolled and randomized to receive the new Td vaccine (study group) or a commercially available Td vaccine (control group). Blood samples were collected prior to and 4 weeks after the vaccination. Between the study and control groups, seroprotection rate, booster response, and geometric mean titer of antibodies against diphtheria and tetanus toxoids were compared after the vaccination. All solicited and unsolicited adverse events and serious adverse events during the 6-week study period were monitored. A total of 164 adolescents received vaccination, and 156 of them were evaluated to assess immunogenicity. The seroprotection rate and geometric mean titer for antibodies against diphtheria were significantly higher in the study group, whereas those against tetanus were significantly higher in the control group. However, all seroprotection rates against diphtheria and tetanus in the study and control groups were high: 100% against diphtheria and tetanus in the study group, and 98.7% against diphtheria and 100% against tetanus in the control group. No significant differences in the frequency of solicited and unsolicited adverse events were observed between the two vaccine groups. The new Td vaccine is highly immunogenic and safe, and this new Td vaccine can be effectively used for preventing diphtheria and tetanus. Copyright © 2015. Published by Elsevier B.V.

  15. The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis.

    Science.gov (United States)

    Griffiths, C E M; Thaçi, D; Gerdes, S; Arenberger, P; Pulka, G; Kingo, K; Weglowska, J; Hattebuhr, N; Poetzl, J; Woehling, H; Wuerth, G; Afonso, M

    2017-04-01

    GP2015 is a proposed etanercept biosimilar. To demonstrate equivalent efficacy, and comparable safety and immunogenicity of GP2015 and the etanercept originator (ETN, Enbrel(®) ) in patients with moderate-to-severe chronic plaque-type psoriasis. In total, 531 eligible patients were randomized 1 : 1 to self-administer GP2015 or ETN twice weekly subcutaneously. Patients with ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 12 were rerandomized to continue the same treatment on a once-weekly dosing schedule or to undergo a sequence of three treatment switches between GP2015 and ETN until week 30. Thereafter, patients continued treatment with the product they had been assigned to last, up to week 52. The difference in PASI 75 (75% improvement from baseline PASI score) response rates at week 12 between GP2015 and ETN (primary end point) was -2·3%. The 95% confidence interval (-9·85 to 5·30) was well contained within the prespecified margin range of -18 to 18. The incidence of treatment-emergent adverse events up to week 52 was comparable between continued GP2015 (59·8%) and ETN (57·3%); switching treatments revealed comparable safety profiles. Antidrug antibodies, all non-neutralizing, were limited to five patients on ETN during treatment period 1, and one patient in the switched ETN group, who had been treated with GP2015 for 12 weeks at the time of the finding. The EGALITY study demonstrated equivalent efficacy and comparable safety and immunogenicity of GP2015 and ETN. The study results provide the final clinical confirmation of biosimilarity and contribute to the totality of the evidence proposing that GP2015 is an etanercept biosimilar. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

  16. Safety and tolerability of 13-valent pneumococcal conjugate vaccine in the elderly

    Science.gov (United States)

    Durando, Paolo; Rosselli, Roberto; Cremonesi, Ilaria; Orsi, Andrea; Albanese, Erika; Barberis, Ilaria; Paganino, Chiara; Trucchi, Cecilia; Martini, Mariano; Marensi, Lorenzo; Turello, Valter; Study Group, the Ligurian Pneumococcal; Bregante, Alessandro; Cacciani, Roberto; Iudici, Rocco; La Marca, Diego; Pedano, Leonardo; Petrucci, Amadio Franco; Santolini, Maria; Sbisà, Valentina; Zacconi, Monica

    2014-01-01

    Background In September 2011 the European Medical Agency authorized the use of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. The same occurred in the US in December 2011 when the Food and Drug Administration approved the use of PCV13 in the same target age-group with indication for the prevention of invasive pneumococcal diseases and community acquired pneumonia sustained by the serotypes contained in the vaccine. The Liguria Region, in Italy, implemented in 2013 an active and free of charge immunization strategy with PCV13 among adults affected by specific risk conditions and the elderly aged ≥70 years. Methods An observational study was performed in order to assess the safety and tolerability of PCV13 among elderly dwelling in the metropolitan area of Genoa, the capital city of Liguria Region. Eligible subjects, who received PCV13 following the public health immunization campaign at the Local Health Unit 3 of Genoa, provided a written informed consent to take part in the study. Eight-hundred-seventy-one subjects were enrolled between October 2013 and May 2014: all were monitored by qualified healthcare personnel for at least 30 min after vaccination at the outpatient clinics, in order to assess any possible sudden reaction. The occurrence of a series of local and systemic solicited reactions and of any unsolicited Adverse Events (AEs) was monitored using a self-administered clinical diary and by regular phone contacts up to 14 and 21 d following immunization, respectively. Moreover, a 6-months follow-up following vaccination was planned in order to monitor Severe Adverse Events (SAEs). Results No sudden reaction occurred in vaccinees at the outpatient clinics. Pain (27.4%) was the most frequent reaction reported by subjects at the injection site, while new muscle pain (13.6%), fatigue (10.7%), and headache (9.9%) resulted the most common systemic reactions. Rates of the main reactions reported in this on-field study resulted

  17. Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen Plasmodium falciparum FVO merozoite surface protein-1 (MSP142 administered intramuscularly with adjuvant system AS01

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    Otsyula Nekoye

    2013-01-01

    Full Text Available Abstract Background The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1 antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. Methods Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 μg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 μg dose with a rabies vaccine comparator. Results In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele previously tested at both study sites. Conclusions Given that the primary

  18. Safety and Immunogenicity of the Recombinant BCG Vaccine AERAS-422 in Healthy BCG-naïve Adults: A Randomized, Active-controlled, First-in-human Phase 1 Trial.

    Science.gov (United States)

    Hoft, Daniel F; Blazevic, Azra; Selimovic, Asmir; Turan, Aldin; Tennant, Jan; Abate, Getahun; Fulkerson, John; Zak, Daniel E; Walker, Robert; McClain, Bruce; Sadoff, Jerry; Scott, Judy; Shepherd, Barbara; Ishmukhamedov, Jasur; Hokey, David A; Dheenadhayalan, Veerabadran; Shankar, Smitha; Amon, Lynn; Navarro, Garnet; Podyminogin, Rebecca; Aderem, Alan; Barker, Lew; Brennan, Michael; Wallis, Robert S; Gershon, Anne A; Gershon, Michael D; Steinberg, Sharon

    2016-05-01

    We report a first-in-human trial evaluating safety and immunogenicity of a recombinant BCG, AERAS-422, over-expressing TB antigens Ag85A, Ag85B, and Rv3407 and expressing mutant perfringolysin. This was a randomized, double-blind, dose-escalation trial in HIV-negative, healthy adult, BCG-naïve volunteers, negative for prior exposure to Mtb, at one US clinical site. Volunteers were randomized 2:1 at each dose level to receive a single intradermal dose of AERAS-422 (>10(5)-BCG (1-8×10(5)CFU). Randomization used an independently prepared randomly generated sequence of treatment assignments. The primary and secondary outcomes were safety and immunogenicity, respectively, assessed in all participants through 182days post-vaccination. ClinicalTrials.gov registration number: NCT01340820. Between Nov 2010 and Aug 2011, 24 volunteers were enrolled (AERAS-422 high dose, n=8; AERAS-422 low dose, n=8; Tice BCG, n=8); all were included in the safety and immunogenicity analyses. All 24 subjects had at least one adverse event, primarily expected local reactions. High dose AERAS-422 vaccination induced Ag85A- and Ag85B-specific lymphoproliferative responses and marked anti-mycobacterial activity in a whole blood bactericidal activity culture assay (WBA), but was associated with varicella zoster virus (VZV) reactivation in two vaccinees. These volunteers displayed high BCG-specific IFN-γ responses pre- and post-vaccination possibly predisposing them to autocrine/paracrine negative regulation of immune control of latent VZV. A systems biology transcriptomal approach identified positive correlations between post-vaccination T cell expression modules and WBA, and negative correlations between post-vaccination monocyte expression modules and WBA. The expression of one key macrophage marker (F4/80) was constitutively elevated in the two volunteers with zoster. The unexpected development of VZV in two of eight healthy adult vaccine recipients resulted in discontinuation of AERAS-422

  19. Immunogenicity and safety of an inactivated quadrivalent influenza vaccine co-administered with a 23-valent pneumococcal polysaccharide vaccine versus separate administration, in adults ≥50years of age: Results from a phase III, randomized, non-inferiority trial.

    Science.gov (United States)

    Ofori-Anyinam, Opokua; Leroux-Roels, Geert; Drame, Mamadou; Aerssens, Annelies; Maes, Cathy; Amanullah, Arshad; Schuind, Anne; Li, Ping; Jain, Varsha K; Innis, Bruce L

    2017-11-01

    We compared co-administration versus separate administration of an inactivated quadrivalent influenza vaccine (IIV4) with a 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults at high risk of complications of influenza and pneumococcal infection. This phase III, placebo-controlled, observer-blind trial (NCT02218697) was conducted in France and Belgium during the 2014-2015 influenza season. Adults≥50years of age meeting their country's vaccination recommendations were randomized 1:1 to co-administration or separate administration. Immunogenicity was assessed by hemagglutination inhibition (HI) titers for IIV4 and 22F-inhibition ELISA for PPV23. Co-primary objectives were to demonstrate non-inferiority of co-administration versus separate administration in terms of geometric mean titer (GMT) ratio for each influenza strain in the IIV4 and geometric mean concentration (GMC) ratio for six pneumococcal serotypes (1, 3, 4, 7F, 14, 19A) in the PPV23 in the per-protocol cohort (N=334). The study met its co-primary objectives, with the upper limit of the 95% confidence interval of the GMT and GMC ratios (separate administration over co-administration) being ≤2.0 for all four antigens of the IIV4 and the six pre-selected serotypes of the PPV23, respectively. Immunogenicity of the IIV4 and PPV23 was similar regardless of administration schedule. In a post hoc analysis pooling participants ≥60years of age from the co-administration and separate administration groups, IIV4 immunogenicity was similar in higher risk adults with comorbidities (diabetes; respiratory, heart, kidney, liver, or neurological diseases; morbid obesity) versus those without. Both vaccines had an acceptable safety and reactogenicity profile; pain was the most common symptom, occurring more often with co-administration than separate administration. The IIV4 and PPV23 can be co-administered without reducing antibody responses reflecting protection against influenza or pneumococcal disease

  20. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

    Directory of Open Access Journals (Sweden)

    Lewiecki EM

    2011-12-01

    Full Text Available E Michael LewieckiNew Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico, USAAbstract: Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL, a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture.Keywords: denosumab, osteoporosis, safety, risk, benefit, FDA

  1. Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies

    Directory of Open Access Journals (Sweden)

    Schweizer A

    2011-02-01

    Full Text Available Anja Schweizer1, Sylvie Dejager2, James E Foley3, Wolfgang Kothny31Novartis Pharma AG, Basel, Switzerland; 2Novartis Pharma SAS, Rueil-Malmaison, France; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAAim: Analyzing safety aspects of a drug from individual studies can lead to difficult-to-interpret results. The aim of this paper is therefore to assess the general safety and tolerability, including incidences of the most common adverse events (AEs, of vildagliptin based on a large pooled database of Phase II and III clinical trials.Methods: Safety data were pooled from 38 studies of ≥12 to ≥104 weeks' duration. AE profiles of vildagliptin (50 mg bid; N = 6116 were evaluated relative to a pool of comparators (placebo and active comparators; N = 6210. Absolute incidence rates were calculated for all AEs, serious AEs (SAEs, discontinuations due to AEs, and deaths.Results: Overall AEs, SAEs, discontinuations due to AEs, and deaths were all reported with a similar frequency in patients receiving vildagliptin (69.1%, 8.9%, 5.7%, and 0.4%, respectively and patients receiving comparators (69.0%, 9.0%, 6.4%, and 0.4%, respectively, whereas drug-related AEs were seen with a lower frequency in vildagliptin-treated patients (15.7% vs 21.7% with comparators. The incidences of the most commonly reported specific AEs were also similar between vildagliptin and comparators, except for increased incidences of hypoglycemia, tremor, and hyperhidrosis in the comparator group related to the use of sulfonylureas.Conclusions: The present pooled analysis shows that vildagliptin was overall well tolerated in clinical trials of up to >2 years in duration. The data further emphasize the value of a pooled analysis from a large safety database versus assessing safety and tolerability from individual studies.Keywords: type 2 diabetes, dipeptidyl peptidase-4, edema, safety, vildagliptin

  2. Safety and Tolerance of D,L-Methadone in Combination with Chemotherapy in Patients with Glioma.

    Science.gov (United States)

    Onken, Julia; Friesen, Claudia; Vajkoczy, Peter; Misch, Martin

    2017-03-01

    D,L-Methadone increases sensitivity toward chemotherapy of different tumor cell populations. We evaluated the safety and tolerance of additional use of D,L-methadone in patients with glioma in combination with chemotherapy. The dosage, duration of therapy and side-effects related to D,L-methadone were recorded in 27 patients. Toxicity was assessed accordingly to the Common Toxicity Criteria (CTC) of the National Cancer Institute. Progression-free survival at 6 months (PFS-6) was assessed. A total of 13 patients reported grade 1-3 nausea at the beginning of the D,L-methadone therapy. Four patients reported persistent side-effects of nausea (CTC Grade 2, n=1) and obstipation (CTC grade 2-3, n=3). PFS-6 of patients with glioblastoma was 80% in those with non-methylated O6-methylguanine-DNA methyltransferase (MGMT) (n=5) and 100% in those with MGMT methylation (n=7). D,L-methadone can be safely combined with standard glioma chemotherapy without increasing the risk of toxicity or vegetative symptoms such as tachycardia, sweating and restlessness. PFS-6 in patients with primary glioblastoma treated this way seems to be at least comparable to that of historic controls. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Assessing drinking water treatment systems for safety against cyanotoxin breakthrough using maximum tolerable values.

    Science.gov (United States)

    Schmidt, Wido; Bornmann, Katrin; Imhof, Lutz; Mankiewicz, Joanna; Izydorczyk, Katarzyna

    2008-06-01

    For assessing the safety of drinking water supplies suffering cyanobacterial blooms in their water source, a methodology is proposed which relates the performance of their current treatment train to the quality of the raw water. The approach considers that different treatment trains can remove algal toxins with different efficiency. Maximum Tolerable (MT-) values of the raw water expressed by cell counts or by biovolumes of cyanobacteria were calculated. Three MT-categories were identified by colours; high risk (red), moderate risk (yellow) and no risk (green). Two treatment facilities using a conventional (1) and polishing train (2) were assessed using this methodology. For most of the time during an algal bloom the water quality could be classified as yellow which means short term higher toxin levels in comparison to the guide line in clear water were found. However, the red classification, indicating a high risk for drinking water quality was never reached. The model proposed can be understood as supplement of the common alert level framework, ALF-concept (Chorus and Bartram, Situation Assessment, Planning and Management. London and New York: E & FN Spon. 1999; House et al., Management Strategies for Toxic Blue Green Algae: Literature Review. Australia: CRC for Water Quality and Treatment. 2004).

  4. Phosphodiesterase-5 inhibitors in management of pulmonary hypertension: safety, tolerability, and efficacy

    Science.gov (United States)

    Buckley, Mitchell S; Staib, Robin L; Wicks, Laura M; Feldman, Jeremy P

    2010-01-01

    Pulmonary arterial hypertension (PAH) is a progressive disease that causes severe disability and has no cure. Over the past 20 years, a variety of treatment options have evolved for the management of PAH. With an expanded therapeutic armamentarium come more complex decisions regarding treatment options. Agent selection depends upon several factors including efficacy, side effect profile, and cost, as well as convenience of administration. We have undertaken a review of phosphodiesterase-5 (PDE-5) inhibitors in PAH with a focus on efficacy and safety. A literature search was conducted using the Medline and Cochrane Central Register of Controlled Trials databases (1966–February 2010) for relevant randomized clinical studies. Overall, 10 studies met our inclusion criteria. Sildenafil was the most commonly studied agent, followed by tadalafil and vardenafil. Most trials found that the PDE-5 inhibitors significantly improved exercise capacity and lowered pulmonary pressures. However, there were conflicting results regarding these agents’ impact on improving cardiac function and functional class. Overall, these medications were effective and well tolerated with a relatively benign side effect profile. The PDE-5 inhibitors are an important option in treating PAH. While most of the published clinical data involved sildenafil, the other PDE-5 inhibitors show promise as well. Further studies are needed to determine the optimal doses of this therapeutic drug class, as well as its effects as adjunctive therapy with other agents in PAH. PMID:21701627

  5. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis.

    Science.gov (United States)

    Lewiecki, E Michael

    2011-01-01

    Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO) is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture.

  6. Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management

    Directory of Open Access Journals (Sweden)

    Luca Dalle Carbonare

    2010-08-01

    Full Text Available Luca Dalle Carbonare, Mirko Zanatta, Adriano Gasparetto, Maria Teresa ValentiClinic of Internal Medicine D, Department of Medicine, University of Verona, ItalyAbstract: Bisphosphonates (BPs are widely used in the treatment of postmenopausal ­osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively. The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can also stimulate osteoblast activity and differentiation. Several randomized control trials have demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover, and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they are generally considered safe, some side effects are reported (esophagitis, acute phase reaction, hypocalcemia, uveitis, and compliance with therapy is often inadequate. In particular, gastrointestinal discomfort is frequent with the older daily oral administrations and is responsible for a high proportion of discontinuation. The most recent weekly and monthly formulations, and in particular the yearly infusion of zoledronate, significantly improve persistence with treatment, and optimize clinical, densitometric, and antifracture outcomes.Keywords: bisphosphonates, osteoporosis, safety, tolerability, zoledronic acid

  7. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis

    Science.gov (United States)

    Lewiecki, E Michael

    2011-01-01

    Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal regulator of osteoclastic bone resorption. Postmenopausal osteoporosis (PMO) is a systemic skeletal disease associated with high levels of RANKL, resulting in a high rate of bone remodeling and an imbalance of bone resorption over bone formation. By inhibiting RANKL in women with PMO, denosumab reduces the rate of bone remodeling, thereby increasing bone mineral density, improving bone strength, and reducing the risk of fractures. In clinical trials of women with osteoporosis and low bone mineral density, denosumab has been well tolerated, with overall rates of adverse events and serious adverse events in women treated with denosumab similar to those receiving placebo. In the largest clinical trial of denosumab for the treatment of women with PMO, there was a significantly greater incidence of cellulitis reported as a serious adverse event, with no difference in the overall incidence of cellulitis, and a significantly lower incidence of the serious adverse event of concussions with denosumab compared with placebo. The evidence supports a favorable balance of benefits versus risks of denosumab for the treatment of PMO. Assessments of the long-term safety of denosumab are ongoing. Denosumab 60 mg subcutaneously every 6 months is an approved treatment for women with PMO who are at high risk for fracture. PMID:22279412

  8. Safety and tolerability of regadenoson for myocardial perfusion imaging - first Danish experience.

    Science.gov (United States)

    Pape, Marianne; Zacho, Helle D; Aarøe, Jens; Eggert Jensen, Svend; Petersen, Lars J

    2016-06-01

    Evaluating safety and tolerability of the selective A2A receptor agonist, regadenoson, in patients referred for single photon emission computed tomography myocardial perfusion imaging (MPI). Observational study of patients referred for MPI stress testing using a 400 μg regadenoson (Rapiscan(®)) bolus. Hemodynamic variables and severity of adverse events (AE) were recorded before, during, and after administration. A total of 232 patients were included. One or more AE were reported in 90% of patients; the AEs were graded mostly mild to moderate in severity, resolved spontaneously, and were mainly dyspnea, headache, and chest pain. No advanced heart block or bronchospasm were seen. Transient ST-segment changes developed in 10 patients. The maximum increase in heart rate was 19 ± 11 beats/minute. The mean systolic blood pressure decreased from 144 to 139 mmHg (p regadenoson. Regadenoson for MPI is easy to use with a high frequency of AEs, which are generally mild in severity, transient, and resolve spontaneously.

  9. Determination of the maximum tolerated dose and the safety index of an experimental fasciolicide in cattle.

    Science.gov (United States)

    Vera, Y; Ibarra, F; Cantó, G J; Soria, O; Castillo, R; Hernández, A

    2006-04-01

    The aim of the present study was to determine the maximum tolerated dose (MTD) and the safety index (SI) of 5-chloro-2-methylthio-6-(1-napthyloxy)1H-benzimidazole, called compound alpha, in cattle. In addition, to search for possible adverse effects after treatment, the measurement of some biochemical, haematological and physiological parameters were also analysed. Eighteen crossbred heifers were divided into six groups of three animals each. Groups 1-5 received a single oral dose of 12, 36, 60, 120 and 180 mg/kg of body weight (bw) of compound alpha. Group 6 served as an untreated control. To determine the biochemical, haematological and enzymatic parameters, sera and blood samples were individually taken at 0, 4, 8, 16, 32, 128, and 720 h after treatment. Physiological parameters such as rectal temperature, heart rate (HR), respiration rate (RR) and ruminal motility were measured at the time intervals mentioned above. Estimation of the MTD and SI was obtained by using the formula reported by the Food and Drug Administration (FDA), the results showing an MTD of 180 mg/kg/bw and an SI of 15 times the recommended clinical dose. Some statistical differences were observed in a few of the biochemical, haematological and enzymatic parameters, the adverse effects being not highly representative. Alterations on HR and RR were statistically different (P<0.05) only in heifers treated with 180 mg.

  10. Safety and Immunogenicity of DTaP5-IPV Compared With DTaP5 Plus IPV as the Fifth Dose in Children 4-6 Years of Age.

    Science.gov (United States)

    Smith, Michael J; Jordanov, Emilia; Sheng, Xiaohua; Tsang, Peter H

    2017-03-01

    Immunogenicity and safety of stand-alone diphtheria, tetanus toxoid, 5-component acellular pertussis vaccine adsorbed, inactivated poliovirus (IPV) combination vaccine (DTaP5-IPV) was compared with separate DTaP5 plus IPV vaccines as fifth dose in children 4-6 years of age. In this phase III, controlled, multicenter, randomized, open-label study, participants were randomized to DTaP5-IPV plus measles/mumps/rubella (MMR) and varicella virus (VZV) vaccines (group 1; N = 324), DTaP5+IPV with MMR and VZV (group 2; N = 327), DTaP5-IPV with/without MMR/VZV (group 3; N = 2419) or DTaP5+IPV with/without MMR/VZV (group 4; N = 302). Immunogenicity endpoints (groups 1 and 2) included booster response rates and antibody geometric mean concentrations (GMCs). Noninferiority of DTaP5-IPV to DTaP5+IPV was evaluated based on differences (groups 1 and 2) in booster rates and postvaccination GMC ratios. Safety endpoints (all groups) included all adverse events. Noninferiority of DTaP5-IPV compared with DTaP5+IPV for all antigens was achieved. Booster rate differences were 5.4% for pertussis toxoid (PT); 7.4% for filamentous hemagglutinin; 3.7% for pertactin (PRN); 4.8% for fimbriae types 2 and 3; -0.1% for tetanus; -1.9% for diphtheria; 3.7% for poliovirus 1; -0.7% for poliovirus 2 and 0.3% for poliovirus 3. GMC ratios were 1.97 for PT; 1.56 for filamentous hemagglutinin; 1.51 for PRN; 1.33 for fimbriae types 2 and 3; 1.17 for tetanus; 1.20 for diphtheria; 1.27 for poliovirus 1; 0.90 for poliovirus 2 and 1.34 for poliovirus 3. Rates of immediate and unsolicited adverse events, solicited injection site reactions and systemic reactions were similar between groups. DTaP5-IPV was safe and immunogenic in children 4-6 years of age.

  11. Safety and immunogenicity of one dose of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines.

    Science.gov (United States)

    Arguedas, A; Soley, C; Loaiza, C; Rincon, G; Guevara, S; Perez, A; Porras, W; Alvarado, O; Aguilar, L; Abdelnour, A; Grunwald, U; Bedell, L; Anemona, A; Dull, P M

    2010-04-19

    This Phase III study evaluates an investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM (Novartis Vaccines), when administered concomitantly or sequentially with two other recommended adolescent vaccines; combined tetanus, reduced diphtheria and acellular pertussis (Tdap), and human papillomavirus (HPV) vaccine. In this single-centre study, 1620 subjects 11-18 years of age, were randomized to three groups (1:1:1) to receive MenACWY-CRM concomitantly or sequentially with Tdap and HPV. Meningococcal serogroup-specific serum bactericidal assay using human complement (hSBA), and antibodies to Tdap antigens and HPV virus-like particles were determined before and 1 month after study vaccinations. Proportions of subjects with hSBA titres > or =1:8 for all four meningococcal serogroups (A, C, W-135, Y) were non-inferior for both concomitant and sequential administration. Immune responses to Tdap and HPV antigens were comparable when these vaccines were given alone or concomitantly with MenACWY-CRM. All vaccines were well tolerated; concomitant or sequential administration did not increase reactogenicity. MenACWY-CRM was well tolerated and immunogenic in subjects 11-18 years of age, with comparable immune responses to the four serogroups when given alone or concomitantly with Tdap or HPV antigens. This is the first demonstration that these currently recommended adolescent vaccines could be administered concomitantly without causing increased reactogenicity. Copyright 2010 Elsevier Ltd. All rights reserved.

  12. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia.

    Science.gov (United States)

    Hovingh, G Kees; Raal, Frederick J; Dent, Ricardo; Stefanutti, Claudia; Descamps, Olivier; Masana, Luis; Lira, Armando; Bridges, Ian; Coll, Blai; Sullivan, David

    Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9, is safe and effective when dosed biweekly (Q2W) or monthly (QM) in patients with heterozygous familial hypercholesterolemia (HeFH) as demonstrated in two 12-week trials: Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD; phase 2) and RUTHERFORD-2 (phase 3). The objective of the study was to evaluate long-term efficacy, safety, and tolerability of evolocumab during open-label extension trials. Patients completing parent trials were re-randomized 2:1 to evolocumab plus standard of care (SOC) or SOC alone for 52 weeks (Open-Label Study of Long-term Evaluation Against LDL-C [OSLER-1]) or 48 weeks (OSLER-2). Evolocumab dosing was 420 mg QM (OSLER-1) and 140 mg Q2W or 420 mg QM (OSLER-2). A pooled analysis of OSLER data was performed from this subset of HeFH patients. Four hundred forty HeFH patients from RUTHERFORD (n = 147) and RUTHERFORD-2 (n = 293) (mean [standard deviation] age 51 [12] years, 58% male, 90% White) were randomized to evolocumab plus SOC (n = 289) or SOC (n = 151). The 48-week period was completed by 425 patients (96.6%). Eight patients discontinued evolocumab plus SOC (2.8%) and 7 discontinued SOC (4.6%). Compared to parent study baseline, patients receiving evolocumab plus SOC experienced a mean 53.6% reduction in low-density lipoprotein cholesterol after 48 weeks. No patient experienced an adverse event leading to permanent evolocumab discontinuation during the 1-year SOC-controlled period. Serious adverse event rates were similar between groups (evolocumab plus SOC, 7.3%; SOC, 8.6%). Continued use of evolocumab added to SOC in patients with HeFH yields persistent and marked low-density lipoprotein cholesterol reductions during 48 weeks of follow-up. Long-term dosing of evolocumab with SOC was safe and well tolerated. Copyright © 2017 National Lipid Association. Published by

  13. Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study

    OpenAIRE

    Townsend, Robert; Desai, Amit; Rammelsberg, Diane; Kowalski, Donna; Simmons, Neal; Kitt, Therese M.

    2015-01-01

    Background Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. Method and Results Healthy males and females were randomized to receive intravenous regadenoson [100??g (3 doses), 200??g (3 doses), or 400??g (2 doses)], or placebo (2 or 3 doses; 0.9% sod...

  14. Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Umeclidinium and Vilanterol Alone and in Combination: A Randomized Crossover Trial

    OpenAIRE

    Kelleher, Dennis L.; Mehta, Rashmi S.; Jean-Francois, Bernadette M.; Preece, Andrew F.; Blowers, James; Crater, Glenn D.; Thomas, Paul

    2012-01-01

    Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting ?2 agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 ?g) and vilanterol (50 ?g) w...

  15. Unveiling the relative efficacy, safety and tolerability of prophylactic medications for migraine: pairwise and network-meta analysis.

    Science.gov (United States)

    He, Aijie; Song, Dehua; Zhang, Lei; Li, Chen

    2017-12-01

    A large number patients struggle with migraine which is classified as a chronic disorder. The relative efficacy, safety and tolerability of prophylactic medications for migraine play a key role in managing this disease. We conducted an extensive literature search for popular prophylactic medications that are used for migraine patients. Pairwise meta-analysis and network meta-analysis (NMA) were carried out sequentially for determining the relative efficacy, safety and tolerability of prophylactic medications. Summary effect for migraine headache days, headache frequency, at least 50% reduction in headache attacks, all-adverse events, nausea, somnolence, dizziness, withdrawal and withdrawal due to adverse events were produced by synthesizing both direct and indirect evidence. Patients with three interventions exhibited significantly less average migraine headache days compared with those treated by placebo (topiramate, propranolol, divalproex). Moreover, topiramate and valproate exhibited a significantly increased likelihood of at least 50% reduction in migraine headache attacks compared to placebo. Patients with topiramate and propranolol also exhibited significantly reduced headache frequency compared to those with placebo. On the other hand, patients with divalproex exhibited significantly higher risk of nausea compared to those with placebo, topiramate, propranolol, gabapentin and amitriptyline. Finally, divalproex was associated with an increased risk of withdrawal compared to placebo and propranolol. Topiramate, propranolol and divalproex may be more efficacious than other prophylactic medications. Besides, the safety and tolerability of divalproex should be further verified by future studies.

  16. A study to assess the safety and tolerability of three toothbrushes.

    Science.gov (United States)

    Papas, Athena S; Martuscelli, Gianluca; Singh, Mabi L; Stone, Constance; Bartizek, Robert D; Topmiller, Krista J; Biesbrock, Aaron R; Walters, Patricia A

    2002-01-01

    This study evaluated the oral soft tissue safety and tolerability of an experimental powered toothbrush (Crest SpinBrush Pro) compared to two leading manual toothbrushes: an advanced-design manual toothbrush (Oral-B CrossAction) and a flat-trimmed toothbrush (Oral-B 40 Indicator). Manual brushes are generally viewed as safe for use, and as such are appropriate controls. A total of 140 subjects was enrolled in this single-center, randomized, examiner-blind parallel study over a four-week test period. Subjects were instructed to brush in their normal manner, twice per day for 60 seconds per use. An oral soft tissue interview and examination were conducted by a trained dentist examiner at baseline, as well as three days and four weeks after baseline to assess clinical signs and symptoms of oral irritation associated with use of the toothbrushes. Overall, there were 19 adverse events reported for 18 subjects (13% of the population). The adverse events were distributed across test groups with five subjects in the experimental powered brush group, eight in the advanced design manual toothbrush group and five in the flat-trimmed toothbrush group experiencing at least one adverse event. The most frequently reported adverse event was localized irritation/inflammation of the gingiva. All adverse events were mild in severity except for one report of severe hyperesthesia (tooth sensitivity) in the advanced-design manual toothbrush group. There were no statistically significant differences between the groups for the proportion of subjects reporting adverse events at either three days or four weeks of product use. The results of this study indicate that daily use with the Crest SpinBrush Pro powered toothbrush is at least as safe as two leading manual toothbrushes.

  17. Effectiveness, tolerability and safety of azithromycin 1% in DuraSite® for acute bacterial conjunctivitis

    Directory of Open Access Journals (Sweden)

    Susannah McLean

    2010-04-01

    Full Text Available Susannah McLean, Aziz SheikhCentre for Population Health Sciences: GP Section, Allergy and Respiratory Research Group, University of Edinburgh, Medical School, Edinburgh, United KingdomPurpose: Bacterial eye infections are commonly treated with topical antibiotics, despite limited evidence of effectiveness. Azithromycin 1% in DuraSite® is a new formulation of azithromycin in a gel polymer designed for use in acute bacterial conjunctivitis.Methods: We conducted systematic searches of the Cochrane Database of Clinical Trials, PubMed and Google Scholar to find randomized controlled trials of “­azithromycin DuraSite®”. These searches of published literature were supplemented with searches for unpublished trials and trials in progress.Results: We found six reports of randomized controlled trials investigating the role of azithromycin 1% in DuraSite® for the management of acute bacterial conjunctivitis. The quality of these trials was judged to be moderate to high. These trials assessed effectiveness, tolerability and safety outcomes, but we found no trials looking at cost-effectiveness. DuraSite® is a relatively stable formulation and so azithromycin 1% in DuraSite® has a simpler dosing schedule than other available topical antibiotics. It appears to be similar to other topical antibiotics in its effectiveness, but minor side effects are quite common.Conclusion: Acute bacterial conjunctivitis is a relatively mild, typically self-limiting, infection. Antibiotics should seldom be required. If, however, a decision to prescribe antibiotics is made, azithromycin 1% in DuraSite® is likely to be broadly comparable in its effectiveness to most other antibiotics used to treat acute bacterial conjunctivitis. Further research is needed to determine its cost-effectiveness.Keywords: conjunctivitis, bacterial eye infection, azithromycin 1% in DuraSite®

  18. How much Baltic salmon can be consumed without exceeding the tolerable safety limit ?

    Energy Technology Data Exchange (ETDEWEB)

    Kristiansen, H.R. [Mobile Nutrients Ltd. (Denmark)

    2004-09-15

    Because Baltic salmon is a top predator preying on sprat, herring and tobis, it is very vulnerable to contamination with dioxin and PCBs. The EU safety limit (SL) for fish is 4 picogram (pg) WHOTEQ g{sup -1} fresh fish. In April 2004, Danish commercial salmon fishing was banned to in the Baltic sea around Bornholm and Gotland (mainly ICES areas 25, 26), because the Food Administration reported dioxin levels exceeding the intervention level of 3 pg g{sup -1} fresh salmon. Their report was based on data from 10 individual salmon, and 3 pooled samples, each with 10 salmon. Since dioxins are widespread in the environment, the human population face a trade off to produce sufficient food that is safe to eat and avoid eating contaminated food. The world population is increasing, and the demand for healthy food is steadily increasing. Consequently, there is a need for risk assessments, where the consequences of eating foods with different grades of contamination is evaluated. The evaluation must be based on data of high quality, and because dioxin accumulation is a slow proces, the risk assessments should consider long time periods of months and years instead of days and weeks. The purpose of the present study is to evaluate the statistical variation of dioxin data from Baltic herring and salmon. The data are used to calculate the quantity of herring and salmon, that humans of different body weight can eat without exceeding the tolerable daily intake (TDI). (In dietary recommendations exposure from dairy products etc. must also be taken into account). A PCDD/F box model is proposed that subtract losses during cooking and postprandially.

  19. Evaluation of the safety, immunogenicity, and protective efficacy of whole inactivated simian immunodeficiency virus (SIV) vaccines with conformationally and functionally intact envelope glycoproteins.

    Science.gov (United States)

    Lifson, Jeffrey D; Rossio, Jeffrey L; Piatak, Michael; Bess, Julian; Chertova, Elena; Schneider, Douglas K; Coalter, Vicky J; Poore, Barbara; Kiser, Rebecca F; Imming, Robert J; Scarzello, Anthony J; Henderson, Louis E; Alvord, W Gregory; Hirsch, Vanessa M; Benveniste, Raoul E; Arthur, Larry O

    2004-07-01

    A novel, general approach to chemical inactivation of retroviruses was used to produce inactivated simian immunodeficiency virus (SIV) particles with functional envelope glycoproteins. Inactivated virions of three different virus isolates (SIVmne E11S, SIVmac239, and SIVmac239 g4,5), prepared by treatment with 2,2'-dithiodipyridine (aldrithol-2, AT-2), were not detectably infectious, in vitro or in vivo. Immunization of pigtailed macaques with inactivated SIVmne E11S particles, without adjuvant, induced both humoral and cellular immune responses. Four of six animals immunized with the inactivated particles did not show measurable SIV RNA in plasma (virus (SIVmne E11S), compared to peak values of > or =10(6) copy Eq/ml in challenged SIV-naive control animals (p = 0.0001). Despite the absence of measurable viral RNA in plasma in these animals, culturable virus and viral DNA were initially detectable in blood and lymph node specimens; in contrast to control animals, SIV DNA could no longer be detected in PBMC by 10 weeks postchallenge in five of six SIV-immunized animals (p = 0.0001). However, vaccines did not resist a sequential rechallenge with the heterologous pathogenic virus SIVsm E660. AT-2-inactivated virus with functional envelope glycoproteins is a novel class of vaccine immunogen and was noninfectious, under conditions of rigorous in vivo challenge, and induced both binding and neutralizing antibody responses, along with cellular immune responses. Results suggest that immunization facilitated effective containment of pathogenic homologous challenge virus. With further optimization, AT-2-inactivated viral particles may be a useful class of immunogen in the development of a vaccine to prevent AIDS.

  20. Safety and immunogenicity of a live oral recombinant cholera vaccine VA1.4: a randomized, placebo controlled trial in healthy adults in a cholera endemic area in Kolkata, India.

    Science.gov (United States)

    Kanungo, Suman; Sen, Bandana; Ramamurthy, Thandavarayan; Sur, Dipika; Manna, Byomkesh; Pazhani, Gururaja P; Chowdhury, Goutam; Jhunjhunwala, Puja; Nandy, Ranjan K; Koley, Hemanta; Bhattacharya, Mihir Kumar; Gupta, Sanjay; Goel, Gaurav; Dey, Bindu; M, Thungapathra; Nair, G Balakrish; Ghosh, Amit; Mahalanabis, Dilip

    2014-01-01

    A live oral cholera vaccine VA 1.4 developed from a non-toxigenic Vibrio cholerae O1 El Tor strain using ctxB gene insertion was further developed into a clinical product following cGMP and was evaluated in a double-blind randomized placebo controlled parallel group two arm trial with allocation ratio of 1∶1 for safety and immunogenicity in men and women aged 18-60 years from Kolkata, India. A lyophilized dose of 1.9×109 CFU (n = 44) or a placebo (n = 43) reconstituted with a diluent was administered within 5 minutes of drinking 100 ml of a buffer solution made of sodium bicarbonate and ascorbic acid and a second dose on day 14. The vaccine did not elicit any diarrhea related adverse events. Other adverse events were rare, mild and similar in two groups. One subject in the vaccine group excreted the vaccine strain on the second day after first dose. The proportion of participants who seroconverted (i.e. had 4-folds or higher rise in reciprocal titre) in the vaccine group were 65.9% (95% CI: 50.1%-79.5%) at both 7 days (i.e. after 1st dose) and 21 days (i.e. after 2nd dose). None of the placebo recipients seroconverted. Anti-cholera toxin antibody was detected in very few recipients of the vaccine. This study demonstrates that VA 1.4 at a single dose of 1.9×109 is safe and immunogenic in adults from a cholera endemic region. No additional benefit after two doses was seen. Clinical Trials Registry-India, National Institute of Medical Statistics (Indian Council of Medical Research) CTRI/2012/04/002582.

  1. Safety and immunogenicity of a live oral recombinant cholera vaccine VA1.4: a randomized, placebo controlled trial in healthy adults in a cholera endemic area in Kolkata, India.

    Directory of Open Access Journals (Sweden)

    Suman Kanungo

    Full Text Available BACKGROUND: A live oral cholera vaccine VA 1.4 developed from a non-toxigenic Vibrio cholerae O1 El Tor strain using ctxB gene insertion was further developed into a clinical product following cGMP and was evaluated in a double-blind randomized placebo controlled parallel group two arm trial with allocation ratio of 1∶1 for safety and immunogenicity in men and women aged 18-60 years from Kolkata, India. METHOD: A lyophilized dose of 1.9×109 CFU (n = 44 or a placebo (n = 43 reconstituted with a diluent was administered within 5 minutes of drinking 100 ml of a buffer solution made of sodium bicarbonate and ascorbic acid and a second dose on day 14. RESULT: The vaccine did not elicit any diarrhea related adverse events. Other adverse events were rare, mild and similar in two groups. One subject in the vaccine group excreted the vaccine strain on the second day after first dose. The proportion of participants who seroconverted (i.e. had 4-folds or higher rise in reciprocal titre in the vaccine group were 65.9% (95% CI: 50.1%-79.5% at both 7 days (i.e. after 1st dose and 21 days (i.e. after 2nd dose. None of the placebo recipients seroconverted. Anti-cholera toxin antibody was detected in very few recipients of the vaccine. CONCLUSION: This study demonstrates that VA 1.4 at a single dose of 1.9×109 is safe and immunogenic in adults from a cholera endemic region. No additional benefit after two doses was seen. TRIAL REGISTRATION: Clinical Trials Registry-India, National Institute of Medical Statistics (Indian Council of Medical Research CTRI/2012/04/002582.

  2. Evaluation of immunogenicity and safety of the new tetanus-reduced diphtheria (Td) vaccines (GC1107) in healthy Korean adolescents: a phase II, double-blind, randomized, multicenter clinical trial.

    Science.gov (United States)

    Rhim, Jung-Woo; Lee, Kyung-Yil; Kim, Sang-Yong; Kim, Jong-Hyun; Kim, Hyun-Hee; Kim, Hwang Min; Choi, Young-Youn; Ma, Sang-Hyuk; Kim, Dong-Ho; Ahn, Dong Ho; Kang, Jin-Han

    2013-04-01

    This phase II clinical trial was conducted to compare the immunogenicity and safety of a newly developed tetanus-reduced diphtheria (Td) vaccine (GC1107-T5.0 and GC1107-T7.5) and control vaccine. This study was also performed to select the proper dose of tetanus toxoid in the new Td vaccines. Healthy adolescents aged between 11 and 12 yr participated in this study. A total of 130 subjects (44 GC1107-T5.0, 42 GC1107-T7.5 and 44 control vaccine) completed a single dose of vaccination. Blood samples were collected from the subjects before and 4 weeks after the vaccination. In this study, all subjects (100%) in both GC1107-T5.0 and GC1107-T7.5 groups showed seroprotective antibody levels (≥ 0.1 U/mL) against diphtheria or tetanus toxoids. After the vaccination, the geometric mean titer (GMT) against diphtheria was significantly higher in Group GC1107-T5.0 (6.53) and GC1107-T7.5 (6.11) than in the control group (3.96). The GMT against tetanus was 18.6 in Group GC1107-T5.0, 19.94 in GC1107-T7.5 and 19.01 in the control group after the vaccination. In this study, the rates of local adverse reactions were 67.3% and 59.1% in GC1107-T5.0 and GC1107-7.5, respectively. No significant differences in the number of adverse reactions, prevalence and degree of severity of the solicited and unsolicited adverse reactions were observed among the three groups. Thus, both newly developed Td vaccines appear to be safe and show good immunogenicity. GC1107-T5.0, which contains relatively small amounts of tetanus toxoid, has been selected for a phase III clinical trial.

  3. Safety, immunogenicity and duration of protection of the RTS,S/AS02(D malaria vaccine: one year follow-up of a randomized controlled phase I/IIb trial.

    Directory of Open Access Journals (Sweden)

    Pedro Aide

    2010-11-01

    Full Text Available The RTS,S/AS02(D vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001. We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D, remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076 over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003.The RTS,S/AS02(D malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028.

  4. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

    Science.gov (United States)

    Solmi, Marco; Murru, Andrea; Pacchiarotti, Isabella; Undurraga, Juan; Veronese, Nicola; Fornaro, Michele; Stubbs, Brendon; Monaco, Francesco; Vieta, Eduard; Seeman, Mary V; Correll, Christoph U; Carvalho, André F

    2017-01-01

    Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed

  5. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.

    Science.gov (United States)

    Vesikari, Timo; Esposito, Susanna; Prymula, Roman; Ypma, Ellen; Kohl, Igor; Toneatto, Daniela; Dull, Peter; Kimura, Alan

    2013-03-09

    Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population. We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants

  6. Immunogenicity and Safety of a Booster Injection of DTap-IPV//Hib (Pentaxim) Administered Concomitantly With Tetravalent Dengue Vaccine in Healthy Toddlers 15-18 Months of Age in Mexico: A Randomized Trial.

    Science.gov (United States)

    Melo, Flor Irene Rodriguez; Morales, José Juan Renteria; De Los Santos, Abiel Homero Mascareñas; Rivas, Enrique; Vigne, Claire; Noriega, Fernando

    2017-06-01

    The live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in a number of dengue endemic countries for individuals ≥9 years of age. Before the integration of any vaccine into childhood vaccination schedules, a lack of immune interference and acceptable safety when coadministered with other recommended vaccines should be demonstrated. This randomized, multi-center phase III trial was conducted in Mexico. Healthy toddlers (n = 732) received a booster dose of a licensed pentavalent combination vaccine [diphtheria, tetanus, acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b (DTaP-IPV//Hib)] either concomitantly or sequentially, with the second dose of CYD-TDV administered as a 3-dose schedule. Antibody titers against diphtheria toxoid, tetanus toxoid and pertussis antigens were measured by enzyme-linked immunosorbent assay. Antibodies against poliovirus and dengue serotypes were measured using a plaque reduction neutralization test. Noninferiority was demonstrated for each of the DTaP-IPV//Hib antigens if the lower limit of the 2-sided 95% confidence interval of the difference in seroconversion rates between the 2 groups (CYD-TDV and placebo) was ≥10%. Safety of both vaccines was assessed. Noninferiority in immune response was demonstrated for all DTaP-IPV//Hib antigens. After 3 doses of CYD-TDV, no difference was observed in the immune response for CYD-TDV between groups. There were no safety concerns during the study. Coadministration of the DTaP-IPV//Hib booster vaccine with CYD-TDV has no observed impact on the immunogenicity or safety profile of the DTaP-IPV//Hib booster vaccine. No difference was observed on the CYD-TDV profile when administered concomitantly or sequentially with the DTaP-IPV//Hib booster vaccine.

  7. Immunogenicity and safety of a high-dose hepatitis B vaccine among patients receiving methadone maintenance treatment: A randomized, double-blinded, parallel-controlled trial.

    Science.gov (United States)

    Shi, Jing; Feng, Yongliang; Gao, Linying; Feng, Dan; Yao, Tian; Shi, Shan; Zhang, Yawei; Liang, Xiaofeng; Wang, Suping

    2017-04-25

    To explore whether the immunization with high-dose (60μg) hepatitis B vaccines in patients receiving methadone maintenance treatment (MMT) could yield a superior protection against hepatitis B infection than did the standard dose (20μg). We conducted a randomized, double-blinded, parallel-controlled trial in MMT patients. Patients with serologically negative hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were randomized in a ratio of 1:1 to receive three intramuscular injections of 20μg or 60μg recombinant hepatitis B vaccine at months 0, 1, and 6. Serum HBsAg and anti-HBs were measured at months 7 and 12 post-vaccination to assess the immunogenicity. A total of 196 MMT patients were randomized and 195 received at least one injection (98 and 97 in 20 and 60μg vaccine groups, respectively). The 60μg vaccine group showed a seroconversion of anti-HBs of 87.3%, high-level response rate of 56.3%, and GMC of 742.9mIU/mL at month 7. While these results were numerically higher than the 20μg group, a statistical difference was not found. HIV infection and concomitant drug abuse were negatively associated with the robust immune responses. 7.7% of MMT patients receiving at least one dose of vaccine reported solicited adverse reactions within 7days after vaccination, 2.6% reported unsolicited adverse reactions within 28days after vaccination. None of the MMT patients reported serious adverse events or became HBsAg positive during the follow-up. The three-dose regimen of 60μg recombinant hepatitis B vaccine at months 0, 1, and 6 can yield a similar immunogenicity among MMT patients as compared to the 20μg vaccine. ClinicalTrials.gov identifier: NCT02991599. Copyright © 2017. Published by Elsevier Ltd.

  8. Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors.

    Directory of Open Access Journals (Sweden)

    Susanne H Sheehy

    Full Text Available Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63 and modified vaccinia virus Ankara (MVA replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1. ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC and FVO (median 1539 SFU/million PBMC, with a mixed CD4(+/CD8(+ phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively that demonstrated growth inhibitory activity in vitro.ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection.ClinicalTrials.gov NCT01095055.

  9. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder.

    Science.gov (United States)

    Moreno, Francisco A; Wiegand, Christopher B; Taitano, E Keolani; Delgado, Pedro L

    2006-11-01

    Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p

  10. Safety, tolerability and clinical efficacy of ultra-rush sublingual immunotherapy among patients suffering from allergic rhinitis.

    Science.gov (United States)

    Balaji, R; Parasuramalu, B G; Chandregowda, B V; Gangaboraiah

    2014-01-01

    Conventional immunotherapy for allergy with 3-5 years of treatment period has poor compliance. Ultra-rush sublingual immunotherapy with a shorter period of treatment can have better compliance. There are very few studies on ultra-rush sublingual immunotherapy all over the world. (1) To determine allergen sensitivity among allergic rhinitis patients. (2) To assess safety, tolerability and clinical efficacy of ultra-rush sublingual immunotherapy. The present study was conducted in Allergy clinic, KIMS Hospital & Research Centre, Bangalore, India from January 2010 to June 2011. After obtaining Institutional Ethics Committee approval, 40 allergic rhinitis patients (according to ARIA guidelines) in the 18-60 years age group who were positive for aeroallergens in skin prick test were recruited for ultra-rush sublingual immunotherapy (20min initial phase and 4-month maintenance phase) and followed for 8 months with symptom and treatment diary. Out of 40 patients, the majority, 36 (90.00%) patients were sensitive to house dust mites. Six patients had seven immediate adverse reactions and seven patients had eight delayed adverse reactions. All subsided without medication or with symptomatic oral medications. All patients tolerated ultra-rush SLIT and there was significant decrease in both symptom-score and treatment received in these patients. Ultra-rush SLIT regimen has excellent safety, tolerability and clinical efficacy among allergic rhinitis patients. Copyright © 2012 SEICAP. Published by Elsevier Espana. All rights reserved.

  11. Pharmacokinetics, Safety, and Tolerability of Vortioxetine Following Single- and Multiple-Dose Administration in Healthy Japanese Adults.

    Science.gov (United States)

    Matsuno, Kumi; Nakamura, Koki; Aritomi, Yutaka; Nishimura, Akira

    2017-09-21

    Three phase 1 randomized single-center studies assessed the pharmacokinetics, safety, and tolerability of vortioxetine after single- and multiple-dose administration in healthy Japanese adults. Study 1 assessed the pharmacokinetics of vortioxetine after administration of single rising doses to men and multiple doses to men and women; study 2 evaluated vortioxetine pharmacokinetics in elderly adults; and study 3 assessed food effects on vortioxetine pharmacokinetics in healthy men. The primary end points included pharmacokinetic parameters of vortioxetine and incidence of adverse events (AEs). Across all studies, 130 participants were randomized and 128 participants completed the studies. Vortioxetine was absorbed and eliminated from plasma slowly, and exposure to vortioxetine increased in an almost dose-proportional manner. No clinically significant differences in the pharmacokinetics of vortioxetine or its metabolites were observed between the sexes in young and elderly adults. Study 3 demonstrated that vortioxetine and its metabolites had similar pharmacokinetics when administered in the fasted and fed states. Importantly, vortioxetine was safe and tolerated, with incidence of AEs comparable to that of placebo. No deaths or serious AEs leading to trial discontinuation were observed. Overall, vortioxetine pharmacokinetics, safety, and tolerability in Japanese adults were comparable to reports in non-Japanese populations. © 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

  12. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial.

    Science.gov (United States)

    Davtyan, Hayk; Ghochikyan, Anahit; Petrushina, Irina; Hovakimyan, Armine; Davtyan, Arpine; Poghosyan, Anna; Marleau, Annette M; Movsesyan, Nina; Kiyatkin, Anatoly; Rasool, Suhail; Larsen, Anna Kirstine; Madsen, Peter Juul; Wegener, Karen Malene; Ditlevsen, Dorte Kornerup; Cribbs, David H; Pedersen, Lars Ostergaard; Agadjanyan, Michael G

    2013-03-13

    The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust "non-self" T-cell responses and the production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.

  13. 17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study.

    Science.gov (United States)

    Martins, Reinaldo M; Maia, Maria de Lourdes S; Farias, Roberto Henrique G; Camacho, Luiz Antonio B; Freire, Marcos S; Galler, Ricardo; Yamamura, Anna Maya Yoshida; Almeida, Luiz Fernando C; Lima, Sheila Maria B; Nogueira, Rita Maria R; Sá, Gloria Regina S; Hokama, Darcy A; de Carvalho, Ricardo; Freire, Ricardo Aguiar V; Pereira Filho, Edson; Leal, Maria da Luz Fernandes; Homma, Akira

    2013-04-01

    To verify if the Bio-Manguinhos 17DD yellow fever vaccine (17DD-YFV) used in lower doses is as immunogenic and safe as the current formulation. Doses from 27,476 IU to 587 IU induced similar seroconversion rates and neutralizing antibodies geometric mean titers (GMTs). Immunity of those who seroconverted to YF was maintained for 10 mo. Reactogenicity was low for all groups. Young and healthy adult males (n = 900) were recruited and randomized into 6 groups, to receive de-escalating doses of 17DD-YFV, from 27,476 IU to 31 IU. Blood samples were collected before vaccination (for neutralization tests to yellow fever, serology for dengue and clinical chemistry), 3 to 7 d after vaccination (for viremia and clinical chemistry) and 30 d after vaccination (for new yellow fever serology and clinical chemistry). Adverse events diaries were filled out by volunteers during 10 d after vaccination. Volunteers were retested for yellow fever and dengue antibodies 10 mo later. Seropositivity for dengue was found in 87.6% of volunteers before vaccination, but this had no significant influence on conclusions. In young healthy adults Bio-Manguinhos/Fiocruz yellow fever vaccine can be used in much lower doses than usual. INTERNATIONAL REGISTER: ISRCTN 38082350.

  14. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial.

    Science.gov (United States)

    Reisinger, Keith S; Block, Stan L; Lazcano-Ponce, Eduardo; Samakoses, Rudiwilai; Esser, Mark T; Erick, Joanne; Puchalski, Derek; Giacoletti, Katherine E D; Sings, Heather L; Lukac, Suzanne; Alvarez, Frances B; Barr, Eliav

    2007-03-01

    Administration of a quadrivalent HPV-6/ 1/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/ 1/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts. As the risk of acquiring HPV significantly rises after sexual debut, HPV vaccines should have the greatest benefit in sexually naive adolescents. We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment. In this randomized, double-blind trial, 1781 sexually naive children were assigned (2:1) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6. Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers (GMTs) and seroconversion rates. Primary analyses were done per-protocol (subjects received 3 doses, had no major protocol violations and were HPV type-specific seronegative at day 1). Adverse experiences were collected by diary card. At month 7, seroconversion rates were > or =99.5% for the 4 vaccine-HPV-types. GMTs and seroconversion rates in boys were noninferior to those in girls (P or =91.5% of vaccine recipients were seropositive, regardless of gender. A higher proportion of vaccine recipients (75.3%) than placebo recipients (50.0%) reported one or more injection-site adverse experiences following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported. In 9- to 15-year-old adolescents, the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen. The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease, particularly cervical cancer and precancers.

  15. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins

    DEFF Research Database (Denmark)

    Cannon, Christopher P; Cariou, Bertrand; Blom, Dirk

    2015-01-01

    AIMS: To compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk...... patients with inadequately controlled hypercholesterolaemia. METHODS AND RESULTS: COMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104-week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins.......04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events. CONCLUSION: In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab...

  16. Study of the efficacy, tolerability, and safety of 2 fixed-dose combination gels in the management of acne vulgaris.

    Science.gov (United States)

    Zouboulis, Christos C; Fischer, Tanja C; Wohlrab, Johannes; Barnard, Jo; Alió, Alessandra B

    2009-10-01

    This study investigated the efficacy, tolerability, and safety of 2 fixed-dose combination gels for the treatment of facial acne: clindamycin 1%-benzoyl peroxide 5% gel with hydrating excipients (C/BPO HE) and adapalene 0.1%-benzoyl peroxide 25% gel (A/BPO). After 12 weeks of once daily treatment, the mean reduction in inflammatory lesion count was 76.8% and 72.2% in the C/BPO HE group and A/BPO group, respectively (P = .076). Significantly more participants achieved treatment success, which was defined as an improvement of 2 grades or more from baseline to week 12 on the investigator's static global assessment (ISGA) scale, with C/BPO HE (30.5% [58/190]) compared with A/BPO (21.8% [42/192]) (P = .046), and treatment success was achieved more quickly with C/BPO HE (P = .035). Both products also reduced noninflammatory (62.2% C/BPO HE vs 6 1.5% A/BPO) and total lesion counts (69.1% C/BPO HE vs 67.1% A/BPO). Despite the overall similar efficacy profile, C/BPO HE was better tolerated and safer than A/BPO. In the tolerability assessments, erythema, dryness, peeling, pruritus, and burning/ stinging were more frequent in the A/BPO group at all time points from week 1 onward (P < .05). Treatment-related adverse events (AEs) occurred in 48.4% (92/190) of participants in the C/BPO HE group compared with 78.6% (151/192) of the A/BPO group. We conclude that C/BPO HE and A/BPO have similar efficacy in treating inflammatory and noninflammatory acne lesions, but C/BPO HE achieves better overall treatment success in less time coupled with a significantly better tolerability profile and notably better safety profile.

  17. Immunogenicity and safety of concomitant administration of meningococcal serogroup B (4CMenB) and serogroup C (MenC-CRM) vaccines in infants: A phase 3b, randomized controlled trial.

    Science.gov (United States)

    P Safadi, Marco Aurelio; Martinon-Torres, Federico; Weckx, Lily Yin; Moreira, Edson Duarte; da Fonseca Lima, Eduardo Jorge; Mensi, Ilhem; Calabresi, Marco; Toneatto, Daniela

    2017-04-11

    After implementation of routine infant MenC vaccination, MenB remains a serious cause of meningococcal disease, yet to be targeted by vaccination programs in several countries. This study (NCT01339923) investigated the immunogenicity and safety of MenC CRM-conjugated vaccine (MenC-CRM) concomitantly administered with MenB vaccine (4CMenB). Infants (N=251) were randomised 1:1 to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM alone (Group 2) at 3 and 5months (M3, M5) and a booster at 12months of age (M12), and pneumococcal vaccine at M3, M5, M7, M12. Antibody responses to meningococcal vaccines were measured at M3, M6, M12, and M13. Non-inferiority of MenC-CRM response in Group 1 vs Group 2 was demonstrated at M6 and M13, if the lower limit of the 95% confidence interval (LL95%CI) of the difference in percentage of infants with hSBA titres ≥1:8 was >-10%. Sufficiency of MenB response was achieved if LL95%CI of the percentage of infants with hSBA titres ≥1:4 against fHbp, NadA and PorA strains was ≥70% at M6 or ≥75% at M13. Adverse events (AEs) were collected for 7days post-vaccination, and serious AEs (SAEs) and medically attended AEs throughout the study. Non-inferiority of MenC response in Group 1 vs Group 2 (LL95%CI -6.4% [M6]; -5.2% [M13]) and sufficiency of MenB response in Group 1 (LL95%CI 92%, 90%, 89% [M6]; 97%, 92%, 93% [M13] against fHbp, NadA, PorA, respectively) were demonstrated. Higher rates of mild to moderate solicited AEs were reported in Group 1. Unsolicited AEs and SAEs incidences were similar across groups. Concomitant administration of MenC-CRM and 4CMenB in infants was immunogenic, resulting in non-inferior responses against MenC compared to MenC-CRM alone and demonstration of sufficient immune response to MenB, after primary and booster vaccination. Reactogenicity was higher for concomitant vaccines administration, but no safety concerns were identified. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial.

    Science.gov (United States)

    Zhu, Feng-Cai; Hu, Shang-Ying; Hong, Ying; Hu, Yue-Mei; Zhang, Xun; Zhang, Yi-Ju; Pan, Qin-Jing; Zhang, Wen-Hua; Zhao, Fang-Hui; Zhang, Cheng-Fu; Yang, Xiaoping; Yu, Jia-Xi; Zhu, Jiahong; Zhu, Yejiang; Chen, Feng; Zhang, Qian; Wang, Hong; Wang, Changrong; Bi, Jun; Xue, Shiyin; Shen, Lingling; Zhang, Yan-Shu; He, Yunkun; Tang, Haiwen; Karkada, Naveen; Suryakiran, Pemmaraju; Bi, Dan; Struyf, Frank

    2017-01-01

    We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV-16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18-associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6-month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV-16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  19. Reduced schedules of 4CMenB vaccine in infants and catch-up series in children: Immunogenicity and safety results from a randomised open-label phase 3b trial.

    Science.gov (United States)

    Martinón-Torres, Federico; Safadi, Marco Aurelio P; Martinez, Alfonso Carmona; Marquez, Pilar Infante; Torres, Juan Carlos Tejedor; Weckx, Lily Yin; Moreira, Edson Duarte; Mensi, Ilhem; Calabresi, Marco; Toneatto, Daniela

    2017-06-16

    This study evaluated the immunogenicity and safety of a licensed meningococcal serogroup B vaccine (4CMenB) administered alone according to reduced schedules in infants or catch-up series in children. In this open-label, multicentre, phase 3b study (NCT01339923), infants randomised 1:1:1 received 4CMenB: 2+1 doses at 3½-5-11months or 6-8-11months of age, 3+1 doses at ages 2½-3½-5-11months. Children aged 2-10years received 2 catch-up doses administered 2months apart. Immune responses were measured by hSBA assays against 4 strains specific for vaccine components fHbp, NadA, PorA and NHBA. Sufficiency of immune responses was defined in groups with 2+1 doses schedules as a lower limit ≥70% for the 97.5% confidence interval of the percentage of infants with hSBA titres ≥4, 1month post-dose 2 for fHbp, NadA, PorA. Adverse events were collected for 7days post-vaccination; serious adverse events (SAEs) throughout the study. 754 infants and 404 children were enrolled. Post-primary vaccination, 98-100% of infants across all groups developed hSBA titres ≥4 for fHbp, NadA, PorA, and 48-77% for NHBA. Sufficiency of immune responses in infants receiving 2+1 schedules was demonstrated for fHbp, NadA, PorA after 2 doses of 4CMenB, as pre-specified criteria were met. Following receipt of 2 catch-up doses, 95-99% of children developed hSBA titres ≥4 for 4CMenB components. Similar safety profiles were observed across groups. A total of 45 SAEs were reported, 3 of which were related to vaccination. Reduced infant schedules and catch-up series in children were immunogenic and safe, having the potential to widen 4CMenB vaccine coverage. GlaxoSmithKline Biologicals SA. Copyright © 2017. Published by Elsevier Ltd.

  20. Safety and tolerability of BAN2401 - a clinical study in Alzheimer's disease with a protofibril selective A beta antibody

    OpenAIRE

    Logovinsky, Veronika; Satlin, Andrew; Lai, Robert; Swanson, Chad; Kaplow, June; Osswald, Gunilla; Basun, Hans; Lannfelt, Lars

    2016-01-01

    Background Several monoclonal antibodies for the treatment of Alzheimer?s disease (AD) have been in development over the last decade. BAN2401 is a monoclonal antibody that selectively binds soluble amyloid ? (A?) protofibrils. Methods Here we describe the first clinical study with BAN2401. Safety and tolerability were investigated in mild to moderate AD. A study design was used with staggered parallel single and multiple ascending doses, from 0.1?mg/kg as a single dose to 10?mg/kg biweekly fo...

  1. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

    OpenAIRE

    Astrup, A; Carraro, R; Finer, N; Harper, A; Kunesova, M; Lean, M E J; Niskanen, L; Rasmussen, M F; Rissanen, A; Rössner, S; Savolainen, M J; Van Gaal, L

    2011-01-01

    Objective: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. Design: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. Subjects: A total of 564 adults (n=90–98 per group; bo...

  2. Safety and Immunogenicity of Cell Culture-Derived A/H3N2 Variant Influenza Vaccines: A Phase I Randomized, Observer-Blind, Dose-Ranging Study.

    Science.gov (United States)

    Johnson, Casey; Hohenboken, Matthew; Poling, Terry; Jaehnig, Peter; Kanesa-Thasan, Niranjan

    2015-07-01

    A/H3N2 variant (H3N2v) influenza may sustain human-to-human transmission, and an available candidate vaccine would be important. In this phase I, randomized, observer-blind, dose-ranging study, 627 healthy subjects ≥ 3 years of age were randomized to receive 2 vaccinations with H3N2c cell-culture-derived vaccine doses containing 3.75 µg, 7.5 µg, or 15 µg hemagglutinin antigen of H3N2v with or without MF59 (registered trademark of Novartis AG) adjuvant (an oil-in-water emulsion). This paper reports Day 43 planned interim data. Single MF59-adjuvanted H3N2c doses elicited immune responses in almost all subjects regardless of antigen and adjuvant dose; the Center for Biologics Evaluation Research and Review (CBER) licensure criteria were met for all groups. Subjects with prevaccination hemagglutination inhibition titers vaccine. Highest antibody titers were observed in the 7.5 µg + 0.25 mL MF59 groups in all age cohorts. MF59-adjuvanted H3N2c vaccines showed the highest rates of solicited local and systemic events, predominately mild or moderate. A single dose of H3N2c vaccine may be immunogenic and supports further development of MF59-adjuvanted H3N2c vaccines, especially for pediatric populations. ClinicalTrials.gov identifier NCT01855945 (http://clinicaltrials.gov/ct2/show/NCT01855945). © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Safety and immunogenicity of fully liquid DTaP₅-IPV-Hib pediatric combination vaccine (Pediacel®) compared to DTaP₃-HBV-IPV/Hib (Infanrix® Hexa) when coadministered with heptavalent pneumococcal conjugate vaccine (PCV7) as a booster at 11-18 months of age: a phase III, modified double-blind, randomized, controlled, multicenter study.

    Science.gov (United States)

    Berner, Reinhard; Boisnard, Florence; Thomas, Stéphane; Mwawasi, Grace; Reynolds, Donna

    2012-07-27

    This study compared the safety and immunogenicity of DTaP₅-IPV-Hib vaccine (followed by monovalent hepatitis B vaccine [HBV]) and DTaP₃-HBV-IPV/Hib vaccines, both coadministered with PCV7, as a fourth-dose booster in toddlers 11-18 months who had a hexavalent vaccine primary series. The fever rate within 4 days of DTaP₅-IPV-Hib was noninferior to DTaP₃-HBV-IPV/Hib. DTaP₅-IPV-Hib induced a marked immune response and had a similar safety and immunogenicity profile compared with DTaP₃-HBV-IPV/Hib. Fully liquid DTaP₅-IPV-Hib can be used as a booster after a hexavalent vaccine primary series; where required, a fourth dose of monovalent HBV can be administered after DTaP₅-IPV-Hib (NCT ID: NCT00355654). Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Immunogenicity and safety of concomitant administration of a measles, mumps and rubella vaccine (M-M-RvaxPro® and a varicella vaccine (VARIVAX® by intramuscular or subcutaneous routes at separate injection sites: a randomised clinical trial

    Directory of Open Access Journals (Sweden)

    Thomas Stéphane

    2009-04-01

    of administration, except varicella-like rashes, which were less frequent in the IM group. Conclusion The immunogenicities of M-M-RvaxPro and VARIVAX administered by the intramuscular route were comparable with those following subcutaneous administration, and the tolerability of the two vaccines was comparable regardless of administration route. Integration of both administration routes in the current European indications for the two vaccines will now allow physicians in Europe to choose their preferred administration route in routine clinical practice. Trial registration ClinicalTrials.gov NCT00432523

  5. Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder

    Directory of Open Access Journals (Sweden)

    James M Martinez

    2015-05-01

    Full Text Available Objective: The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI antidepressants. Methods: A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs, clinical laboratory tests, blood pressure (BP and pulse, and electrocardiograms (ECGs. Results: The analysis included 1260 patients treated with adjunctive edivoxetine and 806 treated with adjunctive placebo. Study completion rates were 85.2% and 84.5% (p=0.994, respectively. Discontinuations due to adverse events were 4.9% and 3.5% (p=0.07, respectively. Significantly more patients in the adjunctive edivoxetine group compared with adjunctive placebo group reported at least one TEAE (56.8 vs 43.7%, p<0.001. The most common TEAEs (occurred ≥5% frequency were hyperhidrosis, nausea, and tachycardia. Mean changes in sitting BP and pulse at the last visit were increased significantly in patients treated with adjunctive edivoxetine compared with adjunctive placebo (SBP: 2.7 vs 0.5 mm Hg, p<0.001; DBP: 4.1 vs 0.8 mm Hg, p<0.001; pulse: 8.8 vs –1.3 bpm, p<0.001. There were no clinically significant changes in laboratory measures. Conclusions: The tolerability and safety profile of edivoxetine as adjunctive treatment to SSRI antidepressants was consistent with its norepinephrine reuptake inhibitor mechanism of action, and was comparable with edivoxetine monotherapy treatment in patients with major depressive disorder.

  6. Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke.

    Science.gov (United States)

    Mori, Etsuro; Minematsu, Kazuo; Nakagawara, Jyoji; Hasegawa, Yasuhiro; Nagahiro, Shinji; Okada, Yasushi; Truelsen, Thomas; Lindsten, Annika; Ogawa, Akira; Yamaguchi, Takenori

    2015-09-01

    This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke. Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 ratio in 2 consecutive cohorts (70 μg/kg and then 90 μg/kg). Included patients had a baseline National Institutes of Health Stroke Scale score of 4 to 24 and occlusion or high-grade stenosis in the middle cerebral artery segment M1 or M2 on magnetic resonance angiography. The incidence of symptomatic intracranial hemorrhage (≤72 hours) was defined as the primary end point. The occurrence of asymptomatic ICH, symptomatic cerebral edemas, and adverse events were other safety outcomes of special interest. Symptomatic intracranial hemorrhage was observed within 72 hours in 2 patients treated with placebo and in 1 patient treated with 70 μg/kg desmoteplase. Any ICH (symptomatic or asymptomatic ICH) within 72 hours were observed in 7 (43.8%) patients treated with placebo, in 8 (50%) patients treated with 70 μg/kg desmoteplase, and in 9 (56.3%) patients treated with 90 μg/kg desmoteplase. Desmoteplase treatment with 70 or 90 μg/kg was not associated with an increased risk of symptomatic cerebral edema compared with placebo. There were no other serious safety concerns associated with desmoteplase. Desmoteplase in both 70 and 90 μg/kg doses had a favorable safety profile and was well tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467. © 2015 American Heart Association, Inc.

  7. Safety and immunogenicity of SC599, an oral live attenuated Shigella dysenteriae type-1 vaccine in healthy volunteers: results of a Phase 2, randomized, double-blind placebo-controlled trial.

    Science.gov (United States)

    Launay, Odile; Sadorge, Christine; Jolly, Nathalie; Poirier, Béatrice; Béchet, Stéphane; van der Vliet, Diane; Seffer, Valérie; Fenner, Nicola; Dowling, Kelly; Giemza, Raphaela; Johnson, Julie; Ndiaye, Anna; Vray, Muriel; Sansonetti, Philippe; Morand, Philippe; Poyart, Claire; Lewis, David; Gougeon, Marie-Lise

    2009-02-18

    SC599 vaccine is a live Shigella dysenteriae 1 strain attenuated by deletion of invasion [icsA], iron chelation [ent, fep] and shiga toxin A subunit [stxA] genes. In a preliminary Phase 1 single dose prospective study, we showed that SC599 vaccine was well tolerated, and the maximum tolerable dose was greater than 10(8) CFU [Sadorge C, Ndiaye A, Beveridge N, Frazer S, Giemza R, Jolly N, et al. Phase 1 clinical trial of live attenuated Shigella dysenteriae type-1 DeltaicsA Deltaent Deltafep DeltastxA:HgR oral vaccine SC599 in healthy human adult volunteers. Vaccine 2008; 26(7):978-8]. In this Phase 2 trial, three groups of volunteers ingested a single dose of SC599 [10(5) CFU, n=38; 10(7) CFU, n=36] or placebo [n=37]. Both 10(5) and 10(7) CFU doses were immunogenic, inducing significant IgA and IgG LPS-specific ASCs and antibody responses, comparable in magnitude to those of other strains that prevented illness following experimental challenge. In the intention to treat analysis, 34.2% and 44.4% IgA ASC responders were detected in the 10(5) and 10(7) CFU groups respectively (p<0001 vs placebo for both groups), as well as 31.6% and 33.3% serum IgA responders (p<001 and p<0.001 vs placebo for 10(5) and 10(7) CFU groups, respectively). No difference between the two vaccine groups was observed. No stxB-specific antibody response was detected in the vaccines. SC599 excretion occurred in 23.7 and 30.6% of subjects in the 10(5) and 10(7) CFU groups, respectively. SC599 vaccine was well tolerated, and the reported adverse events were mainly digestive. These results indicate that a single oral immunization of SC599 vaccine elicits a significant circulating IgA ASC and serum antibody response that may confer protection against the most severe symptoms of Shigellosis in responders to the vaccine.

  8. Immunogenicity, safety and protective efficacy of one dose of the rhesus rotavirus vaccine and serotype 1 and 2 human-rhesus rotavirus reassortants in children from Lima, Peru.

    Science.gov (United States)

    Lanata, C F; Black, R E; Flores, J; Lazo, F; Butron, B; Linares, A; Huapaya, A; Ventura, G; Gil, A; Kapikian, A Z

    1996-02-01

    rotavirus vaccine failed to induce either an adequate serotype-specific seroresponse or serotype-specific protection in children immunized at 2 months of age. Only the RRV vaccine induced a low level of protection against rotavirus diarrhea mainly of serotype G1 specificity. Future studies need to explore whether higher vaccine dose and/or more than one dose would increase the immunogenicity and efficacy of the rotavirus vaccine, especially in developing countries with a high level of baseline rotavirus antibodies.

  9. Safety and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in renal pre-dialysis and dialysis patients.

    Science.gov (United States)

    Gilbert, Christopher L; Stek, Jon E; Villa, Giuseppe; Klopfer, Stephanie O; Martin, Jason C; Schödel, Florian P; Bhuyan, Prakash K

    2014-11-12

    Patients with renal insufficiency are hyporesponsive to vaccination, including to hepatitis B vaccines. A manufacturing process modification for a hepatitis B vaccine (mpHBV) was studied in renal pre-dialysis and dialysis patients. This randomized, open-label, multicenter, estimation study enrolled previously unvaccinated, HBV-seronegative adult dialysis and pre-dialysis patients (N=276, median age 72.0 years). At 0, 1, 6, and 8 months, group 1 received a 1 mL intramuscular dose of mpHBV (containing 40 μg HBsAg) as a single injection, while group 2 received a 1 mL intramuscular dose of a licensed hepatitis B vaccine as two injections (each containing 20 μg HBsAg; 40 μg HBsAg total). Serum antibody to HBsAg (anti-HBs) was measured predose 1, and 1 month postdose 3 and 4. Anti-HBs geometric mean concentration (GMC) and seroprotection rate (SPR, % of subjects with anti-HBs titer ≥10 mIU/mL) were estimated at months 7 and 9. For group 1, month 7 SPR was 48.5% (49/101, 95% CI: 38.4%, 58.7%); with an additional dose, month 9 SPR increased to 66.7% (66/99, 95% CI: 56.5%, 75.8%). For group 2, month 7 SPR was 57.7% (64/111, 95% CI: 47.9%, 67.0%); with an additional dose, month 9 SPR increased to 69.2% (72/104, 95% CI: 59.4%, 77.9%). group 1 GMCs at months 7 and 9 were 27.5 mIU/mL (95% CI: 15.7, 48.0) and 61.7 mIU/mL (95% CI: 34.2, 111.5), respectively. group 2 GMCs at months 7 and 9 were 48.7 mIU/mL (95% CI: 28.7, 82.7) and 115.8 mIU/mL (95% CI: 65.2, 205.5), respectively. There were 22 serious adverse events; none were considered related to study vaccine. Both formulations were immunogenic in this population but required more vaccinations to reach seroprotective levels than comparable regimens in healthy individuals, as expected. The relatively reduced SPRs seen in this population support the need for routine screening and re-dosing in this population. Copyright © 2014. Published by Elsevier Ltd.

  10. Treatment of patients with early and advanced Parkinson's disease with rotigotine transdermal system: age-relationship to safety and tolerability.

    Science.gov (United States)

    Oertel, Wolfgang; LeWitt, Peter; Giladi, Nir; Ghys, Liesbet; Grieger, Frank; Boroojerdi, Babak

    2013-01-01

    Although dopamine agonists (DAs) are sometimes perceived as poorly tolerated by the elderly, there is little clinical evidence to support these concerns. Safety and tolerability of rotigotine have been demonstrated in four 6-month randomized placebo-controlled studies: two in early Parkinson's disease (PD) and two in advanced PD. A post hoc analysis of data from these pivotal trials was carried out to compare the adverse event (AE) profiles of younger and older patient populations. Data from early and advanced PD trials were separately pooled and evaluated using two age cut-offs (age-related differences in incidence were observed. In the early PD pool, nausea (38% vs. 30%) and headache (15% vs. 9%) were more frequent in younger (age cut-off. Using the 75-year cut-off, nausea (36% vs. 21%) was more frequent in younger patients (age cut-off (24% vs. 19%) and falls were more frequent in older patients using the 75-year age cut-off (8% vs. 13%). In this relatively healthy population which included only few patients aged 75 years or older, rotigotine was generally well tolerated regardless of age. Data from more representative PD populations are required to fully assess potential risks of DA therapy in elderly patients. Copyright © 2012. Published by Elsevier Ltd.

  11. Pharmacokinetics, safety, and tolerability of a depot formulation of naltrexone in alcoholics: an open-label trial

    Directory of Open Access Journals (Sweden)

    Koch Monika

    2005-04-01

    Full Text Available Abstract Background Naltrexone is an effective medication for treatment of alcohol dependence, but its efficacy is limited by lack of adherence to the oral dosage form. A long-acting depot formulation of naltrexone may increase adherence. Methods A single site, 6-week open label study was conducted with 16 alcohol dependent subjects each receiving 300 mg of Naltrexone Depot by intramuscular injection. The main outcomes were safety and tolerability of the Naltrexone Depot formulation, blood levels of naltrexone and its main metabolite 6-beta naltrexol, and self-reported alcohol use. All subjects received weekly individual counseling sessions. Results The medication was well tolerated with 88% of subjects completing the 6-week trial. The most common side effect experienced was injection site complications. There were no serious adverse events. Subjects had naltrexone and 6-beta-naltrexol concentrations throughout the trial with mean values ranging from 0.58 ng/mL to 2.04 ng/mL and 1.51 ng/mL to 5.52 ng/mL, respectively, at each sampling time following administration. Compared to baseline, subjects had significantly reduced number of drinks per day, heavy drinking days and proportion of drinking days. Conclusion Naltrexone Depot is safe and well tolerated in alcoholics and these findings support the further investigation of its utility in larger double-blind placebo controlled trials.

  12. The efficacy, safety and tolerability of adapalene versus benzoyl peroxide in the treatment of mild acne vulgaris; a randomized trial.

    Science.gov (United States)

    Babaeinejad, S H; Fouladi, R F

    2013-09-01

    Topical treatments, such as adapalene and benzoyl peroxide (BPO), are popular in mild-to-moderate acne vulgaris. This study aimed to compare the efficacy, safety and tolerability of adapalene and BPO in mild acne vulgaris. In this single-center, randomized, double-blind, clinical trial, 60 patients with mild acne vulgaris received either topical adapalene 0.1% gel or topical BPO 2.5% gel on their face once daily for two months. The changes of acne lesion count (efficacy), any adverse effect (safety), and the patients' overall satisfaction (tolerability) were compared after 3 months of follow-up. In both groups the mean number of noninflammatory, inflammatory and total lesions decreased significantly from baseline (10.77±5.54, 9.73±5.09, and 20.50±7.54, respectively in adapalene group; 11.50±5.92, 8.43±5.45, and 19.93±9.01, respectively in BPO group) to the third month (1.70±1.68, 0.33±0.66, and 0.50±0.78, respectively in adapalene group; 4.23±4.14, 0.33±0.71, and 4.13±4.44, respectively in BPO group; Pacne vulgaris, with a marginal tendency toward the former.

  13. The efficacy, safety, and tolerability of adapalene versus benzoyl peroxide in the treatment of mild acne vulgaris: a randomized trial.

    Science.gov (United States)

    Babaeinejad, S H; Fouladi, R F

    2013-07-01

    Topical treatments, such as adapalene and benzoyl peroxide (BPO), are popular in mild-to-moderate acne vulgaris. This study aimed to compare the efficacy, safety and tolerability of adapalene and BPO in mild acne vulgaris. In this single-center, randomized, double-blind, clinical trial, 60 patients with mild acne vulgaris received either topical adapalene 0.1% gel or topical BPO 2.5% gel on their face once daily for two months. The changes of acne lesion count (efficacy), any adverse effect (safety), and the patients' overall satisfaction (tolerability) were compared after 3 months of follow-up. In both groups the mean number of noninflammatory, inflammatory and total lesions decreased significantly from baseline (10.77±5.54, 9.73±5.09, and 20.50±7.54, respectively in adapalene group; 11.50±5.92, 8.43±5.45, and 19.93±9.01, respectively in BPO group) to the third month (1.70±1.68, 0.33±0.66, and 0.50±0.78, respectively in adapalene group; 4.23±4.14, 0.33±0.71, and 4.13±4.44, respectively in BPO group; Pacne vulgaris, with a marginal tendency toward the former.

  14. Long-term (52 weeks) safety and tolerability of umeclidinium in Japanese patients with chronic obstructive pulmonary disease.

    Science.gov (United States)

    Yamagata, Eiji; Soutome, Toru; Hashimoto, Kenichi; Mihara, Kazuko; Tohda, Yuji

    2016-05-01

    Objective Umeclidinium bromide (UMEC) 62.5 μg is a long-acting muscarinic antagonist (LAMA) that is administered once daily via inhalation for chronic obstructive pulmonary disease (COPD) treatment. The objective of this study was to evaluate the safety and tolerability of long-term treatment with UMEC 125 μg in Japanese patients with COPD. Methods This was a 52 week, multicenter, open-label study to evaluate the safety and tolerability of UMEC 125 μg once daily delivered via a novel dry powder inhaler (nDPI) in Japanese patients with COPD. The primary endpoint was the incidence and severity of all adverse events (AEs) throughout the 52 week treatment period. Clinical trial registration number ClinicalTrials.gov identifier is NCT01702363. Results A total of 153 patients were enrolled in the study. Of these, 131 patients started treatment with UMEC 125 μg, and 111 patients (85%) completed the study. AEs did not differ greatly in incidence over the various time periods (Weeks 0 to 12, 13 to 24, 25 to 36, and 37 to 52 of treatment) and did not increase with continued treatment. The incidence of drug-related AEs associated with the pharmacological effects of LAMAs (including constipation, blurred vision, and thirst) was low. Serious adverse events (SAEs) during the treatment period were reported in 17 patients (13%). SAEs reported in more than one patient were COPD exacerbation and pneumonia (3 patients each, 2%). One SAE of angina pectoris was considered to be drug related. No fatalities were reported during this study. Conclusions No new AEs were identified beyond those attributable to the pharmacological effects of LAMAs. UMEC 125 μg was well tolerated over 52 weeks of treatment in Japanese patients with COPD.

  15. Safety, immunogenicity and persistence of immune response to the combined diphtheria, tetanus, acellular pertussis, poliovirus and Haemophilus influenzae type b conjugate vaccine (DTPa-IPV/Hib) administered in Chinese infants.

    Science.gov (United States)

    Li, Yanping; Li, Rong Cheng; Ye, Qiang; Li, Changgui; Liu, You Ping; Ma, Xiao; Li, Yanan; Zhao, Hong; Chen, Xiaoling; Assudani, Deepak; Karkada, Naveen; Han, Htay Htay; Van Der Meeren, Olivier; Mesaros, Narcisa

    2017-03-04

    We conducted 3 phase III, randomized, open-label, clinical trials assessing the safety, reactogenicity (all studies), immunogenicity (Primary vaccination study) and persistence of immune responses (Booster study) to the combined diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Chinese infants and toddlers. In the Pilot study (NCT00964028), 50 infants (randomized 1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 months of age (Group B). In the Primary study (NCT01086423), 984 healthy infants (randomized 1:1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 (Group B) months of age, or concomitant DTPa/Hib and poliomyelitis (IPV) vaccination at 2-3-4 months of age (Control group); 825 infants received a booster dose of DTPa/Hib and IPV at 18-24 months of age (Booster study; NCT01449812). In the Pilot study, unsolicited symptoms were more frequent in Group A (16 versus 1 infant; mostly upper respiratory tract infection and pyrexia); this observation was attributed to an epidemic outbreak of viral infections. Non-inferiority of 3-dose primary vaccination with DTPa-IPV/Hib over separately administered DTPa/Hib and IPV was demonstrated for Group A (primary objective). Similar antibody concentrations were observed in all groups, except for anti-polyribosyl-ribitol phosphate and anti-poliovirus types 1-3 which were higher in DTPa-IPV/Hib recipients. Protective antibody levels against all vaccine antigens remained high until booster vaccination. Three-dose vaccination with DTPa-IPV/Hib had a clinically acceptable safety profile.

  16. Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen).

    Science.gov (United States)

    Mahendra, B J; Narayana, Dh Ashwath; Agarkhedkar, Sharad; Ravish, H S; Harish, B R; Agarkhedkar, Shalaka; Madhusudana, S N; Belludi, Ashwin; Ahmed, Khaleel; Jonnalagedda, Rekha; Vakil, Hoshang; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

    2015-01-01

    Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.

  17. A clinical trial to assess the immunogenicity and safety of Inactivated Influenza Vaccine (Whole Virion) IP (Pandemic Influenza (H1N1) 2009 Monovalent Vaccine; VaxiFlu-S™) in healthy Indian adult population.

    Science.gov (United States)

    Kubavat, A H; Mittal, R; Patel, P M; Jarsaniya, D H; Pawar, P R

    2011-01-01

    The pandemic of H1N1 2009 influenza has spread world over and low degree of virus transmission has continued in several regions of India. To assess the immunogenicity and safety of Pandemic Influenza (H1N1) 2009 Monovalent Vaccine in healthy adult Indian population. Prospective, open label, multicentric, phase 2/3 clinical trial. Healthy adult Indian subjects belonging to either 18-59 years or ≥ 60 years age groups were enrolled and administered a single 0.5 ml (≥ 15 mcg of hemagglutinin antigen) dose of vaccine in the deltoid muscle. Anti-hemagglutinin antibody titer was assessed at baseline and 21 (± 2) days after vaccination by Hemagglutination Inhibition (HI) test. Safety assessments were done for a period of 42 days. Percentages of appropriate population with 95% confidence intervals calculated, log transformation of the data to calculate Geometric Mean Titers (GMTs) and chi-square test and student's t-test applied for significance testing. 182/198 and 53/63 volunteers in age groups of 18-59 years and ≥ 60 years, respectively, achieved an HI titer ≥ 1 : 40 at Day 21 (91.9% [95% confidence interval: 88.1-95.7%] and 84.1% [75.1-93.2%]; P=0.072). Further, 171/198 and 50/63 volunteers in the respective age groups achieved seroconversion/four-fold increase in titer at Day 21 (86.4% [81.6-91.1%] and 79.4% [69.4-89.4%]; P=0.179). A significant rise of 22.6-fold [18.0-28.4] and 10.5-fold [7.4-15.0] was noted in GMT in the respective age groups (Ppopulation.

  18. Experience with monocomponent acellular pertussis combination vaccines for infants, children, adolescents and adults--a review of safety, immunogenicity, efficacy and effectiveness studies and 15 years of field experience.

    Science.gov (United States)

    Thierry-Carstensen, Birgit; Dalby, Tine; Stevner, Michael A; Robbins, John B; Schneerson, Rachel; Trollfors, Birger

    2013-10-25

    Combination vaccines containing a monocomponent acellular pertussis (aP) vaccine, manufactured at Statens Serum Institut (SSI), Denmark, have successfully controlled Bordetella pertussis infections in Denmark since 1997. The efficacy of this aP vaccine was 71% in a double-blind, randomised and controlled clinical trial. Its safety and immunogenicity have been demonstrated in infants, children, adolescents and adults. In approximately 500,000 children it was effective against pertussis requiring hospitalisation (VE: 93% after 3 doses) and against pertussis not requiring hospitalisation (VE: 78% after 3 doses). IgG antibodies against pertussis toxin (IgG anti-PT) response rates after booster vaccination of adults with tetanus, diphtheria and aP combination vaccine (TdaP) were considerably higher for this monocomponent aP vaccine containing 20μg pertussis toxoid, inactivated by hydrogen peroxide (92.0%), than for two multicomponent aP vaccines inactivated by formaldehyde and/or glutaraldehyde: 3-component aP with 8μg pertussis toxoid (77.2%) and 5-component aP with 2.5μg pertussis toxoid (47.1%), without compromising the safety profile. In Denmark where this monocomponent aP vaccine has been the only pertussis vaccine in use for 15 years, there has been no pertussis epidemic since 2002 (population incidence 36 per 100,000), in contrast to neighbouring countries, where epidemics have occurred. This monocomponent aP vaccine can be used in combination vaccines for primary and booster vaccination against pertussis in all age groups and is an important tool for successful pertussis control. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV-infected adults: a randomized, double-blind clinical trial.

    Science.gov (United States)

    Toft, Lars; Storgaard, Merete; Müller, Martin; Sehr, Peter; Bonde, Jesper; Tolstrup, Martin; Østergaard, Lars; Søgaard, Ole S

    2014-04-15

    We compared the immunogenicity and reactogenicity of Cervarix or Gardasil human papillomavirus (HPV) vaccines in adults infected with the human immunodeficiency virus (HIV). This was a double-blind, controlled trial randomizing HIV-positive adults to receive 3 doses of Cervarix or Gardasil at 0, 1.5, and 6 months. Immunogenicity was evaluated for up to 12 months. Neutralizing anti-HPV-16/18 antibodies were measured by pseudovirion-based neutralization assay. Laboratory tests and diary cards were used for safety assessment. The HPV-DNA status of the participants was determined before and after immunization. Ninety-two participants were included in the study. Anti-HPV-18 antibody titers were higher in the Cervarix group compared with the Gardasil group at 7 and 12 months. No significant differences in anti-HPV-16 antibody titers were found among vaccine groups. Among Cervarix vaccinees, women had higher anti-HPV-16/18 antibody titers compared to men. No sex-specific differences in antibody titers were found in the Gardasil group. Mild injection site reactions were more common in the Cervarix group than in the Gardasil group (91.1% vs 69.6%; P = .02). No serious adverse events occurred. Both vaccines were immunogenic and well tolerated. Compared with Gardasil, Cervarix induced superior vaccine responses among HIV-infected women, whereas in HIV-infected men the difference in immunogenicity was less pronounced.

  20. Pilot, double-blind, randomized, placebo-controlled clinical trial of the supplement food Nyaditum resae® in adults with or without latent TB infection: Safety and immunogenicity.

    Directory of Open Access Journals (Sweden)

    Eva Montané

    Full Text Available Nyaditum resae® (NR is a galenic preparation of heat-killed Mycobacterium manresensis, a new species of the fortuitum complex, that is found in drinkable water, and that has demonstrated to protect against the development of active TB in a murine experimental model that develop human-like lesions.Double-blind, randomized, placebo-controlled Clinical Trial (51 volunteers included. Two different doses of NR and a placebo were tested, the randomization was stratified by Latent Tuberculosis Infection (LTBI-positive (n = 21 and LTBI-negative subjects (n = 30. Each subject received 14 drinkable daily doses for 2 weeks.All patients completed the study. The 46.3% of the overall reported adverse events (AE were considered related to the investigational treatment. None of them were severe (94% were mild and 6% moderate. No statistical differences were found when comparing the median number of AE between the placebo group and both treatment groups. The most common AE reported were gastrointestinal events, most frequently mild abdominal pain and increase in stool frequency. Regarding the immunogenic response, both LTBI-negative and LTBI-positive volunteers treated with NR experienced a global increase on the Treg response, showed both in the population of CD25+CD39-, mainly effector Treg cells, or CD25+CD39+ memory PPD-specific Treg cells.This clinical trial demonstrates an excellent tolerability profile of NR linked to a significant increase in the population of specific effector and memory Tregs in the groups treated with NR in both LTBI-positive and negative subjects. NR shows a promising profile to be used to reduce the risk of active TB.

  1. Immunogenicity of autoantigens.

    Science.gov (United States)

    Backes, Christina; Ludwig, Nicole; Leidinger, Petra; Harz, Christian; Hoffmann, Jana; Keller, Andreas; Meese, Eckart; Lenhof, Hans-Peter

    2011-07-04

    Autoantibodies against self-antigens have been associated not only with autoimmune diseases, but also with cancer and are even found in healthy individuals. The mechanism causing the autoantibody response remains elusive for the majority of the immunogenic antigens. To deepen the understanding of autoantibody responses, we ask whether natural-occurring, autoimmunity-associated and tumor-associated antigens have structural or biological features related to the immune response. To this end, we have carried out the most comprehensive in-silicio study of different groups of autoantigens including large antigen sets identified by our groups combined with publicly available antigen sets. We found evidence for an enrichment of genes with a larger exon length increasing the probability of the occurrence of potential immunogenic features such as mutations, SNPs, immunogenic sequence patterns and structural epitopes, or alternative splicing events. While SNPs seem to play a more central role in autoimmunity, somatic mutations seem to be stronger enriched in tumor-associated antigens. In addition, antigens of autoimmune diseases are different from other antigen sets in that they appear preferentially secreted, have frequently an extracellular location, and they are enriched in pathways associated with the immune system. Furthermore, for autoantibodies in general, we found enrichment of sequence-based properties including coiled-coils motifs, ELR motifs, and Zinc finger DNA-binding motifs. Moreover, we found enrichment of proteins binding to proteins or nucleic acids including RNA and enrichment of proteins that are part of ribosome or spliceosome. Both, homologies to proteins of other species and an enrichment of ancient protein domains indicate that immunogenic proteins are evolutionary conserved and that mimicry might play a central role. Our results provide evidence that proteins which i) are evolutionary conserved, ii) show specific sequence motifs, and iii) are part of

  2. Immunogenicity of autoantigens

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    Keller Andreas

    2011-07-01

    Full Text Available Abstract Background Autoantibodies against self-antigens have been associated not only with autoimmune diseases, but also with cancer and are even found in healthy individuals. The mechanism causing the autoantibody response remains elusive for the majority of the immunogenic antigens. To deepen the understanding of autoantibody responses, we ask whether natural-occurring, autoimmunity-associated and tumor-associated antigens have structural or biological features related to the immune response. To this end, we have carried out the most comprehensive in-silicio study of different groups of autoantigens including large antigen sets identified by our groups combined with publicly available antigen sets. Results We found evidence for an enrichment of genes with a larger exon length increasing the probability of the occurrence of potential immunogenic features such as mutations, SNPs, immunogenic sequence patterns and structural epitopes, or alternative splicing events. While SNPs seem to play a more central role in autoimmunity, somatic mutations seem to be stronger enriched in tumor-associated antigens. In addition, antigens of autoimmune diseases are different from other antigen sets in that they appear preferentially secreted, have frequently an extracellular location, and they are enriched in pathways associated with the immune system. Furthermore, for autoantibodies in general, we found enrichment of sequence-based properties including coiled-coils motifs, ELR motifs, and Zinc finger DNA-binding motifs. Moreover, we found enrichment of proteins binding to proteins or nucleic acids including RNA and enrichment of proteins that are part of ribosome or spliceosome. Both, homologies to proteins of other species and an enrichment of ancient protein domains indicate that immunogenic proteins are evolutionary conserved and that mimicry might play a central role. Conclusions Our results provide evidence that proteins which i are evolutionary conserved

  3. Immunogenicity and safety of purified vero cell rabies vaccine (PVRV) produced by Liaoning Cheng Da Co. under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese adults aged 50 and above.

    Science.gov (United States)

    Wang, Jing; Luo, FengJi; Feng, ZiJian; Li, Li; Bai, YunHua; Ai, Xing; Ma, JianXin; Zhang, Zheng; Shi, NianMin

    2017-01-02

    Two kinds of regimens (2-1-1 and 1-1-1-1-1) can be selected after Zagreb regimen(2-1-1)of PVRV was officially approved in Beijing in January 2015. Up to now, the subjects for most studies about the comparison between Zagreb and Essen regimen are under 50 y old, rarely at and above. Aging of the immune system may result in decreasing efficacy of vaccination, especially for adults aged above 65-70 y. This study compared the safety and immunogenicity of the Zagreb and Essen regimen in Chinese adults aged 50 and above with the goal to provide a supplemental data for this age group. A total of 114 cases were divided into 2 groups randomly, received PVRV under the Zagreb and Essen regimens respectively. Serum samples were collected at D0, D7, D14, D42, D180 and D365 to determine the rabies serum neutralizing antibody by rapid fluorescent focus inhibition test (RFFIT). Safety analyses were made by comparing the AEs in day-3, day-7, and day-(7 + 21) in Zagreb or day-(7 + 28) in Essen by gender and age cohorts. 617 blood samples were obtained. Two groups showed similar immunogenicity, the neutralizing antibody titer of all subjects at D14 and D42 showed >0.5 IU/ml. Under the same regimen, Subjects ≥65 y had lower GMC than those who <65 years from D7 to D365 within 2 groups. This difference was significantly shown on D7, D14, D180 in Zagreb group, and on D180 in Essen group (t = 2.38, p = 0.02; t = 3.78, p < 0.001; t = 2.30, p = 0.03; t = 4.42, p < 0.001). Subjects<65 years had higher seroconversion rate compared to ≥65 y on D7, D180 and D365 in both 2 groups, this difference was also significantly shown on D180, D365 in Zagreb group and on D180 in Essen group (χ 2 = 20.66, p < 0.001; χ 2 = 6.56, p = 0.02; χ 2 = 10.96, p = 0.002). Two regimens all showed favorable performances with mildly or common adverse events (AEs). The incidence of local AEs after 3 d in Essen group was higher than Zagreb group (χ 2 = 9.69, p = 0.002). The most common local AE was pain

  4. Evaluation of clinical safety and tolerance of a Lactobacillus reuteri NCIMB 30242 supplement capsule: a randomized control trial.

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    Jones, Mitchell L; Martoni, Christopher J; Di Pietro, E; Simon, Ryan R; Prakash, Satya

    2012-07-01

    A significant number of human clinical trials have reported no adverse effects associated with consumption of Lactobacillus reuteri (L. reuteri). In the present study, the clinical safety and toxicology of oral ingestion of supplement capsules containing L. reuteri NCIMB 30242 was investigated. A randomized group of 131 subjects received a dose of 2.9×10⁹ CFU L. reuteri NCIMB 30242 capsules (n=67) or placebo capsules (n=64) twice daily for 9 weeks. Clinical chemistry and hematological parameters of safety were analyzed. The frequency, duration and intensity of adverse events (AE)s and clinical significance of safety parameters were recorded for both groups. No clinically significant differences between the probiotic capsule and placebo capsule treated groups were detected in either the blood clinical chemistry or hematology results. The frequency and intensity of AEs was similar in the two groups. These results demonstrate that administration of a twice daily dose of 2.9×10⁹ CFU was safe and well tolerated in the population evaluated over 9 weeks. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  5. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review

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    Solmi M

    2017-06-01

    -generation antipsychotics (SGAs ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. Keywords: antipsychotics, side effects, tolerability, safety, psychosis, psychiatry

  6. Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract.

    Science.gov (United States)

    Heinonen, Tuula; Gaus, Wilhelm

    2015-01-02

    Ginkgo biloba is one of the most widely used herbal remedies in Europe and the US. It may be purchased in different types of formulations, but most of the clinical studies have been performed with the controlled G. biloba extract EGb761(®). Indications include Alzheimers disease, cardiovascular disease, dementia, memory loss, and cerebral ischemia. The pharmacological modes of action cover antioxidant effects, radical scavenging, inhibition of platelet activating factor, alterations in membrane fluidity (signal transduction), and inhibition of glucocorticoid synthesis. Due to the widespread and long-term use of G. biloba - about a million doses of EGb761(®) are sold per day - tolerability and safety are a crucial issue. Based on broad and long-term clinical use of G. biloba extracts, it is regarded as well tolerated in man. Cross matching, a tool we introduced, combines different fields of knowledge and types of data to a consolidated result. In this article, we combine toxicological and clinical data and utilize other sources of information to assess tolerability and safety of G. biloba. It is well known that because of biological differences between animals and man or even between animal species, animal experiments do not necessarily mimic the effects in humans. Therefore, for adequate risk assessment, the relevance of non-clinical toxicological findings should be correlated with human data. The cross matching of toxicological data and results from clinical studies is possible because many toxicological and clinical studies are available on G. biloba. We give an in depth analysis of the modes of action in animals and describe toxicological studies with regard to metabolism, pharmacokinetics, genotoxicity, as well as carcinogenicity (e.g., the Technical Report TR 578 of the US National Toxicology Program). In addition, 75 clinical trials with high methodological quality are summarized. They included a total of 7115 patients treated with G. biloba. Based on this

  7. Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults.

    Science.gov (United States)

    Kester, Kent E; Gray Heppner, D; Moris, Philippe; Ofori-Anyinam, Opokua; Krzych, Urszula; Tornieporth, Nadia; McKinney, Denise; Delchambre, Martine; Ockenhouse, Christian F; Voss, Gerald; Holland, Carolyn; Beckey, Jolie Palensky; Ballou, W Ripley; Cohen, Joe

    2014-11-20

    In an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms. Copyright © 2014

  8. [SAFETY AND IMMUNOGENICITY OF A NATIONAL COMBINED VACCINE AGAINST PERTUSSIS, DIPHTHERIA, TETANUS, HEPATITIS B AND Hib-INFECTION, CONTAINING ACELLULAR PERTUSSIS COMPONENT, DURING IMMUNIZATION OF ADULTS].

    Science.gov (United States)

    Feldblyum, I V; Nikolaeva, A M; Pavroz, K A; Danilina, T V; Sosnina, O Yu; Vyaznikova, T V; Ershov, A E; Trofimov, D M; Polushkina, A V

    2016-01-01

    Study safety, reactogenicity and immunologic effectiveness of a national combined vaccine against diphtheria, pertussis (acellular component), tetanus, hepatitis B and Hib-infection during immunization of volunteers aged 18-60 years. The study was carried out in accordance with ethical standards and requirements, regulated by Helsinki declaration and Good clinical practice (ICHGCP). In a simple non-randomized clinical trial 20 adult volunteers took part, the mean age of those was 46.9 years. Registered: post-vaccination reactions (both local and systemic) were mild and of moderate degree of severity, stopped independently after 2-3 days without administration of drug treatment. Postvaccinal complications were not noted. Parameters of general and biochemical analysis of blood, urine, IgE content in dynamics of immunization were within normal limits. A single administration of aAPDT--HepB+Hib to individuals aged 18-60 years resulted in development of antibodies against all the components of the preparation. Seroconversion factor fluctuated from 6.9 to 53.5: The results obtained allow to recommend the vaccine for evaluation of its safety, reactogenicity, immunologic and prophylaxis effectiveness in randomized clinical observation trials in children.

  9. Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Jan K Buitelaar

    2009-08-01

    Full Text Available Jan K Buitelaar1, J Antoni Ramos-Quiroga2, Miguel Casas2, J J Sandra Kooij3, Asko Niemelä4, Eric Konofal5, Joachim Dejonckheere6, Bradford H Challis7, Rossella Medori81Department of Psychiatry, University Medical Center, St. Radboud and Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands; 2Department of Psychiatry, Hospital Universitari Vall d’Hebron and Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 3PsyQ, Psycho-Medical Programs, Program Adult ADHD, Den Haag, The Netherlands; 4Oulu University Hospital, Department of Psychiatry, Oulu, Finland; 5Groupe Hospitalier Pitie-Salpetriere, Paris, France; 6SGS Life Sciences, Mechelen, Belgium; 7Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA; 8Janssen-Cilag EMEA, Neuss, GermanyAbstract: The osmotic release oral system (OROS methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety and tolerability of OROS methylphenidate in a flexible dose regimen (18–90 mg daily for the treatment of adults diagnosed with ADHD (N = 370. Medication was adjusted to optimize efficacy and tolerability for each patient. Adverse events, vital signs, and laboratory parameters were assessed. Most patients (337; 91% completed the seven-week treatment and the final dispensed dose was 18 mg (8%, 36 mg (29%, 54 mg (34%, 72 mg (20%, or 90 mg (9%. Adverse events were reported in 253 (68% patients and most were mild or moderate in severity; most frequently reported included headache (17%, decreased appetite (13%, and insomnia (11%. Adverse events were rarely serious (<1%; 2/370. Small mean increases in systolic and diastolic blood pressure (both 2.4 mmHg and pulse (3.2 bpm were observed. Body weight decreased

  10. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) when given as a toddler dose to children immunized with PCV7 as infants.

    Science.gov (United States)

    Grimprel, E; Laudat, F; Patterson, S; Baker, S A; Sidhu, M S; Gruber, W C; Emini, E A; Scott, D A

    2011-12-06

    13-Valent pneumococcal conjugate vaccine (PCV13) administered as a 4-dose series in infants, and as a toddler dose in infants previously vaccinated with PCV7 elicited comparable vaccine serotypes IgG responses to the seven common serotypes. PCV13 elicited functional responses to the six additional serotypes in both schedules after the toddler dose. The toddler dose boosted immune responses. The two regimens had comparable safety profiles. A toddler dose of PCV13 given in children previously vaccinated with PCV7 should be effective in preventing pneumococcal disease caused by common serotypes, providing protection against the additional serotypes, and supporting the transition from PCV7 to PCV13. Copyright © 2011. Published by Elsevier Ltd.

  11. The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis.

    Science.gov (United States)

    Nasrallah, Henry A; Earley, Willie; Cutler, Andrew J; Wang, Yao; Lu, Kaifeng; Laszlovszky, István; Németh, György; Durgam, Suresh

    2017-08-24

    5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder. In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia. NCT01104792, NCT00839852.

  12. Use of the ketogenic diet in the neonatal intensive care unit-Safety and tolerability.

    Science.gov (United States)

    Thompson, Lindsey; Fecske, Erin; Salim, Mohammad; Hall, Ara

    2017-02-01

    Drug-resistant epilepsy poses a challenge in neonatal patients, especially those in the neonatal intensive care unit (NICU), who have various secondary comorbidities. We present results of four children with a history of drug-resistant epilepsy for whom a ketogenic diet was initiated and used in the NICU. A nonfasting induction into ketosis over 1-2 weeks was utilized, with gradual increases in the ketogenic ratio every 2-3 days. Data were collected retrospectively from a database, which included medical history, daily progress notes, relevant laboratory data, and imaging and diagnostic information. The ketogenic diet was well tolerated in all cases. The most common side effects observed were constipation, hypoglycemia, and weight loss. Serum β-hydroxybutyrate levels demonstrated improved reliability as a marker of ketosis when compared to urine ketones in this population. Perceived benefits to the infants included improved seizure control, increased alertness, and decreased need for invasive respiratory support. These cases demonstrate that the use of the ketogenic diet for treatment of neonatal encephalopathy and refractory epilepsy can be undertaken safely in the NICU and is well tolerated by carefully screened neonates and infants. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  13. Efficacy, tolerability, and safety of non-pharmacological therapies for chronic pain: An umbrella review on various CAM approaches.

    Science.gov (United States)

    Houzé, Bérengère; El-Khatib, Héjar; Arbour, Caroline

    2017-10-03

    Complementary and alternative medicine (CAM) therapies may be used as a non-pharmacological approach to chronic pain management. While hundreds of trials about individual CAM modality have been conducted, a comprehensive overview of their results is currently lacking for pain clinicians and researchers. This umbrella review synthesized the quality of meta-analytic evidence supporting the efficacy, tolerability and safety of CAM therapies for the management of chronic pain. MEDLINE, EMBASE, CINAHL, and CENTRAL were searched from October 1991 to November 2016. Reviews of clinical trials (randomized and non-randomized) with meta-analysis investigating the utility of any CAM modality for chronic pain were eligible. Pain relief post-intervention was the main outcome and secondary outcomes included patients' adherence and incidence of adverse effects during CAM protocol. Twenty-six reviews (207 clinical trials, >12,000 participants) about 18 CAM modalities, falling under natural products, mind and body practices or other complementary health approaches were included. Inhaled cannabis, graded motor imagery, and Compound Kushen injection (a form of Chinese medicine) were found the most efficient (with moderate-to-high effect sizes and low heterogeneity) and tolerable (≥80% of adherence to study protocols) for chronic pain relief. When reported, adverse effects related to these CAM were minor. Although several CAM were found effective for chronic pain relief, it remains unclear when these modalities are a reasonable choice against or in conjunction with mainstream treatments. In that sense, future research with a clear emphasis on concurrent evaluation of CAM overall efficacy and patient adherence/tolerance is needed. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial

    Science.gov (United States)

    Noguchi-Shinohara, Moeko; Ono, Kenjiro; Hamaguchi, Tsuyoshi; Iwasa, Kazuo; Nagai, Toshitada; Kobayashi, Shoko; Nakamura, Hiroyuki; Yamada, Masahito

    2015-01-01

    The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state) and Study 2 (fed state)]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals. Trial Registration Trial Registration: UMIN-CTR UMIN000004997 PMID:25978046

  15. Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study.

    Science.gov (United States)

    Townsend, Robert; Desai, Amit; Rammelsberg, Diane; Kowalski, Donna; Simmons, Neal; Kitt, Therese M

    2017-02-01

    Regadenoson is a selective A 2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. Healthy males and females were randomized to receive intravenous regadenoson [100 μg (3 doses), 200 μg (3 doses), or 400 μg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects. Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

  16. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial.

    Directory of Open Access Journals (Sweden)

    Dennis L Kelleher

    Full Text Available Umeclidinium bromide (GSK573719; UMEC, a new long-acting muscarinic receptor antagonist (LAMA, is in development with vilanterol (GW642444; VI, a selective long-acting β(2 agonist (LABA, as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD. A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD and pharmacokinetics (PK of inhaled umeclidinium (500 µg and vilanterol (50 µg when administered separately and in combination using a novel dry powder inhaler (NDPI. Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone.Clinicaltrials.gov NCT00976144.

  17. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial.

    Science.gov (United States)

    Kelleher, Dennis L; Mehta, Rashmi S; Jean-Francois, Bernadette M; Preece, Andrew F; Blowers, James; Crater, Glenn D; Thomas, Paul

    2012-01-01

    Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β(2) agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone. Clinicaltrials.gov NCT00976144.

  18. Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications

    Science.gov (United States)

    Chou, Timothy Y; Hong, Bennett Y

    2014-01-01

    Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy. PMID:25187721

  19. Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial.

    Directory of Open Access Journals (Sweden)

    Moeko Noguchi-Shinohara

    Full Text Available The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state and Study 2 (fed state]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals.

  20. Gut feelings of safety: tolerance to the microbiota mediated by innate immune receptors.

    Science.gov (United States)

    Swiatczak, Bartlomiej; Cohen, Irun R

    2015-10-01

    To enable microbial colonization of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Recognition of safety, paradoxically, is mediated by the same environmental sensors that are involved in signaling danger. Indeed, in addition to their well-established role in inducing inflammation in response to stress signals, pattern recognition receptors and a variety of metabolic sensors also promote gut-microbiota symbiosis by responding to "microbial symbiosis factors", "resolution-associated molecular patterns", markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical roles of immune receptors and other environmental sensors define the microbiota signature of an individual. © 2015 The Societies and Wiley Publishing Asia Pty Ltd.

  1. A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults.

    Directory of Open Access Journals (Sweden)

    Sharon Sheehan

    Full Text Available MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB.In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402.Most related adverse events (AEs were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A.Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries.ClinicalTrials.gov NCT01683773.

  2. Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa.

    Science.gov (United States)

    Vesikari, Timo; Rivera, Luis; Korhonen, Tiina; Ahonen, Anitta; Cheuvart, Brigitte; Hezareh, Marjan; Janssens, Winnie; Mesaros, Narcisa

    2017-07-03

    Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV-IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12-15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1-3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued.

  3. Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia.

    Science.gov (United States)

    Dolzhikova, I V; Zubkova, O V; Tukhvatulin, A I; Dzharullaeva, A S; Tukhvatulina, N M; Shcheblyakov, D V; Shmarov, M M; Tokarskaya, E A; Simakova, Y V; Egorova, D A; Scherbinin, D N; Tutykhina, I L; Lysenko, A A; Kostarnoy, A V; Gancheva, P G; Ozharovskaya, T A; Belugin, B V; Kolobukhina, L V; Pantyukhov, V B; Syromyatnikova, S I; Shatokhina, I V; Sizikova, T V; Rumyantseva, I G; Andrus, A F; Boyarskaya, N V; Voytyuk, A N; Babira, V F; Volchikhina, S V; Kutaev, D A; Bel'skih, A N; Zhdanov, K V; Zakharenko, S M; Borisevich, S V; Logunov, D Y; Naroditsky, B S; Gintsburg, A L

    2017-03-04

    Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).

  4. A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 years

    Science.gov (United States)

    Vesikari, Timo; Forstén, Aino; Boutriau, Dominique; Bianco, Véronique; Van der Wielen, Marie; Miller, Jacqueline M.

    2012-01-01

    Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2–10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2–10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908. PMID:23032168

  5. Segurança, imunogenicidade e eficácia da vacina contra o vírus influenza em crianças Safety, immunogenicity and efficacy of influenza vaccine in children

    Directory of Open Access Journals (Sweden)

    Otávio A. L. Cintra

    2006-07-01

    Full Text Available OBJETIVOS: Revisar a imunogenicidade, segurança e eficácia das vacinas trivalentes inativadas e atenuadas contra o vírus influenza em crianças FONTE DOS DADOS: Pesquisa na literatura médica nas bases MEDLINE, LILACS e Biblioteca Cochrane. Artigos de revisão, ensaios clínicos e epidemiológicos foram selecionados para análise no período de 1990 a 2006 SÍNTESE DOS DADOS: A influenza é uma doença infecciosa universal e sazonal que incide em todos os grupos etários e apresenta epidemias anuais caracterizadas por excesso de morbidade e mortalidade. Os idosos e pessoas com comorbidades são grupos de alto risco para influenza grave. Recentemente, foi comprovado que os lactentes saudáveis apresentam morbidade semelhante aos outros grupos de risco, e, portanto, têm indicação para a vacinação contra influenza, que se constitui na ação mais efetiva para a prevenção da infecção por vírus influenza. A segurança das vacinas contra influenza em crianças parece ser adequada, com reações adversas mais observadas do tipo local ou febre. A imunogenicidade em crianças varia de 30 a 90%, sendo diretamente proporcional à idade. A eficácia depende do objetivo primário, podendo ser semelhante ao placebo ou chegar até 91% de eficácia contra infecção comprovada por influenza A. As crianças em idade escolar exercem importante papel na disseminação do vírus influenza, e estudos populacionais mostram imunidade de rebanho. CONCLUSÕES:As vacinas trivalentes contra influenza, inativadas ou atenuadas, são pouco reatogênicas e apresentam imunogenicidade e eficácia variáveis em crianças. A vacinação é efetiva para prevenção de infecção por vírus influenza e para redução de morbidade. Estudos mais potentes de eficácia e segurança em lactentes ainda são desejáveis.OBJECTIVES:To review the immunogenicity, safety and efficacy of inactivated and attenuated trivalent influenza vaccines in children. SOURCES OF DATA: Database

  6. APPRAISAL OF NIMESULIDE EFFICIENCY, TOLERANCE AND SAFETY AMONG CHILDREN WITH JUVENILE ARTHRITIS

    Directory of Open Access Journals (Sweden)

    E.I. Alexeeva

    2007-01-01

    Full Text Available The article analyzes nimesulide application experience among children with juvenile arthritides against the insufficient efficiency of a therapy by other non steroid anti-inflammatory medications. The researchers show that nimesulide is an efficient non steroid anti-inflammatory medication for the patients, suffering from oligo- and limited poly arthritis of the I–II activity degree. Nimesulide also provided for the reliable regression of the clinical and laboratory activity manifestations of a disease and, what is more important, among most patients without applications of the local glucocorticosteroidbassisted therapy. Nimesulide is characterized by good tolerance and low toxicity, which is along with the permit to use it among children aged 2 and over, allows one to consider this drug as one of the medications to choose for the treatment of the inflammatory joint diseases among children.Key words: children, juvenile arthritis, nimesulide.

  7. Continuous 24-hour Intraocular Pressure Monitoring With a Contact Lens Sensor: Safety, Tolerability, and Reproducibility in Glaucoma Patients

    Science.gov (United States)

    Mansouri, Kaweh; Medeiros, Felipe A.; Tafreshi, Ali; Weinreb, Robert N.

    2013-01-01

    Purpose To determine the safety, tolerability, and reproducibility of intraocular pressure (IOP) patterns during repeated continuous 24-hour IOP monitoring with a telemetric contact-lens sensor (CLS). Design Prospective clinical trial. Participants Forty patients with suspect (n=21) or established glaucoma (n=19). Methods Patients participated in two 24-hour IOP monitoring sessions (S1 and S2) at a 1-week interval using the SENSIMED Triggerfish CLS (Sensimed AG, Switzerland). Patients pursued daily activities and sleep behavior was not controlled. The recordings were analyzed for differences between daytime and nighttime data and for reproducibility of signal patterns between the 2 sessions. Pearson correlations were obtained by pairing intervals across sessions. Main Outcome Measures Adverse events (AE), tolerability using the visual analogue score (VAS), and reproducibility of IOP patterns. Results Mean age was 55.5 ± 15.7 years and 60.0% were male. Main AEs were blurred vision (82.5%), conjunctival hyperemia (80.0%), and superficial punctate keratitis (15.0%). Patients reported a mean VAS of 27.2 ± 18.5 (S1) and 23.8 ± 18.7 (S2) (P = 0.216). Positive linear slopes of the sensor signal from the wake to the sleep period were detected for the ‘no glaucoma medication’ group (slope: 0.14 ± 0.15, p < 0.01, S1; slope: 0.12 ± 0.17, p = 0.03, S2) and for the ‘glaucoma medication’ group (slope: 0.03 ± 0.24, p = 0.52, S1; slope: 0.11 ± 0.16, p = 0.02, S2). Overall correlation between the two sessions was 0.59 (0.51 ‘no glaucoma medication’; 0.63 ‘glaucoma medication’) (P = 0.117). Conclusions Repeated use of the CLS demonstrated good safety and tolerability. The recorded IOP patterns showed fair reproducibility, suggesting that data from 24-h continuous IOP monitoring may be useful in the management of glaucoma patients. PMID:22892888

  8. Posttranslational Modifications and the Immunogenicity of Biotherapeutics

    Directory of Open Access Journals (Sweden)

    Roy Jefferis

    2016-01-01

    Full Text Available Whilst the amino acid sequence of a protein is determined by its gene sequence, the final structure and function are determined by posttranslational modifications (PTMs, including quality control (QC in the endoplasmic reticulum (ER and during passage through the Golgi apparatus. These processes are species and cell specific and challenge the biopharmaceutical industry when developing a production platform for the generation of recombinant biologic therapeutics. Proteins and glycoproteins are also subject to chemical modifications (CMs both in vivo and in vitro. The individual is naturally tolerant to molecular forms of self-molecules but nonself variants can provoke an immune response with the generation of anti-drug antibodies (ADA; aggregated forms can exhibit enhanced immunogenicity and QC procedures are developed to avoid or remove them. Monoclonal antibody therapeutics (mAbs are a special case because their purpose is to bind the target, with the formation of immune complexes (ICs, a particular form of aggregate. Such ICs may be removed by phagocytic cells that have antigen presenting capacity. These considerations may frustrate the possibility of ameliorating the immunogenicity of mAbs by rigorous exclusion of aggregates from drug product. Alternate strategies for inducing immunosuppression or tolerance are discussed.

  9. A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy.

    Science.gov (United States)

    Greenberg, David P; Walker, Robert E; Lee, Min-Shi; Reisinger, Keith S; Ward, Joel I; Yogev, Ram; Blatter, Mark M; Yeh, Sylvia H; Karron, Ruth A; Sangli, Chithra; Eubank, Lane; Coelingh, Kathleen L; Cordova, Julie M; August, Marilyn J; Mehta, Harshvardhan B; Chen, Wendy; Mendelman, Paul M

    2005-04-01

    A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.

  10. Efficacy, pharmacokinetics, safety, and tolerability of Flebogamma 10% DIF, a high-purity human intravenous immunoglobulin, in primary immunodeficiency.

    Science.gov (United States)

    Berger, Melvin; Pinciaro, Paul J; Althaus, Arthur; Ballow, Mark; Chouksey, Akhilesh; Moy, James; Ochs, Hans; Stein, Mark

    2010-03-01

    Flebogamma 10% DIF represents an evolution of intravenous immune globulin from the previous 5% product to be administered at higher rates and with smaller infusion volumes. Pathogen safety is enhanced by the combination of multiple methods with different mechanisms of action. The objective of this study as to evaluate the efficacy, pharmacokinetics, and safety of Flebogamma 10% DIF for immunoglobulin replacement therapy in primary immunodeficiency diseases (PIDD). Flebogamma 10% DIF was administered to 46 subjects with well-defined PIDD at a dose of 300-600 mg/kg every 21-28 days for 12 months. Serious bacterial infection rate was 0.025/subject/year. Half-life in serum of the administered IgG was approximately 35 days. No serious treatment-related adverse event (AE) occurred in any patient. Most of the potentially treatment-related AEs occurred during the infusion, accounting for 20% of the 601 infusions administered. Flebogamma 10% DIF is efficacious and safe, has adequate pharmacokinetic properties, and is well-tolerated for the treatment of PIDD.

  11. Safety, Tolerability, and Sensorimotor Effects of Extended-release Dalfampridine in Adults With Cerebral Palsy: A Pilot Study.

    Science.gov (United States)

    Bethoux, Francois; Fatemi, Ali; Fowler, Eileen; Marciniak, Christina; Mayadev, Angeli; Waksman, Joel; Zackowski, Kathleen; Suarez, Gustavo; Blight, Andrew R; Rabinowicz, Adrian L; Carrazana, Enrique

    2017-02-01

    The goal of this study was to evaluate the safety and tolerability of dalfampridine extended release (D-ER) in a pilot study of adults with cerebral palsy (CP) and limited ambulatory ability, and to explore drug effects on sensorimotor function. An initial double-blind, single-dose crossover study was performed in 11 individuals randomized 1:1 to receive D-ER (10 mg) or placebo, followed by a 2-day washout period and the opposite treatment, with evaluation for safety and tolerability. A twice daily dosing, double-blind, placebo-controlled, crossover study was then performed. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: 1 week of D-ER (10 mg BID) or placebo, followed by a 1-week washout and 1 week of the opposite treatment. Key inclusion criteria were age 18 to 70 years, body mass index 18.0 to 30.0 kg/m2, diagnosis of CP, and ability to perform all study procedures. Key exclusion criteria were severe CP, moderate or severe renal impairment, history of nonfebrile seizures, and prior dalfampridine use. Primary outcomes were safety profile and tolerability. Exploratory functional outcomes comprised changes in upper and lower extremity sensorimotor function (grip and pinch strength tests), manual dexterity (Box and Block Tests), and walking speed (Timed 25-Foot Walk). The most pronounced measured functional deficit in each individual was defined as the exploratory primary functional end point. Full crossover data were analyzed by using a mixed effects model. Among the 24 total participants who were randomized to treatment and completed the twice daily dosing phase study, their mean age was 38.6 years (range, 20-62 years), 54% were women, and 83% had spastic CP. Adverse events were consistent with previous D-ER trials, most commonly headache (13% D-ER, 4% placebo), fatigue (13% D-ER, 0% placebo), insomnia (8% D-ER, 4% placebo), diarrhea (4% D-ER, 4% placebo), and nausea (4% D-ER, 4% placebo). The mixed model analysis of full crossover data identified

  12. Gastrointestinal safety and tolerability of oral non-aspirin over-the-counter analgesics.

    Science.gov (United States)

    Moore, Nicholas; Scheiman, James M

    2018-02-08

    Over-the-counter (OTC) analgesics are routinely used worldwide for self-management of various painful conditions. Despite this, there has been little in-depth review of the safety of non-aspirin analgesics at OTC doses. This paper reviews the available literature on the gastrointestinal (GI) and hepatic safety of non-aspirin OTC analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, ketoprofen, diclofenac, and naproxen) and acetaminophen; safety in overdose is also reviewed. Each non-aspirin OTC analgesic has a distinct adverse event (AE) profile, with GI AE rates for OTC dosing in one study ranging from 37% for diclofenac to 7.2% for ibuprofen and 7.6% for acetaminophen; GI effects accounted for 75% of total AEs in the study. Across all studies reviewed here, the risk of serious GI toxicity, including upper GI bleeding and peptic ulcers, was low at OTC doses. By contrast, while both NSAIDs and acetaminophen may be associated with hepatotoxicity and acute liver failure (ALF), the risks associated with acetaminophen are somewhat higher and better documented. Reports of NSAID-associated hepatotoxicity rarely make distinctions by dose, making the risk at OTC doses difficult to assess. Liver injury due to acetaminophen, however, can occur at doses < 4000 mg. Case reports of NSAID-associated overdose are rare, while acetaminophen-containing drugs are a leading cause of overdose and are implicated in up to 97% of ALFs leading to transplant involving overdose. OTC analgesics are effective for self-management of pain; however, they are associated with a low but important rate of GI and hepatic events, as well as a risk of intentional and non-intentional overdose. Given the widespread use of this class of drugs, it is important for healthcare professionals to be mindful of their patients' use of OTC analgesics.

  13. Safety and immunogenicity of vaccination with MART-1 (26-35, 27L), gp100 (209-217, 210M), and tyrosinase (368-376, 370D) in adjuvant with PF-3512676 and GM-CSF in metastatic melanoma.

    Science.gov (United States)

    Tarhini, Ahmad A; Leng, Siyang; Moschos, Stergios J; Yin, Yan; Sander, Cindy; Lin, Yan; Gooding, William E; Kirkwood, John M

    2012-05-01

    The effectivenes of cancer vaccines in inducing CD8(+) T-cell responses remains a challenge, resulting in a need for testing more potent adjuvants. Our objective was to determine the safety and immunogenicity of vaccination against melanoma-related antigens employing MART-1, gp100, and tysosinase paptides combined with the TLR9 agonist PF-3512676 and local granulocyte macrophage-colony stimulating factor in oil emulsion. Using continuous monitoring of safety and a 2-stage design for immunologic efficacy, 20 immune response evaluable patients were targetted. Vaccinations were given subcutaneously on days 1 and 15 per cycle (1cycle=28 d) for up to 13 cycles. Interferon-γ enzyme-linked immunosorbent spot was used as the primary assay measuring the frequency of peripheral antigen-specific CD8(+) T cells at days 50 and 90 compared with baseline (target ≥ 9/20 immunologic responses). Clinical responses were measured by Response Evaluation Criteria In Solid Tumors every 8 weeks. Twenty-two (including 20 immune response evaluable) melanoma patients were enrolled. All had American Joint Committe on Cancer stage IV (5M1a, 6M1b, 11M1c) and most had previously received therapy. Eight had previously treated brain metastases. An average of 3.5 cycles of vaccination per patient was administered. Clinical response data were available for 21 patients. There were 2 partial response and 8 stable disease lasting 2-7 months. One patient with ongoing partial response continued on treatment. At a median follow-up of 7.39 months (range, 3.22-20.47 mo), median progression-free survival was 1.9 months (90% confidence interval, 1.84-3.68) and median overall survival was 13.4 months (90% confidence interval,11.3-∞). No regimen-related grade 3/4/5 toxicities were observed. There were 9/20 patients with positive enzyme-linked immunosorbent spot at day 50 and/or day 90. Our adjuvant regimen combining PF-3512676 and granulocyte macrophage-colony stimulating factor was safe and is worthy of

  14. Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo-pituitary-adrenal axis.

    LENUS (Irish Health Repository)

    Finucane, Francis M

    2008-10-01

    The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol production in pituitary disease. However, areas of uncertainty remain regarding its safety in older people, the optimal duration of the test and its performance in insulin resistant states. Whether basal cortisol concentration can reliably predict an adequate adrenal response to hypoglycaemia remains to be determined.

  15. Tolerance and safety of Lactobacillus paracasei ssp. paracasei in combination with Bifidobacterium animalis ssp. lactis in a prebiotic-containing infant formula: a randomised controlled trial

    NARCIS (Netherlands)

    Vlieger, A.M.; Robroch, A.H.; Van Buuren, S.|info:eu-repo/dai/nl/074806777; Kiers, J.; Rijkers, G.; Benninga, M.A.; te Biesebeke, R.

    2009-01-01

    The addition of probiotics to infant formula has been shown to be an efficient way to increase the number of beneficial bacteria in the intestine in order to promote a gut flora resembling that of breast-fed infants. The objective of the present study was to evaluate the safety and tolerance of a

  16. Tolerance and safety of Lactobacillus paracasei ssp paracasei in combination with Bifidobacterium animalis ssp lactis in a prebiotic-containing infant formula: a randomised controlled trial

    NARCIS (Netherlands)

    Vlieger, Arine M.; Robroch, Afke; van Buuren, Stef; Kiers, Jeroen; Rijkers, Ger; Benninga, Marc A.; te Biesebeke, Rob

    2009-01-01

    The addition of probiotics to infant formula has been shown to be an efficient way to increase the number of beneficial bacteria in the intestine in order to promote a gut flora resembling that of breast-fed infants. The objective of the present study was to evaluate the safety and tolerance of a

  17. Efficacy, safety and tolerability of 3 day azithromycin versus 10 day co-amoxiclav in the treatment of children with acute lower respiratory tract infections

    NARCIS (Netherlands)

    A. Ferwerda (Annemarie); H.A. Moll (Henriëtte); W.C.J. Hop (Wim); J.M. Kouwenberg (Jan); C.V. Tjon Pian Gi

    2001-01-01

    textabstractTo compare the efficacy, safety and tolerability of a 3 day course of azithromycin with a 10 day course of co-amoxiclav in the treatment of children with acute lower respiratory tract infection (LRTI), 118 patients with community-acquired LRTI were

  18. Phase I pharmacokinetic study of the safety and tolerability of lapatinib (GW572016) in combination with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) in patients with solid tumors

    NARCIS (Netherlands)

    Siegel-Lakhai, Wandena S.; Beijnen, Jos H.; Vervenne, Walter L.; Boot, Henk; Keessen, Marianne; Versola, Melissa; Koch, Kevin M.; Smith, Deborah A.; Pandite, Lini; Richel, Dirk J.; Schellens, Jan H. M.

    2007-01-01

    Purpose: This phase I study was designed to determine the optimally tolerated regimen (OTR), safety, and clinical activity of lapatinib in combination with FOLFOX4 [oxaliplatin/leucovorin/ 5-fluorouracil (5-FU)] in patients with solid tumors. Furthermore, the pharmacokinetics of lapatinib,

  19. Safety and tolerability of β3-adrenoceptor agonists in the treatment of overactive bladder syndrome - insight from transcriptosome and experimental studies

    NARCIS (Netherlands)

    Michel, Martin C.; Gravas, Stavros

    2016-01-01

    We have reviewed the safety and tolerability of β3-adrenoceptor agonists, specifically mirabegron and solabegron, a newly emerging drug class for the treatment of the overactive bladder syndrome. We discuss them mechanistically in the context of expression and other preclinical data. Based on a

  20. An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

    NARCIS (Netherlands)

    Oude Lashof, A.M.L.; Bock, R. de; Herbrecht, R.; Pauw, B.E. de; Krcmery, V.; Aoun, M.; Akova, M.; Cohen, J.; Siffnerova, H.; Egyed, M.; Ellis, M.; Marinus, A.; Sylvester, R.J.; Kullberg, B.J.

    2004-01-01

    Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised

  1. Long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis

    NARCIS (Netherlands)

    Luger, T. A.; Lahfa, M.; Fölster-Holst, R.; Gulliver, W. P.; Allen, R.; Molloy, S.; Barbier, N.; Paul, C.; Bos, J. D.

    2004-01-01

    OBJECTIVE: This randomized, double-blind, multi-centre study compared the long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids (TCS) in 658 adults with moderate-severe atopic dermatitis (AD). METHODS: Patients applied either pimecrolimus or TCS (i.e. 0.1%

  2. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB : systematic review and meta-analysis

    NARCIS (Netherlands)

    Sotgiu, Giovanni; Centis, Rosella; D'Ambrosio, Lia; Alffenaar, Jan-William C.; Anger, Holly A.; Caminero, Jose A.; Castiglia, Paolo; De Lorenzo, Saverio; Ferrara, Giovanni; Koh, Won-Jung; Schecter, Giesela F.; Shim, Tae S.; Singla, Rupak; Skrahina, Alena; Spanevello, Antonio; Udwadia, Zarir F.; Villar, Miquel; Zampogna, Elisabetta; Zellweger, Jean-Pierre; Zumla, Alimuddin; Migliori, Giovanni Battista

    2012-01-01

    Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from

  3. Safety and tolerability of combination therapy vs. standard treatment alone for patients with previously treated non-small cell lung cancer | Center for Cancer Research

    Science.gov (United States)

    Dr. James Gulley is leading a team to test the safety and tolerability of the combination of nivolumab and CV301 to see if it can improve the survival for patientis with metastatic non-small cell lung cancer.  Learn more...

  4. Intragastric balloon for treatment-resistant obesity: safety, tolerance, and efficacy of 1-year balloon treatment followed by a 1-year balloon-free follow-up

    NARCIS (Netherlands)

    Mathus-Vliegen, Elisabeth M. H.; Tytgat, Guido N. J.

    2005-01-01

    Background: Prior efforts to treat obesity with intragastric balloons were thwarted by high complication rates. Therefore, fundamental requirements for optimal balloon designs were defined. The aim of the present study was to investigate the effectiveness, the safety; and the tolerance of a new

  5. Li-Ion Electrolytes with Improved Safety and Tolerance to High-Voltage Systems

    Science.gov (United States)

    Smart, Marshall C.; Bugga, Ratnakumar V.; Prakash, Surya; Krause, Frederick C.

    2013-01-01

    Given that lithium-ion (Li-ion) technology is the most viable rechargeable energy storage device for near-term applications, effort has been devoted to improving the safety characteristics of this system. Therefore, extensive effort has been devoted to developing nonflammable electrolytes to reduce the flammability of the cells/battery. A number of promising electrolytes have been developed incorporating flame-retardant additives, and have been shown to have good performance in a number of systems. However, these electrolyte formulations did not perform well when utilizing carbonaceous anodes with the high-voltage materials. Thus, further development was required to improve the compatibility. A number of Li-ion battery electrolyte formulations containing a flame-retardant additive [i.e., triphenyl phosphate (TPP)] were developed and demonstrated in high-voltage systems. These electrolytes include: (1) formulations that incorporate varying concentrations of the flame-retardant additive (from 5 to 15%), (2) the use of mono-fluoroethylene carbonate (FEC) as a co-solvent, and (3) the use of LiBOB as an electrolyte additive intended to improve the compatibility with high-voltage systems. Thus, improved safety has been provided without loss of performance in the high-voltage, high-energy system.

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