Clinical development of Ebola vaccines

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Sridhar, Saranya

2015-01-01

The ongoing outbreak of Ebola virus disease in West Africa highlighted the lack of a licensed drug or vaccine to combat the disease and has renewed the urgency to develop a pipeline of Ebola vaccines. A number of different vaccine platforms are being developed by assessing preclinical efficacy in animal models and expediting clinical development. Over 15 different vaccines are in preclinical development and 8 vaccines are now in different stages of clinical evaluation. These vaccines include DNA vaccines, virus-like particles and viral vectors such as live replicating vesicular stomatitis virus (rVSV), human and chimpanzee adenovirus, and vaccinia virus. Recently, in preliminary results reported from the first phase III trial of an Ebola vaccine, the rVSV-vectored vaccine showed promising efficacy. This review charts this rapidly advancing area of research focusing on vaccines in clinical development and discusses the future opportunities and challenges faced in the licensure and deployment of Ebola vaccines. PMID:26668751

Dengue vaccines: Challenges, development, current status and prospects

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A Ghosh

2015-01-01

Full Text Available Infection with dengue virus (DENV is the most rapidly spreading mosquito-borne viral disease in the world. The clinical spectrum of dengue, caused by any of the four serotypes of DENV, ranges from mild self-limiting dengue fever to severe dengue, in the form dengue hemorrhagic fever (DHF and dengue shock syndrome (DSS. Increased rates of hospitalization due to severe dengue, during outbreaks, result in massive economic losses and strained health services. In the absence of specific antiviral therapy, control of transmission of DENV by vector management is the sole method available for decreasing dengue-associated morbidity. Since vector control strategies alone have not been able to satisfactorily achieve reduction in viral transmission, the implementation of a safe, efficacious and cost-effective dengue vaccine as a supplementary measure is a high public health priority. However, the unique and complex immunopathology of dengue has complicated vaccine development. Dengue vaccines have also been challenged by critical issues like lack of animal models for the disease and absence of suitable markers of protective immunity. Although no licensed dengue vaccine is yet available, several vaccine candidates are under phases of development, including live attenuated virus vaccines, live chimeric virus vaccines, inactivated virus vaccines, subunit vaccines, DNA vaccines and viral-vectored vaccines. Although some vaccine candidates have progressed from animal trials to phase II and III in humans, a number of issues regarding implementation of dengue vaccine in countries like India still need to be addressed. Despite the current limitations, collaborative effects of regulatory bodies like World Health Organization with vaccine manufacturers and policy makers, to facilitate vaccine development and standardize field trials can make a safe and efficacious dengue vaccine a reality in near future.

Screening of Viral Pathogens from Pediatric Ileal Tissue Samples after Vaccination

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Laura Hewitson

2014-01-01

Full Text Available In 2010, researchers reported that the two US-licensed rotavirus vaccines contained DNA or DNA fragments from porcine circovirus (PCV. Although PCV, a common virus among pigs, is not thought to cause illness in humans, these findings raised several safety concerns. In this study, we sought to determine whether viruses, including PCV, could be detected in ileal tissue samples of children vaccinated with one of the two rotavirus vaccines. A broad spectrum, novel DNA detection technology, the Lawrence Livermore Microbial Detection Array (LLMDA, was utilized, and confirmation of viral pathogens using the polymerase chain reaction (PCR was conducted. The LLMDA technology was recently used to identify PCV from one rotavirus vaccine. Ileal tissue samples were analyzed from 21 subjects, aged 15–62 months. PCV was not detected in any ileal tissue samples by the LLMDA or PCR. LLMDA identified a human rotavirus A from one of the vaccinated subjects, which is likely due to a recent infection from a wild type rotavirus. LLMDA also identified human parechovirus, a common gastroenteritis viral infection, from two subjects. Additionally, LLMDA detected common gastrointestinal bacterial organisms from the Enterobacteriaceae, Bacteroidaceae, and Streptococcaceae families from several subjects. This study provides a survey of viral and bacterial pathogens from pediatric ileal samples, and may shed light on future studies to identify pathogen associations with pediatric vaccinations.

Development of Recombinant Vaccine Using Herpesvirus of Turkey (Hvt as Vector for Several Viral Diseases in Poultry Industry

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Risza Hartawan

2011-03-01

Full Text Available Herpesvirus of turkey (HVT has been utilised as live vaccine against Marek’s disease in poultry industry world-wide for many years. However, the potency of HVT is not limited on the Marek’s disease only. Along with rapid development of recombinant technique, the potency of HVT can be broaden for other diseases. As naturally apathogenic virus, HVT is a suitable candidate as vector vaccine to express important antigens of viral pathogens. Several researches have been dedicated to design HVT recombinant vaccine by inserting gene of important virus, such as Marek’s disease virus (MDV, immuno bursal disease virus (IBDV, Newcastle disease virus (NDV and Avian Influenza virus (AIV. Therefore, the future recombinant of HVT has been expected to be better in performance along with the improvement of recombinant technique.

Biodegradable nanoparticle-entrapped vaccine induces cross-protective immune response against a virulent heterologous respiratory viral infection in pigs.

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Varun Dwivedi

Full Text Available Biodegradable nanoparticle-based vaccine development research is unexplored in large animals and humans. In this study, we illustrated the efficacy of nanoparticle-entrapped UV-killed virus vaccine against an economically important respiratory viral disease of pigs called porcine reproductive and respiratory syndrome virus (PRRSV. We entrapped PLGA [poly (lactide-co-glycolides] nanoparticles with killed PRRSV antigens (Nano-KAg and detected its phagocytosis by pig alveolar macrophages. Single doses of Nano-KAg vaccine administered intranasally to pigs upregulated innate and PRRSV specific adaptive responses. In a virulent heterologous PRRSV challenge study, Nano-KAg vaccine significantly reduced the lung pathology and viremia, and the viral load in the lungs. Immunologically, enhanced innate and adaptive immune cell population and associated cytokines with decreased secretion of immunosuppressive mediators were observed at both mucosal sites and blood. In summary, we demonstrated the benefits of intranasal delivery of nanoparticle-based viral vaccine in eliciting cross-protective immune response in pigs, a potential large animal model.

Development of Novel Vaccines against Enterovirus-71

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Yee, Pinn Tsin Isabel; Poh, Chit Laa

2015-01-01

The hand, foot and mouth disease is caused by a group of Enteroviruses such as Enterovirus 71 (EV-A71) and Coxsackievirus CV-A5, CV-A8, and CV-A16. Mild symptoms of EV-A71 infection in children range from high fever, vomiting, rashes and ulcers in mouth but can produce more severe symptoms such as brainstem and cerebellar encephalitis, leading up to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents against EV-A71 to prevent further fatalities. Research groups have developed experimental inactivated vaccines, recombinant Viral Protein 1 (VP1) vaccine and virus-like particles (VLPs). The inactivated EV-A71 vaccine is considered the safest viral vaccine, as there will be no reversion to the infectious wild type strain. The recombinant VP1 vaccine is a cost-effective immunogen, while VLPs contain an arrangement of epitopes that can elicit neutralizing antibodies against the virus. As each type of vaccine has its advantages and disadvantages, increased studies are required in the development of such vaccines, whereby high efficacy, long-lasting immunity, minimal risk to those vaccinated, safe and easy production, low cost, dispensing the need for refrigeration and convenient delivery are the major goals in their design. PMID:26729152

Viral respiratory diseases: vaccines and antivirals.

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Lennette, E H

1981-01-01

Acute respiratory diseases, most of which are generally attributed to viruses, account for about 6% of all deaths and for about 60% of the deaths associated with all respiratory disease. The huge cost attributable to viral respiratory infections as a result of absenteeism and the disruption of business and the burden of medical care makes control of these diseases an important objective. The viruses that infect the respiratory tract fall taxonomically into five viral families. Although immunoprophylaxis would appear to be the logical approach, the development of suitable vaccines has been confronted with numerous obstacles, including antigenic drift and shift in the influenzaviruses, the large number of antigenically distinct immunotypes among rhinoviruses, the occurrence after immunization of rare cases of a severe form of the disease following subsequent natural infection with respiratory syncytial virus, and the risk of oncogenicity of adenoviruses for man. Considerable expenditure on the development of new antiviral drugs has so far resulted in only three compounds that are at present officially approved and licensed for use in the USA. Efforts to improve the tools available for control should continue and imaginative and inventive approaches are called for. However, creativity and ingenuity must operate within the constraints imposed by economic, political, ethical, and legal considerations.

Virus detection by PCR following vaccination of naive calves with intranasal or injectable multivalent modified-live viral vaccines.

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Walz, Paul H; Newcomer, Benjamin W; Riddell, Kay P; Scruggs, Daniel W; Cortese, Victor S

2017-09-01

We evaluated duration of PCR-positive results following administration of modified-live viral (MLV) vaccines to beef calves. Twenty beef calves were randomly assigned to either group 1 and vaccinated intranasally with a MLV vaccine containing bovine alphaherpesvirus 1 (BoHV-1), bovine respiratory syncytial virus (BRSV), and bovine parainfluenza virus 3 (BPIV-3), or to group 2 and vaccinated subcutaneously with a MLV vaccine containing bovine viral diarrhea virus 1 and 2 (BVDV-1, -2), BoHV-1, BRSV, and BPIV-3. Deep nasopharyngeal swabs (NPS) and transtracheal washes (TTW) were collected from all calves, and whole blood was collected from group 2 calves and tested by PCR. In group 1, the proportions of calves that tested PCR-positive to BVDV, BoHV-1, BRSV, and BPIV-3 on any sample at any time were 0%, 100%, 100%, and 10%, respectively. In group 1 calves, 100% of calves became PCR-positive for BoHV-1 by day 3 post-vaccination and 100% of calves became PCR-positive for BRSV by day 7 post-vaccination. In group 2, the proportions of calves that tested positive to BVDV, BoHV-1, BRSV, and BPIV-3 on any sample at any time were 50%, 40%, 10%, and 0%, respectively. All threshold cycle (Ct) values were >30 in group 2 calves, irrespective of virus; however, Ct values PCR-positive results for BoHV-1 and BRSV. All calves were PCR-negative for all viruses after day 28. Following intranasal MLV viral vaccination, PCR results and Ct values for BRSV and BoHV-1 suggest that attempts to differentiate vaccine virus from natural infection is unreliable.

Development of a challenge-protective vaccine concept by modification of the viral RNA-dependent RNA polymerase of canine distemper virus.

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Silin, D; Lyubomska, O; Ludlow, M; Duprex, W P; Rima, B K

2007-12-01

We demonstrate that insertion of the open reading frame of enhanced green fluorescent protein (EGFP) into the coding sequence for the second hinge region of the viral L (large) protein (RNA-dependent RNA polymerase) attenuates a wild-type canine distemper virus. Moreover, we show that single intranasal immunization with this recombinant virus provides significant protection against challenge with the virulent parental virus. Protection against wild-type challenge was gained either after recovery of cellular immunity postimmunization or after development of neutralizing antibodies. Insertion of EGFP seems to result in overattenuation of the virus, while our previous experiments demonstrated that the insertion of an epitope tag into a similar position did not affect L protein function. Thus, a desirable level of attenuation could be reached by manipulating the length of the insert (in the second hinge region of the L protein), providing additional tools for optimization of controlled attenuation. This strategy for controlled attenuation may be useful for a "quick response" in vaccine development against well-known and "new" viral infections and could be combined efficiently with other strategies of vaccine development and delivery systems.

Vaccines against viral hemorrhagic fevers: non-human primate models.

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Carrion, Ricardo; Patterson, Jean L

2011-06-01

Viral hemorrhagic fevers are a group of disease syndromes caused by infection with certain RNA viruses. The disease is marked by a febrile response, malaise, coagulopathy and vascular permeability culminating in death. Case fatality rates can reach 90% depending on the etiologic agent. Currently, there is no approved antiviral treatment. Because of the high case fatality, risk of importation and the potential to use these agents as biological weapons, development of countermeasures to these agents is a high priority. The sporadic nature of disease outbreaks and the ethical issues associated with conducting a human trial for such diseases make human studies impractical; therefore, development of countermeasures must occur in relevant animal models. Non-human primates are superior models to study infectious disease because their immune system is similar to humans and they are good predictors of efficacy in vaccine development and other intervention strategies. This review article summarizes viral hemorrhagic fever non-human primate models.

Adventitious agents in viral vaccines: lessons learned from 4 case studies.

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Petricciani, John; Sheets, Rebecca; Griffiths, Elwyn; Knezevic, Ivana

2014-09-01

Since the earliest days of biological product manufacture, there have been a number of instances where laboratory studies provided evidence for the presence of adventitious agents in a marketed product. Lessons learned from such events can be used to strengthen regulatory preparedness for the future. We have therefore selected four instances where an adventitious agent, or a signal suggesting the presence of an agent, was found in a viral vaccine, and have developed a case study for each. The four cases are: a) SV40 in polio vaccines; b) bacteriophage in measles and polio vaccines; c) reverse transcriptase in measles and mumps vaccines; and d) porcine circovirus and porcine circovirus DNA sequences in rotavirus vaccines. The lessons learned from each event are discussed. Based in part on those experiences, certain scientific principles have been identified by WHO that should be considered in regulatory risk evaluation if an adventitious agent is found in a marketed vaccine in the future. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Recent advances in vaccine development for herpes simplex virus types I and II.

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Coleman, Jeffrey L; Shukla, Deepak

2013-04-01

Despite recent advances in vaccine design and strategies, latent infection with herpes simplex virus (HSV) remains a formidable challenge. Approaches involving live-attenuated viruses and inactivated viral preparations were popular throughout the twentieth century. In the past ten years, many vaccine types, both prophylactic or therapeutic, have contained a replication-defective HSV, viral DNA or glycoproteins. New research focused on the mechanism of immune evasion by the virus has involved developing vaccines with various gene deletions and manipulations combined with the use of new and more specific adjuvants. In addition, new "prime-boost" methods of strengthening the vaccine efficacy have proven effective, but there have also been flaws with some recent strategies that appear to have compromised vaccine efficacy in humans. Given the complicated lifecycle of HSV and its unique way of spreading from cell-to-cell, it can be concluded that the development of an ideal vaccine needs new focus on cell-mediated immunity, better understanding of the latent viral genome and serious consideration of gender-based differences in immunity development among humans. This review summarizes recent developments made in the field and sheds light on some potentially new ways to conquer the problem including development of dual-action prophylactic microbicides that prohibit viral entry and, in addition, induce a strong antigen response.

Diverse uses of feathers with emphasis on diagnosis of avian viral infections and vaccine virus monitoring

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I Davidson

2009-09-01

Full Text Available The large amounts of feathers produced by the poultry industry, that is considered as a waste was explored for possible uses in various industries, such as meals for animals, biofuels, biodegradable plastic materials, combating water pollution and more. That review mentions these uses, but concentrate on the utilization of feathers for the diagnosis of viral infections and for monitoring vaccine viruses in chickens after vaccination. The viral diseases in which diagnosis using nucleic acids extracted from the feather shafts was described are, Marek's disease virus, circoviruses, chicken anemia virus, fowlpox virus, avian retroviruses, avian influenza virus and infectious laryngotracheitis virus. In two cases, of Marek's disease virus and of infectious laryngotracheitis virus, the differentiation of vaccine and wild-type viruses from feather shafts was made possible, thus allowing for monitoring the vaccination efficacy. The present review demonstrates also the stability of DNA viruses in feather shafts, and the possible evaluation of environmental dissemination of pathogens. When viruses are transmitted vertically, like in the cases of the retrovirus REV, a teratogenic effect on the development of feathers of the day-old newly hatched chick might occur in the case of avian influenza and the chicken anemia virus, which might indicate on a viral infection.

A potential disruptive technology in vaccine development: gene-based vaccines and their application to infectious diseases.

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Kaslow, David C

2004-10-01

Vaccine development requires an amalgamation of disparate disciplines and has unique economic and regulatory drivers. Non-viral gene-based delivery systems, such as formulated plasmid DNA, are new and potentially disruptive technologies capable of providing 'cheaper, simpler, and more convenient-to-use' vaccines. Typically and somewhat ironically, disruptive technologies have poorer product performance, at least in the near-term, compared with the existing conventional technologies. Because successful product development requires that the product's performance must meet or exceed the efficacy threshold for a desired application, the appropriate selection of the initial product applications for a disruptive technology is critical for its successful evolution. In this regard, the near-term successes of gene-based vaccines will likely be for protection against bacterial toxins and acute viral and bacterial infections. Recent breakthroughs, however, herald increasing rather than languishing performance improvements in the efficacy of gene-based vaccines. Whether gene-based vaccines ultimately succeed in eliciting protective immunity in humans to persistent intracellular pathogens, such as HIV, malaria and tuberculosis, for which the conventional vaccine technologies have failed, remains to be determined. A success against any one of the persistent intracellular pathogens would be sufficient proof that gene-based vaccines represent a disruptive technology against which future vaccine technologies will be measured.

Recommendations pertaining to the use of viral vaccines: Influenza ...

African Journals Online (AJOL)

Here we provide recommendations for the use of viral vaccines in anticipation of the 2014 southern hemisphere influenza season. For a review of the 2013 influenza season, please refer to the National Institute for Communicable Diseases, National Health Laboratory Service website (http://www.nicd.ac.za).

Parental views on childhood vaccination against viral gastroenteritis-a qualitative interview study.

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Lugg, Fiona V; Butler, Christopher C; Evans, Meirion R; Wood, Fiona; Francis, Nick A

2015-08-01

Gastroenteritis (GE) causes significant morbidity, especially in young children. A vaccine against rotavirus, a common cause of viral GE (vGE), was added to the childhood immunization schedule in the UK in July 2013 and further related vaccines are under development. To explore parents' beliefs about vGE and their attitudes towards vaccinating. Qualitative interview study with parents of children who had recently experienced an episode of GE. Twenty-eight semi-structured interviews were conducted over the phone with parents. Interviews were audio-recorded, transcribed and analysed using standard thematic approaches. Parents varied in their perception of the threat posed by GE, and parents who did not perceive GE as serious were less enthusiastic about vaccines. Other parents were supportive of vaccines in general and considered benefits to their child, their family and the wider community. Many parents said that they lacked knowledge about efficacy and effectiveness of GE vaccines but their underlying belief about the seriousness of illness motivated their attitudes. Acceptability of GE vaccines to parents could be improved by providing more information on both the burden of illness and the impact of rotavirus vaccine in other comparable countries. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Advances in the development of vaccines for dengue fever

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Simmons M

2012-05-01

Full Text Available Monika Simmons1, Nimfa Teneza-Mora1, Robert Putnak21Viral and Rickettsial Diseases Department, Naval Medical Research Center, 2Division of Viral Diseases, Walter Reed Army Institute of Research, Silver Spring, MD, USAAbstract: Dengue fever is caused by the mosquito-borne dengue virus (DENV serotypes 1–4, and is the most common arboviral infection of humans in subtropical and tropical regions of the world. There are currently no prophylaxis or treatment options in the form of vaccines or antivirals, leaving vector control the only method of prevention. A particular challenge with DENV is that a successful vaccine has to be effective against all four serotypes without predisposing for antibody-mediated enhanced disease. In this review, we discuss the current lead vaccine candidates in clinical trials, as well as some second-generation vaccine candidates undergoing preclinical evaluation. In addition, we discuss DENV epidemiology, clinical disease and strategies used for Flavivirus antivirals in the past, the development of new DENV therapeutics, and their potential usefulness for prophylaxis and treatment.Keywords: tetravalent dengue vaccine, live attenuated vaccine, purified inactivated vaccine, DNA vaccine, antibody-dependent enhancement, antivirals

Single-cycle immunodeficiency viruses provide strategies for uncoupling in vivo expression levels from viral replicative capacity and for mimicking live-attenuated SIV vaccines

International Nuclear Information System (INIS)

Kuate, Seraphin; Stahl-Hennig, Christiane; Haaft, Peter ten; Heeney, Jonathan; Ueberla, Klaus

2003-01-01

To reduce the risks associated with live-attenuated immunodeficiency virus vaccines, single-cycle immunodeficiency viruses (SCIVs) were developed by primer complementation and production of the vaccine in the absence of vif in a vif-independent cell line. After a single intravenous injection of SCIVs into rhesus monkeys, peak viral RNA levels of 10 3 to 10 4 copies/ml plasma were observed, indicating efficient expression of SCIV in the vaccinee. After booster immunizations with SCIVs, SIV-specific humoral and cellular immune responses were observed. Although the vaccine doses used in this pilot study could not protect vaccinees from subsequent intravenous challenge with pathogenic SIVmac239, our results demonstrate that the novel SCIV approach allows us to uncouple in vivo expression levels from the viral replicative capacity facilitating the analysis of the relationship between viral expression levels or viral genes and immune responses induced by SIV

Comparison of reproductive protection against bovine viral diarrhea virus provided by multivalent viral vaccines containing inactivated fractions of bovine viral diarrhea virus 1 and 2.

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Walz, Paul H; Riddell, Kay P; Newcomer, Benjamin W; Neill, John D; Falkenberg, Shollie M; Cortese, Victor S; Scruggs, Daniel W; Short, Thomas H

2018-04-23

Bovine viral diarrhea virus (BVDV) is an important viral cause of reproductive disease, immune suppression and clinical disease in cattle. The objective of this study was to compare reproductive protection in cattle against the impacts of bovine viral diarrhea virus (BVDV) provided by three different multivalent vaccines containing inactivated BVDV. BVDV negative beef heifers and cows (n = 122) were randomly assigned to one of four groups. Groups A-C (n = 34/group) received two pre-breeding doses of one of three commercially available multivalent vaccines containing inactivated fractions of BVDV 1 and BVDV 2, and Group D (n = 20) served as negative control and received two doses of saline prior to breeding. Animals were bred, and following pregnancy diagnosis, 110 cattle [Group A (n = 31); Group B (n = 32); Group C (n = 31); Group D (n = 16)] were subjected to a 28-day exposure to cattle persistently infected (PI) with BVDV (1a, 1b and 2a). Of the 110 pregnancies, 6 pregnancies resulted in fetal resorption with no material for testing. From the resultant 104 pregnancies, BVDV transplacental infections were demonstrated in 73 pregnancies. The BVDV fetal infection rate (FI) was calculated at 13/30 (43%) for Group A cows, 27/29 (93%) for Group B cows, 18/30 (60%) for Group C cows, and 15/15 (100%) for Group D cows. Statistical differences were observed between groups with respect to post-vaccination antibody titers, presence and duration of viremia in pregnant cattle, and fetal infection rates in offspring from BVDV-exposed cows. Group A vaccination resulted in significant protection against BVDV infection as compared to all other groups based upon outcome measurements, while Group B vaccination did not differ in protection against BVDV infection from control Group D. Ability of inactivated BVDV vaccines to provide protection against BVDV fetal infection varies significantly among commercially available products; however, in this challenge

IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8⁺ T cell avidity following HIV-1 recombinant pox viral vaccination.

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Wijesundara, Danushka K; Jackson, Ronald J; Tscharke, David C; Ranasinghe, Charani

2013-09-23

We have shown that mucosal HIV-1 recombinant pox viral vaccination can induce high, avidity HIV-specific CD8(+) T cells with reduced interleukin (IL)-4 and IL-13 expression compared to, systemic vaccine delivery. In the current study how these cytokines act to regulate anti-viral CD8(+) T, cell avidity following HIV-1 recombinant pox viral prime-boost vaccination was investigated. Out of a panel of T cell avidity markers tested, only CD8 expression levels were found to be enhanced on, KdGag197-205 (HIV)-specific CD8(+) T cells obtained from IL-13(-/-), IL-4(-/-) and signal transducer and, activator of transcription of 6 (STAT6)(-/-) mice compared to wild-type (WT) controls following, vaccination. Elevated CD8 expression levels in this instance also correlated with polyfunctionality, (interferon (IFN)-γ, tumour necorsis factor (TNF)-α and IL-2 production) and the avidity of HIVspecific CD8(+) T cells. Furthermore, mucosal vaccination and vaccination with the novel adjuvanted IL-13 inhibitor (i.e. IL-13Rα2) vaccines significantly enhanced CD8 expression levels on HIV-specific CD8(+), T cells, which correlated with avidity. Using anti-CD8 antibodies that blocked CD8 availability on CD8(+), T cells, it was established that CD8 played an important role in increasing HIV-specific CD8(+) T cell avidity and polyfunctionality in IL-4(-/-), IL-13(-/-) and STAT6(-/-) mice compared to WT controls, following vaccination. Collectively, our data demonstrate that IL-4 and IL-13 dampen CD8 expression levels on anti-viral CD8(+) T cells, which can down-regulate anti-viral CD8(+) T cell avidity and, polyfunctionality following HIV-1 recombinant pox viral vaccination. These findings can be exploited to, design more efficacious vaccines not only against HIV-1, but many chronic infections where high, avidity CD8(+) T cells help protection. Copyright © 2013 Elsevier Ltd. All rights reserved.

Recombinant vaccines against T. gondii: comparison between homologous and heterologous vaccination protocols using two viral vectors expressing SAG1.

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Mendes, Érica Araújo; Fonseca, Flavio G; Casério, Bárbara M; Colina, Janaína P; Gazzinelli, Ricardo Tostes; Caetano, Braulia C

2013-01-01

The use of recombinant viral vectors expressing T. gondii antigens is a safe and efficient approach to induce immune response against the parasite and a valuable tool for vaccine development. We have previously protected mice from toxoplasmosis by immunizing the animals with an adenovirus expressing the protein SAG1 (AdSAG1) of T. gondii. We are now looking for ways to improve the vaccination strategy and enhance protection. One limitation of homologous vaccinations (sequential doses of the same vector) is induction of anti-vector immune response that blocks cell transduction, restricts transgene expression and, consequently, compromises the overall outcome of vaccination. One way to avert the effects of anti-vector response is to use different viruses in prime and boost (heterologous vaccination). Bearing this in mind, we generated a modified Vaccinia Virus Ankara encoding SAG1 (MVASAG1), to be tested as boost agent after prime with AdSAG1. Although minor differences were observed in the magnitude of the anti-SAG1 immune response induced by each vaccination protocol, the heterologous immunization with AdSAG1 followed by MVASAG1 resulted in improved capacity to control brain cyst formation in a model of chronic toxoplasmosis in C57BL/6 mice.

Recombinant vaccines against T. gondii: comparison between homologous and heterologous vaccination protocols using two viral vectors expressing SAG1.

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Érica Araújo Mendes

Full Text Available The use of recombinant viral vectors expressing T. gondii antigens is a safe and efficient approach to induce immune response against the parasite and a valuable tool for vaccine development. We have previously protected mice from toxoplasmosis by immunizing the animals with an adenovirus expressing the protein SAG1 (AdSAG1 of T. gondii. We are now looking for ways to improve the vaccination strategy and enhance protection. One limitation of homologous vaccinations (sequential doses of the same vector is induction of anti-vector immune response that blocks cell transduction, restricts transgene expression and, consequently, compromises the overall outcome of vaccination. One way to avert the effects of anti-vector response is to use different viruses in prime and boost (heterologous vaccination. Bearing this in mind, we generated a modified Vaccinia Virus Ankara encoding SAG1 (MVASAG1, to be tested as boost agent after prime with AdSAG1. Although minor differences were observed in the magnitude of the anti-SAG1 immune response induced by each vaccination protocol, the heterologous immunization with AdSAG1 followed by MVASAG1 resulted in improved capacity to control brain cyst formation in a model of chronic toxoplasmosis in C57BL/6 mice.

Recombinant vaccines and the development of new vaccine strategies

Energy Technology Data Exchange (ETDEWEB)

Nascimento, I.P.; Leite, L.C.C. [Centro de Biotecnologia, Instituto Butantan, São Paulo, SP (Brazil)

2012-09-07

Vaccines were initially developed on an empirical basis, relying mostly on attenuation or inactivation of pathogens. Advances in immunology, molecular biology, biochemistry, genomics, and proteomics have added new perspectives to the vaccinology field. The use of recombinant proteins allows the targeting of immune responses focused against few protective antigens. There are a variety of expression systems with different advantages, allowing the production of large quantities of proteins depending on the required characteristics. Live recombinant bacteria or viral vectors effectively stimulate the immune system as in natural infections and have intrinsic adjuvant properties. DNA vaccines, which consist of non-replicating plasmids, can induce strong long-term cellular immune responses. Prime-boost strategies combine different antigen delivery systems to broaden the immune response. In general, all of these strategies have shown advantages and disadvantages, and their use will depend on the knowledge of the mechanisms of infection of the target pathogen and of the immune response required for protection. In this review, we discuss some of the major breakthroughs that have been achieved using recombinant vaccine technologies, as well as new approaches and strategies for vaccine development, including potential shortcomings and risks.

Recombinant vaccines and the development of new vaccine strategies

Directory of Open Access Journals (Sweden)

I.P. Nascimento

2012-12-01

Full Text Available Vaccines were initially developed on an empirical basis, relying mostly on attenuation or inactivation of pathogens. Advances in immunology, molecular biology, biochemistry, genomics, and proteomics have added new perspectives to the vaccinology field. The use of recombinant proteins allows the targeting of immune responses focused against few protective antigens. There are a variety of expression systems with different advantages, allowing the production of large quantities of proteins depending on the required characteristics. Live recombinant bacteria or viral vectors effectively stimulate the immune system as in natural infections and have intrinsic adjuvant properties. DNA vaccines, which consist of non-replicating plasmids, can induce strong long-term cellular immune responses. Prime-boost strategies combine different antigen delivery systems to broaden the immune response. In general, all of these strategies have shown advantages and disadvantages, and their use will depend on the knowledge of the mechanisms of infection of the target pathogen and of the immune response required for protection. In this review, we discuss some of the major breakthroughs that have been achieved using recombinant vaccine technologies, as well as new approaches and strategies for vaccine development, including potential shortcomings and risks.

Recombinant vaccines and the development of new vaccine strategies

International Nuclear Information System (INIS)

Nascimento, I.P.; Leite, L.C.C.

2012-01-01

Vaccines were initially developed on an empirical basis, relying mostly on attenuation or inactivation of pathogens. Advances in immunology, molecular biology, biochemistry, genomics, and proteomics have added new perspectives to the vaccinology field. The use of recombinant proteins allows the targeting of immune responses focused against few protective antigens. There are a variety of expression systems with different advantages, allowing the production of large quantities of proteins depending on the required characteristics. Live recombinant bacteria or viral vectors effectively stimulate the immune system as in natural infections and have intrinsic adjuvant properties. DNA vaccines, which consist of non-replicating plasmids, can induce strong long-term cellular immune responses. Prime-boost strategies combine different antigen delivery systems to broaden the immune response. In general, all of these strategies have shown advantages and disadvantages, and their use will depend on the knowledge of the mechanisms of infection of the target pathogen and of the immune response required for protection. In this review, we discuss some of the major breakthroughs that have been achieved using recombinant vaccine technologies, as well as new approaches and strategies for vaccine development, including potential shortcomings and risks

Development of an enhanced bovine viral diarrhea virus subunit vaccine based on E2 glycoprotein fused to a single chain antibody which targets to antigen-presenting cells

Directory of Open Access Journals (Sweden)

Andrea Pecora

2015-03-01

Full Text Available Bovine viral diarrhea virus (BVDV is an important cause of economic losses worldwide. E2 is an immunodominant protein and a promising candidate to develop subunit vaccines. To improve its immunogenicity, a truncated E2 (tE2 was fused to a single chain antibody named APCH, which targets to antigen-presenting cells. APCH-tE2 and tE2 proteins were expressed in the baculovirus system and their immunogenicity was firstly compared in guinea pigs. APCH-tE2 vaccine was the best one to evoke a humoral response, and for this reason, it was selected for a cattle vaccination experiment. All the bovines immunized with 1.5 µg of APCH-tE2 developed high levels of neutralizing antibodies against BVDV up to a year post-immunization, demonstrating its significant potential as a subunit vaccine. This novel vaccine is undergoing scale-up and was transferred to the private sector. Nowadays, it is being evaluated for registration as the first Argentinean subunit vaccine for cattle.

Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production.

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Tapia, Felipe; Vázquez-Ramírez, Daniel; Genzel, Yvonne; Reichl, Udo

2016-03-01

With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 10(7) cells/mL or even 10(8) cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to

Next-Generation Dengue Vaccines: Novel Strategies Currently Under Development

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Anna P. Durbin

2011-09-01

Full Text Available Dengue has become the most important arboviral infection worldwide with more than 30 million cases of dengue fever estimated to occur each year. The need for a dengue vaccine is great and several live attenuated dengue candidate vaccines are proceeding through clinical evaluation. The need to induce a balanced immune response against all four DENV serotypes with a single vaccine has been a challenge for dengue vaccine developers. A live attenuated DENV chimeric vaccine produced by Sanofi Pasteur has recently entered Phase III evaluation in numerous dengue-endemic regions of the world. Viral interference between serotypes contained in live vaccines has required up to three doses of the vaccine be given over a 12-month period of time. For this reason, novel DENV candidate vaccines are being developed with the goal of achieving a protective immune response with an immunization schedule that can be given over the course of a few months. These next-generation candidates include DNA vaccines, recombinant adenovirus vectored vaccines, alphavirus replicons, and sub-unit protein vaccines. Several of these novel candidates will be discussed.

Next-generation dengue vaccines: novel strategies currently under development.

Science.gov (United States)

Durbin, Anna P; Whitehead, Stephen S

2011-10-01

Dengue has become the most important arboviral infection worldwide with more than 30 million cases of dengue fever estimated to occur each year. The need for a dengue vaccine is great and several live attenuated dengue candidate vaccines are proceeding through clinical evaluation. The need to induce a balanced immune response against all four DENV serotypes with a single vaccine has been a challenge for dengue vaccine developers. A live attenuated DENV chimeric vaccine produced by Sanofi Pasteur has recently entered Phase III evaluation in numerous dengue-endemic regions of the world. Viral interference between serotypes contained in live vaccines has required up to three doses of the vaccine be given over a 12-month period of time. For this reason, novel DENV candidate vaccines are being developed with the goal of achieving a protective immune response with an immunization schedule that can be given over the course of a few months. These next-generation candidates include DNA vaccines, recombinant adenovirus vectored vaccines, alphavirus replicons, and sub-unit protein vaccines. Several of these novel candidates will be discussed.

DNA vaccination of rainbow trout against viral hemorrhagic septicemia virus: A dose-response and time-course study

DEFF Research Database (Denmark)

Lorenzen, Ellen; Einer-Jensen, Katja; Martinussen, T.

2000-01-01

Viral hemorrhagic septicemia (VHS) in rainbow trout Oncorhynchus mykiss is caused by VHS virus (VHSV), which belongs to the rhabdovirus family. Among the different strategies for immunizing fish with a recombinant vaccine, genetic immunization has recently proven to be highly effective. To further...... investigate the potential for protecting fish against VHS by DNA vaccination, experiments were conducted to determine the amount of plasmid DNA needed for induction of protective immunity. The time to onset of immunity and the duration of protection following administration of a protective vaccine dose were...... serologically different from the isolate used for vaccine development. Following administration of 1 mug of a DNA vaccine, significant protection against VHS was observed in the fish as early as 8 d postvaccination. At 168 d postvaccination, the fish had increased in size by a factor of 10 and protection...

Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant

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Shailbala Singh

2014-10-01

Full Text Available Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer, a synthetic glycolipid agonist of natural killer T (NKT cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.

Comparison of reproductive protection against bovine viral diarrhea virus provided by multivalent viral vaccines containing inactivated fractions of bovine viral diarrhea virus 1 and 2

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The objective of this study was to compare reproductive protection in cattle against the impacts of bovine viral diarrhea virus (BVDV) provided by three different multivalent vaccines containing inactivated BVDV. Beef heifers and cows (n=122), seronegative and virus negative for BVDV, were randomly ...

Development of an enhanced bovine viral diarrhea virus subunit vaccine based on E2 glycoprotein fused to a single chain antibody which targets to antigen-presenting cells.

Science.gov (United States)

Pecora, Andrea; Malacari, Darío A; Pérez Aguirreburualde, María S; Bellido, Demian; Escribano, José M; Dus Santos, María J; Wigdorovitz, Andrés

2015-01-01

Bovine viral diarrhea virus (BVDV) is an important cause of economic losses worldwide. E2 is an immunodominant protein and a promising candidate to develop subunit vaccines. To improve its immunogenicity, a truncated E2 (tE2) was fused to a single chain antibody named APCH, which targets to antigen-presenting cells. APCH-tE2 and tE2 proteins were expressed in the baculovirus system and their immunogenicity was firstly compared in guinea pigs. APCH-tE2 vaccine was the best one to evoke a humoral response, and for this reason, it was selected for a cattle vaccination experiment. All the bovines immunized with 1.5 μg of APCH-tE2 developed high levels of neutralizing antibodies against BVDV up to a year post-immunization, demonstrating its significant potential as a subunit vaccine. This novel vaccine is undergoing scale-up and was transferred to the private sector. Nowadays, it is being evaluated for registration as the first Argentinean subunit vaccine for cattle. Copyright © 2014 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Viral Aetiology of Acute Flaccid Paralysis Surveillance Cases, before and after Vaccine Policy Change from Oral Polio Vaccine to Inactivated Polio Vaccine

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T. S. Saraswathy Subramaniam

2014-01-01

Full Text Available Since 1992, surveillance for acute flaccid paralysis (AFP cases was introduced in Malaysia along with the establishment of the National Poliovirus Laboratory at the Institute for Medical Research. In 2008, the Ministry of Health, Malaysia, approved a vaccine policy change from oral polio vaccine to inactivated polio vaccine (IPV. Eight states started using IPV in the Expanded Immunization Programme, followed by the remaining states in January 2010. The objective of this study was to determine the viral aetiology of AFP cases below 15 years of age, before and after vaccine policy change from oral polio vaccine to inactivated polio vaccine. One hundred and seventy-nine enteroviruses were isolated from the 3394 stool specimens investigated between 1992 and December 2012. Fifty-six out of 107 virus isolates were polioviruses and the remaining were non-polio enteroviruses. Since 2009 after the sequential introduction of IPV in the childhood immunization programme, no Sabin polioviruses were isolated from AFP cases. In 2012, the laboratory AFP surveillance was supplemented with environmental surveillance with sewage sampling. Thirteen Sabin polioviruses were also isolated from sewage in the same year, but no vaccine-derived poliovirus was detected during this period.

Vacinas contra varicela e vacina quádrupla viral Varicella vaccines and measles, mumps, rubella, and varicella vaccine

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Lucia Ferro Bricks

2006-07-01

Full Text Available OBJETIVOS: Apresentar uma revisão atualizada sobre os estudos de eficácia, eventos adversos e esquema vacinal da vacina contra varicela e a nova apresentação combinada com a vacina contra sarampo, caxumba e rubéola. FONTES DOS DADOS: Revisão bibliográfica utilizando a base de dados MEDLINE e LILACS no período de 1999 a 2006. SÍNTESE DOS DADOS: A vacina contra varicela tem uma eficácia entre 70 a 90% contra a infecção e 95 a 98% de proteção contra as formas graves. É uma vacina bem tolerada e pouco reatogênica. Após o seu licenciamento, foram comprovados apenas três casos de transmissão do vírus vacinal de pessoas previamente saudáveis para contatos domiciliares, que desenvolveram doença leve. Apesar das evidências de que a proteção conferida pela vacina pode diminuir com o passar dos anos, ainda não é possível afirmar que seja necessário, no momento, a aplicação de uma segunda dose, tendo em vista a exposição ao vírus selvagem. Após a vacinação universal, as chances de estímulo natural deverão diminuir, e muito provavelmente será necessário a aplicação de doses de reforço. Recentemente foi licenciada a vacina quádrupla viral, um produto combinado com a vacina contra sarampo, caxumba, rubéola e varicela com elevadas taxas de soroconversão. CONCLUSÃO:A vacina contra varicela é recomendada pela Sociedade Brasileira de Pediatria (SBP para as crianças a partir de 1 ano de idade. Esperamos que, em breve, a vacina quádrupla viral esteja disponível no Brasil, pois o uso de vacinas combinadas possibilita uma maior cobertura vacinal.OBJECTIVES: To present an up-to-date review of studies investigating the efficacy, adverse events and vaccination regimens of the varicella vaccine and the new presentation combined with the vaccine for measles, mumps and rubella. SOURCES OF DATA: Bibliographic review of the MEDLINE and LILACS databases covering the period 1999 to 2006 SUMMARY OF THE FINDINGS: The varicella

The yellow fever 17D vaccine virus as a vector for the expression of foreign proteins: development of new live flavivirus vaccines

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Myrna C Bonaldo

2000-01-01

Full Text Available The Flaviviridae is a family of about 70 mostly arthropod-borne viruses many of which are major public health problems with members being present in most continents. Among the most important are yellow fever (YF, dengue with its four serotypes and Japanese encephalitis virus. A live attenuated virus is used as a cost effective, safe and efficacious vaccine against YF but no other live flavivirus vaccines have been licensed. The rise of recombinant DNA technology and its application to study flavivirus genome structure and expression has opened new possibilities for flavivirus vaccine development. One new approach is the use of cDNAs encopassing the whole viral genome to generate infectious RNA after in vitro transcription. This methodology allows the genetic mapping of specific viral functions and the design of viral mutants with considerable potential as new live attenuated viruses. The use of infectious cDNA as a carrier for heterologous antigens is gaining importance as chimeric viruses are shown to be viable, immunogenic and less virulent as compared to the parental viruses. The use of DNA to overcome mutation rates intrinsic of RNA virus populations in conjunction with vaccine production in cell culture should improve the reliability and lower the cost for production of live attenuated vaccines. The YF virus despite a long period ignored by researchers probably due to the effectiveness of the vaccine has made a come back, both in nature as human populations grow and reach endemic areas as well as in the laboratory being a suitable model to understand the biology of flaviviruses in general and providing new alternatives for vaccine development through the use of the 17D vaccine strain.

Novel adjuvants & delivery vehicles for vaccines development: a road ahead.

Science.gov (United States)

Mohan, Teena; Verma, Priyanka; Rao, D Nageswara

2013-11-01

The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines.

Attacking Postoperative Metastases using Perioperative Oncolytic Viruses and Viral Vaccines

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Tai, Lee-Hwa; Auer, Rebecca

2014-01-01

Surgical resection of solid primary malignancies is a mainstay of therapy for cancer patients. Despite being the most effective treatment for these tumors, cancer surgery has been associated with impaired metastatic clearance due to immunosuppression. In preclinical surgery models and human cancer patients, we and others have demonstrated a profound suppression of both natural killer (NK) and T cell function in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Oncolytic viruses (OV) were originally designed to selectively infect and replicate in tumors, with the primary objective of directly lysing cancer cells. It is becoming increasingly clear, however, that OV infection results in a profound inflammatory reaction within the tumor, initiating innate and adaptive immune responses against it that is critical for its therapeutic benefit. This anti-tumor immunity appears to be mediated predominantly by NK and cytotoxic T cells. In preclinical models, we found that preoperative OV prevents postoperative NK cell dysfunction and attenuates tumor dissemination. Due to theoretical safety concerns of administering live virus prior to surgery in cancer patients, we characterized safe, attenuated versions of OV, and viral vaccines that could stimulate NK cells and reduce metastases when administered in the perioperative period. In cancer patients, we observed that in vivo infusion with oncolytic vaccinia virus and ex vivo stimulation with viral vaccines promote NK cell activation. These preclinical studies provide a novel and clinically relevant setting for OV therapy. Our challenge is to identify safe and promising OV therapies that will activate NK and T cells in the perioperative period preventing the establishment of micrometastatic disease in cancer patients. PMID:25161958

Cold-Adapted Viral Attenuation (CAVA): Highly Temperature Sensitive Polioviruses as Novel Vaccine Strains for a Next Generation Inactivated Poliovirus Vaccine.

Science.gov (United States)

Sanders, Barbara P; de Los Rios Oakes, Isabel; van Hoek, Vladimir; Bockstal, Viki; Kamphuis, Tobias; Uil, Taco G; Song, Yutong; Cooper, Gillian; Crawt, Laura E; Martín, Javier; Zahn, Roland; Lewis, John; Wimmer, Eckard; Custers, Jerome H H V; Schuitemaker, Hanneke; Cello, Jeronimo; Edo-Matas, Diana

2016-03-01

The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV) is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA) poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4-9.9 Log10TCID50/ml) on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature) anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the highly productive

Comparative Pathogenesis and Systems Biology for Biodefense Virus Vaccine Development

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Gavin C. Bowick

2010-01-01

Full Text Available Developing vaccines to biothreat agents presents a number of challenges for discovery, preclinical development, and licensure. The need for high containment to work with live agents limits the amount and types of research that can be done using complete pathogens, and small markets reduce potential returns for industry. However, a number of tools, from comparative pathogenesis of viral strains at the molecular level to novel computational approaches, are being used to understand the basis of viral attenuation and characterize protective immune responses. As the amount of basic molecular knowledge grows, we will be able to take advantage of these tools not only to rationally attenuate virus strains for candidate vaccines, but also to assess immunogenicity and safety in silico. This review discusses how a basic understanding of pathogenesis, allied with systems biology and machine learning methods, can impact biodefense vaccinology.

A novel DNA vaccine technology conveying protection against a lethal herpes simplex viral challenge in mice.

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Julie L Dutton

Full Text Available While there are a number of licensed veterinary DNA vaccines, to date, none have been licensed for use in humans. Here, we demonstrate that a novel technology designed to enhance the immunogenicity of DNA vaccines protects against lethal herpes simplex virus 2 (HSV-2 challenge in a murine model. Polynucleotides were modified by use of a codon optimization algorithm designed to enhance immune responses, and the addition of an ubiquitin-encoding sequence to target the antigen to the proteasome for processing and to enhance cytotoxic T cell responses. We show that a mixture of these codon-optimized ubiquitinated and non-ubiquitinated constructs encoding the same viral envelope protein, glycoprotein D, induced both B and T cell responses, and could protect against lethal viral challenge and reduce ganglionic latency. The optimized vaccines, subcloned into a vector suitable for use in humans, also provided a high level of protection against the establishment of ganglionic latency, an important correlate of HSV reactivation and candidate endpoint for vaccines to proceed to clinical trials.

FIRST APPLICATION EXPERIENCE OF THE QUADRIVALENT VACCINE FOR PREVENTION OF THE PAPILLOMA VIRAL INFECTION AND CERVICAL CANCER

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M.G. Galitskaya

2008-01-01

Full Text Available In this article, the authors demonstrate high spread of the human papilloma viral contamination and danger, which this virus poses for the health of population. Taking into account that this is the only virus, for which it is proved that there are properties for inducing the neoplastic process in the human body, the interest revealed by the scientists from all over the world towards the creation of a specific vaccine is beyond any doubt. The researchers showed the results of application of the primary vaccine prevention for papilloma viral infection abroad. They have also highlighted their own experience in vaccination, which is probably most valuable for the pediatricians, who understand the reality of a danger and attempt to avert it.Key words: human papilloma virus, prevalence, papillomatosis, oncogenous properties, prevention.

Reverse Genetics Approaches for the Development of Influenza Vaccines

Science.gov (United States)

Nogales, Aitor; Martínez-Sobrido, Luis

2016-01-01

Influenza viruses cause annual seasonal epidemics and occasional pandemics of human respiratory disease. Influenza virus infections represent a serious public health and economic problem, which are most effectively prevented through vaccination. However, influenza viruses undergo continual antigenic variation, which requires either the annual reformulation of seasonal influenza vaccines or the rapid generation of vaccines against potential pandemic virus strains. The segmented nature of influenza virus allows for the reassortment between two or more viruses within a co-infected cell, and this characteristic has also been harnessed in the laboratory to generate reassortant viruses for their use as either inactivated or live-attenuated influenza vaccines. With the implementation of plasmid-based reverse genetics techniques, it is now possible to engineer recombinant influenza viruses entirely from full-length complementary DNA copies of the viral genome by transfection of susceptible cells. These reverse genetics systems have provided investigators with novel and powerful approaches to answer important questions about the biology of influenza viruses, including the function of viral proteins, their interaction with cellular host factors and the mechanisms of influenza virus transmission and pathogenesis. In addition, reverse genetics techniques have allowed the generation of recombinant influenza viruses, providing a powerful technology to develop both inactivated and live-attenuated influenza vaccines. In this review, we will summarize the current knowledge of state-of-the-art, plasmid-based, influenza reverse genetics approaches and their implementation to provide rapid, convenient, safe and more effective influenza inactivated or live-attenuated vaccines. PMID:28025504

Ebola hemorrhagic Fever and the current state of vaccine development.

Science.gov (United States)

Hong, Joo Eun; Hong, Kee-Jong; Choi, Woo Young; Lee, Won-Ja; Choi, Yeon Hwa; Jeong, Chung-Hyeon; Cho, Kwang-Il

2014-12-01

Current Ebola virus outbreak in West Africa already reached the total number of 1,323 including 729 deaths by July 31st. the fatality is around 55% in the southeastern area of Guinea, Sierra Leone, Liberia, and Nigeria. The number of patients with Ebola Hemorrhagic Fever (EHF) was continuously increasing even though the any effective therapeutics or vaccines has not been developed yet. The Ebola virus in Guinea showed 98% homology with Zaire Ebola Virus. Study of the pathogenesis of Ebola virus infection and assess of the various candidates of vaccine have been tried for a long time, especially in United States and some European countries. Even though the attenuated live vaccine and DNA vaccine containing Ebola viral genes were tested and showed efficacy in chimpanzees, those candidates still need clinical tests requiring much longer time than the preclinical development to be approved for the practical treatment. It can be expected to eradicate Ebola virus by a safe and efficient vaccine development similar to the case of smallpox virus which was extinguished from the world by the variola vaccine.

Reverse spillover of avian viral vaccine strains from domesticated poultry to wild birds.

Science.gov (United States)

Rohaim, M A; El Naggar, R F; Helal, A M; Hussein, H A; Munir, Muhammad

2017-06-16

Transmission of viruses from the commercial poultry to wild birds is an emerging paradigm of livestock-wildlife interface. Here, we report the identification and isolation of vaccine strains of avian paramyxovirus serotype 1 (APMV1) and avian coronaviruses (ACoV) from different wild bird species across eight Egyptian governorates between January 2014 and December 2015. Surveillance of avian respiratory viruses in free-ranging wild birds (n=297) identified three species that harboured or excreted APMV1 and ACoVs. Genetic characterization and phylogenetic analysis of recovered viruses revealed a close association with the most widely utilized vaccine strains in the country. These results highlight the potential spillover of vaccine-viruses probably due to extensive use of live-attenuated vaccines in the commercial poultry, and close interaction between domesticated and wild bird populations. Further exploring the full spectrum of vaccine-derived viral vaccine strains in wild birds might help to assess the emergence of future wild-birds origin viruses. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Safety of the novel influenza viral vector Brucella abortus vaccine in pregnant heifers

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Kaissar Tabynov

2016-01-01

Full Text Available ABSTRACT: The present study provides the first information about the safety of a new influenza viral vector vaccine expressing the Brucella ribosomal protein L7/L12 or Omp16 containing the adjuvant Montanide Gel01 in pregnant heifers. Immunization of pregnant heifers was conducted via the conjunctival (n=10 or subcutaneous (n=10 route using cross prime and booster vaccination schedules at an interval of 28 days. The vector vaccine was evaluated in comparison with positive control groups vaccinated with B. abortus S19 (n=10 or B. abortus RB51 (n=10 and a negative (PBS+Montanide Gel01; n=10 control group. Clinical studies, thermometry, assessment of local reactogenicity and observation of abortion showed that the vector vaccine via the conjunctival or subcutaneous route was completely safe for pregnant heifers compared to the commercial vaccines B. abortus S19 or B. abortus RB51. The only single adverse event was the formation of infiltration at the site of subcutaneous injection; this reaction was not observed for the conjunctival route.

Development of DNA vaccines for fish

DEFF Research Database (Denmark)

Heppell, Joël; Lorenzen, Niels; Armstrong, Neil K.

1998-01-01

Disease control is one of the major concerns in the aquaculture industry. However, there are no vaccines available for the prevention of many piscine infectious diseases, especially those of viral and parasitic origin. DNA-based vaccination could circumvent several problems associated with tradit......Disease control is one of the major concerns in the aquaculture industry. However, there are no vaccines available for the prevention of many piscine infectious diseases, especially those of viral and parasitic origin. DNA-based vaccination could circumvent several problems associated...... with traditional methods of immunization, but little is known on its efficacy in fish. The luciferase and lacZ reporter genes were used to characterize expression of plasmid-encoded genes in rainbow trout and zebra fish injected intramuscularly. For a given dose of DNA, the luciferase activity was higher in fish...... than in mouse muscle. The enzyme activity in fish peaked with 1 μg of DNA and remained constant for over 12 weeks, but it was not limited to the injected muscle since luciferase activity was also detected in the gills. Thin sections of rainbow trout muscle injected with the lacZ reporter gene showed...

Viral Vectors for Use in the Development of Biodefense Vaccines

Science.gov (United States)

2005-06-17

Shigella species Dengue Salmonella Filoviruses Listeria monocytogenes Ebola Campylobacter jejuni Marburg Yersinia entercolitica Viruses (Caliciviruses...Orthopoxvirus genus containing the monkey - J.S. Lee et al. / Advanced Drug Delivery Reviews 57 (2005) 1293–1314 1297 Approved for public release. Distribution...four monkeys vaccinated with V-LSGPC produced antibodies specific for LSV. After challenge, the four monkeys developed a febrile illness with low

Characterization of Inherent Particles and Mechanism of Thermal Stress Induced Particle Formation in HSV-2 Viral Vaccine Candidate.

Science.gov (United States)

Li, Lillian; Kirkitadze, Marina; Bhandal, Kamaljit; Roque, Cristopher; Yang, Eric; Carpick, Bruce; Rahman, Nausheen

2017-11-10

Vaccine formulations may contain visible and/or subvisible particles, which can vary in both size and morphology. Extrinsic particles, which are particles not part of the product such as foreign contaminants, are generally considered undesirable and should be eliminated or controlled in injectable products. However, biological products, in particular vaccines, may also contain particles that are inherent to the product. Here we focus on the characterization of visible and subvisible particles in a live, replication-deficient viral vaccine candidate against HSV genital herpes in an early developmental stage. HSV-2 viral vaccine was characterized using a panel of analytical methods, including Fourier transform infrared spectroscopy (FTIR), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, liquid chromatography-mass spectrometry (LC-MS), light microscopy, transmission electron microscopy (TEM), micro-flow imaging (MFI), dynamic light scattering (DLS), right angle light scattering (RALS), and intrinsic fluorescence. Particles in HSV-2 vaccine typically ranged from hundreds of nanometers to hundreds of micrometers in size and were determined to be inherent to the product. The infectious titer did not correlate with any trend in subvisible particle concentration and size distribution as shown by DLS, MFI, and TEM under stressed conditions. This suggested that particle changes in the submicron range were related to HSV-2 virion structure and had direct impact on biological activity. It was also observed that subvisible and visible particles could induce aggregation in the viral product. The temperature induced aggregation was observed by RALS, intrinsic fluorescence, and DLS. The increase of subvisible particle size with temperature could be fitted to a two-step thermokinetic model. Visible and subvisible particles were found to be inherent to the HSV-2 viral vaccine product. The mechanism of protein aggregation was discussed and a two

Hepatitis Vaccines

OpenAIRE

Ogholikhan, Sina; Schwarz, Kathleen B.

2016-01-01

Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B ...

Two doses of bovine viral diarrhea virus DNA vaccine delivered by electroporation induce long-term protective immune responses.

Science.gov (United States)

van Drunen Littel-van den Hurk, Sylvia; Lawman, Zoe; Snider, Marlene; Wilson, Don; van den Hurk, Jan V; Ellefsen, Barry; Hannaman, Drew

2013-02-01

Bovine viral diarrhea virus (BVDV) is a pathogen of major importance in cattle, so there is a need for new effective vaccines. DNA vaccines induce balanced immune responses and are relatively inexpensive and thus promising for both human and veterinary applications. In this study, newborn calves with maternal antibodies were vaccinated intramuscularly (i.m.) with a BVDV E2 DNA vaccine with the TriGrid Delivery System for i.m. delivery (TDS-IM). Two doses of this vaccine spaced 6 or 12 weeks apart were sufficient to induce significant virus-neutralizing antibody titers, numbers of activated T cells, and reduction in viral shedding and clinical presentations after BVDV-2 challenge. In contrast to the placebo-treated animals, the vaccinated calves did not lose any weight, which is an excellent indicator of the well-being of an animal and has a significant economic impact. Furthermore, the interval between the two vaccinations did not influence the magnitude of the immune responses or degree of clinical protection, and a third immunization was not necessary or beneficial. Since electroporation may enhance not only the magnitude but also the duration of immunity after DNA immunization, the interval between vaccination and challenge was extended in a second trial, which showed that two doses of this E2 DNA vaccine again significantly reduced clinical disease against BVDV for several months. These results are promising and support this technology for use against infectious diseases in cattle and large species, including humans, in general.

Canine Distemper Viral Inclusions in Blood Cells of Four Vaccinated Dogs

OpenAIRE

McLaughlin, Bruce G.; Adams, Pamela S.; Cornell, William D.; Elkins, A. Darrel

1985-01-01

Four cases of canine distemper were detected by the presence of numerous cytoplasmic inclusions in various circulating blood cells. Fluorescent antibody techniques and electron microscopy confirmed the identity of the viral inclusions. The cases occurred in the same geographic area and within a short time span. All four dogs had been vaccinated against canine distemper, but stress or other factors may have compromised their immune status. The possibility of an unusually virulent virus strain ...

Role of complement and antibodies in controlling infection with pathogenic simian immunodeficiency virus (SIV in macaques vaccinated with replication-deficient viral vectors

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Strasak Alexander

2009-06-01

Full Text Available Abstract Background We investigated the interplay between complement and antibodies upon priming with single-cycle replicating viral vectors (SCIV encoding SIV antigens combined with Adeno5-SIV or SCIV pseudotyped with murine leukemia virus envelope boosting strategies. The vaccine was applied via spray-immunization to the tonsils of rhesus macaques and compared with systemic regimens. Results Independent of the application regimen or route, viral loads were significantly reduced after challenge with SIVmac239 (p Conclusion The heterologous prime-boost strategy with replication-deficient viral vectors administered exclusively via the tonsils did not induce any neutralizing antibodies before challenge. However, after challenge, comparable SIV-specific humoral immune responses were observed in all vaccinated animals. Immunization with single cycle immunodeficiency viruses mounts humoral immune responses comparable to live-attenuated immunodeficiency virus vaccines.

Viral O-GalNAc peptide epitopes

DEFF Research Database (Denmark)

Olofsson, Sigvard; Blixt, Klas Ola; Bergström, Tomas

2016-01-01

Viral envelope glycoproteins are major targets for antibodies that bind to and inactivate viral particles. The capacity of a viral vaccine to induce virus-neutralizing antibodies is often used as a marker for vaccine efficacy. Yet the number of known neutralization target epitopes is restricted o...

Next Generation Respiratory Viral Vaccine System: Advanced and Emerging Bioengineered Human Lung Epithelia Model (HLEM) Organoid Technology

Science.gov (United States)

Goodwin, Thomas J.; Schneider, Sandra L.; MacIntosh, Victor; Gibbons, Thomas F.

2010-01-01

Acute respiratory infections, including pneumonia and influenza, are the S t" leading cause of United States and worldwide deaths. Newly emerging pathogens signaled the need for an advanced generation of vaccine technology.. Human bronchial-tracheal epithelial tissue was bioengineered to detect, identify, host and study the pathogenesis of acute respiratory viral disease. The 3-dimensional (3D) human lung epithelio-mesechymal tissue-like assemblies (HLEM TLAs) share characteristics with human respiratory epithelium: tight junctions, desmosomes, microvilli, functional markers villin, keratins and production of tissue mucin. Respiratory Syntial Virus (RSV) studies demonstrate viral growth kinetics and membrane bound glycoproteins up to day 20 post infection in the human lung-orgainoid infected cell system. Peak replication of RSV occurred on day 10 at 7 log10 particles forming units per ml/day. HLEM is an advanced virus vaccine model and biosentinel system for emergent viral infectious diseases to support DoD global surveillance and military readiness.

Standardization and assessment of cell culture media quantities in roller poly ethylene terephthalate bottles employed in the industrial rabies viral vaccine production.

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Jagannathan, S; Chaansha, S; Rajesh, K; Santhiya, T; Charles, C; Venkataramana, K N

2009-09-15

Vero cells are utilized for production of rabies vaccine. This study deals with the optimize quantity media require for the rabies vaccine production in the smooth roller surface. The rabies virus (Pasteur vaccine strain) is infected to monolayer of the various experimented bottles. To analyze the optimal quantity of media for the production of rabies viral harvest during the process of Vero cell derived rabies vaccine. The trials are started from 200 to 400 mL (PTARV-1, PTARV-2, PTARV-3, PTARV-4 and PTARV-5). The samples are taken in an appropriate time intervals for analysis of In Process Quality Control (IPQC) tests. The collected viral harvests are further processed to rabies vaccine in a pilot level and in addition to scale up an industrial level. Based on the evaluation the PTARV-2 (250 mL) show highly encouraging results for the Vero cell derived rabies vaccine production.

Virus like particle-based vaccines against emerging infectious disease viruses.

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Liu, Jinliang; Dai, Shiyu; Wang, Manli; Hu, Zhihong; Wang, Hualin; Deng, Fei

2016-08-01

Emerging infectious diseases are major threats to human health. Most severe viral disease outbreaks occur in developing regions where health conditions are poor. With increased international travel and business, the possibility of eventually transmitting infectious viruses between different countries is increasing. The most effective approach in preventing viral diseases is vaccination. However, vaccines are not currently available for numerous viral diseases. Virus-like particles (VLPs) are engineered vaccine candidates that have been studied for decades. VLPs are constructed by viral protein expression in various expression systems that promote the selfassembly of proteins into structures resembling virus particles. VLPs have antigenicity similar to that of the native virus, but are non-infectious as they lack key viral genetic material. VLP vaccines have attracted considerable research interest because they offer several advantages over traditional vaccines. Studies have shown that VLP vaccines can stimulate both humoral and cellular immune responses, which may offer effective antiviral protection. Here we review recent developments with VLP-based vaccines for several highly virulent emerging or re-emerging infectious diseases. The infectious agents discussed include RNA viruses from different virus families, such as the Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Togaviridae families.

First peptide vaccine providing protection against viral infection in the target animal: studies of canine parvovirus in dogs.

OpenAIRE

Langeveld, J P; Casal, J I; Osterhaus, A D; Cortés, E; de Swart, R; Vela, C; Dalsgaard, K; Puijk, W C; Schaaper, W M; Meloen, R H

1994-01-01

textabstractA synthetic peptide vaccine which protects dogs against challenge with virulent canine parvovirus is described. The amino acid sequence used was discovered in previous studies on the immunogenic properties of previously mapped antigenic sites and represents the amino-terminal region of viral protein VP2. As with marker vaccines, it is possible to discriminate between vaccinated dogs that have not been exposed to the virus and dogs that have been infected with the virus. The protec...

Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection

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Leo Swadling

2016-08-01

Full Text Available An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV infection, as an adjunct to newly developed directly-acting antivirals (DAA, or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3 vector and a modified vaccinia Ankara (MVA, encoding the non-structural proteins of HCV (NSmut, used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with interferon/ribavirin therapy, determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated with the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T-cell responses were rarely detected, and the overall magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV-specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFα production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced, showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T-cell response. Full-length, next-generation sequencing of the circulating virus demonstrated that T

Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development.

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Volz, A; Sutter, G

2017-01-01

Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology. © 2017 Elsevier Inc. All rights reserved.

Single-epitope DNA vaccination prevents exhaustion and facilitates a broad antiviral CD8+ T cell response during chronic viral infection

DEFF Research Database (Denmark)

Bartholdy, Christina; Stryhn, Anette; Christensen, Jan Pravsgaard

2004-01-01

Induction of a monospecific antiviral CD8+ T cell response may pose a risk to the host due to the narrow T cell response induced. At the individual level, this may result in selection of CD8+ T cell escape variants, particularly during chronic viral infection. Second, prior immunization toward a ...... with escape variants. These findings underscore that a monospecific vaccine may induce efficient protective immunity given the right set of circumstances....... of DNA vaccines encoding immunodominant epitopes of lymphocytic choriomeningitis virus (LCMV). We analyzed the spectrum of the CD8+ T cell response and the susceptibility to infection in H-2(b) and H-2(d) mice. Priming for a monospecific, CD8+ T cell response did not render mice susceptible to viral...... variants. Thus, vaccinated mice were protected against chronic infection with LCMV, and no evidence indicating biologically relevant viral escape was obtained. In parallel, a broad and sustained CD8+ T cell response was generated upon infection, and in H-2(d) mice epitope spreading was observed. Even after...

Seroprevalence of some bovine viral respiratory diseases among non vaccinated cattle in Saudi Arabia

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Mohamed Abd El Fatah Mahmoud

2013-02-01

Full Text Available Aim: Four viral pathogens, bovine viral diarrhea virus (BVDV, and bovine herpes virus type 1 (BHV-1, bovine parainfluenza type 3 virus (PI-3V, bovine respiratory syncytial virus (BRSV are mainly associated with bovine respiratory diseases that cause major economic losses in the dairy cattle industry. This study aimed to document exposure of cattle in Saudi Arabia to infectious BVDV, BHV-1, PI-3V and BRSV viruses in non vaccinated cattle in order to obtain epidemiological and immunological information. Materials and Methods: In the present study, 460 random serum samples obtained from non vaccinated cattle in five districts (Riyadh, Eastern Province, Jizan, Najran, Asir of Saudi Arabia between January to March 2011. These samples were tested for presence of antibodies against BVDV, BHV-1, BRSV and PIV-3 by commercial indirect ELISA kits. Results: Our findings displayed that Seropositivity rates were 26 % for BVD, 17.4 % for BHV-1, 69.1 % for PI-3V and 75.6 % for BRSV in the sampled population. In addition, coinfections with more than one virus were considerably common among non-vaccinated dairy cattle. Conclusion: These results indicate that exposure to these agents is common within the study areas. Preventive and control measures against these infectious agents should therefore be adopted. [Vet World 2013; 6(1.000: 1-4

Phage display as a promising approach for vaccine development

OpenAIRE

Aghebati-Maleki, Leili; Bakhshinejad, Babak; Baradaran, Behzad; Motallebnezhad, Morteza; Aghebati-Maleki, Ali; Nickho, Hamid; Yousefi, Mehdi; Majidi, Jafar

2016-01-01

Bacteriophages are specific antagonists to bacterial hosts. These viral entities have attracted growing interest as optimal vaccine delivery vehicles. Phages are well-matched for vaccine design due to being highly stable under harsh environmental conditions, simple and inexpensive large scale production, and potent adjuvant capacities. Phage vaccines have efficient immunostimulatory effects and present a high safety profile because these viruses have made a constant relationship with the mamm...

NaVirCept - Nucleic Acid-Based Anti-Viral Project

International Nuclear Information System (INIS)

Stephen, E. R.; Wong, J.; Van Loon, D.

2007-01-01

Vaccines are generally considered to be the most effective countermeasures to bacterial and viral diseases, however, licensed vaccines against many disease agents are either not available or their efficacies have not been demonstrated. Vaccines are generally agent specific in terms of treatment spectrum and are subject to defeat through natural mutation or through directed efforts. With respect to viral therapeutics, one of the major limitations associated with antiviral drugs is acquired drug resistance caused by antigenic shift or drift. A number of next-generation prophylactic and/or therapeutic measures are on the horizon. Of these, nucleic acid-based drugs are showing great antiviral potential. These drugs elicit long-lasting, broad spectrum protective immune responses, especially to respiratory viral pathogens. The Nucleic Acid-Based Antiviral (NaVirCept) project provides the opportunity to demonstrate the effectiveness of novel medical countermeasures against military-significant endemic and other viral threat agents. This project expands existing DRDC drug delivery capability development, in the form of proprietary liposome intellectual property, by coupling it with leading-edge nucleic acid-based technology to deliver effective medical countermeasures that will protect deployed personnel and the warfighter against a spectrum of viral disease agents. The technology pathway will offer a means to combat emerging viral diseases or modified threat agents such as the bird flu or reconstructed Spanish flu without going down the laborious, time-consuming and expensive paths to develop countermeasures for each new and/or emerging viral disease organism.(author)

Rational design of human metapneumovirus live attenuated vaccine candidates by inhibiting viral mRNA cap methyltransferase.

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Zhang, Yu; Wei, Yongwei; Zhang, Xiaodong; Cai, Hui; Niewiesk, Stefan; Li, Jianrong

2014-10-01

The paramyxoviruses human respiratory syncytial virus (hRSV), human metapneumovirus (hMPV), and human parainfluenza virus type 3 (hPIV3) are responsible for the majority of pediatric respiratory diseases and inflict significant economic loss, health care costs, and emotional burdens. Despite major efforts, there are no vaccines available for these viruses. The conserved region VI (CR VI) of the large (L) polymerase proteins of paramyxoviruses catalyzes methyltransferase (MTase) activities that typically methylate viral mRNAs at positions guanine N-7 (G-N-7) and ribose 2'-O. In this study, we generated a panel of recombinant hMPVs carrying mutations in the S-adenosylmethionine (SAM) binding site in CR VI of L protein. These recombinant viruses were specifically defective in ribose 2'-O methylation but not G-N-7 methylation and were genetically stable and highly attenuated in cell culture and viral replication in the upper and lower respiratory tracts of cotton rats. Importantly, vaccination of cotton rats with these recombinant hMPVs (rhMPVs) with defective MTases triggered a high level of neutralizing antibody, and the rats were completely protected from challenge with wild-type rhMPV. Collectively, our results indicate that (i) amino acid residues in the SAM binding site in the hMPV L protein are essential for 2'-O methylation and (ii) inhibition of mRNA cap MTase can serve as a novel target to rationally design live attenuated vaccines for hMPV and perhaps other paramyxoviruses, such as hRSV and hPIV3. Human paramyxoviruses, including hRSV, hMPV, and hPIV3, cause the majority of acute upper and lower respiratory tract infections in humans, particularly in infants, children, the elderly, and immunocompromised individuals. Currently, there is no licensed vaccine available. A formalin-inactivated vaccine is not suitable for these viruses because it causes enhanced lung damage upon reinfection with the same virus. A live attenuated vaccine is the most promising

Relationship of HIV Reservoir Characteristics with Immune Status and Viral Rebound Kinetics in an HIV Therapeutic Vaccine Study

Science.gov (United States)

Li, Jonathan Z.; Heisey, Andrea; Ahmed, Hayat; Wang, Hongying; Zheng, Lu; Carrington, Mary; Wrin, Terri; Schooley, Robert T.; Lederman, Michael M.; Kuritzkes, Daniel R.

2014-01-01

Objectives To evaluate the impact of therapeutic HIV vaccination on the HIV reservoir, and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics. Design Retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine. Methods Participants received vaccine/placebo at weeks 0, 4, and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia (RV) were quantified at weeks 0, 8, and 38. HIV-specific CD4+/CD8+ activity were assessed by an intracellular cytokine staining assay. Results At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4+ interferon-γ-producing cells (CA-RNA: r = −0.23, P=0.03 and CA-DNA: r = −0.28, P<0.01, N=93). Therapeutic HIV vaccination induced HIV-specific CD4+ activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable RV at week 8 had higher frequencies of HIV-specific CD4+ and CD8+ interferon-γ-producing cells (undetectable versus detectable RV: 277 versus 161 CD4+ cells/106 lymphocytes, P=0.03 and 1326 versus 669 CD8+ cells/106 lymphocytes, P=0.04). Pre-ATI CA-RNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P<0.01 and CA-DNA: r = 0.47, P<0.01). Conclusions Vaccine-induced T-cell responses were associated with a modest transient effect on RV, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics. PMID:25254301

[Viral hepatitis in travellers].

Science.gov (United States)

Abreu, Cândida

2007-01-01

Considering the geographical asymmetric distribution of viral hepatitis A, B and E, having a much higher prevalence in the less developed world, travellers from developed countries are exposed to a considerable and often underestimated risk of hepatitis infection. In fact a significant percentage of viral hepatitis occurring in developed countries is travel related. This results from globalization and increased mobility from tourism, international work, humanitarian and religious missions or other travel related activities. Several studies published in Europe and North America shown that more than 50% of reported cases of hepatitis A are travel related. On the other hand frequent outbreaks of hepatitis A and E in specific geographic areas raise the risk of infection in these restricted zones and that should be clearly identified. Selected aspects related with the distribution of hepatitis A, B and E are reviewed, particularly the situation in Portugal according to the published studies, as well as relevant clinical manifestations and differential diagnosis of viral hepatitis. Basic prevention rules considering enteric transmitted hepatitis (hepatitis A and hepatitis E) and parenteral transmitted (hepatitis B) are reviewed as well as hepatitis A and B immunoprophylaxis. Common clinical situations and daily practice "pre travel" advice issues are discussed according to WHO/CDC recommendations and the Portuguese National Vaccination Program. Implications from near future availability of a hepatitis E vaccine, a currently in phase 2 trial, are highlighted. Potential indications for travellers to endemic countries like India, Nepal and some regions of China, where up to 30% of sporadic cases of acute viral hepatitis are caused by hepatitis E virus, are considered. Continued epidemiological surveillance for viral hepatitis is essential to recognize and control possible outbreaks, but also to identify new viral hepatitis agents that may emerge as important global health

Influenza viral vectors expressing the Brucella OMP16 or L7/L12 proteins as vaccines against B. abortus infection.

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Tabynov, Kaissar; Sansyzbay, Abylai; Kydyrbayev, Zhailaubay; Yespembetov, Bolat; Ryskeldinova, Sholpan; Zinina, Nadezhda; Assanzhanova, Nurika; Sultankulova, Kulaisan; Sandybayev, Nurlan; Khairullin, Berik; Kuznetsova, Irina; Ferko, Boris; Egorov, Andrej

2014-04-10

We generated novel, effective candidate vaccine against Brucella abortus based on recombinant influenza viruses expressing the Brucella ribosomal protein L7/L12 or outer membrane protein (Omp)-16 from the NS1 open reading frame. The main purpose of this work was to evaluate the safety, immunogenicity and protectiveness of vaccine candidate in laboratory animals. Four recombinant influenza A viral constructs of the subtypes Н5N1 or H1N1 expressing the Brucella proteins L7/L12 or Omp16 were obtained by a reverse genetics method: Flu-NS1-124-L7/L12-H5N1, Flu-NS1-124-Omp16-H5N1, Flu-NS1-124-L7/L12-H1N1 and Flu-NS1-124-Omp16-H1N1. Despite of substantial modification of NS1 gene, all constructs replicated well and were retain their Brucella inserts over five passages in embryonated chicken eggs (CE). Administration of the mono- or bivalent vaccine formulation via prime-boost intranasal (i.n.), conjunctival (c.) or subcutaneous (s.c.) immunization was safe in mice; no deaths, body weight loss or pathomorphological changes were observed over 56 days. Moreover, guinea pigs vaccinated i.n. with vaccine vectors did not shed the vaccine viruses through their upper respiratory tract after the prime and booster vaccination. These findings confirmed the replication-deficient phenotype of viral vectors. The highest antibody response to Brucella antigen was obtained with constructs expressing L7/L12 (ELISA, GMT 242.5-735.0); whereas the highest T-cell immune response- with construct expressing Omp16 (ELISPOT, 337 ± 52-651 ± 45 spots/4×105cells), which was comparable (P > 0.05) to the response induced by the commercial vaccine B. abortus 19. Interestingly, c. immunization appeared to be optimal for eliciting T-cell immune response. In guinea pigs, the highest protective efficacy after challenge with B. abortus 544 was achieved with Omp16 expressing constructs in both monovalent or bivalent vaccine formulations; protective efficacy was comparable to those induced by

Noninvasive vaccination against infectious diseases.

Science.gov (United States)

Zheng, Zhichao; Diaz-Arévalo, Diana; Guan, Hongbing; Zeng, Mingtao

2018-04-06

The development of a successful vaccine, which should elicit a combination of humoral and cellular responses to control or prevent infections, is the first step in protecting against infectious diseases. A vaccine may protect against bacterial, fungal, parasitic, or viral infections in animal models, but to be effective in humans there are some issues that should be considered, such as the adjuvant, the route of vaccination, and the antigen-carrier system. While almost all licensed vaccines are injected such that inoculation is by far the most commonly used method, injection has several potential disadvantages, including pain, cross contamination, needlestick injury, under- or overdosing, and increased cost. It is also problematic for patients from rural areas of developing countries, who must travel to a hospital for vaccine administration. Noninvasive immunizations, including oral, intranasal, and transcutaneous administration of vaccines, can reduce or eliminate pain, reduce the cost of vaccinations, and increase their safety. Several preclinical and clinical studies as well as experience with licensed vaccines have demonstrated that noninvasive vaccine immunization activates cellular and humoral immunity, which protect against pathogen infections. Here we review the development of noninvasive immunization with vaccines based on live attenuated virus, recombinant adenovirus, inactivated virus, viral subunits, virus-like particles, DNA, RNA, and antigen expression in rice in preclinical and clinical studies. We predict that noninvasive vaccine administration will be more widely applied in the clinic in the near future.

Development of inactivated-local isolate vaccine for infectious bronchitis

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Darminto

1999-06-01

Full Text Available Infectious bronchitis (IB is an acute highly contagious viral respiratory disease of poultry caused by coronavirus. The disease causes high mortality in young chicks, reduce body weight gain in broilers and remarkable drop in egg production. IB can only be controlled by vaccination, but due to the antigenic variation among serotypes of IB viruses, the effective IB vaccine should be prepared from local isolates. The aim of this research is to develop inactivated IB vaccine derived from local IB isolates. Local isolates of IB viruses designated as I-37, I-269 and PTS-III were propagated respectively in specific pathogen free (SPF chicken eggs, the viruses then were inactivated by formaline at final concentration of 1:1,000. Subsequently, the inactivated viruses were mixed and emulsified in oil emulsion adjuvant with sorbitant mono-oleic as an emulsifier. The vaccine then was tested for its safety, potency and efficacy in broiler chickens. Birds inoculated twice with a two-week interval by inactivated vaccine did not show any adverse reaction, either systemic or local reaction. The inoculated birds developed antibody responses with high titre, while antibody of the control birds remain negative. In addition, efficacy test which was conducted in broilers demonstrated that birds vaccinated by live-commercial vaccine and boosted three weeks later by Balitvet inactivated vaccine showed high level of antibody production which provided high level of protection against challenged virus (76% against I-37, 92% against I-269 and 68% against PTS-III challenge viruses. From this study, it can be concluded that inactivated local IB vaccine is considered to be safe, potent and efficacious. The vaccine stimulates high titre of antibody responses, which provide high level of protection against challenged viruses.

DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.

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Melanie Thompson

Full Text Available GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA boost vaccine (GOVX-B11, was undertaken in HIV infected participants on antiretroviral treatment (ART to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI. Nine men who began antiretroviral therapy (ART within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.clinicaltrials.gov NCT01378156.

DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.

Science.gov (United States)

Thompson, Melanie; Heath, Sonya L; Sweeton, Bentley; Williams, Kathy; Cunningham, Pamela; Keele, Brandon F; Sen, Sharon; Palmer, Brent E; Chomont, Nicolas; Xu, Yongxian; Basu, Rahul; Hellerstein, Michael S; Kwa, Suefen; Robinson, Harriet L

2016-01-01

GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine. clinicaltrials.gov NCT01378156.

A Brief Review of Computer-Assisted Approaches to Rational Design of Peptide Vaccines

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Ashesh Nandy

2016-05-01

Full Text Available The growing incidences of new viral diseases and increasingly frequent viral epidemics have strained therapeutic and preventive measures; the high mutability of viral genes puts additional strains on developmental efforts. Given the high cost and time requirements for new drugs development, vaccines remain as a viable alternative, but there too traditional techniques of live-attenuated or inactivated vaccines have the danger of allergenic reactions and others. Peptide vaccines have, over the last several years, begun to be looked on as more appropriate alternatives, which are economically affordable, require less time for development and hold the promise of multi-valent dosages. The developments in bioinformatics, proteomics, immunogenomics, structural biology and other sciences have spurred the growth of vaccinomics where computer assisted approaches serve to identify suitable peptide targets for eventual development of vaccines. In this mini-review we give a brief overview of some of the recent trends in computer assisted vaccine development with emphasis on the primary selection procedures of probable peptide candidates for vaccine development.

Identification and development of a promising novel mumps vaccine candidate strain.

Science.gov (United States)

Liang, Yan; Ma, Shaohui; Liu, Longding; Zhao, Hongling; Wang, Lichun; Jiang, Li; Xie, Zhongping; Dong, Chenghong; Li, Qihan

2010-12-01

Mumps epidemics are usually caused by airborne transmission of mumps virus (MuV) and have high morbidity in non-immunized children. Epidemiological studies in many regions of China show that the genotype F viral strain is the most prevalent. However, the genotype A strain is currently used to prepare vaccines. Regional epidemiological MuV data suggest a significant application for the development of live attenuated mumps vaccines targeting specific genotypes. This article reports the isolation and culture of a genotype F MuV candidate strain that could be used to prepare a live attenuated mumps vaccine. This strain is shown to have good immunological efficacy and stability in neurovirulence evaluations. This work should facilitate the implementation of mumps vaccination in mainland China by targeting the most prevalent MuV genotype, genotype F. Copyright © 2010 Institut Pasteur. Published by Elsevier SAS. All rights reserved.

Exploiting the yeast L-A viral capsid for the in vivo assembly of chimeric VLPs as platform in vaccine development and foreign protein expression.

Directory of Open Access Journals (Sweden)

Frank Powilleit

Full Text Available A novel expression system based on engineered variants of the yeast (Saccharomyces cerevisiae dsRNA virus L-A was developed allowing the in vivo assembly of chimeric virus-like particles (VLPs as a unique platform for a wide range of applications. We show that polypeptides fused to the viral capsid protein Gag self-assemble into isometric VLP chimeras carrying their cargo inside the capsid, thereby not only effectively preventing proteolytic degradation in the host cell cytosol, but also allowing the expression of a per se cytotoxic protein. Carboxyterminal extension of Gag by T cell epitopes from human cytomegalovirus pp65 resulted in the formation of hybrid VLPs that strongly activated antigen-specific CD8(+ memory T cells ex vivo. Besides being a carrier for polypeptides inducing antigen-specific immune responses in vivo, VLP chimeras were also shown to be effective in the expression and purification of (i a heterologous model protein (GFP, (ii a per se toxic protein (K28 alpha-subunit, and (iii a particle-associated and fully recyclable biotechnologically relevant enzyme (esterase A. Thus, yeast viral Gag represents a unique platform for the in vivo assembly of chimeric VLPs, equally attractive and useful in vaccine development and recombinant protein production.

Branched-linear and agglomerate protein polymers as vaccine platforms.

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Wang, Leyi; Xia, Ming; Huang, Pengwei; Fang, Hao; Cao, Dianjun; Meng, Xiang-Jin; McNeal, Monica; Jiang, Xi; Tan, Ming

2014-09-01

Many viral structural proteins and their truncated domains share a common feature of homotypic interaction forming dimers, trimers, and/or oligomers with various valences. We reported previously a simple strategy for construction of linear and network polymers through the dimerization feature of viral proteins for vaccine development. In this study, technologies were developed to produce more sophisticated polyvalent complexes through both the dimerization and oligomerization natures of viral antigens. As proof of concept, branched-linear and agglomerate polymers were made via fusions of the dimeric glutathione-s-transferase (GST) with either a tetrameric hepatitis E virus (HEV) protruding protein or a 24-meric norovirus (NoV) protruding protein. Furthermore, a monomeric antigen, either the M2e epitope of influenza A virus or the VP8* antigen of rotavirus, was inserted and displayed by the polymer platform. All resulting polymers were easily produced in Escherichia coli at high yields. Immunization of mice showed that the polymer vaccines induced significantly higher specific humoral and T cell responses than those induced by the dimeric antigens. Additional evidence in supporting use of polymer vaccines included the significantly higher neutralization activity and protective immunity of the polymer vaccines against the corresponding viruses than those of the dimer vaccines. Thus, our technology for production of polymers containing different viral antigens offers a strategy for vaccine development against infectious pathogens and their associated diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine.

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Durando, Paolo; Iudici, Rocco; Alicino, Cristiano; Alberti, Marisa; de Florentis, Daniela; Ansaldi, Filippo; Icardi, Giancarlo

2011-01-01

Vaccination is universally considered as the principal measure for the control of influenza, which represents a significant burden worldwide, both from a health-care and a socio-economic viewpoint. Conventional non-adjuvanted trivalent influenza vaccines (TIVs) have been recognized as having some deficiencies, such as suboptimal immunogenicity particularly in the elderly, in patients with severe chronic diseases and immunocompromized, indeed, those groups of the population at higher risk of developing severe complications following influenza infection, when compared to healthy adults. Moreover, the protection offered by conventional vaccines may be reduced by periodic antigenic drifts, resulting in a mismatch between the circulating and vaccinal viral strains. Another gap regarding currently available vaccines is related to the egg-based manufacturing system for their production: not only the length of time involved with the latter but also the limited capacity of this platform technology represent a major limitation for the active prevention of influenza, which is particularly important in the case of a new pandemic strain. New technologies used in vaccine composition, administration and manufacture have led to major advances during the last few years, and clinical researchers have continued to work hard, investigating several different strategies to improve the performance of influenza vaccines: namely, the addition of different adjuvants (i.e., MF59- and AS03-vaccines, virosomal formulations), the use of alternative routes of administration or manufacture (i.e., intradermal, nasal and oral vaccines and cell culture- and reverse genetic-based vaccines) or of high doses of antigen, and the development of DNA-vaccines, or the use of conserved viral epitopes (i.e., the extracellular portion of the M2 protein, the nucleoprotein and some domains of the hemagglutinin), in the attempt to produce a "universal target" antigen vaccine. The knowledge acquired represents a

A simple and rapid approach to develop recombinant avian herpesvirus vectored vaccines using CRISPR/Cas9 system.

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Tang, Na; Zhang, Yaoyao; Pedrera, Miriam; Chang, Pengxiang; Baigent, Susan; Moffat, Katy; Shen, Zhiqiang; Nair, Venugopal; Yao, Yongxiu

2018-01-29

Herpesvirus of turkeys (HVT) has been successfully used as live vaccine against Marek's disease (MD) worldwide for more than 40 years either alone or in combination with other serotypes. HVT is also widely used as a vector platform for generation of recombinant vaccines against a number of avian diseases such as infectious bursal disease (IBD), Newcastle disease (ND) and avian influenza (AI) using conventional recombination methods or recombineering tools on cloned viral genomes. In the present study, we describe the application of CRISPR/Cas9-based genome editing as a rapid and efficient method of generating HVT recombinants expressing VP2 protein of IBDV. This approach offers an efficient method to introduce other viral antigens into the HVT genome for rapid development of recombinant vaccines. Copyright © 2018 The Pirbright Institute. Published by Elsevier Ltd.. All rights reserved.

Avian metapneumovirus excretion in vaccinated and non-vaccinated specified pathogen free laying chickens.

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Hess, M; Huggins, M B; Mudzamiri, R; Heincz, U

2004-02-01

Vaccinated and non-vaccinated specified pathogen-free White Leghorn laying chickens were challenged at peak of lay by the intravenous or oculonasal route with a virulent avian metapneumovirus (aMPV) subtype B chicken strain. Severe clinical signs and a drop in egg production were induced in the non-vaccinated intravenously challenged birds whereas the vaccinates were not affected. Live virus excretion was demonstrated in the faeces and respiratory tract of non-vaccinated hens for up to 7 days post intravenous challenge. After oculonasal challenge, virus excretion could only be demonstrated in the respiratory tract for up to 5 days. No live virus excretion was found in either the faeces or the respiratory tract of vaccinated birds. Concurrent with live virus isolation, the presence of viral RNA was demonstrated by single reverse transcription-polymerase chain reaction (RT-PCR). Nested RT-PCR was more sensitive and viral RNA could be detected in non-vaccinated birds up to 28 days post either intravenous or oculonasal challenge, at which time the experiment was terminated. Viral RNA was detected for up to 12 days in vaccinated birds. This is the first study investigating excretion of aMPV and viral RNA in vaccinated and non-vaccinated laying hens challenged under experimental conditions. The results are of importance with regard to the persistence of aMPV and the appropriate diagnostic detection method in laying birds.

A New Scientific Paradigm may be Needed to Finally Develop an HIV Vaccine.

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Esparza, José

2015-01-01

The bulk of current HIV vaccine research is conducted within the infectious disease paradigm that has been very successful in developing vaccines against many other viral diseases. Different HIV vaccine concepts, based on the induction of neutralizing antibodies and/or cell mediated immunity, have been developed and clinically tested over the last 30 years, resulting in a few small successes and many disappointments. As new scientific knowledge is obtained, HIV vaccine concepts are constantly modified with the hope that the newly introduced tweaks (or paradigm drifts) will provide the solution to one of the most difficult challenges that modern biomedical research is confronting. Efficacy trials have been critical in guiding HIV vaccine development. However, from the five phase III efficacy trials conducted to date, only one (RV144) resulted in modest efficacy. The results from RV144 were surprising in many ways, including the identified putative correlates of protection (or risk), which did not include neutralizing antibodies or cytotoxic T-cells. The solution to the HIV vaccine challenge may very well come from approaches based on the current paradigm. However, at the same time, out-of-the-paradigm ideas should be systematically explored to complement the current efforts. New mechanisms are needed to identify and support the innovative research that will hopefully accelerate the development of an urgently needed HIV vaccine.

[Emergent viral infections

NARCIS (Netherlands)

Galama, J.M.D.

2001-01-01

The emergence and re-emergence of viral infections is an ongoing process. Large-scale vaccination programmes led to the eradication or control of some viral infections in the last century, but new viruses are always emerging. Increased travel is leading to a rise in the importation of exotic

Targeting of non-dominant antigens as a vaccine strategy to broaden T-cell responses during chronic viral infection

DEFF Research Database (Denmark)

Holst, Peter Johannes; Jensen, Benjamin Anderschou Holbech; Ragonnaud, Emeline

2015-01-01

In this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that vaccination targeting non-dominant epitopes facilita......In this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that vaccination targeting non-dominant epitopes...... was lost over time in T cells specific for the dominant T cell epitopes, and these cells were fully capable of expanding in response to a new viral challenge. Overall, our data suggests a potential for broadening of the antiviral CD8+ T-cell response by selecting non-dominant antigens to be targeted...

Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections

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Stanfield, Brent; Kousoulas, Konstantin Gus

2015-01-01

Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections. PMID:27114893

[Vaccination against viral hepatitis A and B in adults aged over 40 years--antibody persistence and immune memory].

Science.gov (United States)

Chlibek, R; Smetana, J; Bostíková, V; Splino, M

2011-09-01

Primary vaccination with combined vaccine against viral hepatitis A (VHA) and viral hepatitis B (VHB) induces higher anti-hepatitis B surface (anti-HBs) antibody responses and similar anti-hepatitis A virus (anti-HAV) antibody responses in adults aged over 40 years in comparison with concomitant monovalent vaccines against VHA and VHB. Th e objectives were to assess, in a clinical study, persistence of anti-HAV and anti-HBs antibodies in adults aged over 40 years four years after primary VHA/VHB vaccination and antibody response following a booster dose of the vaccine. Five hundred and ninety-six subjects aged > 40 years were vaccinated with three doses of the combined VHA/VHB vaccine at Months 0, 1, 6 (HAB group) or with concomitant VHA and VHB vaccines at Months 0, 6 and 0, 1, 6 (ENG+HAV and HBVX+VAQ, respectively). Blood samples were collected one month following primary vaccination (Month 7) and then at one-year intervals for four years after the booster dose with the same vaccine as used for the primary vaccination. The anti-HBs and anti-HAV antibody levels were determined prior to the booster dose and at days 14 and 30 after the booster dose. At Month 7, > 97% of study subjects were seropositive for anti-HAV antibodies in all groups analyzed. Four years after primary vaccination, anti-HAV antibody seropositivity persisted in > 93% of study subjects, increasing to > 99% after the booster dose. At Month 7, the highest proportion of study subjects with anti-HBs antibody levels > or = 10 mIU/ml was found in the HAB group (91.7% versus 79.7% in the ENG+HAV group versus 71.0% in the HBVX+VAQ group). Four years after vaccination, anti-HBs antibody levels of 10 mIU/ml persisted in 57.1% of the HAB study subjects in comparison with 40.1% and 26.6% of the study subjects in the ENG+HAV and HBVX+VAQ groups, respectively. One month after the booster dose, anti-HBs antibody levels increased and antibody levels > or = 10 mIU/ml was achived in 95.2% of study subjects in the

Respiratory Syncytial Virus Vaccines

OpenAIRE

Dudas, Robert A.; Karron, Ruth A.

1998-01-01

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness (LRI) in infants and children worldwide and causes significant LRI in the elderly and in immunocompromised patients. The goal of RSV vaccination is to prevent serious RSV-associated LRI. There are several obstacles to the development of successful RSV vaccines, including the need to immunize very young infants, who may respond inadequately to vaccination; the existence of two antigenically d...

Animal Models for Influenza Viruses: Implications for Universal Vaccine Development

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Irina Margine

2014-10-01

Full Text Available Influenza virus infections are a significant cause of morbidity and mortality in the human population. Depending on the virulence of the influenza virus strain, as well as the immunological status of the infected individual, the severity of the respiratory disease may range from sub-clinical or mild symptoms to severe pneumonia that can sometimes lead to death. Vaccines remain the primary public health measure in reducing the influenza burden. Though the first influenza vaccine preparation was licensed more than 60 years ago, current research efforts seek to develop novel vaccination strategies with improved immunogenicity, effectiveness, and breadth of protection. Animal models of influenza have been essential in facilitating studies aimed at understanding viral factors that affect pathogenesis and contribute to disease or transmission. Among others, mice, ferrets, pigs, and nonhuman primates have been used to study influenza virus infection in vivo, as well as to do pre-clinical testing of novel vaccine approaches. Here we discuss and compare the unique advantages and limitations of each model.

Effects of vaccination against viral haemorrhagic disease and myxomatosis on long-term mortality rates of European wild rabbits.

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Calvete, C; Estrada, R; Lucientes, J; Osacar, J J; Villafuerte, R

2004-09-25

The effects of vaccination against myxomatosis and viral haemorrhagic disease (VHD) on long-term mortality rates in European rabbits (Oryctolagus cuniculus) were studied from 1993 to 1996 by radiotracking a free-living population of wild rabbits. During the three months after immunisation, unvaccinated young rabbits weighing between 180 and 600 g were 13.6 times more likely to die than vaccinated young rabbits. In adult rabbits, vaccination did not significantly decrease mortality, mainly owing to the high proportion of rabbits which had previously been exposed to the antigens of both diseases. Compared with adult rabbits with natural antibodies to VHD, rabbits without these antibodies were 5.2 times more likely to die of VHD during annual outbreaks.

LIVE ATTENUATED VACCINES FOR THE IMMUNOPROPHYLAXIS

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O. A. Shamsutdinova

2017-01-01

Full Text Available The review focuses on the history of the production of live antiviral vaccines and their use for the prevention of infectious diseases. It was noted that before the beginning of the 20th century, only three live vaccines were developed and put into practice — against smallpox, rabies, plague. The discovery of D. Enders, T.H. Weller and F.Ch. Robins of the ability of the polio virus, and then of a number of other viruses, to reproduce in vitro in cell cultures of various types, greatly expanded the studies on the production of attenuated strains of viruses for live vaccines. The historical stages of obtaining and introducing live vaccines for the prevention of smallpox, poliomyelitis, measles, rubella, and mumps are highlighted. Arguments in favor of the use of associated vaccine preparations for the prevention of viral infections are presented. Various variants of the strategy and tactics of using live vaccines, which are used for specific prevention of viral infections in different countries, are described. The review provides information on technological methods for obtaining antiviral vaccines. The publications testifying to the development of specific reactions in immunized vaccine strains of measles, mumps, poliomyelitis and rubella viruses, such as aseptic meningitis (vaccine strains of mumps virus, acute arthritis (vaccine rubella virus strains, temperature reactions, rash (vaccine strains of the virus Measles, vaccine-associated paralytic poliomyelitis (VAPP vaccine vaccine poliovirus. It is particularly noted that the long experience of vaccine prevention both in Russia and abroad convincingly shows that the risk of developing post-vaccination complications is incommensurably lower than the risk of causing harm to health from the corresponding infections. It is concluded that despite introduction of new third and fourth generation vaccines into practice, live attenuated vaccines do not lose their significance and are used in vaccine

Ebola virus: immune mechanisms of protection and vaccine development.

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Nyamathi, Adeline M; Fahey, John L; Sands, Heather; Casillas, Adrian M

2003-04-01

Vaccination is one of our most powerful antiviral strategies. Despite the emergence of deadly viruses such as Ebola virus, vaccination efforts have focused mainly on childhood communicable diseases. Although Ebola virus was once believed to be limited to isolated outbreaks in distant lands, forces of globalization potentiate outbreaks anywhere in the world through incidental transmission. Moreover, since this virus has already been transformed into weapon-grade material, the potential exists for it to be used as a biological weapon with catastrophic consequences for any population vulnerable to attack. Ebola hemorrhagic fever (EHF) is a syndrome that can rapidly lead to death within days of symptom onset. The disease directly affects the immune system and vascular bed, with correspondingly high mortality rates. Patients with severe disease produce dangerously high levels of inflammatory cytokines, which destroy normal tissue and microcirculation, leading to profound capillary leakage, renal failure, and disseminated intravascular coagulation. Vaccine development has been fraught with obstacles, primarily of a biosafety nature. Case reports of acutely ill patients with EHF showing improvement with the transfusion of convalescent plasma are at odds with animal studies demonstrating further viral replication with the same treatment. Using mRNA extracted from bone marrow of Ebola survivors, human monoclonal antibodies against Ebola virus surface protein have been experimentally produced and now raise the hope for the development of a safe vaccine.

Evolution of Live-Attenuated HIV Vaccines

NARCIS (Netherlands)

Berkhout, Ben

2011-01-01

Despite intensive research since the viral pathogen was discovered some 25 years ago, not much progress has been reported on the development of a safe vaccine that protects against human immunodeficiency virus type 1. A vaccine approach that has been abandoned because its safety cannot be guaranteed

An influenza viral vector Brucella abortus vaccine induces good cross-protection against Brucella melitensis infection in pregnant heifers.

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Tabynov, Kaissar; Ryskeldinova, Sholpan; Sansyzbay, Abylai

2015-07-17

Brucella melitensis can be transmitted and cause disease in cattle herds as a result of inadequate management of mixed livestock farms. Ideally, vaccines against Brucella abortus for cattle should also provide cross-protection against B. melitensis. Previously we created a novel influenza viral vector B. abortus (Flu-BA) vaccine expressing the Brucella ribosomal proteins L7/L12 or Omp16. This study demonstrated Flu-BA vaccine with adjuvant Montanide Gel01 provided 100% protection against abortion in vaccinated pregnant heifers and good cross-protection of the heifers and their calves or fetuses (90-100%) after challenge with B. melitensis 16M; the level of protection provided by Flu-BA was comparable to the commercial vaccine B. abortus S19. In terms of the index of infection and colonization of Brucella in tissues, both vaccines demonstrated significant (P=0.02 to P<0.0001) protection against B. melitensis 16M infection compared to the negative control group (PBS+Montanide Gel01). Thus, we conclude the Flu-BA vaccine provides cross-protection against B. melitensis infection in pregnant heifers. Copyright © 2015 Elsevier Ltd. All rights reserved.

Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease.

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Richner, Justin M; Jagger, Brett W; Shan, Chao; Fontes, Camila R; Dowd, Kimberly A; Cao, Bin; Himansu, Sunny; Caine, Elizabeth A; Nunes, Bruno T D; Medeiros, Daniele B A; Muruato, Antonio E; Foreman, Bryant M; Luo, Huanle; Wang, Tian; Barrett, Alan D; Weaver, Scott C; Vasconcelos, Pedro F C; Rossi, Shannan L; Ciaramella, Giuseppe; Mysorekar, Indira U; Pierson, Theodore C; Shi, Pei-Yong; Diamond, Michael S

2017-07-13

The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with multiple viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

DHEC: Vaccinations

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Data, Maps - SC Public Health Diseases and Conditions Flu Tuberculosis STD/HIV and Viral Hepatitis Zika Illnesses E. coli Listeriosis Salmonella Hepatitis A Shellfish Monitoring and Regulation Certified Shippers Vaccines Teen and Preteen Vaccines Vaccines Needed for School Admission Related Topics Perinatal Hepatitis

Vaccine Development against Zoonotic Hepatitis E Virus: Open Questions and Remaining Challenges

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Yuchen Nan

2018-02-01

Full Text Available Hepatitis E virus (HEV is a fecal-orally transmitted foodborne viral pathogen that causes acute hepatitis in humans and is responsible for hepatitis E outbreaks worldwide. Since the discovery of HEV as a zoonotic agent, this virus has been isolated from a variety of hosts with an ever-expanding host range. Recently, a subunit HEV vaccine developed for the prevention of human disease was approved in China, but is not yet available to the rest of the world. Meanwhile, notable progress and knowledge has been made and revealed in recent years to better understand HEV biology and infection, including discoveries of quasi-enveloped HEV virions and of a new function of the HEV-ORF3 product. However, the impact of these new findings on the development of a protective vaccine against zoonotic HEV infection requires further discussion. In this review, hallmark characteristics of HEV zoonosis, the history of HEV vaccine development, and recent discoveries in HEV virology are described. Moreover, special attention is focused on quasi-enveloped HEV virions and the potential role of the HEV-ORF3 product as antibody-neutralization target on the surface of quasi-enveloped HEV virions to provide new insights for the future development of improved vaccines against zoonotic HEV infection.

Vaccine Development against Zoonotic Hepatitis E Virus: Open Questions and Remaining Challenges

Science.gov (United States)

Nan, Yuchen; Wu, Chunyan; Zhao, Qin; Sun, Yani; Zhang, Yan-Jin; Zhou, En-Min

2018-01-01

Hepatitis E virus (HEV) is a fecal-orally transmitted foodborne viral pathogen that causes acute hepatitis in humans and is responsible for hepatitis E outbreaks worldwide. Since the discovery of HEV as a zoonotic agent, this virus has been isolated from a variety of hosts with an ever-expanding host range. Recently, a subunit HEV vaccine developed for the prevention of human disease was approved in China, but is not yet available to the rest of the world. Meanwhile, notable progress and knowledge has been made and revealed in recent years to better understand HEV biology and infection, including discoveries of quasi-enveloped HEV virions and of a new function of the HEV-ORF3 product. However, the impact of these new findings on the development of a protective vaccine against zoonotic HEV infection requires further discussion. In this review, hallmark characteristics of HEV zoonosis, the history of HEV vaccine development, and recent discoveries in HEV virology are described. Moreover, special attention is focused on quasi-enveloped HEV virions and the potential role of the HEV-ORF3 product as antibody-neutralization target on the surface of quasi-enveloped HEV virions to provide new insights for the future development of improved vaccines against zoonotic HEV infection. PMID:29520257

A Perspective on the Development of Plant-Made Vaccines in the Fight against Ebola Virus

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Rosales-Mendoza, Sergio; Nieto-Gómez, Ricardo; Angulo, Carlos

2017-01-01

The Ebola virus (EBOV) epidemic indicated a great need for prophylactic and therapeutic strategies. The use of plants for the production of biopharmaceuticals is a concept being adopted by the pharmaceutical industry, with an enzyme for human use currently commercialized since 2012 and some plant-based vaccines close to being commercialized. Although plant-based antibodies against EBOV are under clinical evaluation, the development of plant-based vaccines against EBOV essentially remains an unexplored area. The current technologies for the production of plant-based vaccines include stable nuclear expression, transient expression mediated by viral vectors, and chloroplast expression. Specific perspectives on how these technologies can be applied for developing anti-EBOV vaccines are provided, including possibilities for the design of immunogens as well as the potential of the distinct expression modalities to produce the most relevant EBOV antigens in plants considering yields, posttranslational modifications, production time, and downstream processing. PMID:28344580

Increased cellular immune responses and CD4+ T-cell proliferation correlate with reduced plasma viral load in SIV challenged recombinant simian varicella virus - simian immunodeficiency virus (rSVV-SIV vaccinated rhesus macaques

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Pahar Bapi

2012-08-01

Full Text Available Abstract Background An effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rSVV vector – simian immunodeficiency virus (SIV envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1. Findings The purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals. Conclusions Increased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.

Particle-based vaccines for HIV-1 infection.

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Young, Kelly R; Ross, Ted M

2003-06-01

The use of live-attenuated viruses as vaccines has been successful for the control of viral infections. However, the development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge. HIV infects cells of the immune system and results in a severe immunodeficiency. In addition, the ability of the virus to adapt to immune pressure and the ability to reside in an integrated form in host cells present hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes from different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immunity, however, a live-attenuated vaccine for HIV is problematic. The possibility of a live-attenuated vaccine to revert to a pathogenic form or recombine with a wild-type or defective virus in an infected individual is a drawback to this approach. Therefore, these vaccines are currently only being tested in non-human primate models. Live-attenuated vaccines are effective in stimulating immunity, however challenged animals rarely clear viral infection and the degree of attenuation directly correlates with the protection of animals from disease. Another particle-based vaccine approach for HIV involves the use of virus-like particles (VLPs). VLPs mimic the viral particle without causing an immunodeficiency disease. HIV-like particles (HIV-LP) are defined as self-assembling, non-replicating, nonpathogenic, genomeless particles that are similar in size and conformation to intact virions. A variety of VLPs for both HIV and SIV are currently in pre-clinical and clinical trials. This review focuses on the current knowledge regarding the immunogenicity and safety of particle-based vaccine strategies for HIV-1.

Hepatitis Vaccines

Directory of Open Access Journals (Sweden)

Sina Ogholikhan

2016-03-01

Full Text Available Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver.

Hepatitis Vaccines

Science.gov (United States)

Ogholikhan, Sina; Schwarz, Kathleen B.

2016-01-01

Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

Screening for viral extraneous agents in live-attenuated avian vaccines by using a microbial microarray and sequencing

DEFF Research Database (Denmark)

Olesen, Majken Lindholm; Jørgensen, Lotte Leick; Blixenkrone-Møller, Merete

2018-01-01

The absence of extraneous agents (EA) in the raw material used for production and in finished products is one of the principal safety elements related to all medicinal products of biological origin, such as live-attenuated vaccines. The aim of this study was to investigate the applicability...... of the Lawrence Livermore Microbial detection array version 2 (LLMDAv2) combined with whole genome amplification and sequencing for screening for viral EAs in live-attenuated vaccines and specific pathogen-free (SPF) eggs.We detected positive microarray signals for avian endogenous retrovirus EAV-HP and several...... viruses belonging to the Alpharetrovirus genus in all analyzed vaccines and SPF eggs. We used a microarray probe mapping approach to evaluate the presence of intact retroviral genomes, which in addition to PCR analysis revealed that several of the positive microarray signals were most likely due to cross...

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Path to a Dengue Vaccine: Learning from Human Natural Dengue Infection Studies and Vaccine Trials.

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de Silva, Aravinda M; Harris, Eva

2018-06-01

Dengue virus (DENV) is the most common arthropod-borne viral disease of humans. Although effective vaccines exist against other flaviviral diseases like yellow fever and Japanese encephalitis, dengue vaccine development is complicated by the presence of four virus serotypes and the possibility of partial immunity enhancing dengue disease severity. Several live attenuated dengue vaccines are being tested in human clinical trials. Initial results are mixed, with variable efficacy depending on DENV serotype and previous DENV exposure. Here, we highlight recent discoveries about the human antibody response to DENV and propose guidelines for advancing development of safe and effective dengue vaccines. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Prime-booster vaccination of cattle with an influenza viral vector Brucella abortus vaccine induces a long-term protective immune response against Brucella abortus infection.

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Tabynov, Kaissar; Yespembetov, Bolat; Ryskeldinova, Sholpan; Zinina, Nadezhda; Kydyrbayev, Zhailaubay; Kozhamkulov, Yerken; Inkarbekov, Dulat; Sansyzbay, Abylai

2016-01-20

This study analyzed the duration of the antigen-specific humoral and T-cell immune responses and protectiveness of a recently-developed influenza viral vector Brucella abortus (Flu-BA) vaccine expressing Brucella proteins Omp16 and L7/L12 and containing the adjuvant Montadine Gel01 in cattle. At 1 month post-booster vaccination (BV), both humoral (up to 3 months post-BV; GMT IgG ELISA titer 214±55 to 857±136, with a prevalence of IgG2a over IgG1 isotype antibodies) and T-cell immune responses were observed in vaccinated heifers (n=35) compared to control animals (n=35, injected with adjuvant/PBS only). A pronounced T-cell immune response was induced and maintained for 12 months post-BV, as indicated by the lymphocyte stimulation index (2.7±0.4 to 10.1±0.9 cpm) and production of IFN-γ (13.7±1.7 to 40.0±3.0 ng/ml) at 3, 6, 9, and 12 months post-BV. Prime-boost vaccination provided significant protection against B. abortus infection at 3, 6, 9 and 12 months (study duration) post-BV (7 heifers per time point; alpha=0.03-0.01 vs. control group). Between 57.1 and 71.4% of vaccinated animals showed no signs of B. abortus infection (or Brucella isolation) at 3, 6, 9 and 12 months post-BV; the severity of infection, as indicated by the index of infection (P=0.0003 to Brucella colonization (P=0.03 to abortus infection was also observed among pregnant vaccinated heifers (alpha=0.03), as well as their fetuses and calves (alpha=0.01), for 12 months post-BV. Additionally, 71.4% of vaccinated heifers calved successfully whereas all pregnant control animals aborted (alpha=0.01). Prime-boost vaccination of cattle with Flu-BA induces an antigen-specific humoral and pronounced T cell immune response and most importantly provides good protectiveness, even in pregnant heifers, for at least 12 months post-BV. Copyright © 2015 Elsevier Ltd. All rights reserved.

Improved vaccine protection against retrovirus infection after co-administration of adenoviral vectors encoding viral antigens and type I interferon subtypes

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Groitl Peter

2011-09-01

Full Text Available Abstract Background Type I interferons (IFNs exhibit direct antiviral effects, but also distinct immunomodulatory properties. In this study, we analyzed type I IFN subtypes for their effect on prophylactic adenovirus-based anti-retroviral vaccination of mice against Friend retrovirus (FV or HIV. Results Mice were vaccinated with adenoviral vectors encoding FV Env and Gag proteins alone or in combination with vectors encoding IFNα1, IFNα2, IFNα4, IFNα5, IFNα6, IFNα9 or IFNβ. Only the co-administration of adenoviral vectors encoding IFNα2, IFNα4, IFNα6 and IFNα9 resulted in strongly improved immune protection of vaccinated mice from subsequent FV challenge infection with high control over FV-induced splenomegaly and reduced viral loads. The level of protection correlated with augmented virus-specific CD4+ T cell responses and enhanced antibody titers. Similar results were obtained when mice were vaccinated against HIV with adenoviral vectors encoding HIV Env and Gag-Pol in combination with various type I IFN encoding vectors. Here mainly CD4+ T cell responses were enhanced by IFNα subtypes. Conclusions Our results indicate that certain IFNα subtypes have the potential to improve the protective effect of adenovirus-based vaccines against retroviruses. This correlated with augmented virus-specific CD4+ T cell and antibody responses. Thus, co-expression of select type I IFNs may be a valuable tool for the development of anti-retroviral vaccines.

BVDV vaccination in North America: risks versus benefits.

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Griebel, Philip J

2015-06-01

The control and prevention of bovine viral diarrhea virus (BVDV) infections has provided substantial challenges. Viral genetic variation, persistent infections, and viral tropism for immune cells have complicated disease control strategies. Vaccination has, however, provided an effective tool to prevent acute systemic infections and increase reproductive efficiency through fetal protection. There has been substantial controversy about the safety and efficacy of BVDV vaccines, especially when comparing killed versus modified-live viral (MLV) vaccines. Furthermore, numerous vaccination protocols have been proposed to protect the fetus and ensure maternal antibody transfer to the calf. These issues have been further complicated by reports of immune suppression during natural infections and following vaccination. While killed BVDV vaccines provide the greatest safety, their limited immunogenicity makes multiple vaccinations necessary. In contrast, MLV BVDV vaccines induce a broader range of immune responses with a longer duration of immunity, but require strategic vaccination to minimize potential risks. Vaccination strategies for breeding females and young calves, in the face of maternal antibody, are discussed. With intranasal vaccination of young calves it is possible to avoid maternal antibody interference and induce immune memory that persists for 6-8 months. Thus, with an integrated vaccination protocol for both breeding cows and calves it is possible to maximize disease protection while minimizing vaccine risks.

Control of Ebola hemorrhagic fever: vaccine development and our Ebola project in Sierra Leone.

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Watanabe, Tokiko; Kawaoka, Yoshihiro

2016-01-01

Since December 2013, West Africa has experienced the worst Ebola virus outbreak in recorded history. Of the 28,639 cases reported to the World Health Organization as of March 2016, nearly half (14,124) occurred in Sierra Leone. With a case fatality rate of approximately 40%, this outbreak has claimed the lives of 11,316 individuals. No FDA-approved vaccines or drugs are available to prevent or treat Ebola virus infection. Experimental vaccines and therapies are being developed; however, their safety and efficacy are still being evaluated. Therefore, there is an urgent need to develop control measures to prevent or limit future Ebola virus outbreaks.Previously, we developed a replication-defective Ebola virus that lacks the coding region for the essential viral transcription activator VP30 (Ebola ΔVP30 virus). Here, we evaluated the vaccine efficacy of Ebola ΔVP30 virus in a non-human primate model and describe our collaborative Ebola project in Sierra Leone.

Live virus vaccines based on a yellow fever vaccine backbone: standardized template with key considerations for a risk/benefit assessment.

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Monath, Thomas P; Seligman, Stephen J; Robertson, James S; Guy, Bruno; Hayes, Edward B; Condit, Richard C; Excler, Jean Louis; Mac, Lisa Marie; Carbery, Baevin; Chen, Robert T

2015-01-01

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viruses inserted into the backbone of another virus (so-called "chimeric virus vaccines"). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus, Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were exchanged for the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the transparency and comparability of

Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial.

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Smith, Larry R; Wloch, Mary K; Chaplin, Jennifer A; Gerber, Michele; Rolland, Alain P

2013-09-25

2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK) delivery system designed to enhance plasmid expression. The vaccine's planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV⁺) recipients of an allogeneic hematopoietic stem cell transplant (HCT). A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV⁺ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial.

Immune Modulation of NYVAC-Based HIV Vaccines by Combined Deletion of Viral Genes that Act on Several Signalling Pathways

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Carmen Elena Gómez

2017-12-01

Full Text Available An HIV-1 vaccine continues to be a major target to halt the AIDS pandemic. The limited efficacy of the RV144 phase III clinical trial with the canarypox virus-based vector ALVAC and a gp120 protein component led to the conclusion that improved immune responses to HIV antigens are needed for a more effective vaccine. In non-human primates, the New York vaccinia virus (NYVAC poxvirus vector has a broader immunogenicity profile than ALVAC and has been tested in clinical trials. We therefore analysed the HIV immune advantage of NYVAC after removing viral genes that act on several signalling pathways (Toll-like receptors—TLR—interferon, cytokines/chemokines, as well as genes of unknown immune function. We generated a series of NYVAC deletion mutants and studied immune behaviour (T and B cell to HIV antigens and to the NYVAC vector in mice. Our results showed that combined deletion of selected vaccinia virus (VACV genes is a valuable strategy for improving the immunogenicity of NYVAC-based vaccine candidates. These immune responses were differentially modulated, positive or negative, depending on the combination of gene deletions. The deletions also led to enhanced antigen- or vector-specific cellular and humoral responses. These findings will facilitate the development of optimal NYVAC-based vaccines for HIV and other diseases.

Rotavirus vaccine strain transmission by vaccinated infants in the foster home.

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Miura, Hiroki; Kawamura, Yoshiki; Sugata, Ken; Koshiyama, Nozomi; Yoshikawa, Akiko; Komoto, Satoshi; Taniguchi, Koki; Ihira, Masaru; Yoshikawa, Tetsushi

2017-01-01

Previous studies have demonstrated the transmission of rotavirus vaccine strains from vaccinated children to nonvaccinated siblings. We sought to fully elucidate the safety of rotavirus (RV) vaccination in closed contact circumstance, such as the foster home for future assessment of the vaccine safety in an neonatal intensive care unit. Stool samples were collected from 4 RV vaccinated (160 samples) and 23 unvaccinated (766 samples) infants. RV viral RNA loads were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). RV vaccine strain RNA was persistently detected in stool samples collected from the four vaccine recipients and one unvaccinated infant, but not in the stool samples collected from the 22 other unvaccinated infants. The unvaccinated infant who tested positive for the RV vaccine strain was vaccinated prior to enrollment in this study. The quantitative real-time RT-PCR data revealed a peak viral RNA load 1 week after vaccination followed by a gradual decrease. The current study suggests that RV vaccination may be safe in a close contact environment because there was limited transmission from RV vaccinated to unvaccinated infants. J. Med. Virol. 89:79-84, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Live Virus Vaccines Based on a Yellow Fever Vaccine Backbone: Standardized Template with Key Considerations for a Risk/Benefit Assessment*

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Monath, Thomas P.; Seligman, Stephen J.; Robertson, James S.; Guy, Bruno; Hayes, Edward B.; Condit, Richard C.; Excler, Jean Louis; Mac, Lisa Marie; Carbery, Baevin; Chen, Robert T

2015-01-01

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viruses inserted into the backbone of another virus (so-called “chimeric virus vaccines”). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were replaced by the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the transparency and comparability of

Mucosal vaccination with heterologous viral vectored vaccine targeting subdominant SIV accessory antigens strongly inhibits early viral replication

DEFF Research Database (Denmark)

Xu, Huanbin; Andersson, Anne-Marie Carola; Ragonnaud, Emeline

2017-01-01

Conventional HIV T cell vaccine strategies have not been successful in containing acute peak viremia, nor in providing long-term control. We immunized rhesus macaques intramuscularly and rectally using a heterologous adenovirus vectored SIV vaccine regimen encoding normally weakly immunogenic tat...

The yellow fever 17D vaccine virus: molecular basis of viral attenuation and its use as an expression vector

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Galler R.

1997-01-01

Full Text Available The yellow fever (YF virus is the prototype flavivirus. The use of molecular techniques has unraveled the basic mechanisms of viral genome structure and expression. Recent trends in flavivirus research include the use of infectious clone technology with which it is possible to recover virus from cloned cDNA. Using this technique, mutations can be introduced at any point of the viral genome and their resulting effect on virus phenotype can be assessed. This approach has opened new possibilities to study several biological viral features with special emphasis on the issue of virulence/attenuation of the YF virus. The feasibility of using YF virus 17D vaccine strain, for which infectious cDNA is available, as a vector for the expression of heterologous antigens is reviewed

Vaccine development for syphilis.

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Lithgow, Karen V; Cameron, Caroline E

2017-01-01

Syphilis, caused by the spirochete Treponema pallidum subspecies pallidum, continues to be a globally prevalent disease despite remaining susceptible to penicillin treatment. Syphilis vaccine development is a viable preventative approach that will serve to complement public health-oriented syphilis prevention, screening and treatment initiatives to deliver a two-pronged approach to stemming disease spread worldwide. Areas covered: This article provides an overview of the need for development of a syphilis vaccine, summarizes significant information that has been garnered from prior syphilis vaccine studies, discusses the critical aspects of infection that would have to be targeted by a syphilis vaccine, and presents the current understanding within the field of the correlates of protection needed to be achieved through vaccination. Expert commentary: Syphilis vaccine development should be considered a priority by industry, regulatory and funding agencies, and should be appropriately promoted and supported.

Vaccination of Ferrets for Rabies and Distemper.

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Wade, Laura L

2018-01-01

Companion ferrets need to be vaccinated against 2 viral diseases that cause neurologic illness: canine distemper and rabies. Although not common in ferrets, both viruses are fatal in ferrets and rabies virus is also fatal in humans. In this article, we provide a basic review of the 2 diseases, highlighting key neurologic concerns. We also review and update current vaccine concerns from a practitioner's perspective, including available vaccines, vaccine schedule recommendations, vaccine reactions, and risk assessment. Last, we mention the ferret and its use in cutting-edge vaccine development. Copyright © 2017 Elsevier Inc. All rights reserved.

Sustainable vaccine development: a vaccine manufacturer's perspective.

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Rappuoli, Rino; Hanon, Emmanuel

2018-05-08

Vaccination remains the most cost-effective public health intervention after clean water, and the benefits impressively outweigh the costs. The efforts needed to fulfill the steadily growing demands for next-generation and novel vaccines designed for emerging pathogens and new indications are only realizable in a sustainable business model. Vaccine development can be fast-tracked through strengthening international collaborations, and the continuous innovation of technologies to accelerate their design, development, and manufacturing. However, these processes should be supported by a balanced project portfolio, and by managing sustainable vaccine procurement strategies for different types of markets. Collectively this will allow a gradual shift to a more streamlined and profitable vaccine production, which can significantly contribute to the worldwide effort to shape global health. Copyright © 2018 GlaxoSmithKine Biologicals SA. Published by Elsevier Ltd.. All rights reserved.

Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases.

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Skeate, Joseph G; Woodham, Andrew W; Einstein, Mark H; Da Silva, Diane M; Kast, W Martin

2016-06-02

Carcinomas of the anogenital tract, in particular cervical cancer, remains one of the most common cancers in women, and represent the most frequent gynecological malignancies and the fourth leading cause of cancer death in women worldwide. Human papillomavirus (HPV)-induced lesions are immunologically distinct in that they express viral antigens, which are necessary to maintain the cancerous phenotype. The causal relationship between HPV infection and anogenital cancer has prompted substantial interest in the development of therapeutic vaccines against high-risk HPV types targeting the viral oncoproteins E6 and E7. This review will focus on the most recent clinical trials for immunotherapies for mucosal HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced diseases. Progress in peptide- and protein-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune checkpoint inhibition, immune response modifiers, and adoptive cell therapy for HPV will be discussed.

Oligomeric recombinant H5 HA1 vaccine produced in bacteria protects ferrets from homologous and heterologous wild-type H5N1 influenza challenge and controls viral loads better than subunit H5N1 vaccine by eliciting high-affinity antibodies.

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Verma, Swati; Dimitrova, Milena; Munjal, Ashok; Fontana, Juan; Crevar, Corey J; Carter, Donald M; Ross, Ted M; Khurana, Surender; Golding, Hana

2012-11-01

Recombinant hemagglutinin from influenza viruses with pandemic potential can be produced rapidly in various cell substrates. In this study, we compared the functionality and immunogenicity of bacterially produced oligomeric or monomeric HA1 proteins from H5N1 (A/Vietnam/1203/04) with those of the egg-based licensed subunit H5N1 (SU-H5N1) vaccine in ferrets challenged with homologous or heterologous H5N1 highly pathogenic influenza strains. Ferrets were vaccinated twice with the oligomeric or monomeric rHA1 or with SU-H5N1 (Sanofi Pasteur) emulsified with Titermax adjuvant and were challenged with wild-type homologous (A/Vietnam/1203/04; clade 1) or heterologous (A/Whooperswan/Mongolia/244/2005; clade 2.2) virus. Only the oligomeric rHA1 (not the monomeric rHA1) immunogen and the SU-H5N1 vaccine provided protection against the lethality and morbidity of homologous and heterologous highly pathogenic H5N1. Oligomeric rHA1 generated more cross-neutralizing antibodies and higher levels of serum antibody binding to HA1, with stronger avidity and a better IgG/IgM ratio, than monomeric HA1 and SU-H5N1 vaccines, as determined by surface plasmon resonance (SPR). Importantly, viral loads after heterologous H5N1 challenge were more efficiently controlled in ferrets vaccinated with the oligomeric rHA1 immunogen than in SU-H5N1-vaccinated ferrets. The reduction of viral loads in the nasal washes correlated strongly with higher-avidity antibodies to oligomeric rHA1 derived from H5N1 clade 1 and clade 2.2 viruses, as measured by SPR. This is the first study to show the role of antibody avidity for the HA1 globular head domain in reduction of viral loads in the upper respiratory tract, which could significantly reduce viral transmission.

Humoral Immunity to Primary Smallpox Vaccination: Impact of Childhood versus Adult Immunization on Vaccinia Vector Vaccine Development in Military Populations.

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Bonnie M Slike

Full Text Available Modified Vaccinia virus has been shown to be a safe and immunogenic vector platform for delivery of HIV vaccines. Use of this vector is of particular importance to the military, with the implementation of a large scale smallpox vaccination campaign in 2002 in active duty and key civilian personnel in response to potential bioterrorist activities. Humoral immunity to smallpox vaccination was previously shown to be long lasting (up to 75 years and protective. However, using vaccinia-vectored vaccine delivery for other diseases on a background of anti-vector antibodies (i.e. pre-existing immunity may limit their use as a vaccine platform, especially in the military. In this pilot study, we examined the durability of vaccinia antibody responses in adult primary vaccinees in a healthy military population using a standard ELISA assay and a novel dendritic cell neutralization assay. We found binding and neutralizing antibody (NAb responses to vaccinia waned after 5-10 years in a group of 475 active duty military, born after 1972, who were vaccinated as adults with Dryvax®. These responses decreased from a geometric mean titer (GMT of 250 to baseline (30 years with a GMT of 210 (range 112-3234. This data suggests limited durability of antibody responses in adult vaccinees compared to those vaccinated in childhood and further that adult vaccinia recipients may benefit similarly from receipt of a vaccinia based vaccine as those who are vaccinia naïve. Our findings may have implications for the smallpox vaccination schedule and support the ongoing development of this promising viral vector in a military vaccination program.

CRISPR/Cas9-Advancing Orthopoxvirus Genome Editing for Vaccine and Vector Development.

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Okoli, Arinze; Okeke, Malachy I; Tryland, Morten; Moens, Ugo

2018-01-22

The clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (Cas9) technology is revolutionizing genome editing approaches. Its high efficiency, specificity, versatility, flexibility, simplicity and low cost have made the CRISPR/Cas9 system preferable to other guided site-specific nuclease-based systems such as TALENs (Transcription Activator-like Effector Nucleases) and ZFNs (Zinc Finger Nucleases) in genome editing of viruses. CRISPR/Cas9 is presently being applied in constructing viral mutants, preventing virus infections, eradicating proviral DNA, and inhibiting viral replication in infected cells. The successful adaptation of CRISPR/Cas9 to editing the genome of Vaccinia virus paves the way for its application in editing other vaccine/vector-relevant orthopoxvirus (OPXV) strains. Thus, CRISPR/Cas9 can be used to resolve some of the major hindrances to the development of OPXV-based recombinant vaccines and vectors, including sub-optimal immunogenicity; transgene and genome instability; reversion of attenuation; potential of spread of transgenes to wildtype strains and close contacts, which are important biosafety and risk assessment considerations. In this article, we review the published literature on the application of CRISPR/Cas9 in virus genome editing and discuss the potentials of CRISPR/Cas9 in advancing OPXV-based recombinant vaccines and vectors. We also discuss the application of CRISPR/Cas9 in combating viruses of clinical relevance, the limitations of CRISPR/Cas9 and the current strategies to overcome them.

Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates.

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Marzi, Andrea; Halfmann, Peter; Hill-Batorski, Lindsay; Feldmann, Friederike; Shupert, W Lesley; Neumann, Gabriele; Feldmann, Heinz; Kawaoka, Yoshihiro

2015-04-24

Zaire ebolavirus is the causative agent of the current outbreak of hemorrhagic fever disease in West Africa. Previously, we showed that a whole Ebola virus (EBOV) vaccine based on a replication-defective EBOV (EBOVΔVP30) protects immunized mice and guinea pigs against lethal challenge with rodent-adapted EBOV. Here, we demonstrate that EBOVΔVP30 protects nonhuman primates against lethal infection with EBOV. Although EBOVΔVP30 is replication-incompetent, we additionally inactivated the vaccine with hydrogen peroxide; the chemically inactivated vaccine remained antigenic and protective in nonhuman primates. EBOVΔVP30 thus represents a safe, efficacious, whole-EBOV vaccine candidate that differs from other EBOV vaccine platforms in that it presents all viral proteins and the viral RNA to the host immune system, which might contribute to protective immune responses. Copyright © 2015, American Association for the Advancement of Science.

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game.

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van der Sanden, Sabine M G; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C; Brooks, Paula; O'Donnell, Jason; Jones, Les P; Brown, Cedric; Tompkins, S Mark; Oberste, M Steven; Karpilow, Jon; Tripp, Ralph A

2016-02-15

Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work

Recombinant Listeria monocytogenes as a Live Vaccine Vehicle for the Induction of Protective Anti-Viral Cell-Mediated Immunity

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Shen, Hao; Slifka, Mark K.; Matloubian, Mehrdad; Jensen, Eric R.; Ahmed, Rafi; Miller, Jeff F.

1995-04-01

Listeria monocytogenes (LM) is a Gram-positive bacterium that is able to enter host cells, escape from the endocytic vesicle, multiply within the cytoplasm, and spread directly from cell to cell without encountering the extracellular milieu. The ability of LM to gain access to the host cell cytosol allows proteins secreted by the bacterium to efficiently enter the pathway for major histocompatibility complex class I antigen processing and presentation. We have established a genetic system for expression and secretion of foreign antigens by recombinant strains, based on stable site-specific integration of expression cassettes into the LM genome. The ability of LM recombinants to induce protective immunity against a heterologous pathogen was demonstrated with lymphocytic choriomeningitis virus (LCMV). LM strains expressing the entire LCMV nucleoprotein or an H-2L^d-restricted nucleoprotein epitope (aa 118-126) were constructed. Immunization of mice with LM vaccine strains conferred protection against challenge with virulent strains of LCMV that otherwise establish chronic infection in naive adult mice. In vivo depletion of CD8^+ T cells from vaccinated mice abrogated their ability to clear viral infection, showing that protective anti-viral immunity was due to CD8^+ T cells.

Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines.

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See, Raymond H; Petric, Martin; Lawrence, David J; Mok, Catherine P Y; Rowe, Thomas; Zitzow, Lois A; Karunakaran, Karuna P; Voss, Thomas G; Brunham, Robert C; Gauldie, Jack; Finlay, B Brett; Roper, Rachel L

2008-09-01

Although the 2003 severe acute respiratory syndrome (SARS) outbreak was controlled, repeated transmission of SARS coronavirus (CoV) over several years makes the development of a SARS vaccine desirable. We performed a comparative evaluation of two SARS vaccines for their ability to protect against live SARS-CoV intranasal challenge in ferrets. Both the whole killed SARS-CoV vaccine (with and without alum) and adenovirus-based vectors encoding the nucleocapsid (N) and spike (S) protein induced neutralizing antibody responses and reduced viral replication and shedding in the upper respiratory tract and progression of virus to the lower respiratory tract. The vaccines also diminished haemorrhage in the thymus and reduced the severity and extent of pneumonia and damage to lung epithelium. However, despite high neutralizing antibody titres, protection was incomplete for all vaccine preparations and administration routes. Our data suggest that a combination of vaccine strategies may be required for effective protection from this pathogen. The ferret may be a good model for SARS-CoV infection because it is the only model that replicates the fever seen in human patients, as well as replicating other SARS disease features including infection by the respiratory route, clinical signs, viral replication in upper and lower respiratory tract and lung damage.

Vaccines 'on demand': science fiction or a future reality.

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Ulmer, Jeffrey B; Mansoura, Monique K; Geall, Andrew J

2015-02-01

Self-amplifying mRNA vaccines are being developed as a platform technology with potential to be used for a broad range of targets. The synthetic production methods for their manufacture, combined with the modern tools of bioinformatics and synthetic biology, enable these vaccines to be produced rapidly from an electronic gene sequence. Preclinical proof of concept has so far been achieved for influenza, respiratory syncytial virus, rabies, Ebola, cytomegalovirus, human immunodeficiency virus and malaria. This editorial highlights the key milestones in the discovery and development of self-amplifying mRNA vaccines, and reviews how they might be used as a rapid response platform. The paper points out how future improvements in RNA vector design and non-viral delivery may lead to decreases in effective dose and increases in production capacity. The prospects for non-viral delivery of self-amplifying mRNA vaccines are very promising. Like other types of nucleic acid vaccines, these vaccines have the potential to draw on the positive attributes of live-attenuated vaccines while obviating many potential safety limitations. Hence, this approach could enable the concept of vaccines on demand as a rapid response to a real threat rather than the deployment of strategic stockpiles based on epidemiological predictions for possible threats.

Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial

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Michele Gerber

2013-09-01

Full Text Available 2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB and phosphoprotein 65 (pp65 formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK delivery system designed to enhance plasmid expression. The vaccine’s planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV+ recipients of an allogeneic hematopoietic stem cell transplant (HCT. A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV+ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial.

Vaccine development: From concept to early clinical testing.

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Cunningham, Anthony L; Garçon, Nathalie; Leo, Oberdan; Friedland, Leonard R; Strugnell, Richard; Laupèze, Béatrice; Doherty, Mark; Stern, Peter

2016-12-20

In the 21st century, an array of microbiological and molecular allow antigens for new vaccines to be specifically identified, designed, produced and delivered with the aim of optimising the induction of a protective immune response against a well-defined immunogen. New knowledge about the functioning of the immune system and host pathogen interactions has stimulated the rational design of vaccines. The design toolbox includes vaccines made from whole pathogens, protein subunits, polysaccharides, pathogen-like particles, use of viral/bacterial vectors, plus adjuvants and conjugation technology to increase and broaden the immune response. Processes such as recombinant DNA technology can simplify the complexity of manufacturing and facilitate consistent production of large quantities of antigen. Any new vaccine development is greatly enhanced by, and requires integration of information concerning: 1. Pathogen life-cycle & epidemiology. Knowledge of pathogen structure, route of entry, interaction with cellular receptors, subsequent replication sites and disease-causing mechanisms are all important to identify antigens suitable for disease prevention. The demographics of infection, specific risk groups and age-specific infection rates determine which population to immunise, and at what age. 2. Immune control & escape. Interactions between the host and pathogen are explored, with determination of the relative importance of antibodies, T-cells of different types and innate immunity, immune escape strategies during infection, and possible immune correlates of protection. This information guides identification and selection of antigen and the specific immune response required for protection. 3. Antigen selection & vaccine formulation. The selected antigen is formulated to remain suitably immunogenic and stable over time, induce an immune response that is likely to be protective, plus be amenable to eventual scale-up to commercial production. 4. Vaccine preclinical

76 FR 55397 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

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2011-09-07

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug... public. Name of Committee: Vaccines and Related Biological Products Advisory Committee. General Function... Laboratory of Method Development, Division of Viral Products, Office of Vaccines Research and Review, Center...

Preclinical assessment of viral vectored and protein vaccines targeting the Duffy-binding protein region II of Plasmodium vivax

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Simone C de Cassan

2015-07-01

Full Text Available Malaria vaccine development has largely focused on Plasmodium falciparum; however a reawakening to the importance of P. vivax has spurred efforts to develop vaccines against this difficult to treat and at times severe form of relapsing malaria, which constitutes a significant proportion of human malaria cases worldwide. The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII with the human Duffy antigen receptor for chemokines (DARC, makes this antigen an attractive vaccine candidate against blood-stage P. vivax. Here, we generated both preclinical and clinically-compatible adenoviral and poxviral vectored vaccine candidates expressing the Salvador I allele of PvDBP_RII – including human adenovirus serotype 5 (HAdV5, chimpanzee adenovirus serotype 63 (ChAd63 and modified vaccinia virus Ankara (MVA vectors. We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime, or in ‘mixed-modality’ adenovirus prime – protein-in-adjuvant boost regimes (using a recombinant protein PvDBP_RII protein antigen formulated in Montanide®ISA720 or Abisco®100 adjuvants. Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay. In recent years, recombinant ChAd63 and MVA vectors have been quickly translated into human clinical trials for numerous antigens from P. falciparum as well as a growing number of other pathogens. The vectors reported here are immunogenic in small animals, elicit antibodies against PvDBP_RII and have recently entered clinical trials which will provide the first assessment of the safety and immunogenicity of the PvDBP_RII antigen in humans.

Human leukocyte antigen and cytokine receptor gene polymorphisms associated with heterogeneous immune responses to mumps viral vaccine.

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Ovsyannikova, Inna G; Jacobson, Robert M; Dhiman, Neelam; Vierkant, Robert A; Pankratz, V Shane; Poland, Gregory A

2008-05-01

Mumps outbreaks continue to occur throughout the world, including in highly vaccinated populations. Vaccination against mumps has been successful; however, humoral and cellular immune responses to mumps vaccines vary significantly from person to person. We set out to assess whether HLA and cytokine gene polymorphisms are associated with variations in the immune response to mumps viral vaccine. To identify genetic factors that might contribute to variations in mumps vaccine-induced immune responses, we performed HLA genotyping in a group of 346 healthy schoolchildren (12-18 years of age) who previously received 2 doses of live mumps vaccine. Single-nucleotide polymorphisms (minor allele frequency of >5%) in cytokine and cytokine receptor genes were genotyped for a subset of 118 children. Median values for mumps-specific antibody titers and lymphoproliferative stimulation indices were 729 IU/mL and 4.8, respectively. Girls demonstrated significantly higher mumps antibody titers than boys, indicating gender-linked genetic differences in humoral immune response. Significant associations were found between the HLA-DQB1*0303 alleles and lower mumps-specific antibody titers. An interesting finding was the association of several HLA class II alleles with mumps-specific lymphoproliferation. Alleles of the DRB1 (*0101, *0301, *0801, *1001, *1201, and *1302), DQA1 (*0101, *0105, *0401, and *0501), and DQB1 (*0201, *0402, and *0501) loci were associated with significant variations in lymphoproliferative immune responses to mumps vaccine. Additional associations were observed with single-nucleotide polymorphisms in the interleukin-10RA, interleukin-12RB1, and interleukin-12RB2 cytokine receptor genes. Minor alleles for 4 single-nucleotide polymorphisms within interleukin-10RA and interleukin-12RB genes were associated with variations in humoral and cellular immune responses to mumps vaccination. These data suggest the important role of HLA and immunoregulatory cytokine receptor

Large-scale adenovirus and poxvirus-vectored vaccine manufacturing to enable clinical trials.

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Kallel, Héla; Kamen, Amine A

2015-05-01

Efforts to make vaccines against infectious diseases and immunotherapies for cancer have evolved to utilize a variety of heterologous expression systems such as viral vectors. These vectors are often attenuated or engineered to safely deliver genes encoding antigens of different pathogens. Adenovirus and poxvirus vectors are among the viral vectors that are most frequently used to develop prophylactic vaccines against infectious diseases as well as therapeutic cancer vaccines. This mini-review describes the trends and processes in large-scale production of adenovirus and poxvirus vectors to meet the needs of clinical applications. We briefly describe the general principles for the production and purification of adenovirus and poxvirus viral vectors. Currently, adenovirus and poxvirus vector manufacturing methods rely on well-established cell culture technologies. Several improvements have been evaluated to increase the yield and to reduce the overall manufacturing cost, such as cultivation at high cell densities and continuous downstream processing. Additionally, advancements in vector characterization will greatly facilitate the development of novel vectored vaccine candidates. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cross-protective peptide vaccine against influenza A viruses developed in HLA-A*2402 human immunity model.

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Toru Ichihashi

Full Text Available BACKGROUND: The virus-specific cytotoxic T lymphocyte (CTL induction is an important target for the development of a broadly protective human influenza vaccine, since most CTL epitopes are found on internal viral proteins and relatively conserved. In this study, the possibility of developing a strain/subtype-independent human influenza vaccine was explored by taking a bioinformatics approach to establish an immunogenic HLA-A24 restricted CTL epitope screening system in HLA-transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: HLA-A24 restricted CTL epitope peptides derived from internal proteins of the H5N1 highly pathogenic avian influenza A virus were predicted by CTL epitope peptide prediction programs. Of 35 predicted peptides, six peptides exhibited remarkable cytotoxic activity in vivo. More than half of the mice which were subcutaneously vaccinated with the three most immunogenic and highly conserved epitopes among three different influenza A virus subtypes (H1N1, H3N2 and H5N1 survived lethal influenza virus challenge during both effector and memory CTL phases. Furthermore, mice that were intranasally vaccinated with these peptides remained free of clinical signs after lethal virus challenge during the effector phase. CONCLUSIONS/SIGNIFICANCE: This CTL epitope peptide selection system can be used as an effective tool for the development of a cross-protective human influenza vaccine. Furthermore this vaccine strategy can be applicable to the development of all intracellular pathogens vaccines to induce epitope-specific CTL that effectively eliminate infected cells.

Therapeutic Vaccination for HPV Induced Cervical Cancers

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Joeli A. Brinkman

2007-01-01

Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

Coated microneedle arrays for transcutaneous delivery of live virus vaccines

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Vrdoljak, Anto; McGrath, Marie G.; Carey, John B.; Draper, Simon J.; Hill, Adrian V.S.; O’Mahony, Conor; Crean, Abina M.; Moore, Anne C.

2011-01-01

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses ...

Genotyping assay for differentiation of wild-type and vaccine viruses in subjects immunized with live attenuated influenza vaccine.

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Victoria Matyushenko

Full Text Available Live attenuated influenza vaccines (LAIVs are considered as safe and effective tool to control influenza in different age groups, especially in young children. An important part of the LAIV safety evaluation is the detection of vaccine virus replication in the nasopharynx of the vaccinees, with special attention to a potential virus transmission to the unvaccinated close contacts. Conducting LAIV clinical trials in some geographical regions with year-round circulation of influenza viruses warrants the development of robust and reliable tools for differentiating vaccine viruses from wild-type influenza viruses in nasal pharyngeal wash (NPW specimens of vaccinated subjects. Here we report the development of genotyping assay for the detection of wild-type and vaccine-type influenza virus genes in NPW specimens of young children immunized with Russian-backbone seasonal trivalent LAIV using Sanger sequencing from newly designed universal primers. The new primer set allowed amplification and sequencing of short fragments of viral genes in NPW specimens and appeared to be more sensitive than conventional real-time RT-PCR protocols routinely used for the detection and typing/subtyping of influenza virus in humans. Furthermore, the new assay is capable of defining the origin of wild-type influenza virus through BLAST search with the generated sequences of viral genes fragments.

Human capital gaps in vaccine development: an issue for global vaccine development and global health.

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Cawein, Andrea; Emini, Emilio; Watson, Michael; Dailey, Joanna; Donnelly, John; Tresnan, Dina; Evans, Tom; Plotkin, Stanley; Gruber, William

2017-05-01

Despite the success of vaccines in reducing the morbidity and mortality associated with infectious diseases, many infectious diseases, both newly emerging and well known, lack vaccines. The global capability for beginning-to-end vaccine development has become limited, primarily owing to a scarcity of human capital necessary to guide the development of novel vaccines from the laboratory to the marketplace. Here, we identify and discuss the gaps in human capital necessary for robust vaccine development and make recommendations to begin to address these deficiencies. © 2017 New York Academy of Sciences.

Plant viral nanoparticles-based HER2 vaccine: Immune response influenced by differential transport, localization and cellular interactions of particulate carriers.

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Shukla, Sourabh; Myers, Jay T; Woods, Sarah E; Gong, Xingjian; Czapar, Anna E; Commandeur, Ulrich; Huang, Alex Y; Levine, Alan D; Steinmetz, Nicole F

2017-03-01

Cancer vaccines are designed to elicit an endogenous adaptive immune response that can successfully recognize and eliminate residual or recurring tumors. Such approaches can potentially overcome shortcomings of passive immunotherapies by generating long-lived therapeutic effects and immune memory while limiting systemic toxicities. A critical determinant of vaccine efficacy is efficient transport and delivery of tumor-associated antigens to professional antigen presenting cells (APCs). Plant viral nanoparticles (VNPs) with natural tropism for APCs and a high payload carrying capacity may be particularly effective vaccine carriers. The applicability of VNP platform technologies is governed by stringent structure-function relationships. We compare two distinct VNP platforms: icosahedral cowpea mosaic virus (CPMV) and filamentous potato virus X (PVX). Specifically, we evaluate in vivo capabilities of engineered VNPs delivering human epidermal growth factor receptor 2 (HER2) epitopes for therapy and prophylaxis of HER2 + malignancies. Our results corroborate the structure-function relationship where icosahedral CPMV particles showed significantly enhanced lymph node transport and retention, and greater uptake by/activation of APCs compared to filamentous PVX particles. These enhanced immune cell interactions and transport properties resulted in elevated HER2-specific antibody titers raised by CPMV- vs. PVX-based peptide vaccine. The 'synthetic virology' field is rapidly expanding with numerous platforms undergoing development and preclinical testing; our studies highlight the need for systematic studies to define rules guiding the design and rational choice of platform, in the context of peptide-vaccine display technologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthetic generation of influenza vaccine viruses for rapid response to pandemics.

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Dormitzer, Philip R; Suphaphiphat, Pirada; Gibson, Daniel G; Wentworth, David E; Stockwell, Timothy B; Algire, Mikkel A; Alperovich, Nina; Barro, Mario; Brown, David M; Craig, Stewart; Dattilo, Brian M; Denisova, Evgeniya A; De Souza, Ivna; Eickmann, Markus; Dugan, Vivien G; Ferrari, Annette; Gomila, Raul C; Han, Liqun; Judge, Casey; Mane, Sarthak; Matrosovich, Mikhail; Merryman, Chuck; Palladino, Giuseppe; Palmer, Gene A; Spencer, Terika; Strecker, Thomas; Trusheim, Heidi; Uhlendorff, Jennifer; Wen, Yingxia; Yee, Anthony C; Zaveri, Jayshree; Zhou, Bin; Becker, Stephan; Donabedian, Armen; Mason, Peter W; Glass, John I; Rappuoli, Rino; Venter, J Craig

2013-05-15

During the 2009 H1N1 influenza pandemic, vaccines for the virus became available in large quantities only after human infections peaked. To accelerate vaccine availability for future pandemics, we developed a synthetic approach that very rapidly generated vaccine viruses from sequence data. Beginning with hemagglutinin (HA) and neuraminidase (NA) gene sequences, we combined an enzymatic, cell-free gene assembly technique with enzymatic error correction to allow rapid, accurate gene synthesis. We then used these synthetic HA and NA genes to transfect Madin-Darby canine kidney (MDCK) cells that were qualified for vaccine manufacture with viral RNA expression constructs encoding HA and NA and plasmid DNAs encoding viral backbone genes. Viruses for use in vaccines were rescued from these MDCK cells. We performed this rescue with improved vaccine virus backbones, increasing the yield of the essential vaccine antigen, HA. Generation of synthetic vaccine seeds, together with more efficient vaccine release assays, would accelerate responses to influenza pandemics through a system of instantaneous electronic data exchange followed by real-time, geographically dispersed vaccine production.

Mucosal vaccination with recombinant poxvirus vaccines protects ferrets against symptomatic CDV infection.

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Welter, J; Taylor, J; Tartaglia, J; Paoletti, E; Stephensen, C B

1999-01-28

Canine distemper virus (CDV) infection of ferrets causes a disease characterized by fever, erythema, conjunctivitis and leukocytopenia, similar clinically to measles except for the fatal neurologic sequelae of CDV. We vaccinated juvenile ferrets twice at 4-week intervals by the intranasal or intraduodenal route with attenuated vaccinia (NYVAC) or canarypox virus (ALVAC) constructs containing the CDV hemagglutinin and fusion genes. Controls were vaccinated with the same vectors expressing rabies glycoprotein. Animals were challenged intranasally 4 weeks after the second vaccination with virulent CDV. Body weights, white blood cell (WBC) counts and temperatures were monitored and ferrets were observed daily for clinical signs of infection. WBCs were assayed for the presence of viral RNA by RT-PCR. Intranasally vaccinated animals survived challenge with no virologic or clinical evidence of infection. Vaccination by the intraduodenal route did not provide complete protection. All control animals developed typical distemper. Ferrets can be effectively protected against distemper by mucosal vaccination with poxvirus vaccines.

Herpes simplex virus-2 in the genital mucosa: insights into the mucosal host response and vaccine development.

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Lee, Amanda J; Ashkar, Ali A

2012-02-01

Herpes simplex virus (HSV)-2 is the predominant cause of genital herpes and has been implicated in HIV infection and transmission. Thus far, vaccines developed against HSV-2 have been clinically ineffective in preventing infection. This review aims to summarize the innate and adaptive immune responses against HSV-2 and examines the current status of vaccine development. Both innate and adaptive immune responses are essential for an effective primary immune response and the generation of immunity. The innate response involves Toll-like receptors, natural killer cells, plasmacytoid dendritic cells, and type I, II, and III interferons. The adaptive response requires a balance between CD4+ and CD8+ T-cells for optimal viral clearance. T-regulatory cells may be involved, although their exact function has yet to be determined. Current vaccine development involves the use of HSV-2 peptides or attenuated/replication-defective HSV-2 to generate adaptive anti-HSV-2 immune responses, however the generation of innate responses may also be an important consideration. Although vaccine development has primarily focused on the adaptive response, arguments for innate involvement are emerging. A greater understanding of the innate and adaptive processes underlying the response to HSV-2 infection will provide the foundation for the development of an effective vaccine.

Is It Time for Vaccination to "Go Viral"?

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Philip, Roy K; Shapiro, Marla; Paterson, Pauline; Glismann, Steffen; Van Damme, Pierre

2016-12-01

To promote and sustain excellent vaccination coverage, while preserving the key core values of ethics, truth, transparency and trust, the vaccine community should adopt modern digital communication strategies. This article summarizes our views-as experts in multidisciplinary field of vaccinology (consisting of an anthropologist, a public health policy advisor, a vaccine industry expert, a health care journalist and a practicing physician)-which were presented at a satellite symposium held at the 33rd European Society of Paediatric Infectious Disease conference in Leipzig, Germany, in May 2015. This article aims to suggest and recommend strategies to promote vaccination awareness, and highlight proactive measures for building, maintaining and enhancing trust in vaccination through innovative communication and evidence-based interaction with the end user. We believe that converting the results of vaccine research into a successful vaccination program, and replacing misinformation with evidence-based communication, will require a multidisciplinary approach that embraces modern digital and tailored applications to reach out to all populations.

Impact of sex steroid ablation on viral, tumour and vaccine responses in aged mice.

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Tracy S P Heng

Full Text Available Recent evidence suggests that the decline in resistance to viral infections with age occurs predominantly as a result of a gradual loss of naïve antigen-specific T cells. As such, restoration of the naïve T cell repertoire to levels seen in young healthy adults may improve defence against infection in the aged. We have previously shown that sex steroid ablation (SSA rejuvenates the ageing thymus and increases thymic export of naïve T cells, but it remains unclear whether T cell responses are improved. Using mouse models of clinically relevant diseases, we now demonstrate that SSA increases the number of naïve T cells able to respond to antigen, thereby enhancing effector responses in aged mice. Specifically, aged mice exhibit a delay in clearing influenza A virus, which correlates with diminished specific cytotoxic activity. This is due to a decreased magnitude of response and not an intrinsic defect in effector T cell function. Upon SSA, aged mice exhibit increased T cell responsiveness that restores efficient viral clearance. We further demonstrate that SSA decreases the incidence of an inducible tumour in aged mice and can potentially increase their responsiveness to a low-dose human papillomavirus vaccine in clearing pre-formed tumours. As thymectomy abrogates the increase in T cell numbers and responsiveness following SSA, we propose that the T cell effects of SSA are dependent on thymic reactivation and subsequent replenishment of the peripheral T cell pool with newly emigrated naïve T cells. These findings have important implications for strategies to improve protection from infection and responsiveness to vaccination in the aged.

Prime-boost vaccination using DNA and whole inactivated virus vaccines provides limited protection against virulent feline immunodeficiency virus.

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Dunham, Stephen P; Bruce, Jennifer; Klein, Dieter; Flynn, J Norman; Golder, Matthew C; MacDonald, Susan; Jarrett, Oswald; Neil, James C

2006-11-30

Protection against feline immunodeficiency virus (FIV) has been achieved using a variety of vaccines notably whole inactivated virus (WIV) and DNA. However protection against more virulent isolates, typical of those encountered in natural infections, has been difficult to achieve. In an attempt to improve protection against virulent FIV(GL8), we combined both DNA and WIV vaccines in a "prime-boost" approach. Thirty cats were divided into four groups receiving vaccinations and one unvaccinated control group. Following viral challenge, two vaccinated animals, one receiving DNA alone and one the prime-boost vaccine remained free of viraemia, whilst all controls became viraemic. Animals vaccinated with WIV showed apparent early enhancement of infection at 2 weeks post challenge (pc) with higher plasma viral RNA loads than control animals or cats immunised with DNA alone. Despite this, animals vaccinated with WIV or DNA alone showed significantly lower proviral loads in peripheral blood mononuclear cells and mesenteric lymph node cells, whilst those receiving the DNA-WIV prime-boost vaccine showed significantly lower proviral loads in PBMC, than control animals, at 35 weeks pc. Therefore both DNA and WIV vaccines conferred limited protection against viral challenge but the combination of WIV and DNA in a prime-boost approach appeared to offer no significant advantage over either vaccine alone.

Multivalent display of proteins on viral nanoparticles using molecular recognition and chemical ligation strategies

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Venter, P. Arno; Dirksen, Anouk; Thomas, Diane; Manchester, Marianne; Dawson, Philip E.; Schneemann, Anette

2011-01-01

Multivalent display of heterologous proteins on viral nanoparticles forms a basis for numerous applications in nanotechnology, including vaccine development, targeted therapeutic delivery and tissue-specific bio-imaging. In many instances, precise placement of proteins is required for optimal functioning of the supramolecular assemblies, but orientation- and site-specific coupling of proteins to viral scaffolds remains a significant technical challenge. We have developed two strategies that allow for controlled attachment of a variety of proteins on viral particles using covalent and noncovalent principles. In one strategy, an interaction between domain 4 of anthrax protective antigen and its receptor was used to display multiple copies of a target protein on virus-like particles. In the other, expressed protein ligation and aniline-catalyzed oximation was used to covalently display a model protein. The latter strategy, in particular, yielded nanoparticles that induced potent immune responses to the coupled protein, suggesting potential applications in vaccine development. PMID:21545187

Simultaneous subcutaneous and conjunctival administration of the influenza viral vector based Brucella abortus vaccine to pregnant heifers provides better protection against B. abortus 544 infection than the commercial B. abortus S19 vaccine.

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Tabynov, Kaissar; Orynbayev, Mukhit; Renukaradhya, Gourapura J; Sansyzbay, Abylai

2016-09-30

In this study, we explored possibility of increasing the protective efficacy of our novel influenza viral vector based B. abortus vaccine (Flu-BA) in pregnant heifers by adapting an innovative method of vaccine delivery. We administered the vaccine concurrently via the conjunctival and subcutaneous routes to pregnant heifers, and these routes were previously tested individually. The Flu-BA vaccination of pregnant heifers (n=9) against a challenge B. abortus 544 infection provided protection from abortion, infection of heifers and fetuses/calves by 88.8%, 100% and 100%, respectively (alpha=0.004-0.0007 vs. negative control; n=7). Our candidate vaccine using this delivery method provided slightly better protection than the commercial B. abortus S19 vaccine in pregnant heifers (n=8), which provided protection from abortion, infection of heifers and fetuses/calves by 87.5%, 75% and 87.5%, respectively. This improved method of the Flu-BA vaccine administration is highly recommended for the recovery of farms which has high prevalence of brucellosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immune responses to rAAV6: The influence of canine parvovirus vaccination and neonatal administration of viral vector

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Andrea L H Arnett

2011-11-01

Full Text Available Recombinant adeno-associated viral (rAAV vectors promote long-term gene transfer in many animal species. Significant effort has focused on the evaluation of rAAV delivery and the immune response in both murine and canine models of neuromuscular disease. However, canines provided for research purposes are routinely vaccinated against canine parvovirus (CPV. rAAV and CPV possess significant homology and are both parvoviruses. Thus, any immune response generated to CPV vaccination has the potential to cross-react with rAAV vectors. In this study, we investigated the immune response to rAAV6 delivery in a cohort of CPV-vaccinated canines and evaluated multiple vaccination regimens in a mouse model of CPV-vaccination. We show that CPV-vaccination stimulates production of neutralizing antibodies with minimal cross-reactivity to rAAV6. In addition, no significant differences were observed in the magnitude of the rAAV6-directed immune response between CPV-vaccinated animals and controls. Moreover, CPV-vaccination did not inhibit rAAV6-mediated transduction. We also evaluated the immune response to early rAAV6-vaccination in neonatal mice. The influence of maternal hormones and cytokines leads to a relatively permissive state in the neonate. We hypothesized that immaturity of the immune system would permit induction of tolerance to rAAV6 when delivered during the neonatal period. Mice were vaccinated with rAAV6 at 1 or 5 days of age, and subsequently challenged with rAAV6 exposure during adulthood via two sequential IM injections, one month apart. All vaccinated animals generated a significant neutralizing antibody response to rAAV6-vaccination that was enhanced following IM injection in adulthood. Taken together, these data demonstrate that the immune response raised against rAAV6 is distinct from that which is elicited by the standard parvoviral vaccines and is sufficient to prevent stable tolerization in neonatal mice.

CRISPR/Cas9—Advancing Orthopoxvirus Genome Editing for Vaccine and Vector Development

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Okoli, Arinze; Okeke, Malachy I.; Tryland, Morten; Moens, Ugo

2018-01-01

The clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (Cas9) technology is revolutionizing genome editing approaches. Its high efficiency, specificity, versatility, flexibility, simplicity and low cost have made the CRISPR/Cas9 system preferable to other guided site-specific nuclease-based systems such as TALENs (Transcription Activator-like Effector Nucleases) and ZFNs (Zinc Finger Nucleases) in genome editing of viruses. CRISPR/Cas9 is presently being applied in constructing viral mutants, preventing virus infections, eradicating proviral DNA, and inhibiting viral replication in infected cells. The successful adaptation of CRISPR/Cas9 to editing the genome of Vaccinia virus paves the way for its application in editing other vaccine/vector-relevant orthopoxvirus (OPXV) strains. Thus, CRISPR/Cas9 can be used to resolve some of the major hindrances to the development of OPXV-based recombinant vaccines and vectors, including sub-optimal immunogenicity; transgene and genome instability; reversion of attenuation; potential of spread of transgenes to wildtype strains and close contacts, which are important biosafety and risk assessment considerations. In this article, we review the published literature on the application of CRISPR/Cas9 in virus genome editing and discuss the potentials of CRISPR/Cas9 in advancing OPXV-based recombinant vaccines and vectors. We also discuss the application of CRISPR/Cas9 in combating viruses of clinical relevance, the limitations of CRISPR/Cas9 and the current strategies to overcome them. PMID:29361752

Deinococcus Mn2+-peptide complex: A novel approach to alphavirus vaccine development.

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Gayen, Manoshi; Gupta, Paridhi; Morazzani, Elaine M; Gaidamakova, Elena K; Knollmann-Ritschel, Barbara; Daly, Michael J; Glass, Pamela J; Maheshwari, Radha K

2017-06-22

Over the last ten years, Chikungunya virus (CHIKV), an Old World alphavirus has caused numerous outbreaks in Asian and European countries and the Americas, making it an emerging pathogen of great global health importance. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, on the other hand, has been developed as a bioweapon in the past due to its ease of preparation, aerosol dispersion and high lethality in aerosolized form. Currently, there are no FDA approved vaccines against these viruses. In this study, we used a novel approach to develop inactivated vaccines for VEEV and CHIKV by applying gamma-radiation together with a synthetic Mn-decapeptide-phosphate complex (MnDpPi), based on manganous-peptide-orthophosphate antioxidants accumulated in the extremely radiation-resistant bacterium Deinococcus radiodurans. Classical gamma-irradiated vaccine development approaches are limited by immunogenicity-loss due to oxidative damage to the surface proteins at the high doses of radiation required for complete virus-inactivation. However, addition of MnDpPi during irradiation process selectively protects proteins, but not the nucleic acids, from the radiation-induced oxidative damage, as required for safe and efficacious vaccine development. Previously, this approach was used to develop a bacterial vaccine. In the present study, we show that this approach can successfully be applied to protecting mice against viral infections. Irradiation of VEEV and CHIKV in the presence of MnDpPi resulted in substantial epitope preservation even at supra-lethal doses of gamma-rays (50,000Gy). Irradiated viruses were found to be completely inactivated and safe in vivo (neonatal mice). Upon immunization, VEEV inactivated in the presence of MnDpPi resulted in drastically improved protective efficacy. Thus, the MnDpPi-based gamma-inactivation approach described here can readily be applied to developing vaccines against any pathogen of interest in a fast and cost

Viral evasion of intracellular DNA and RNA sensing

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Chan, Ying Kai; Gack, Michaela U.

2016-01-01

The co-evolution of viruses with their hosts has led to the emergence of viral pathogens that are adept at evading or actively suppressing host immunity. Pattern recognition receptors (PRRs) are key components of antiviral immunity that detect conserved molecular features of viral pathogens and initiate signalling that results in the expression of antiviral genes. In this Review, we discuss the strategies that viruses use to escape immune surveillance by key intracellular sensors of viral RNA or DNA, with a focus on RIG-I-like receptors (RLRs), cyclic GMP–AMP synthase (cGAS) and interferon-γ (IFNγ)-inducible protein 16 (IFI16). Such viral strategies include the sequestration or modification of viral nucleic acids, interference with specific post-translational modifications of PRRs or their adaptor proteins, the degradation or cleavage of PRRs or their adaptors, and the sequestration or relocalization of PRRs. An understanding of viral immune-evasion mechanisms at the molecular level may guide the development of vaccines and antivirals. PMID:27174148

Development of a novel, single-cycle replicable rift valley Fever vaccine.

Directory of Open Access Journals (Sweden)

Shin Murakami

2014-03-01

Full Text Available Rift Valley fever virus (RVFV (genus Phlebovirus, family Bunyaviridae is an arbovirus that causes severe disease in humans and livestock in sub-Saharan African countries. Although the MP-12 strain of RVFV is a live attenuated vaccine candidate, neuroinvasiveness and neurovirulence of MP-12 in mice may be a concern when vaccinating certain individuals, especially those that are immunocompromised. We have developed a novel, single-cycle replicable MP-12 (scMP-12, which carries an L RNA, M RNA mutant encoding a mutant envelope protein lacking an endoplasmic reticulum retrieval signal and defective for membrane fusion function, and S RNA encoding N protein and green fluorescent protein. The scMP-12 underwent efficient amplification, then formed plaques and retained the introduced mutation after serial passages in a cell line stably expressing viral envelope proteins. However, inoculation of the scMP-12 into naïve cells resulted in a single round of viral replication, and production of low levels of noninfectious virus-like particles. Intracranial inoculation of scMP-12 into suckling mice did not cause clinical signs or death, a finding which demonstrated that the scMP-12 lacked neurovirulence. Mice immunized with a single dose of scMP-12 produced neutralizing antibodies, whose titers were higher than in mice immunized with replicon particles carrying L RNA and S RNA encoding N protein and green fluorescent protein. Moreover, 90% of the scMP-12-immunized mice were protected from wild-type RVFV challenge by efficiently suppressing viremia and replication of the challenge virus in the liver and the spleen. These data demonstrated that scMP-12 is a safe and immunogenic RVFV vaccine candidate.

Effect of a mouse mammary tumor virus-derived protein vaccine on primary tumor development in mice

NARCIS (Netherlands)

Creemers, P.; Ouwehand, J.; Bentveizen, P.

1978-01-01

The vaccines used in this study were derived from purified murine mammary tumor virus (MuMTV) preparations. Approximately 60% of the protein fractions consisted of the major viral membrane glycoprotein gp52. Inoculation sc of 10 pg MuMTV-S-derived vaccine significantly delayed the appearance of

Construction and analysis of experimental DNA vaccines against megalocytivirus.

Science.gov (United States)

Zhang, Min; Hu, Yong-Hua; Xiao, Zhi-Zhong; Sun, Yun; Sun, Li

2012-11-01

Iridoviruses are large double-stranded DNA viruses with icosahedral capsid. The Iridoviridae family contains five genera, one of which is Megalocytivirus. Megalocytivirus has emerged in recent years as an important pathogen to a wide range of marine and freshwater fish. In this study, we aimed at developing effective genetic vaccines against megalocytivirus affecting farmed fish in China. For this purpose, we constructed seven DNA vaccines based on seven genes of rock bream iridovirus isolate 1 from China (RBIV-C1), a megalocytivirus with a host range that includes Japanese flounder (Paralichthys olivaceus) and turbot (Scophthalmus maximus). The protective potentials of these vaccines were examined in a turbot model. The results showed that after vaccination via intramuscular injection, the vaccine plasmids were distributed in spleen, kidney, muscle, and liver, and transcription of the vaccine genes and production of the vaccine proteins were detected in these tissues. Following challenge with a lethal-dose of RBIV-C1, fish vaccinated with four of the seven DNA vaccines exhibited significantly higher levels of survival compared to control fish. Of these four protective DNA vaccines, pCN86, which is a plasmid that expresses an 86-residue viral protein, induced the highest protection. Immunological analysis showed that pCN86 was able to (i) stimulate the respiratory burst of head kidney macrophages at 14 d, 21 d, and 28 d post-vaccination, (ii) upregulate the expression of immune relevant genes involved in innate and adaptive immunity, and (iii) induce production of serum antibodies that, when incubated with RBIV-C1 before infection, significantly reduced viral loads in kidney and spleen following viral infection of turbot. Taken together, these results indicate that pCN86 is an effective DNA vaccine that may be used in the control of megalocytivirus-associated diseases in aquaculture. Copyright © 2012 Elsevier Ltd. All rights reserved.

Biotechnology and genetic engineering in the new drug development. Part II. Monoclonal antibodies, modern vaccines and gene therapy.

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Stryjewska, Agnieszka; Kiepura, Katarzyna; Librowski, Tadeusz; Lochyński, Stanisław

2013-01-01

Monoclonal antibodies, modern vaccines and gene therapy have become a major field in modern biotechnology, especially in the area of human health and fascinating developments achieved in the past decades are impressive examples of an interdisciplinary interplay between medicine, biology and engineering. Among the classical products from cells one can find viral vaccines, monoclonal antibodies, and interferons, as well as recombinant therapeutic proteins. Gene therapy opens up challenging new areas. In this review, a definitions of these processes are given and fields of application and products, as well as the future prospects, are discussed.

Vaxvec: The first web-based recombinant vaccine vector database and its data analysis

Science.gov (United States)

Deng, Shunzhou; Martin, Carly; Patil, Rasika; Zhu, Felix; Zhao, Bin; Xiang, Zuoshuang; He, Yongqun

2015-01-01

A recombinant vector vaccine uses an attenuated virus, bacterium, or parasite as the carrier to express a heterologous antigen(s). Many recombinant vaccine vectors and related vaccines have been developed and extensively investigated. To compare and better understand recombinant vectors and vaccines, we have generated Vaxvec (http://www.violinet.org/vaxvec), the first web-based database that stores various recombinant vaccine vectors and those experimentally verified vaccines that use these vectors. Vaxvec has now included 59 vaccine vectors that have been used in 196 recombinant vector vaccines against 66 pathogens and cancers. These vectors are classified to 41 viral vectors, 15 bacterial vectors, 1 parasitic vector, and 1 fungal vector. The most commonly used viral vaccine vectors are double-stranded DNA viruses, including herpesviruses, adenoviruses, and poxviruses. For example, Vaxvec includes 63 poxvirus-based recombinant vaccines for over 20 pathogens and cancers. Vaxvec collects 30 recombinant vector influenza vaccines that use 17 recombinant vectors and were experimentally tested in 7 animal models. In addition, over 60 protective antigens used in recombinant vector vaccines are annotated and analyzed. User-friendly web-interfaces are available for querying various data in Vaxvec. To support data exchange, the information of vaccine vectors, vaccines, and related information is stored in the Vaccine Ontology (VO). Vaxvec is a timely and vital source of vaccine vector database and facilitates efficient vaccine vector research and development. PMID:26403370

Effects of TLR agonists and viral infection on cytokine and TLR expression in Atlantic salmon (Salmo salar).

Science.gov (United States)

Arnemo, Marianne; Kavaliauskis, Arturas; Gjøen, Tor

2014-10-01

The development of efficient and cheap vaccines against several aquatic viruses is necessary for a sustainable fish farming industry. Toll-like receptor (TLR) ligands have already been used as good adjuvants in human vaccines. With more understanding of TLR expression, function, and ligand specificity in fish, more efficient adjuvants for fish viral vaccines can be developed. In this paper, we examine all known TLRs in Atlantic salmon (Salmo salar) and demonstrate that head kidney and spleen are the main organs expressing TLRs in salmon. We also show that adherent head kidney leucocytes from salmon are able to respond to many of the known agonists for human TLRs, and that viral infection can induce up-regulation of several TLRs. These findings substantiate these receptors' role in immune responses to pathogens in salmonids making their ligands attractive as vaccine adjuvant candidates. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tomorrow's vector vaccines for small ruminants.

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Kyriakis, C S

2015-12-14

Inactivated and attenuated vaccines have contributed to the control or even the eradication of significant animal pathogens. However, these traditional vaccine technologies have limitations and disadvantages. Inactivated vaccines lack efficacy against certain pathogens, while attenuated vaccines are not always as safe. New technology vaccines, namely DNA and recombinant viral vector vaccines, are being developed and tested against pathogens of small ruminants. These vaccines induce both humoral and cellular immune responses, are safe to manufacture and use and can be utilized in strategies for differentiation of infected from vaccinated animals. Although there are more strict regulatory requirements for the safety standards of these vaccines, once a vaccine platform is evaluated and established, effective vaccines can be rapidly produced and deployed in the field to prevent spread of emerging pathogens. The present article offers an introduction to these next generation technologies and examples of vaccines that have been tested against important diseases of sheep and goats. Copyright © 2015 Elsevier B.V. All rights reserved.

Evolving perception on the benefits of vaccination as a foot and mouth disease control policy: contributions of South America.

Science.gov (United States)

Bergmann, Ingrid E; Malirat, Viviana; Falczuk, Abraham J

2005-12-01

Within the past decade, changes in perceptions on the benefits of vaccination as an appropriate tool to achieve complete foot and mouth disease eradication have become evident. The former negative view was derived from misconceptions, resulting mainly from the belief that vaccines are not entirely effective and that vaccination masks asymptomatic viral circulation. The advent in the 1990s of vaccination policies implemented within a strategic eradication plan in South America, and during recurrence of the disease in disease-free regions contributed towards generating more reliable and visible outcomes of vaccination programs, paving the way towards a new perception. Particularly relevant was the development and application of novel serodiagnostic approaches to assess silent viral circulation, irrespective of vaccination. The use in South America of vaccination allied to serosurveys to accompany viral clarification during eradication campaigns and after emergencies clearly established the importance of this control tool to stop the spread of viral infection. This alliance gave input to break many myths associated with the use of vaccines, including the belief that immunized carrier animals pose an epidemiologic risk. This experience launched new concepts that supported the internationally recognized status of foot and mouth disease-free regions with vaccination and the 'vaccination to live' policy as an alternative to 'stamping out'.

Immunogenicity of a modified-live virus vaccine against bovine viral diarrhea virus types 1 and 2, infectious bovine rhinotracheitis virus, bovine parainfluenza-3 virus, and bovine respiratory syncytial virus when administered intranasally in young calves.

Science.gov (United States)

Xue, Wenzhi; Ellis, John; Mattick, Debra; Smith, Linda; Brady, Ryan; Trigo, Emilio

2010-05-14

The immunogenicity of an intranasally-administered modified-live virus (MLV) vaccine in 3-8 day old calves was evaluated against bovine viral diarrhea virus (BVDV) types 1 and 2, infectious bovine rhinotracheitis (IBR) virus, parainfluenza-3 (PI-3) virus and bovine respiratory syncytial virus (BRSV). Calves were intranasally vaccinated with a single dose of a multivalent MLV vaccine and were challenged with one of the respective viruses three to four weeks post-vaccination in five separate studies. There was significant sparing of diseases in calves intranasally vaccinated with the MLV vaccine, as indicated by significantly fewer clinical signs, lower rectal temperatures, reduced viral shedding, greater white blood cell and platelet counts, and less severe pulmonary lesions than control animals. This was the first MLV combination vaccine to demonstrate efficacy against BVDV types 1 and 2, IBR, PI-3 and BRSV in calves 3-8 days of age. Copyright 2010 Elsevier Ltd. All rights reserved.

Vaccines for the 21st century

Science.gov (United States)

Delany, Isabel; Rappuoli, Rino; De Gregorio, Ennio

2014-01-01

In the last century, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases. It is believed that vaccines save at least 2–3 million lives per year worldwide. Smallpox has been eradicated and polio has almost disappeared worldwide through global vaccine campaigns. Most of the viral and bacterial infections that traditionally affected children have been drastically reduced thanks to national immunization programs in developed countries. However, many diseases are not yet preventable by vaccination, and vaccines have not been fully exploited for target populations such as elderly and pregnant women. This review focuses on the state of the art of recent clinical trials of vaccines for major unmet medical needs such as HIV, malaria, TB, and cancer. In addition, we describe the innovative technologies currently used in vaccine research and development including adjuvants, vectors, nucleic acid vaccines, and structure-based antigen design. The hope is that thanks to these technologies, more diseases will be addressed in the 21st century by novel preventative and therapeutic vaccines. PMID:24803000

Genetic heterogeneity of L-Zagreb mumps virus vaccine strain.

Science.gov (United States)

Kosutic-Gulija, Tanja; Forcic, Dubravko; Santak, Maja; Ramljak, Ana; Mateljak-Lukacevic, Sanja; Mazuran, Renata

2008-07-10

The most often used mumps vaccine strains Jeryl Lynn (JL), RIT4385, Urabe-AM9, L-Zagreb and L-3 differ in immunogenicity and reactogenicity. Previous analyses showed that JL, Urabe-AM9 and L-3 are genetically heterogeneous. We identified the heterogeneity of L-Zagreb throughout the entire genome. Two major variants were defined: variant A being identical to the consensus sequence of viral seeds and vaccine(s) and variant B which differs from variant A in three nucleotide positions. The difference between viral variants in L-Zagreb strain is insufficient for distinct viral strains to be defined. We demonstrated that proportion of variants in L-Zagreb viral population depends on cell substrate used for viral replication in vitro and in vivo. L-Zagreb strain should be considered as a single strain composed of at least two variant viral genomes.

Transcutaneous delivery of T Cell-inducing viral vector Malaria vaccines by microneedle patches

OpenAIRE

2011-01-01

There is an urgent need for improvements to existing vaccine delivery technologies to run parallel with the development of new-generation vaccines. The burdens of needle-based immunisation strategies are exacerbated by poor resource provision in such areas as sub-Saharan Africa, where annual malaria mortality stands at 860,000. Needle-free delivery of vaccine to the skin holds promise for improved immunogenicity with lower doses of vaccine, in addition to significant logistical advantages. Va...

76 FR 36367 - National Vaccine Injury Compensation Program: Revisions to the Vaccine Injury Table

Science.gov (United States)

2011-06-22

... hepatitis A, trivalent influenza, meningococcal, and human papillomavirus vaccines. The Secretary is now... within the time period prescribed. IV. Vaccines containing A. Chronic arthritis.. 7-42 days. rubella... days. virus (e.g., MMR, MR, M). purpura. B. Vaccine-Strain 6 months. Measles Viral Infection in an...

Global issues related to enteric viral infections.

Science.gov (United States)

Desselberger, Ulrich

2014-01-01

Acute viral gastroenteritis is a major health issue worldwide and is associated with high annual mortality, particularly in children of developing countries. Rotaviruses, caliciviruses and astroviruses are the main causes. Accurate diagnoses are possible by recently developed molecular techniques. In many setups, zoonotic transmission is an important epidemiological factor. Treatment consists of rehydration and is otherwise symptomatic. The worldwide introduction of universal rotavirus vaccination of infants has significantly reduced rotavirus disease and mortality.

Current Ebola vaccines

Science.gov (United States)

Hoenen, Thomas; Groseth, Allison; Feldmann, Heinz

2012-01-01

Introduction Ebolaviruses cause severe viral hemorrhagic fever in humans and non-human primates, with case fatality rates of up to 90%. Currently, neither a specific treatment nor a vaccine licensed for use in humans is available. However, a number of vaccine candidates have been developed in the last decade that are highly protective in non-human primates, the gold standard animal model for Ebola hemorrhagic fever. Areas covered This review analyzes a number of scenarios for the use of ebolavirus vaccines, discusses the requirements for ebolavirus vaccines in these scenarios, and describes current ebolavirus vaccines. Among these vaccines are recombinant Adenoviruses, recombinant Vesicular Stomatitis viruses, recombinant Human Parainfluenza viruses and virus-like particles. Interestingly, one of these vaccine platforms, based on recombinant Vesicular Stomatitis viruses, has also demonstrated post-exposure protection in non-human primates. Expert opinion The most pressing remaining challenge is now to move these vaccine candidates forward into human trials and towards licensure. In order to achieve this, it will be necessary to establish the mechanisms and correlates of protection for these vaccines, and to continue to demonstrate their safety, particularly in potentially immunocompromised populations. However, already now there is sufficient evidence that, from a scientific perspective, a vaccine protective against ebolaviruses is possible. PMID:22559078

Coated microneedle arrays for transcutaneous delivery of live virus vaccines.

Science.gov (United States)

Vrdoljak, Anto; McGrath, Marie G; Carey, John B; Draper, Simon J; Hill, Adrian V S; O'Mahony, Conor; Crean, Abina M; Moore, Anne C

2012-04-10

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8(+) T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices. Copyright © 2011 Elsevier B.V. All rights reserved.

Coated microneedle arrays for transcutaneous delivery of live virus vaccines

Science.gov (United States)

Vrdoljak, Anto; McGrath, Marie G.; Carey, John B.; Draper, Simon J.; Hill, Adrian V.S.; O’Mahony, Conor; Crean, Abina M.; Moore, Anne C.

2016-01-01

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8+ T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices. PMID:22245683

Murine CMV Expressing the High Affinity NKG2D Ligand MULT-1: A Model for the Development of Cytomegalovirus-Based Vaccines

Directory of Open Access Journals (Sweden)

Lea Hiršl

2018-05-01

Full Text Available The development of a vaccine against human cytomegalovirus (CMV has been a subject of long-term medical interest. The research during recent years identified CMV as an attractive vaccine vector against infectious diseases and tumors. The immune response to CMV persists over a lifetime and its unique feature is the inflationary T cell response to certain viral epitopes. CMV encodes numerous genes involved in immunoevasion, which are non-essential for virus growth in vitro. The deletion of those genes results in virus attenuation in vivo, which enables us to dramatically manipulate its virulence and the immune response. We have previously shown that the murine CMV (MCMV expressing RAE-1γ, one of the cellular ligands for the NKG2D receptor, is highly attenuated in vivo but retains the ability to induce a strong CD8+ T cell response. Here, we demonstrate that recombinant MCMV expressing high affinity NKG2D ligand murine UL16 binding protein-like transcript (MULT-1 (MULT-1MCMV inserted in the place of its viral inhibitor is dramatically attenuated in vivo in a NK cell-dependent manner, both in immunocompetent adult mice and in immunologically immature newborns. MULT-1MCMV was more attenuated than the recombinant virus expressing RAE-1γ. Despite the drastic sensitivity to innate immune control, MULT-1MCMV induced an efficient CD8+ T cell response to viral and vectored antigens. By using in vitro assay, we showed that similar to RAE-1γMCMV, MULT-1 expressing virus provided strong priming of CD8+ T cells. Moreover, MULT-1MCMV was able to induce anti-viral antibodies, which after passing the transplacental barrier protect offspring of immunized mothers from challenge infection. Altogether, this study further supports the concept that CMV expressing NKG2D ligand possesses excellent characteristics to serve as a vaccine or vaccine vector.

Impact of BRICS’ investment in vaccine development on the global vaccine market

Science.gov (United States)

Milstien, Julie; Schmitt, Sarah

2014-01-01

Abstract Brazil, the Russian Federation, India, China and South Africa – the countries known as BRICS – have made considerable progress in vaccine production, regulation and development over the past 20 years. In 1993, all five countries were producing vaccines but the processes used were outdated and non-standardized, there was little relevant research and there was negligible international recognition of the products. By 2014, all five countries had strong initiatives for the development of vaccine technology and had greatly improved their national regulatory capacity. South Africa was then the only BRICS country that was not completely producing vaccines. South Africa is now in the process of re-establishing its own vaccine production and passing beyond the stage of simply importing, formulating and filling vaccine bulks. Changes in the public sector’s price per dose of selected vaccines, the global market share represented by products from specific manufacturers, and the attractiveness, for multinational companies, of partnership and investment opportunities in BRICS companies have all been analysed. The results indicate that the BRICS countries have had a major impact on vaccine price and availability, with much of that impact attributable to the output of Indian vaccine manufacturers. China is expected to have a greater impact soon, given the anticipated development of Chinese vaccine manufacturers in the near future. BRICS’ accomplishments in the field of vaccine development are expected to reshape the global vaccine market and accelerate access to vaccines in the developing world. The challenge is to turn these expectations into strategic actions and practical outcomes. PMID:24940018

Impact of BRICS' investment in vaccine development on the global vaccine market.

Science.gov (United States)

Kaddar, Miloud; Milstien, Julie; Schmitt, Sarah

2014-06-01

Brazil, the Russian Federation, India, China and South Africa--the countries known as BRICS--have made considerable progress in vaccine production, regulation and development over the past 20 years. In 1993, all five countries were producing vaccines but the processes used were outdated and non-standardized, there was little relevant research and there was negligible international recognition of the products. By 2014, all five countries had strong initiatives for the development of vaccine technology and had greatly improved their national regulatory capacity. South Africa was then the only BRICS country that was not completely producing vaccines. South Africa is now in the process of re-establishing its own vaccine production and passing beyond the stage of simply importing, formulating and filling vaccine bulks. Changes in the public sector's price per dose of selected vaccines, the global market share represented by products from specific manufacturers, and the attractiveness, for multinational companies, of partnership and investment opportunities in BRICS companies have all been analysed. The results indicate that the BRICS countries have had a major impact on vaccine price and availability, with much of that impact attributable to the output of Indian vaccine manufacturers. China is expected to have a greater impact soon, given the anticipated development of Chinese vaccine manufacturers in the near future. BRICS' accomplishments in the field of vaccine development are expected to reshape the global vaccine market and accelerate access to vaccines in the developing world. The challenge is to turn these expectations into strategic actions and practical outcomes.

An Atypical Local Vesicular Reaction to the Yellow Fever Vaccine

OpenAIRE

Wauters, Robert H.; Hernandez, Camellia L.; Petersen, Maureen M.

2017-01-01

Yellow fever vaccine is a live attenuated viral inoculation indicated for patients traveling to endemic areas. The vaccine is generally well tolerated with minimal adverse effects. Typical side effects include malaise, pain at the injection site, and, albeit rarely, immediate hypersensitivity reactions. We present a case of a rare adverse reaction to yellow fever vaccine in which a patient developed vesicular lesions resulting in bullae and circumferential hyperpigmentation.

An Atypical Local Vesicular Reaction to the Yellow Fever Vaccine.

Science.gov (United States)

Wauters, Robert H; Hernandez, Camellia L; Petersen, Maureen M

2017-09-19

Yellow fever vaccine is a live attenuated viral inoculation indicated for patients traveling to endemic areas. The vaccine is generally well tolerated with minimal adverse effects. Typical side effects include malaise, pain at the injection site, and, albeit rarely, immediate hypersensitivity reactions. We present a case of a rare adverse reaction to yellow fever vaccine in which a patient developed vesicular lesions resulting in bullae and circumferential hyperpigmentation.

Genetic heterogeneity of L-Zagreb mumps virus vaccine strain

Directory of Open Access Journals (Sweden)

Mateljak-Lukacevic Sanja

2008-07-01

Full Text Available Abstract Background The most often used mumps vaccine strains Jeryl Lynn (JL, RIT4385, Urabe-AM9, L-Zagreb and L-3 differ in immunogenicity and reactogenicity. Previous analyses showed that JL, Urabe-AM9 and L-3 are genetically heterogeneous. Results We identified the heterogeneity of L-Zagreb throughout the entire genome. Two major variants were defined: variant A being identical to the consensus sequence of viral seeds and vaccine(s and variant B which differs from variant A in three nucleotide positions. The difference between viral variants in L-Zagreb strain is insufficient for distinct viral strains to be defined. We demonstrated that proportion of variants in L-Zagreb viral population depends on cell substrate used for viral replication in vitro and in vivo. Conclusion L-Zagreb strain should be considered as a single strain composed of at least two variant viral genomes.

Genetic heterogeneity of L-Zagreb mumps virus vaccine strain

Science.gov (United States)

Kosutic-Gulija, Tanja; Forcic, Dubravko; Šantak, Maja; Ramljak, Ana; Mateljak-Lukacevic, Sanja; Mazuran, Renata

2008-01-01

Background The most often used mumps vaccine strains Jeryl Lynn (JL), RIT4385, Urabe-AM9, L-Zagreb and L-3 differ in immunogenicity and reactogenicity. Previous analyses showed that JL, Urabe-AM9 and L-3 are genetically heterogeneous. Results We identified the heterogeneity of L-Zagreb throughout the entire genome. Two major variants were defined: variant A being identical to the consensus sequence of viral seeds and vaccine(s) and variant B which differs from variant A in three nucleotide positions. The difference between viral variants in L-Zagreb strain is insufficient for distinct viral strains to be defined. We demonstrated that proportion of variants in L-Zagreb viral population depends on cell substrate used for viral replication in vitro and in vivo. Conclusion L-Zagreb strain should be considered as a single strain composed of at least two variant viral genomes. PMID:18616793

Overview of Current Humman Papilloma Virus (HPV Vaccination

Directory of Open Access Journals (Sweden)

Cumhur Artuk

2013-06-01

Full Text Available Persistent viral infection with high-risk human papillomavirus (HPV genotypes causes virtually all cancer of the cervix. The same HPV genotypes (“types” also cause cases of anal cancer. Cervical cancer is the third most frequent cancer in women worldwide after breast and colorectal cancers. It ranks fourth of women’s cancers according to the mortality ratio. Two vaccines have been developed against HPV infection; one is a quadrivalent vaccine (Gardasil™ and the other is a bivalent vaccine (Cervarix™. This topic will cover issues related to HPV infections, routine HPV immunization recommendations, vaccination in special patient populations, the cost-effectiveness of HPV vaccination, and vaccine safety. [TAF Prev Med Bull 2013; 12(3.000: 327-334

Overview of measles and mumps vaccine: origin, present, and future of vaccine production.

Science.gov (United States)

Betáková, T; Svetlíková, D; Gocník, M

2013-01-01

Measles and mumps are common viral childhood diseases that can cause serious complications. Vaccination remains the most efficient way to control the spread of these viruses. The manufacturing capability for viral vaccines produced in embryonated hen eggs and conventional/classical cell substrates, such as chicken embryo fibroblast or primary dog kidney cell substrates, is no longer sufficient. This limitation can be overcome by utilizing other recognized cell substrates such as Madin Darby Canine Kidney (MDCK), Chinese Hamster Ovary (CHO), Vero (monkey origin) cells, MRC-5 (human diploid) or as an alternative, introducing new cell substrates of human or avian origin. A very important factor in vaccine production is the safety and immunogenicity of the final vaccine, where the proper choice of cell substrate used for virus propagation is made. All substrates used in vaccine production must be fully characterized to avoid the contamination of hidden unknown pathogens which is difficult to achieve in primary cell substrates.

Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease

Energy Technology Data Exchange (ETDEWEB)

Hwang, Hye Suk; Lee, Young-Tae; Kim, Ki-Hye; Park, Soojin; Kwon, Young-Man; Lee, Youri; Ko, Eun-Ju; Jung, Yu-Jin [Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States); Lee, Jong Seok [Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States); National Institute of Biological Resources, Incheon (Korea, Republic of); Kim, Yu-Jin [Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States); Lee, Yu-Na; Kim, Min-Chul [Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States); Animal and Plant Quarantine Agency, Gyeonggi-do, Gimcheon, Gyeongsangbukdo (Korea, Republic of); Cho, Minkyoung [Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States); Kang, Sang-Moo, E-mail: skang24@gsu.edu [Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States)

2016-07-15

A safe and effective vaccine against respiratory syncytial virus (RSV) should confer protection without causing vaccine-enhanced disease. Here, using a cotton rat model, we investigated the protective efficacy and safety of an RSV combination vaccine composed of F-encoding plasmid DNA and virus-like particles containing RSV fusion (F) and attachment (G) glycoproteins (FFG-VLP). Cotton rats with FFG-VLP vaccination controlled lung viral replication below the detection limit, and effectively induced neutralizing activity and antibody-secreting cell responses. In comparison with formalin inactivated RSV (FI-RSV) causing severe RSV disease after challenge, FFG-VLP vaccination did not cause weight loss, airway hyper-responsiveness, IL-4 cytokines, histopathology, and infiltrates of proinflammatory cells such as eosinophils. FFG-VLP was even more effective in preventing RSV-induced pulmonary inflammation than live RSV infections. This study provides evidence that FFG-VLP can be developed into a safe and effective RSV vaccine candidate. - Highlights: • Combined RSV FFG VLP vaccine is effective in inducing F specific responses. • FFG VLP vaccine confers RSV neutralizing activity and viral control in cotton rats. • Cotton rats with RSV FFG VLP vaccination do not show vaccine-enhanced disease. • Cotton rats with FFG VLP vaccine induce F specific antibody secreting cell responses. • Cotton rats with FFG VLP do not induce lung cellular infiltrates and Th2 cytokine.

Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease

International Nuclear Information System (INIS)

Hwang, Hye Suk; Lee, Young-Tae; Kim, Ki-Hye; Park, Soojin; Kwon, Young-Man; Lee, Youri; Ko, Eun-Ju; Jung, Yu-Jin; Lee, Jong Seok; Kim, Yu-Jin; Lee, Yu-Na; Kim, Min-Chul; Cho, Minkyoung; Kang, Sang-Moo

2016-01-01

A safe and effective vaccine against respiratory syncytial virus (RSV) should confer protection without causing vaccine-enhanced disease. Here, using a cotton rat model, we investigated the protective efficacy and safety of an RSV combination vaccine composed of F-encoding plasmid DNA and virus-like particles containing RSV fusion (F) and attachment (G) glycoproteins (FFG-VLP). Cotton rats with FFG-VLP vaccination controlled lung viral replication below the detection limit, and effectively induced neutralizing activity and antibody-secreting cell responses. In comparison with formalin inactivated RSV (FI-RSV) causing severe RSV disease after challenge, FFG-VLP vaccination did not cause weight loss, airway hyper-responsiveness, IL-4 cytokines, histopathology, and infiltrates of proinflammatory cells such as eosinophils. FFG-VLP was even more effective in preventing RSV-induced pulmonary inflammation than live RSV infections. This study provides evidence that FFG-VLP can be developed into a safe and effective RSV vaccine candidate. - Highlights: • Combined RSV FFG VLP vaccine is effective in inducing F specific responses. • FFG VLP vaccine confers RSV neutralizing activity and viral control in cotton rats. • Cotton rats with RSV FFG VLP vaccination do not show vaccine-enhanced disease. • Cotton rats with FFG VLP vaccine induce F specific antibody secreting cell responses. • Cotton rats with FFG VLP do not induce lung cellular infiltrates and Th2 cytokine.

Viral infections in transplant recipients.

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Razonable, R R; Eid, A J

2009-12-01

Solid organ and hematopoietic stem cell transplant recipients are uniquely predisposed to develop clinical illness, often with increased severity, due to a variety of common and opportunistic viruses. Patients may acquire viral infections from the donor (donor-derived infections), from reactivation of endogenous latent virus, or from the community. Herpes viruses, most notably cytomegalovirus and Epstein Barr virus, are the most common among opportunistic viral pathogens that cause infection after solid organ and hematopoietic stem cell transplantation. The polyoma BK virus causes opportunistic clinical syndromes predominantly in kidney and allogeneic hematopoietic stem cell transplant recipients. The agents of viral hepatitis B and C present unique challenges particularly among liver transplant recipients. Respiratory viral illnesses due to influenza, respiratory syncytial virus, and parainfluenza virus may affect all types of transplant recipients, although severe clinical disease is observed more commonly among lung and allogeneic hematopoietic stem cell transplant recipients. Less common viral infections affecting transplant recipients include those caused by adenoviruses, parvovirus B19, and West Nile virus. Treatment for viruses with proven effective antiviral drug therapies should be complemented by reduction in the degree of immunosuppression. For others with no proven antiviral drugs for therapy, reduction in the degree of immunosuppression remains as the sole effective strategy for management. Prevention of viral infections is therefore of utmost importance, and this may be accomplished through vaccination, antiviral strategies, and aggressive infection control measures.

Evaluation of experimental vaccines for bovine viral diarrhea in bovines, ovines and guinea pigs Evaluación de vacunas experimentales para la diarrea viral bovina en bovinos, ovinos y cobayos

Directory of Open Access Journals (Sweden)

F. Fernández

2009-06-01

Full Text Available The bovine viral diarrhea virus (BVDV infection control should be based on elimination of persistently infected animals and on immunization through vaccination, to prevent fetal infection. However, the efficacy of inactivated BVDV vaccines is variable due to its low immunogenicity. This study evaluated the humoral immune response against homologous and heterologous strains of 7 inactivated BVDV vaccines, in bovines and two experimental models (ovine and guinea pig which might be used to test candidate vaccines. Vaccines formulated with BVDV Singer, Oregon, NADL, and multivalent, induced seroconversion in the three animal models studied, reaching antibody titres higher than 2. Vaccine containing 125C -genotype 2- only induced a low antibody response in ovine, while VS-115 NCP vaccine was not immunogenic. Furthermore, bovine sera at 60 dpv presented homologous as well as heterologous antibody response, indicating a high degree of cross-reactivity among the strains studied. However, when bovine sera were tested against the Argentine field strain 00-693, they showed the lowest levels of cross-reactivity, suggesting the need of continued surveillance to identify and characterize emerging field BVDV strains. Finally, optimal correlations between bovine-ovine and bovine-guinea pig models were observed, indicating that two alternative species could replace bovines when testing the immunogenicity of BVDV candidate vaccines.El control del virus de la diarrea viral bovina (VDVB se basa en la eliminación de animales persistentemente infectados, y la inmunización de hembras para prevenir infecciones fetales. La eficiencia de estas vacunas es variable por su baja inmunogenicidad. Se evaluó la respuesta inmune humoral contra virus homólogos y heterólogos de 7 vacunas experimentales inactivadas del VDVB en bovinos y en dos modelos experimentales (ovinos y cobayos. Las vacunas conteniendo VDVB Singer, Oregon, NADL y polivalentes indujeron seroconversión en

[Development of new vaccines].

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González-Romo, Fernando; Picazo, Juan J

2015-10-01

Recent and important advances in the fields of immunology, genomics, functional genomics, immunogenetics, immunogenomics, bioinformatics, microbiology, genetic engineering, systems biology, synthetic biochemistry, proteomics, metabolomics and nanotechnology, among others, have led to new approaches in the development of vaccines. The better identification of ideal epitopes, the strengthening of the immune response due to new adjuvants, and the search of new routes of vaccine administration, are good examples of advances that are already a reality and that will favour the development of more vaccines, their use in indicated population groups, or its production at a lower cost. There are currently more than 130 vaccines are under development against the more wished (malaria or HIV), difficult to get (CMV or RSV), severe re-emerging (Dengue or Ebola), increasing importance (Chagas disease or Leishmania), and nosocomial emerging (Clostridium difficile or Staphylococcus aureus) infectious diseases. Copyright © 2015. Published by Elsevier España, S.L.U.

Development of canine herpesvirus based antifertility vaccines for foxes using bacterial artificial chromosomes.

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Strive, Tanja; Hardy, Christopher M; French, Nigel; Wright, John D; Nagaraja, Nitin; Reubel, Gerhard H

2006-02-13

Using bacterial artificial chromosome (BAC) technology, a canine herpesvirus (CHV)-based recombinant vaccine vector was produced for the development of an antifertility vaccine for foxes. Infectious viruses were recovered following transfection of canid cells with a BAC plasmid carrying the complete CHV genome. In vitro growth characteristics of BAC-derived viruses were similar to that of wildtype (wt)-CHV. Two recombinant antigens, fox zona pellucida protein subunit 3 (fZPC) and enhanced green fluorescent protein (EGFP) as control antigen, were inserted into thymidine kinase (TK) locus of the CHV genome and shown to be efficiently expressed in vitro. Inoculation of foxes with transgenic CHVs induced CHV specific antibodies, but was innocuous and failed to elicit transgene-specific antibody responses. Infectious virus or viral DNA was not detected in mucosal secretions or tissues of vaccinated foxes. The CHV-BAC system proved to be a quick and reliable method to manipulate the CHV genome. It will help to readily apply changes in the vector design in order to improve virus replication in vivo.

Prior DNA vaccination does not interfere with the live-attenuated measles vaccine.

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Premenko-Lanier, Mary; Rota, Paul; Rhodes, Gary; Bellini, William; McChesney, Michael

2004-01-26

The currently used live-attenuated measles vaccine is very effective although maternal antibody prevents its administration prior to 6 months of age. We are investigating the ability of a DNA vaccine encoding the measles viral hemagglutinin, fusion and nucleoprotein to protect newborn infants from measles. Here, we show that a measles DNA vaccine protects juvenile macaques from pathogenic measles virus challenge and that macaques primed and boosted with this DNA vaccine have anemnestic antibody and cell-mediated responses after vaccination with a live-attenuated canine distemper-measles vaccine. Therefore, this DNA vaccine administered to newborn infants may not hinder the subsequent use of live-attenuated measles vaccine.

Vaccine platform recombinant measles virus.

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Mühlebach, Michael D

2017-10-01

The classic development of vaccines is lengthy, tedious, and may not necessarily be successful as demonstrated by the case of HIV. This is especially a problem for emerging pathogens that are newly introduced into the human population and carry the inherent risk of pandemic spread in a naïve population. For such situations, a considerable number of different platform technologies are under development. These are also under development for pathogens, where directly derived vaccines are regarded as too complicated or even dangerous due to the induction of inefficient or unwanted immune responses causing considerable side-effects as for dengue virus. Among platform technologies are plasmid-based DNA vaccines, RNA replicons, single-round infectious vector particles, or replicating vaccine-based vectors encoding (a) critical antigen(s) of the target pathogens. Among the latter, recombinant measles viruses derived from vaccine strains have been tested. Measles vaccines are among the most effective and safest life-attenuated vaccines known. Therefore, the development of Schwarz-, Moraten-, or AIK-C-strain derived recombinant vaccines against a wide range of mostly viral, but also bacterial pathogens was quite straightforward. These vaccines generally induce powerful humoral and cellular immune responses in appropriate animal models, i.e., transgenic mice or non-human primates. Also in the recent first clinical phase I trial, the results have been quite encouraging. The trial indicated the expected safety and efficacy also in human patients, interestingly independent from the level of prevalent anti-measles immunity before the trial. Thereby, recombinant measles vaccines expressing additional antigens are a promising platform for future vaccines.

Proof of principle for epitope-focused vaccine design

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Correia, Bruno E.; Bates, John T.; Loomis, Rebecca J.; Baneyx, Gretchen; Carrico, Chris; Jardine, Joseph G.; Rupert, Peter; Correnti, Colin; Kalyuzhniy, Oleksandr; Vittal, Vinayak; Connell, Mary J.; Stevens, Eric; Schroeter, Alexandria; Chen, Man; MacPherson, Skye; Serra, Andreia M.; Adachi, Yumiko; Holmes, Margaret A.; Li, Yuxing; Klevit, Rachel E.; Graham, Barney S.; Wyatt, Richard T.; Baker, David; Strong, Roland K.; Crowe, James E.; Johnson, Philip R.; Schief, William R.

2014-03-01

Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.

Understanding HIV infection for the design of a therapeutic vaccine. Part II: Vaccination strategies for HIV.

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de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A

2015-05-01

HIV infection leads to a gradual loss CD4(+) T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive lifelong adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore, there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. Copyright © 2014. Published by Elsevier Masson SAS.

Regulatory T cell frequencies and phenotypes following anti-viral vaccination.

Directory of Open Access Journals (Sweden)

A Charlotte M T de Wolf

Full Text Available Regulatory T cells (Treg function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays investigated, but the impact of vaccination on Treg homeostasis is still largely unknown. This may be a relevant safety aspect, since loss of tolerance through reduced Treg may trigger autoimmunity. In exploratory clinical trials, healthy adults were vaccinated with an influenza subunit vaccine plus or minus the adjuvant MF59®, an adjuvanted hepatitis B subunit vaccine or a live attenuated yellow fever vaccine. Frequencies and phenotypes of resting (rTreg and activated (aTreg subpopulations of circulating CD4+ Treg were determined and compared to placebo immunization. Vaccination with influenza vaccines did not result in significant changes in Treg frequencies and phenotypes. Vaccination with the hepatitis B vaccine led to slightly increased frequencies of both rTreg and aTreg subpopulations and a decrease in expression of functionality marker CD39 on aTreg. The live attenuated vaccine resulted in a decrease in rTreg frequency, and an increase in expression of activation marker CD25 on both subpopulations, possibly indicating a conversion from resting to migratory aTreg due to vaccine virus replication. To study the more local effects of vaccination on Treg in lymphoid organs, we immunized mice and analyzed the CD4+ Treg frequency and phenotype in draining lymph nodes and spleen. Vaccination resulted in a transient local decrease in Treg frequency in lymph nodes, followed by a systemic Treg increase in the spleen. Taken together, we showed that vaccination with vaccines with an already established safe profile have only minimal impact on frequencies and characteristics of Treg over time. These findings may serve as a bench-mark of inter-individual variation

Working towards dengue as a vaccine-preventable disease: challenges and opportunities.

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Shrivastava, Ambuj; Tripathi, Nagesh K; Dash, Paban K; Parida, Manmohan

2017-10-01

Dengue is an emerging viral disease that affects the human population around the globe. Recent advancements in dengue virus research have opened new avenues for the development of vaccines against dengue. The development of a vaccine against dengue is a challenging task because any of the four serotypes of dengue viruses can cause disease. The development of a dengue vaccine aims to provide balanced protection against all the serotypes. Several dengue vaccine candidates are in the developmental stages such as inactivated, live attenuated, recombinant subunit, and plasmid DNA vaccines. Area covered: The authors provide an overview of the progress made in the development of much needed dengue vaccines. The authors include their expert opinion and their perspectives for future developments. Expert opinion: Human trials of a live attenuated tetravalent chimeric vaccine have clearly demonstrated its potential as a dengue vaccine. Other vaccine candidate molecules such as DENVax, a recombinant chimeric vaccine andTetraVax, are at different stages of development at this time. The authors believe that the novel strategies for testing and improving the immune response of vaccine candidates in humans will eventually lead to the development of a successful dengue vaccine in future.

M cell-targeting strategy facilitates mucosal immune response and enhances protection against CVB3-induced viral myocarditis elicited by chitosan-DNA vaccine.

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Ye, Ting; Yue, Yan; Fan, Xiangmei; Dong, Chunsheng; Xu, Wei; Xiong, Sidong

2014-07-31

Efficient delivery of antigen to mucosal associated lymphoid tissue is a first and critical step for successful induction of mucosal immunity by vaccines. Considering its potential transcytotic capability, M cell has become a more and more attractive target for mucosal vaccines. In this research, we designed an M cell-targeting strategy by which mucosal delivery system chitosan (CS) was endowed with M cell-targeting ability via conjugating with a CPE30 peptide, C terminal 30 amino acids of clostridium perfringens enterotoxin (CPE), and then evaluated its immune-enhancing ability in the context of coxsackievirus B3 (CVB3)-specific mucosal vaccine consisting of CS and a plasmid encoding CVB3 predominant antigen VP1. It had shown that similar to CS-pVP1, M cell-targeting CPE30-CS-pVP1 vaccine appeared a uniform spherical shape with about 300 nm diameter and +22 mV zeta potential, and could efficiently protect DNA from DNase I digestion. Mice were orally immunized with 4 doses of CPE30-CS-pVP1 containing 50 μg pVP1 at 2-week intervals and challenged with CVB3 4 weeks after the last immunization. Compared with CS-pVP1 vaccine, CPE30-CS-pVP1 vaccine had no obvious impact on CVB3-specific serum IgG level and splenic T cell immune responses, but significantly increased specific fecal SIgA level and augmented mucosal T cell immune responses. Consequently, much milder myocarditis and lower viral load were witnessed in CPE30-CS-pVP1 immunized group. The enhanced immunogenicity and immunoprotection were associated with the M cell-targeting ability of CPE30-CS-pVP1 which improved its mucosal uptake and transcytosis. Our findings indicated that CPE30-CS-pVP1 may represent a novel prophylactic vaccine against CVB3-induced myocarditis, and this M cell-targeting strategy indeed could be applied as a promising and universal platform for mucosal vaccine development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tat protein vaccination of cynomolgus macaques influences SHIV-89.6P cy243 epitope variability.

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Ridolfi, Barbara; Genovese, Domenico; Argentini, Claudio; Maggiorella, Maria Teresa; Sernicola, Leonardo; Buttò, Stefano; Titti, Fausto; Borsetti, Alessandra; Ensoli, Barbara

2008-02-01

In a previous study we showed that vaccination with the native Tat protein controlled virus replication in five out of seven monkeys against challenge with the simian human immunodeficiency virus (SHIV)-89.6P cy243 and that this protection correlated with T helper (Th)-1 response and cytotoxic T lymphocyte (CTL) activity. To address the evolution of the SHIV-89.6P cy243 both in control and vaccinated infected monkeys, the sequence of the human immunodeficiency virus (HIV)-1 Tat protein and the C2-V3 Env region of the proviral-DNA-derived clones were analyzed in both control and vaccinated but unprotected animals. We also performed analysis of the T cell epitope using a predictive epitope model taking into consideration the phylogeny of the variants. Our results suggest that even though the viral evolution observed in both groups of monkeys was directed toward variations in the major histocompatibility complex (MHC)-I epitopes, in the control animals it was associated with mutational escape of such epitopes. On the contrary, it is possible that viral evolution in the vaccinated monkeys was linked to mutations that arose to keep high the viral fitness. In the vaccinated animals the reduction of epitope variability, obtained prompting the immune system by vaccination and inducing a specific immunological response against virus, was able to reduce the emergence of escape mutants. Thus the intervention of host's selective forces in driving CTL escape mutants and in modulating viral fitness appeared to be different in the two groups of monkeys. We concluded that in the vaccinated unprotected animals, vaccination with the Tat protein induced a broad antiviral response, as demonstrated by the reduced ability to develop escape mutants, which is known to help in the control of viral replication.

Vaccine-induced canine distemper in a lesser panda.

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Bush, M; Montali, R J; Brownstein, D; James, A E; Appel, M J

1976-11-01

A fatal disease occurred in a lesser panda (Ailurus fulgens) 2 weeks after vaccination with modified live distemper vaccine. The disease clinically resembled canine distemper. Pathologically there was giant cell pneumonia, with canine distemper viral inclusion bodies in pulmonary and digestive tract epithelium. Viral isolates were indicative of an attenuated strain rather than virulent types.

Viral subversion of the immune system

International Nuclear Information System (INIS)

Gillet, L.; Vanderplasschen, A.

2005-01-01

The continuous interactions between host and viruses during their co-evolution have shaped not only the immune system but also the countermeasures used by viruses. Studies in the last decade have described the diverse arrays of pathways and molecular targets that are used by viruses to elude immune detection or destruction, or both. These include targeting of pathways for major histocompatibility complex class I and class II antigen presentation, natural killer cell recognition, apoptosis, cytokine signalling, and complement activation. This paper provides an overview of the viral immune-evasion mechanisms described to date. It highlights the contribution of this field to our understanding of the immune system, and the importance of understanding this aspect of the biology of viral infection to develop efficacious and safe vaccines. (author)

The Challenges and Opportunities for Development of a T-Cell Epitope-Based Herpes Simplex Vaccine

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Kuo, Tiffany; Wang, Christine; Badakhshan, Tina; Chilukuri, Sravya; BenMohamed, Lbachir

2014-01-01

The infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a half billion individuals worldwide. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. HSV-1 infections are more prevalent than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. While genital herpes in mainly caused by HSV-2 infections, in recent years, there is an increase in the proportion of genital herpes caused by HSV-1 infections in young adults, which reach 50% in some western societies. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries their development has been notoriously difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One “common denominator” among previously failed clinical herpes vaccine trials is that they either used a whole virus or whole viral proteins, which contain both pathogenic “symptomatic” and protective “asymptomatic” antigens/epitopes. In this report, we continue to advocate that using an “asymptomatic” epitope-based vaccine strategy that selectively incorporates protective epitopes which: (i) are exclusively recognized, in vitro, by effector memory CD4+ and CD8+ TEM cells from “naturally” protected seropositive asymptomatic individuals; and (ii) protect, in vivo, human leukocyte antigen (HLA) transgenic animal models from ocular and genital herpes infections and diseases, could be the answer to many of the scientific challenges facing HSV vaccine

Immune complex-based vaccine for pig protection against parvovirus.

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Roić, B; Cajavec, S; Ergotić, N; Lipej, Z; Madić, J; Lojkić, M; Pokrić, B

2006-02-01

The insoluble immune complexes (ICs) were prepared under the conditions of double immunodiffusion in gel, using the suspension of the ultrasound treated PK-15 cell-line infected with porcine parvovirus (PPV) containing both viral particles and viral proteins, as well as pig or rabbit anti-PPV polyclonal immune sera. The immunodiffusion performed in an agarose gel allows only viral subunits with a molecular mass equal to or less than 1000 kDa, rather than the viral particles, to diffuse through the gel and reach the point where the immunoprecipitate is to be formed. The immunoprecipitation under the conditions of the diffusion ensures the optimal, i.e. equimolar ratio of both immunoprecipitating components, antibody/antigen in the IC. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the Western blot analyses showed the ICs were composed of two proteins, a protein in which molecular mass corresponded to the VP2 of the PPV and a protein with a molecular mass of the IgG. This suggests that the ICs are mainly composed of the VP2 antigen and IgG class antibodies. The potency of the IC-vaccines prepared in the form of a water-in-oil-in-water emulsion was compared with that of a commercially available, inactivated oil vaccine. The vaccination of gilts, 6 weeks before mating, with the IC containing allogeneic pig antibodies, resulted in the development of high and long-lasting anti-PPV antibody titres, similar to those generated by the licenced vaccine (P > 0.01). The content of the virus material administered by the IC was twice lower than that in the licenced vaccine. Neither systemic nor local reactions were observed in the gilts during the period of the trial with the IC vaccine. The number of viable piglets per litter varied between 9 and 12 and no signs of the PPV infection were detected. Rabbits were used as one of the alternative laboratory animal models accepted for the testing of the vaccine against the PPV. The rabbit humoral immune response

Collaborative vaccine development: partnering pays.

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Ramachandra, Rangappa

2008-01-01

Vaccine development, supported by infusions of public and private venture capital, is re-entering a golden age as one of the fastest growing sectors in the life-sciences industry. Demand is driven by great unmet need in underdeveloped countries, increased resistance to current treatments, bioterrorism, and for prevention indications in travelers, pediatric, and adult diseases. Production systems are becoming less reliant on processes such as egg-based manufacturing, while new processes can help to optimize vaccines. Expeditious development hinges on efficient study conduct, which is greatly enhanced through research partnerships with specialized contract research organizations (CROs) that are licensed and knowledgeable in the intricacies of immunology and with the technologic and scientific foundation to support changing timelines and strategies inherent to vaccine development. The CRO often brings a more objective assessment for probability of success and may offer alternative development pathways. Vaccine developers are afforded more flexibility and are free to focus on innovation and internal core competencies. Functions readily outsourced to a competent partner include animal model development, safety and efficacy studies, immunotoxicity and immunogenicity, dose response studies, and stability and potency testing. These functions capitalize on the CRO partner's regulatory and scientific talent and expertise, and reduce infrastructure expenses for the vaccine developer. Successful partnerships result in development efficiencies, elimination or reduced redundancies, and improved time to market. Keys to success include honest communications, transparency, and flexibility.

Prospects of HA-Based Universal Influenza Vaccine

Directory of Open Access Journals (Sweden)

Anwar M. Hashem

2015-01-01

Full Text Available Current influenza vaccines afford substantial protection in humans by inducing strain-specific neutralizing antibodies (Abs. Most of these Abs target highly variable immunodominant epitopes in the globular domain of the viral hemagglutinin (HA. Therefore, current vaccines may not be able to induce heterosubtypic immunity against the divergent influenza subtypes. The identification of broadly neutralizing Abs (BnAbs against influenza HA using recent technological advancements in antibody libraries, hybridoma, and isolation of single Ab-secreting plasma cells has increased the interest in developing a universal influenza vaccine as it could provide life-long protection. While these BnAbs can serve as a source for passive immunotherapy, their identification represents an important step towards the design of such a universal vaccine. This review describes the recent advances and approaches used in the development of universal influenza vaccine based on highly conserved HA regions identified by BnAbs.

A novel multi-antigen virally vectored vaccine against Mycobacterium avium subspecies paratuberculosis.

Directory of Open Access Journals (Sweden)

Tim J Bull

Full Text Available BACKGROUND: Mycobacterium avium subspecies paratuberculosis causes systemic infection and chronic intestinal inflammation in many species including primates. Humans are exposed through milk and from sources of environmental contamination. Hitherto, the only vaccines available against Mycobacterium avium subspecies paratuberculosis have been limited to veterinary use and comprised attenuated or killed organisms. METHODS: We developed a vaccine comprising a fusion construct designated HAV, containing components of two secreted and two cell surface Mycobacterium avium subspecies paratuberculosis proteins. HAV was transformed into DNA, human Adenovirus 5 (Ad5 and Modified Vaccinia Ankara (MVA delivery vectors. Full length expression of the predicted 95 kDa fusion protein was confirmed. PRINCIPAL FINDINGS: Vaccination of naïve and Mycobacterium avium subspecies paratuberculosis infected C57BL/6 mice using DNA-prime/MVA-boost or Ad5-prime/MVA-boost protocols was highly immunogenic resulting in significant IFN-gamma ELISPOT responses by splenocytes against recombinant vaccine antigens and a range of HAV specific peptides. This included strong recognition of a T-cell epitope GFAEINPIA located near the C-terminus of the fusion protein. Antibody responses to recombinant vaccine antigens and HAV specific peptides but not GFAEINPIA, also occurred. No immune recognition of vaccine antigens occurred in any sham vaccinated Mycobacterium avium subspecies paratuberculosis infected mice. Vaccination using either protocol significantly attenuated pre-existing Mycobacterium avium subspecies paratuberculosis infection measured by qPCR in spleen and liver and the Ad5-prime/MVA-boost protocol also conferred some protection against subsequent challenge. No adverse effects of vaccination occurred in any of the mice. CONCLUSIONS/SIGNIFICANCE: A range of modern veterinary and clinical vaccines for the treatment and prevention of disease caused by Mycobacterium avium

A novel multi-antigen virally vectored vaccine against Mycobacterium avium subspecies paratuberculosis.

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Bull, Tim J; Gilbert, Sarah C; Sridhar, Saranya; Linedale, Richard; Dierkes, Nicola; Sidi-Boumedine, Karim; Hermon-Taylor, John

2007-11-28

Mycobacterium avium subspecies paratuberculosis causes systemic infection and chronic intestinal inflammation in many species including primates. Humans are exposed through milk and from sources of environmental contamination. Hitherto, the only vaccines available against Mycobacterium avium subspecies paratuberculosis have been limited to veterinary use and comprised attenuated or killed organisms. We developed a vaccine comprising a fusion construct designated HAV, containing components of two secreted and two cell surface Mycobacterium avium subspecies paratuberculosis proteins. HAV was transformed into DNA, human Adenovirus 5 (Ad5) and Modified Vaccinia Ankara (MVA) delivery vectors. Full length expression of the predicted 95 kDa fusion protein was confirmed. Vaccination of naïve and Mycobacterium avium subspecies paratuberculosis infected C57BL/6 mice using DNA-prime/MVA-boost or Ad5-prime/MVA-boost protocols was highly immunogenic resulting in significant IFN-gamma ELISPOT responses by splenocytes against recombinant vaccine antigens and a range of HAV specific peptides. This included strong recognition of a T-cell epitope GFAEINPIA located near the C-terminus of the fusion protein. Antibody responses to recombinant vaccine antigens and HAV specific peptides but not GFAEINPIA, also occurred. No immune recognition of vaccine antigens occurred in any sham vaccinated Mycobacterium avium subspecies paratuberculosis infected mice. Vaccination using either protocol significantly attenuated pre-existing Mycobacterium avium subspecies paratuberculosis infection measured by qPCR in spleen and liver and the Ad5-prime/MVA-boost protocol also conferred some protection against subsequent challenge. No adverse effects of vaccination occurred in any of the mice. A range of modern veterinary and clinical vaccines for the treatment and prevention of disease caused by Mycobacterium avium subspecies paratuberculosis are needed. The present vaccine proved to be highly

Sieve analysis in HIV-1 vaccine efficacy trials.

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Edlefsen, Paul T; Gilbert, Peter B; Rolland, Morgane

2013-09-01

The genetic characterization of HIV-1 breakthrough infections in vaccine and placebo recipients offers new ways to assess vaccine efficacy trials. Statistical and sequence analysis methods provide opportunities to mine the mechanisms behind the effect of an HIV vaccine. The release of results from two HIV-1 vaccine efficacy trials, Step/HVTN-502 (HIV Vaccine Trials Network-502) and RV144, led to numerous studies in the last 5 years, including efforts to sequence HIV-1 breakthrough infections and compare viral characteristics between the vaccine and placebo groups. Novel genetic and statistical analysis methods uncovered features that distinguished founder viruses isolated from vaccinees from those isolated from placebo recipients, and identified HIV-1 genetic targets of vaccine-induced immune responses. Studies of HIV-1 breakthrough infections in vaccine efficacy trials can provide an independent confirmation to correlates of risk studies, as they take advantage of vaccine/placebo comparisons, whereas correlates of risk analyses are limited to vaccine recipients. Through the identification of viral determinants impacted by vaccine-mediated host immune responses, sieve analyses can shed light on potential mechanisms of vaccine protection.

Simultaneous approach using systemic, mucosal and transcutaneous routes of immunization for development of protective HIV-1 vaccines.

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Belyakov, I M; Ahlers, J D

2011-01-01

Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4(+) and CD8(+) T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4(+) and CD8(+) responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4(+) and CD8(+) CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8(+) CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti-viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection.

Application of radiation technology in vaccines development.

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Seo, Ho Seong

2015-07-01

One of the earliest methods used in the manufacture of stable and safe vaccines is the use of chemical and physical treatments to produce inactivated forms of pathogens. Although these types of vaccines have been successful in eliciting specific humoral immune responses to pathogen-associated immunogens, there is a large demand for the development of fast, safe, and effective vaccine manufacturing strategies. Radiation sterilization has been used to develop a variety of vaccine types, because it can eradicate chemical contaminants and penetrate pathogens to destroy nucleic acids without damaging the pathogen surface antigens. Nevertheless, irradiated vaccines have not widely been used at an industrial level because of difficulties obtaining the necessary equipment. Recent successful clinical trials of irradiated vaccines against pathogens and tumors have led to a reevaluation of radiation technology as an alternative method to produce vaccines. In the present article, we review the challenges associated with creating irradiated vaccines and discuss potential strategies for developing vaccines using radiation technology.

Model for product development of vaccines against neglected tropical diseases: a vaccine against human hookworm.

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Bottazzi, Maria Elena; Brown, Ami Shah

2008-12-01

This article provides an overview of the advances in product development and technology transfer of the vaccine against human hookworm, with particular emphasis on the lessons learned and the challenges of developing a vaccine in the nonprofit sector. The comprehensive approach to vaccine development established by the Human Hookworm Vaccine Initiative (HHVI) identifies key operational and technical aspects that are essential for a successful partnership with a developing country vaccine manufacturer. This article also highlights the importance of a global access roadmap to guide the vaccine development program. The advancement of new products for the control of neglected tropical diseases portends great challenges for global access, including aspects related to vaccine design, product development and manufacture, vaccine introduction and distribution, financing, knowledge dissemination and intellectual property management. With only three vaccines for neglected tropical diseases in clinical trials - hookworm, leishmaniasis and schistosomiasis - we are at the nascent stages of developing vaccines for neglected populations. Product development public-private partnerships, such as the HHVI, continue to show great promise on this front and will eventually provide significant control tools for achieving millennium development goals related to poverty reduction, as well as child and maternal health.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 3 - Vaccines.

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Robinson, L; Knight-Jones, T J D; Charleston, B; Rodriguez, L L; Gay, C G; Sumption, K J; Vosloo, W

2016-06-01

This study assessed research knowledge gaps in the field of FMDV (foot-and-mouth disease virus) vaccines. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD vaccine research. Vaccines play a vital role in FMD control, used both to limit the spread of the virus during epidemics in FMD-free countries and as the mainstay of disease management in endemic regions, particularly where sanitary controls are difficult to apply. Improvements in the performance or cost-effectiveness of FMD vaccines will allow more widespread and efficient disease control. FMD vaccines have changed little in recent decades, typically produced by inactivation of whole virus, the quantity and stability of the intact viral capsids in the final preparation being key for immunogenicity. However, these are exciting times and several promising novel FMD vaccine candidates have recently been developed. This includes the first FMD vaccine licensed for manufacture and use in the USA; this adenovirus-vectored FMD vaccine causes in vivo expression of viral capsids in vaccinated animals. Another promising vaccine candidate comprises stabilized empty FMDV capsids produced in vitro in a baculovirus expression system. Recombinant technologies are also being developed to improve otherwise conventionally produced inactivated vaccines, for example, by creating a chimeric vaccine virus to increase capsid stability and by inserting sequences into the vaccine virus for desired antigen expression. Other important areas of ongoing research include enhanced adjuvants, vaccine quality control procedures and predicting vaccine protection from immune correlates, thus reducing dependency on animal challenge studies. Globally, the degree of independent vaccine evaluation is highly variable, and this is essential for vaccine quality. Previously neglected, the

Vaccine development against Leishmania donovani

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Amrita eDas

2012-05-01

Full Text Available Visceral leishmaniasis (VL caused by Leishmania donovani and Leishmania infantum/ chagasi represents the second most challenging infectious disease worldwide, affecting nearly 500,000 people and 60,000 deaths annually. Zoonotic VL (ZVL caused by L. infantum is re-emergent canid zoonoses which represents a complex epidemiological cycle in New world where domestic dogs serve as reservoir host responsible for potentially fatal human infection where dog culling is the only control measure for eliminating reservoir host. Lifelong immunity in human against reinfection has motivated several attempts in developing prophylactic vaccines against the disease but very few have progressed beyond experimental stage. Absence of any licensed vaccine along with high toxicity and increasing resistance to the current chemotherapeutic drugs has further complicated the situation in endemic regions of the world. Advances in vaccinology, including recombinant proteins, novel antigen-delivery systems/adjuvants, heterologous prime-boost regimens and strategies for intracellular antigen presentation, have contributed to recent advances in vaccine development against VL. Attempts to develop an effective vaccine for use in domestic dogs in areas of canine VL should be pursued for preventing human infection. Studies in animal models and human patients have revealed the pathogenic mechanisms of disease progression and features of protective immunity. This review will summarize the accumulated knowledge about pathogenesis, immune response and prerequisites for protective immunity against human VL. Authors will discuss promising vaccine targets, their developmental status and future prospects in a quest for rational vaccine development against VL. In addition, several challenges such as safety issues, a renewed and coordinated commitment to basic research, preclinical studies and trial design will be addressed to overcome the problems faced in developing effective vaccines

Progress in Brucella vaccine development

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YANG, Xinghong; SKYBERG, Jerod A.; CAO, Ling; CLAPP, Beata; THORNBURG, Theresa; PASCUAL, David W.

2012-01-01

Brucella spp. are zoonotic, facultative intracellular pathogens, which cause animal and human disease. Animal disease results in abortion of fetuses; in humans, it manifests flu-like symptoms with an undulant fever, with osteoarthritis as a common complication of infection. Antibiotic regimens for human brucellosis patients may last several months and are not always completely effective. While there are no vaccines for humans, several licensed live Brucella vaccines are available for use in livestock. The performance of these animal vaccines is dependent upon the host species, dose, and route of immunization. Newly engineered live vaccines, lacking well-defined virulence factors, retain low residual virulence, are highly protective, and may someday replace currently used animal vaccines. These also have possible human applications. Moreover, due to their enhanced safety and efficacy in animal models, subunit vaccines for brucellosis show great promise for their application in livestock and humans. This review summarizes the progress of brucellosis vaccine development and presents an overview of candidate vaccines. PMID:23730309

Improved influenza viral vector based Brucella abortus vaccine induces robust B and T-cell responses and protection against Brucella melitensis infection in pregnant sheep and goats

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Mailybayeva, Aigerim; Yespembetov, Bolat; Ryskeldinova, Sholpan; Zinina, Nadezhda; Sansyzbay, Abylai; Renukaradhya, Gourapura J.; Petrovsky, Nikolai

2017-01-01

We previously developed a potent candidate vaccine against bovine brucellosis caused by Brucella abortus using the influenza viral vector expressing Brucella Omp16 and L7/L12 proteins (Flu-BA). Our success in the Flu-BA vaccine trial in cattle and results of a pilot study in non-pregnant small ruminants prompted us in the current study to test its efficacy against B. melitensis infection in pregnant sheep and goats. In this study, we improved the Flu-BA vaccine formulation and immunization method to achieve maximum efficacy and safety. The Flu-BA vaccine formulation had two additional proteins Omp19 and SOD, and administered thrice with 20% Montanide Gel01 adjuvant, simultaneously by both subcutaneous and conjunctival routes at 21 days intervals in pregnant sheep and goats. At 42 days post-vaccination (DPV) we detected antigen-specific IgG antibodies predominantly of IgG2a isotype but also IgG1, and also detected a strong lymphocyte recall response with IFN-γ production. Importantly, our candidate vaccine prevented abortion in 66.7% and 77.8% of pregnant sheep and goats, respectively. Furthermore, complete protection (absence of live B. melitensis 16M) was observed in 55.6% and 66.7% of challenged sheep and goats, and 72.7% and 90.0% of their fetuses (lambs/yeanlings), respectively. The severity of B. melitensis 16M infection in vaccinated sheep and goats and their fetuses (index of infection and rates of Brucella colonization in tissues) was significantly lower than in control groups. None of the protection parameters after vaccination with Flu-BA vaccine were statistically inferior to protection seen with the commercial B. melitensis Rev.1 vaccine (protection against abortion and vaccination efficacy, alpha = 0.18–0.34, infection index, P = 0.37–0.77, Brucella colonization, P = 0.16 to P > 0.99). In conclusion, our improved Flu-BA vaccine formulation and delivery method were found safe and effective in protecting pregnant sheep and goats against adverse

Status of vaccine research and development of vaccines for herpes simplex virus.

Science.gov (United States)

Johnston, Christine; Gottlieb, Sami L; Wald, Anna

2016-06-03

Herpes simplex virus type-1 (HSV-1) and -2 (HSV-2) are highly prevalent global pathogens which commonly cause recurrent oral and genital ulcerations. Less common but more serious complications include meningitis, encephalitis, neonatal infection, and keratitis. HSV-2 infection is a significant driver of the HIV epidemic, increasing the risk of HIV acquisition 3 fold. As current control strategies for genital HSV-2 infection, including antiviral therapy and condom use, are only partially effective, vaccines will be required to reduce infection. Both preventive and therapeutic vaccines for HSV-2 are being pursued and are in various stages of development. We will provide an overview of efforts to develop HSV-2 vaccines, including a discussion of the clinical need for an HSV vaccine, and status of research and development with an emphasis on recent insights from trials of vaccine candidates in clinical testing. In addition, we will touch upon aspects of HSV vaccine development relevant to low and middle income countries. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

Advances and challenges in malaria vaccine development.

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Crompton, Peter D; Pierce, Susan K; Miller, Louis H

2010-12-01

Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.

Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates.

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Merika T Koday

Full Text Available Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. We investigated immunogenicity and protective efficacy of a multi-antigen (MA universal influenza DNA vaccine consisting of HA, M2, and NP antigens in cynomolgus macaques. Following challenge with a heterologous pandemic H1N1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. The MA DNA vaccine induced robust serum and mucosal antibody responses but these high antibody titers were not broadly neutralizing. In contrast, the vaccine induced broadly-reactive NP specific T cell responses that cross-reacted with the challenge virus and inversely correlated with lower viral loads and inflammation. These results demonstrate that a MA DNA vaccine that induces strong cross-reactive T cell responses can, independent of neutralizing antibody, mediate significant cross-protection in a nonhuman primate model and further supports development as an effective approach to induce broad protection against circulating and emerging influenza strains.

Virulence, immunogenicity and vaccine properties of a novel chimeric pestivirus

DEFF Research Database (Denmark)

Rasmussen, Thomas Bruun; Uttenthal, Åse; Reimann, Ilona

2007-01-01

A chimeric pestivirus of border disease virus Gifhorn and bovine viral diarrhea virus CP7 (Meyers et al., 1996) was constructed. Virulence, immunogenicity and vaccine properties of the chimeric virus were studied in a vaccination–challenge experiment in pigs. The chimeric virus proved...... to be avirulent and neither chimeric virus nor viral RNA was detected in serum after vaccination. The safety of the vaccine was tested by horizontal transmission to sentinel pigs, which remained uninfected. The vaccine efficacy was examined by challenge infection with classical swine fever virus (CSFV) Eystrup...

Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

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Samantha Sayers

2012-01-01

Full Text Available Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO in the Web Ontology Language (OWL format.

Vaxjo: a web-based vaccine adjuvant database and its application for analysis of vaccine adjuvants and their uses in vaccine development.

Science.gov (United States)

Sayers, Samantha; Ulysse, Guerlain; Xiang, Zuoshuang; He, Yongqun

2012-01-01

Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format.

Vaccines and Immunization Practice.

Science.gov (United States)

Hogue, Michael D; Meador, Anna E

2016-03-01

Vaccines are among most cost-effective public health strategies. Despite effective vaccines for many bacterial and viral illnesses, tens of thousands of adults and hundreds of children die each year in the United States from vaccine-preventable diseases. Underutilization of vaccines requires rethinking the approach to incorporating vaccines into practice. Arguably, immunizations could be a part all health care encounters. Shared responsibility is paramount if deaths are to be reduced. This article reviews the available vaccines in the US market, as well as practice recommendations of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices. Copyright © 2016 Elsevier Inc. All rights reserved.

Mapping Determinants of Virus Neutralization and Viral Escape for Rational Design of a Hepatitis C Virus Vaccine

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Mei-Le Keck

2018-05-01

Full Text Available Hepatitis C virus (HCV continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses. For highly variable viruses, such as HCV, isolation and characterization of monoclonal antibodies mediating broad virus neutralization are an important guide for vaccine design. The viral envelope glycoproteins, E1 and E2, are the main targets of these antibodies. Epitopes on the E2 protein have been studied more extensively than epitopes on E1, due to higher antibody targeting that reflects these epitopes having higher degrees of immunogenicity. E2 epitopes are overall organized in discrete clusters of overlapping epitopes that ranged from high conservation to high variability. Other epitopes on E1 and E1E2 also are targets of neutralizing antibodies. Taken together, these regions are important for vaccine design. Another element in vaccine design is based on information on how the virus escapes from broadly neutralizing antibodies. Escape mutations can occur within the epitopes that are involved in antibody binding and in regions that are not involved in their epitopes, but nonetheless reduce the efficiency of neutralizing antibodies. An understanding on the specificities of a protective B cell response, the molecular locations of these epitopes on E1, E2, and E1E2, and the mechanisms, which enable the virus to negatively modulate neutralizing antibody responses to these regions will provide the necessary guidance for vaccine design.

Development of Streptococcus agalactiae vaccines for tilapia.

Science.gov (United States)

Liu, Guangjin; Zhu, Jielian; Chen, Kangming; Gao, Tingting; Yao, Huochun; Liu, Yongjie; Zhang, Wei; Lu, Chengping

2016-12-21

Vaccination is a widely accepted and effective method to prevent most pathogenic diseases in aquaculture. Various species of tilapia, especially Nile tilapia Oreochromis niloticus, are farmed worldwide because of their high consumer demand. Recently, the tilapia-breeding industry has been hampered by outbreaks of Streptococcus agalactiae infection, which cause high mortality and huge economic losses. Many researchers have attempted to develop effective S. agalactiae vaccines for tilapia. This review provides a summary of the different kinds of S. agalactiae vaccines for tilapia that have been developed recently. Among the various vaccine types, inactivated S. agalactiae vaccines showed superior protection efficiency when compared with live attenuated, recombinant and DNA vaccines. With respect to vaccination method, injecting the vaccine into tilapia provided the most effective immunoprotection. Freund's incomplete adjuvant appeared to be suitable for tilapia vaccines. Other factors, such as immunization duration and number, fish size and challenge dose, also influenced the vaccine efficacy.

Prophylactic and Therapeutic Vaccination against Hepatitis C Virus (HCV: Developments and Future Perspectives

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Marian E. Major

2009-08-01

Full Text Available Studies in patients and chimpanzees that spontaneously clear Hepatitis C Virus (HCV have demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism regarding prophylactic HCV vaccines and a number of studies in the chimpanzee model have been performed, all of which resulted in modified infections after challenge but did not always prevent persistence of the virus. Therapeutic vaccine strategies have also been pursued in an effort to reduce the costs and side effects associated with anti-viral drug treatment. This review summarizes the studies performed thus far in both patients and chimpanzees for prophylactic and therapeutic vaccination, assesses the progress made and future perspectives.

AIDS vaccine: Present status and future challenges

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Nigam P

2006-01-01

Full Text Available Development of a preventive vaccine for HIV is the best hope of controlling the AIDS pandemic. HIV has, however, proved a difficult pathogen to vaccinate against because of its very high mutation rate and capability to escape immune responses. Neutralizing antibodies that can neutralize diverse field strains have so far proved difficult to induce. Adjuvanting these vaccines with cytokine plasmids and a "prime-boost," approach is being evaluated in an effort to induce both CTL and antibody responses and thereby have immune responses active against both infected cells and free viral particles, thereby necessitating fewer doses of recombinant protein to reach maximum antibodies titers. Although obstacles exist in evaluation of candidate HIV vaccines, evidence from natural history studies, new molecular tools in virology and immunology, new adjuvants, new gene expression systems, new antigen delivery systems, recent discoveries in HIV entry and pathogenesis, and promising studies of candidate vaccines in animal models have provided reasons to hope that developing a safe and effective AIDS vaccine is possible and within reach.

Vaccines against enteric infections for the developing world

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Czerkinsky, Cecil; Holmgren, Jan

2015-01-01

Since the first licensure of the Sabin oral polio vaccine more than 50 years ago, only eight enteric vaccines have been licensed for four disease indications, and all are given orally. While mucosal vaccines offer programmatically attractive tools for facilitating vaccine deployment, their development remains hampered by several factors: —limited knowledge regarding the properties of the gut immune system during early life;—lack of mucosal adjuvants, limiting mucosal vaccine development to live-attenuated or killed whole virus and bacterial vaccines;—lack of correlates/surrogates of mucosal immune protection; and—limited knowledge of the factors contributing to oral vaccine underperformance in children from developing countries.There are now reasons to believe that the development of safe and effective mucosal adjuvants and of programmatically sound intervention strategies could enhance the efficacy of current and next-generation enteric vaccines, especially in lesser developed countries which are often co-endemic for enteric infections and malnutrition. These vaccines must be safe and affordable for the world's poorest, confer long-term protection and herd immunity, and must be able to contain epidemics. PMID:25964464

Vaccines for emerging infectious diseases: Lessons from MERS coronavirus and Zika virus.

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Maslow, Joel N

2017-12-02

The past decade and a half has been characterized by numerous emerging infectious diseases. With each new threat, there has been a call for rapid vaccine development. Pathogens such as the Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the Zika virus represent either new viral entities or viruses emergent in new geographic locales and characterized by novel complications. Both serve as paradigms for the global spread that can accompany new pathogens. In this paper, we review the epidemiology and pathogenesis of MERS-CoV and Zika virus with respect to vaccine development. The challenges in vaccine development and the approach to clinical trial design to test vaccine candidates for disease entities with a changing epidemiology are discussed.

A Mouse Model of Enterovirus D68 Infection for Assessment of the Efficacy of Inactivated Vaccine

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Chao Zhang

2018-01-01

Full Text Available In recent years, enterovirus D68 (EVD68 has been reported increasingly to be associated with severe respiratory tract infections and acute flaccid myelitis (AFM in children all over the world. Yet, no effective vaccines or antiviral drugs are currently available for EVD68. Although several experimental animal models have been developed, immunogenicity and protective efficacy of inactivated EVD68 vaccines has not been fully evaluated. To promote the development of vaccines, we established an Institute of Cancer Research (ICR suckling mouse model of EVD68 infection in this study. The results showed that ICR neonatal mice up to about nine days of age were susceptible to infection with EVD68 clinical strain US/MO/14-18947 by intraperitoneal injection. The infected mice exhibited progressive limb paralysis prior to death and the mortality of mice was age- and virus dose-dependent. Tissue viral load analysis showed that limb muscle and spinal cord were the major sites of viral replication. Moreover, histopathologic examination revealed the severe necrosis of the limb and juxtaspinal muscles, suggesting that US/MO/14-18947 has a strong tropism toward muscle tissues. Additionally, β-propiolactone-inactivated EVD68 vaccine showed high purity and quality and induced robust EVD68-specific neutralizing antibody responses in adult mice. Importantly, results from both antisera transfer and maternal immunization experiments clearly showed that inactivated EVD68 vaccine was able to protect against lethal viral infection in the mouse model. In short, these results demonstrate the successful establishment of the mouse model of EVD68 infection for evaluating candidate vaccines against EVD68 and also provide important information for the development of inactivated virus-based EVD68 vaccines.

Mucosal immunization with recombinant adenoviral vectors expressing murine gammaherpesvirus-68 genes M2 and M3 can reduce latent viral load.

Science.gov (United States)

Hoegh-Petersen, Mette; Thomsen, Allan R; Christensen, Jan P; Holst, Peter J

2009-11-12

Gammaherpesviruses establish life-long latent infections in their hosts. If the host becomes immunosuppressed, these viruses may reactivate and cause severe disease, and even in immunocompetent individuals the gammaherpesviruses are presumed to have an oncogenic potential. Murine gammaherpesvirus-68 (MHV-68) is a member of the Gammaherpesvirinae subfamily and represents a useful murine model for this category of infections, in which new vaccination strategies may initially be evaluated. Two attenuated variants of MHV-68 have successfully been used as vaccines, but the oncogenic potential of the gammaherpesvirinae speaks against using a similar approach in humans. DNA immunization with plasmids encoding the MHV-68 genes M2 or M3 caused a reduction in either acute or early latent viral load, respectively, but neither immunization had an effect at times later than 14 days post-infection. Adenovirus-based vaccines are substantially more immunogenic than DNA vaccines and can be applied to induce mucosal immunity. Here we show that a significant reduction of the late viral load in the spleens, at 60 days post-infection, was achieved when immunizing mice both intranasally and subcutaneously with adenoviral vectors encoding both M2 and M3. Additionally we show that M3 immunization prevented the usual development of virus-induced splenomegaly at 2-3 weeks post-infection. This is the first time that immunization with a non-replicating vaccine has lead to a significantly reduced viral load at time points beyond 14 days post-infection, and thus demonstrates that a non-replicating vaccine may successfully be employed to reduce the viral burden during chronic gammaherpesvirus infection.

Microneedle patches for vaccination in developing countries.

Science.gov (United States)

Arya, Jaya; Prausnitz, Mark R

2016-10-28

Millions of people die of infectious diseases each year, mostly in developing countries, which could largely be prevented by the use of vaccines. While immunization rates have risen since the introduction of the Expanded Program on Immunization (EPI), there remain major challenges to more effective vaccination in developing countries. As a possible solution, microneedle patches containing an array of micron-sized needles on an adhesive backing have been developed to be used for vaccine delivery to the skin. These microneedle patches can be easily and painlessly applied by pressing against the skin and, in some designs, do not leave behind sharps waste. The patches are single-dose, do not require reconstitution, are easy to administer, have reduced size to simplify storage, transportation and waste disposal, and offer the possibility of improved vaccine immunogenicity, dose sparing and thermostability. This review summarizes vaccination challenges in developing countries and discusses advantages that microneedle patches offer for vaccination to address these challenges. We conclude that microneedle patches offer a powerful new technology that can enable more effective vaccination in developing countries. Copyright © 2015. Published by Elsevier B.V.

Vaccination of rhesus macaques with a vif-deleted simian immunodeficiency virus proviral DNA vaccine

International Nuclear Information System (INIS)

Sparger, Ellen E.; Dubie, Robert A.; Shacklett, Barbara L.; Cole, Kelly S.; Chang, W.L.; Luciw, Paul A.

2008-01-01

Studies in non-human primates, with simian immunodeficiency virus (SIV) and simian/human immunodeficiency virus (SHIV) have demonstrated that live-attenuated viral vaccines are highly effective; however these vaccine viruses maintain a low level of pathogenicity. Lentivirus attenuation associated with deletion of the viral vif gene carries a significantly reduced risk for pathogenicity, while retaining the potential for virus replication of low magnitude in the host. This report describes a vif-deleted simian immunodeficiency virus (SIV)mac239 provirus that was tested as an attenuated proviral DNA vaccine by inoculation of female rhesus macaques. SIV-specific interferon-γ enzyme-linked immunospot responses of low magnitude were observed after immunization with plasmid containing the vif-deleted SIV provirus. However, vaccinated animals displayed strong sustained virus-specific T cell proliferative responses and increasing antiviral antibody titers. These immune responses suggested either persistent vaccine plasmid expression or low level replication of vif-deleted SIV in the host. Immunized and unvaccinated macaques received a single high dose vaginal challenge with pathogenic SIVmac251. A transient suppression of challenge virus load and a greater median survival time was observed for vaccinated animals. However, virus loads for vaccinated and unvaccinated macaques were comparable by twenty weeks after challenge and overall survival curves for the two groups were not significantly different. Thus, a vif-deleted SIVmac239 proviral DNA vaccine is immunogenic and capable of inducing a transient suppression of pathogenic challenge virus, despite severe attenuation of the vaccine virus

Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis virus vaccines.

Science.gov (United States)

Markoff, L

2000-05-26

Although an effective killed virus vaccine to prevent illness due to Japanese encephalitis virus (JEV) infection exists, many authorities recognize that a safe, effective live JEV vaccine is desirable in order to reduce the cost and the number of doses of vaccine required per immunization. A large-scale clinical efficacy trail for such a vaccine would be both unethical and impractical. Therefore, a surrogate for the efficacy of JE vaccines should be established. Detection of virus-neutralizing antibodies in sera of vaccinees could constitute such a surrogate for efficacy. Field studies of vaccinees in endemic areas and studies done in mice already exist to support this concept. Also, titers of virus-neutralizing antibodies are already accepted as a surrogate for the efficacy of yellow fever virus vaccines and for the efficacy of other viral vaccines as well. In developing a correlation between N antibody titers and protection from JEV infection, standard procedures must be validated and adopted for both measuring N antibodies and for testing in animals. A novel live virus vaccine could be tested in the mouse and/or the monkey model of JEV infection to establish a correlation between virus-neutralizing antibodies elicited by the vaccines and protection from encephalitis. In addition, sera of subjects receiving the novel live JEV vaccine in early clinical trials could be passively transferred to mice or monkeys in order to establish the protective immunogenicity of the vaccine in humans. A monkey model for JEV infection was recently established by scientists at WRAIR in the US. From this group, pools of JEV of known infectivity for Rhesus macaques may be obtained for testing of immunity elicited by live JE vaccine virus.

Viral aetiology influenza like illnesses in Santa Cruz, Bolivia (2010-2012).

Science.gov (United States)

Delangue, Julie; Roca Sanchez, Yelin; Piorkowski, Géraldine; Bessaud, Maël; Baronti, Cécile; Thirion-Perrier, Laurence; Mafayle, Roxana Loayza; Ardaya, Cinthia Avila; Aguilera, Gabriela Añez; Guzman, Jimmy Revollo; Riera, Javier Lora; de Lamballerie, Xavier

2014-02-24

Acute respiratory infections represent a serious public health issue worldwide but virological aetiologies of Influenza Like Illnesses (ILIs) remain largely unknown in developing countries. This study represents the first attempt to characterise viral aetiologies of ILIs in Bolivia. It was performed in Santa Cruz city from January 2010 to September 2012, based on 564 naso-pharyngeal swabs collected in a National Reference Laboratory and real-time PCR techniques, viral cultures and phylogenetic analyses. 50.2% of samples were positive for at least one virus with influenza viruses (Flu A: ~15%; Flu B: ~9%), rhinoviruses (~8%), coronaviruses (~5%) and hRSV (~4%) being the most frequently identified. The pattern of viral infections varied according to age groups. The elucidation rate was the highest (>60%) amongst patients under 10 yo and the lowest (Bolivia in the study period, originating from Central and North America, Europe, Asia and Australia. Our results emphasise the requirement for a reinforced epidemiological and genetic follow-up of influenza and other ILIs in Bolivia to further inform the preparation of vaccines used in the region, guide vaccination campaigns and improve the medical management of patients.

Conjugate Meningococcal Vaccines Development: GSK Biologicals Experience

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Jacqueline M. Miller

2011-01-01

Full Text Available Meningococcal diseases are serious threats to global health, and new vaccines specifically tailored to meet the age-related needs of various geographical areas are required. This paper focuses on the meningococcal conjugate vaccines developed by GSK Biologicals. Two combined conjugate vaccines were developed to help protect infants and young children in countries where the incidence of meningococcal serogroup C or serogroup C and Y disease is important: Hib-MenC-TT vaccine, which offers protection against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases, is approved in several countries; and Hib-MenCY-TT vaccine, which adds N. meningitidis serogroup Y antigen, is currently in the final stages of development. Additionally, a tetravalent conjugate vaccine (MenACWY-TT designed to help protect against four meningococcal serogroups is presently being evaluated for global use in all age groups. All of these vaccines were shown to be highly immunogenic and to have clinically acceptable safety profiles.

Conjugate Meningococcal Vaccines Development: GSK Biologicals Experience

Science.gov (United States)

Miller, Jacqueline M.; Mesaros, Narcisa; Van Der Wielen, Marie; Baine, Yaela

2011-01-01

Meningococcal diseases are serious threats to global health, and new vaccines specifically tailored to meet the age-related needs of various geographical areas are required. This paper focuses on the meningococcal conjugate vaccines developed by GSK Biologicals. Two combined conjugate vaccines were developed to help protect infants and young children in countries where the incidence of meningococcal serogroup C or serogroup C and Y disease is important: Hib-MenC-TT vaccine, which offers protection against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases, is approved in several countries; and Hib-MenCY-TT vaccine, which adds N. meningitidis serogroup Y antigen, is currently in the final stages of development. Additionally, a tetravalent conjugate vaccine (MenACWY-TT) designed to help protect against four meningococcal serogroups is presently being evaluated for global use in all age groups. All of these vaccines were shown to be highly immunogenic and to have clinically acceptable safety profiles. PMID:21991444

Advanced Vaccine Candidates for Lassa Fever

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Igor S. Lukashevich

2012-10-01

Full Text Available Lassa virus (LASV is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF. LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered.

Virus-Like-Vaccines against HIV.

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Andersson, Anne-Marie C; Schwerdtfeger, Melanie; Holst, Peter J

2018-02-11

Protection against chronic infections has necessitated the development of ever-more potent vaccination tools. HIV seems to be the most challenging foe, with a remarkable, poorly immunogenic and fragile surface glycoprotein and the ability to overpower the cell immune system. Virus-like-particle (VLP) vaccines have emerged as potent inducers of antibody and helper T cell responses, while replication-deficient viral vectors have yielded potent cytotoxic T cell responses. Here, we review the emerging concept of merging these two technologies into virus-like-vaccines (VLVs) for the targeting of HIV. Such vaccines are immunologically perceived as viruses, as they infect cells and produce VLPs in situ, but they only resemble viruses, as the replication defective vectors and VLPs cannot propagate an infection. The inherent safety of such a platform, despite robust particle production, is a distinct advantage over live-attenuated vaccines that must balance safety and immunogenicity. Previous studies have delivered VLVs encoded in modified Vaccinia Ankara vectors and we have developed the concept into a single-reading adenovirus-based technology capable of eliciting robust CD8⁺ and CD4⁺ T cells responses and trimer binding antibody responses. Such vaccines offer the potential to display the naturally produced immunogen directly and induce an integrated humoral and cellular immune response.

Progress on adenovirus-vectored universal influenza vaccines.

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Xiang, Kui; Ying, Guan; Yan, Zhou; Shanshan, Yan; Lei, Zhang; Hongjun, Li; Maosheng, Sun

2015-01-01

Influenza virus (IFV) infection causes serious health problems and heavy financial burdens each year worldwide. The classical inactivated influenza virus vaccine (IIVV) and live attenuated influenza vaccine (LAIV) must be updated regularly to match the new strains that evolve due to antigenic drift and antigenic shift. However, with the discovery of broadly neutralizing antibodies that recognize conserved antigens, and the CD8(+) T cell responses targeting viral internal proteins nucleoprotein (NP), matrix protein 1 (M1) and polymerase basic 1 (PB1), it is possible to develop a universal influenza vaccine based on the conserved hemagglutinin (HA) stem, NP, and matrix proteins. Recombinant adenovirus (rAd) is an ideal influenza vaccine vector because it has an ideal stability and safety profile, induces balanced humoral and cell-mediated immune responses due to activation of innate immunity, provides 'self-adjuvanting' activity, can mimic natural IFV infection, and confers seamless protection against mucosal pathogens. Moreover, this vector can be developed as a low-cost, rapid-response vaccine that can be quickly manufactured. Therefore, an adenovirus vector encoding conserved influenza antigens holds promise in the development of a universal influenza vaccine. This review will summarize the progress in adenovirus-vectored universal flu vaccines and discuss future novel approaches.

Development of Mycoplasma hyopneumoniae Recombinant Vaccines.

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Marchioro, Silvana Beutinger; Simionatto, Simone; Dellagostin, Odir

2016-01-01

Mycoplasma hyopneumoniae is the etiological agent of swine enzootic pneumonia (EP), a disease that affects swine production worldwide. Vaccination is the most cost-effective strategy for the control and prevention of the disease. Research using genome-based approach has the potential to elucidate the biology and pathogenesis of M. hyopneumoniae and contribute to the development of more effective vaccines. Here, we describe the protocol for developing M. hyopneumoniae recombinant vaccines using reverse vaccinology approaches.

Vaccines against enteric infections for the developing world.

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Czerkinsky, Cecil; Holmgren, Jan

2015-06-19

Since the first licensure of the Sabin oral polio vaccine more than 50 years ago, only eight enteric vaccines have been licensed for four disease indications, and all are given orally. While mucosal vaccines offer programmatically attractive tools for facilitating vaccine deployment, their development remains hampered by several factors: -limited knowledge regarding the properties of the gut immune system during early life; -lack of mucosal adjuvants, limiting mucosal vaccine development to live-attenuated or killed whole virus and bacterial vaccines; -lack of correlates/surrogates of mucosal immune protection; and -limited knowledge of the factors contributing to oral vaccine underperformance in children from developing countries. There are now reasons to believe that the development of safe and effective mucosal adjuvants and of programmatically sound intervention strategies could enhance the efficacy of current and next-generation enteric vaccines, especially in lesser developed countries which are often co-endemic for enteric infections and malnutrition. These vaccines must be safe and affordable for the world's poorest, confer long-term protection and herd immunity, and must be able to contain epidemics. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

WHO policy development processes for a new vaccine: case study of malaria vaccines

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Cheyne James

2010-06-01

Full Text Available Abstract Background Recommendations from the World Health Organization (WHO are crucial to inform developing country decisions to use, or not, a new intervention. This article analysed the WHO policy development process to predict its course for a malaria vaccine. Methods The decision-making processes for one malaria intervention and four vaccines were classified through (1 consultations with staff and expert advisors to WHO's Global Malaria Programme (GMP and Immunization, Vaccines and Biologicals Department (IVB; (2 analysis of the procedures and recommendations of the major policy-making bodies of these groups; (3 interviews with staff of partnerships working toward new vaccine availability; and (4 review and analyses of evidence informing key policy decisions. Case description WHO policy formulation related to use of intermittent preventive treatment in infancy (IPTi and the following vaccine interventions: Haemophilus influenzae type b conjugate vaccine (Hib, pneumococcal conjugate vaccine (PCV, rotavirus vaccine (RV, and human papillomavirus vaccine (HPV, five interventions which had relatively recently been through systematic WHO policy development processes as currently constituted, was analysed. Required information was categorized in three areas defined by a recent WHO publication on development of guidelines: safety and efficacy in relevant populations, implications for costs and population health, and localization of data to specific epidemiological situations. Discussion and evaluation Data needs for a malaria vaccine include safety; the demonstration of efficacy in a range of epidemiological settings in the context of other malaria prevention interventions; and information on potential rebound in which disease increases subsequent to the intervention. In addition, a malaria vaccine would require attention to additional factors, such as costs and cost-effectiveness, supply and demand, impact of use on other interventions, and

Vaccine process technology.

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Josefsberg, Jessica O; Buckland, Barry

2012-06-01

The evolution of vaccines (e.g., live attenuated, recombinant) and vaccine production methods (e.g., in ovo, cell culture) are intimately tied to each other. As vaccine technology has advanced, the methods to produce the vaccine have advanced and new vaccine opportunities have been created. These technologies will continue to evolve as we strive for safer and more immunogenic vaccines and as our understanding of biology improves. The evolution of vaccine process technology has occurred in parallel to the remarkable growth in the development of therapeutic proteins as products; therefore, recent vaccine innovations can leverage the progress made in the broader biotechnology industry. Numerous important legacy vaccines are still in use today despite their traditional manufacturing processes, with further development focusing on improving stability (e.g., novel excipients) and updating formulation (e.g., combination vaccines) and delivery methods (e.g., skin patches). Modern vaccine development is currently exploiting a wide array of novel technologies to create safer and more efficacious vaccines including: viral vectors produced in animal cells, virus-like particles produced in yeast or insect cells, polysaccharide conjugation to carrier proteins, DNA plasmids produced in E. coli, and therapeutic cancer vaccines created by in vitro activation of patient leukocytes. Purification advances (e.g., membrane adsorption, precipitation) are increasing efficiency, while innovative analytical methods (e.g., microsphere-based multiplex assays, RNA microarrays) are improving process understanding. Novel adjuvants such as monophosphoryl lipid A, which acts on antigen presenting cell toll-like receptors, are expanding the previously conservative list of widely accepted vaccine adjuvants. As in other areas of biotechnology, process characterization by sophisticated analysis is critical not only to improve yields, but also to determine the final product quality. From a regulatory

Progress and controversies in developing cancer vaccines

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Speiser Daniel E

2005-04-01

Full Text Available Abstract Immunotherapy has become a standard approach for cancer management, through the use of cytokines (eg: interleukin-2 and monoclonal antibodies. Cancer vaccines hold promise as another form of immunotherapy, and there has been substantial progress in identifying shared antigens recognized by T cells, in developing vaccine approaches that induce antigen-specific T cell responses in cancer patients, and in developing new technology for monitoring immune responses in various human tissue compartments. Dramatic clinical regressions of human solid tumors have occurred with some cancer vaccines, but the rate of those responses remains low. This article is part of a 2-part point:counterpoint series on peptide vaccines and adoptive therapy approaches for cancer. The current status of cancer vaccination, and associated challenges, are discussed. Emphasis is placed on the need to increase our knowledge of cancer immunobiology, as well as to improve monitoring of cellular immune function after vaccination. Progress in both areas will facilitate development of effective cancer vaccines, as well as of adoptive therapy. Effective cancer vaccines promise to be useful for treatment and prevention of cancer at low cost and with low morbidity.

Nanotechnology and vaccine development

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Mi-Gyeong Kim

2014-10-01

Full Text Available Despite the progress of conventional vaccines, improvements are clearly required due to concerns about the weak immunogenicity of these vaccines, intrinsic instability in vivo, toxicity, and the need for multiple administrations. To overcome such problems, nanotechnology platforms have recently been incorporated into vaccine development. Nanocarrier-based delivery systems offer an opportunity to enhance the humoral and cellular immune responses. This advantage is attributable to the nanoscale particle size, which facilitates uptake by phagocytic cells, the gut-associated lymphoid tissue, and the mucosa-associated lymphoid tissue, leading to efficient antigen recognition and presentation. Modifying the surfaces of nanocarriers with a variety of targeting moieties permits the delivery of antigens to specific cell surface receptors, thereby stimulating specific and selective immune responses. In this review, we introduce recent advances in nanocarrier-based vaccine delivery systems, with a focus on the types of carriers, including liposomes, emulsions, polymer-based particles, and carbon-based nanomaterials. We describe the remaining challenges and possible breakthroughs, including the development of needle-free nanotechnologies and a fundamental understanding of the in vivo behavior and stability of the nanocarriers in nanotechnology-based delivery systems.

A DNA vaccine against yellow fever virus: development and evaluation.

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Milton Maciel

2015-04-01

Full Text Available Attenuated yellow fever (YF virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE, aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies.

A DNA vaccine against yellow fever virus: development and evaluation.

Science.gov (United States)

Maciel, Milton; Cruz, Fábia da Silva Pereira; Cordeiro, Marli Tenório; da Motta, Márcia Archer; Cassemiro, Klécia Marília Soares de Melo; Maia, Rita de Cássia Carvalho; de Figueiredo, Regina Célia Bressan Queiroz; Galler, Ricardo; Freire, Marcos da Silva; August, Joseph Thomas; Marques, Ernesto T A; Dhalia, Rafael

2015-04-01

Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE) or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE), aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies.

A DNA Vaccine against Yellow Fever Virus: Development and Evaluation

Science.gov (United States)

Maciel, Milton; Cruz, Fábia da Silva Pereira; Cordeiro, Marli Tenório; da Motta, Márcia Archer; Cassemiro, Klécia Marília Soares de Melo; Maia, Rita de Cássia Carvalho; de Figueiredo, Regina Célia Bressan Queiroz; Galler, Ricardo; Freire, Marcos da Silva; August, Joseph Thomas; Marques, Ernesto T. A.; Dhalia, Rafael

2015-01-01

Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE) or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE), aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies. PMID:25875109

New animal vaccines could keep more African farmers in business ...

International Development Research Centre (IDRC) Digital Library (Canada)

2013-06-24

Jun 24, 2013 ... Canadian and African scientists are developing new vaccines to combat ... Potter says CBPP was once rampant in North America, Europe, the UK, and ... on a variety of viral diseases affecting sheep, goats, pigs, and cattle: ...

Leishmaniasis vaccine candidates for development: a global overview.

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Khamesipour, Ali; Rafati, Sima; Davoudi, Noushin; Maboudi, Fereidoun; Modabber, Farrokh

2006-03-01

A vaccine against different forms of leishmaniasis should be feasible considering the wealth of information on genetics and biology of the parasite, clinical and experimental immunology of leishmaniasis, and the availability of vaccines that can protect experimental animals against challenge with different Leishmania species. However, there is no vaccine against any form of leishmaniasis for general human use. One major factor is the lack of a conceived market for human leishmaniasis vaccines. Hence pharmaceutical industries involved in vaccine development are not interested in investing millions of dollars and a decade that is required for developing a new vaccine. Besides, leishmaniasis is a local/regional problem and not a global one. According to the estimates of the World Health Organization, 90 per cent of visceral leishmaniasis occurs in five countries (Bangladesh, Brazil, India, Nepal and Sudan). Those in need are amongst the poorest people in these countries. It should therefore be the objectives of these countries to develop a vaccine. Fortunately, both Brazil and India have designated the control of visceral leishmaniasis as a top priority for their respective Ministries of Health. The purpose of this review is to present only the vaccines in use and those in development for use in dogs or humans. This is not an exhaustive review of vaccine discovery or the principles of clinical immunology underlying vaccine development.

Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

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Yingying Xu

2014-07-01

Full Text Available Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated lymphoid tissues (NALT. Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents.

Vaccines for emerging infectious diseases: Lessons from MERS coronavirus and Zika virus

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Maslow, Joel N.

2017-01-01

ABSTRACT The past decade and a half has been characterized by numerous emerging infectious diseases. With each new threat, there has been a call for rapid vaccine development. Pathogens such as the Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the Zika virus represent either new viral entities or viruses emergent in new geographic locales and characterized by novel complications. Both serve as paradigms for the global spread that can accompany new pathogens. In this paper, we review the epidemiology and pathogenesis of MERS-CoV and Zika virus with respect to vaccine development. The challenges in vaccine development and the approach to clinical trial design to test vaccine candidates for disease entities with a changing epidemiology are discussed. PMID:28846484

DENGUE VACCINE, CHALLENGES, DEVELOPMENT AND STRATEGIES

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Dewi Marbawati

2014-08-01

Full Text Available ABSTRAKPenyakit demam Dengue endemik di lebih dari 100 negara di dunia. Obat anti virus Dengue efektif belum ditemukan danpengendalian vektor dinilai kurang efektif, sehingga diperlukan upaya pencegahan dengan vaksinasi. Vaksin Dengue yangideal adalah murah, mencakup 4 serotipe, efektif dalam memberikan kekebalan, cukup diberikan sekali seumur hidup, aman,memberi kekebalan jangka panjang, stabil dalam penyimpanan dan stabil secara genetis (tidak bermutasi. Beberapakandidat vaksin yang telah dan sedang dikembangkan oleh para peneliti di seluruh dunia adalah tetravalent live attenuatedvaccine, vaksin Chimera (ChimeriVax, vaksin subunit dan vaksin DNA. Vaksin Dengue dipandang sebagai pendekatan yangefektif dan berkesinambungan dalam mengendalikan penyakit Dengue. Tahun 2003 telah terbentuk Pediatric DengueVaccine Initiative (PDVI, yaitu sebuah konsorsium internasional yang bergerak dalam advokasi untuk meyakinkanmasyarakat internasional akan penting dan mendesaknya vaksin Dengue. Konsorsium vaksin Dengue Indonesia saat iniberupaya mengembangkan vaksin Dengue dengan menggunakan strain virus lokal.Kata kunci: Dengue, virus, vaksinABSTRACTDengue fever is endemic in more than 100 countries in the world. The effective dengue antiviral drug has not been found yet,and vector control is considered less effective. Prevention program by vaccination is needed. An ideal dengue vaccine shouldbe inexpensive, covering four serotypes (tetravalent, effective in providing immunity, given once a lifetime, safe, stable instorage and genetically. Several vaccine candidates have been and are being developed included attenuated tetravalentvaccine, ChimeriVax, sub- unit vaccines and DNA vaccines. Dengue vaccine is seen as an effective and sustainable approachto controll Dengue infection. In 2003, Pediatric Dengue Vaccine Initiative (PDVI has been formed as an internationalconsortium involved in advocacy to convince the international community about the essence and urgency

Strategies for Cancer Vaccine Development

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Matteo Vergati

2010-01-01

Full Text Available Treating cancer with vaccines has been a challenging field of investigation since the 1950s. Over the years, the lack of effective active immunotherapies has led to the development of numerous novel strategies. However, the use of therapeutic cancer vaccines may be on the verge of becoming an effective modality. Recent phase II/III clinical trials have achieved hopeful results in terms of overall survival. Yet despite these encouraging successes, in general, very little is known about the basic immunological mechanisms involved in vaccine immunotherapy. Gaining a better understanding of the mechanisms that govern the specific immune responses (i.e., cytotoxic T lymphocytes, CD4 T helper cells, T regulatory cells, cells of innate immunity, tumor escape mechanisms elicited by each of the various vaccine platforms should be a concern of cancer vaccine clinical trials, along with clinical benefits. This review focuses on current strategies employed by recent clinical trials of therapeutic cancer vaccines and analyzes them both clinically and immunologically.

Status of vaccine research and development of vaccines for leishmaniasis.

Science.gov (United States)

Gillespie, Portia M; Beaumier, Coreen M; Strych, Ulrich; Hayward, Tara; Hotez, Peter J; Bottazzi, Maria Elena

2016-06-03

A number of leishmaniasis vaccine candidates are at various stages of pre-clinical and clinical development. Leishmaniasis is a vector-borne neglected tropical disease (NTD) caused by a protozoan parasite of the genus Leishmania and transmitted to humans by the bite of a sand fly. Visceral leishmaniasis (VL, kala-azar) is a high mortality NTD found mostly in South Asia and East Africa, while cutaneous leishmaniasis (CL) is a disfiguring NTD highly endemic in the Middle East, Central Asia, North Africa, and the Americas. Estimates attribute 50,000 annual deaths and 3.3 million disability-adjusted life years to leishmaniasis. There are only a few approved drug treatments, no prophylactic drug and no vaccine. Ideally, an effective vaccine against leishmaniasis will elicit long-lasting immunity and protect broadly against VL and CL. Vaccines such as Leish-F1, F2 and F3, developed at IDRI and designed based on selected Leishmania antigen epitopes, have been in clinical trials. Other groups, including the Sabin Vaccine Institute in collaboration with the National Institutes of Health are investigating recombinant Leishmania antigens in combination with selected sand fly salivary gland antigens in order to augment host immunity. To date, both VL and CL vaccines have been shown to be cost-effective in economic modeling studies. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

A comparative analysis of influenza vaccination programs.

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Shweta Bansal

2006-10-01

Full Text Available BACKGROUND: The threat of avian influenza and the 2004-2005 influenza vaccine supply shortage in the United States have sparked a debate about optimal vaccination strategies to reduce the burden of morbidity and mortality caused by the influenza virus. METHODS AND FINDINGS: We present a comparative analysis of two classes of suggested vaccination strategies: mortality-based strategies that target high-risk populations and morbidity-based strategies that target high-prevalence populations. Applying the methods of contact network epidemiology to a model of disease transmission in a large urban population, we assume that vaccine supplies are limited and then evaluate the efficacy of these strategies across a wide range of viral transmission rates and for two different age-specific mortality distributions. We find that the optimal strategy depends critically on the viral transmission level (reproductive rate of the virus: morbidity-based strategies outperform mortality-based strategies for moderately transmissible strains, while the reverse is true for highly transmissible strains. These results hold for a range of mortality rates reported for prior influenza epidemics and pandemics. Furthermore, we show that vaccination delays and multiple introductions of disease into the community have a more detrimental impact on morbidity-based strategies than mortality-based strategies. CONCLUSIONS: If public health officials have reasonable estimates of the viral transmission rate and the frequency of new introductions into the community prior to an outbreak, then these methods can guide the design of optimal vaccination priorities. When such information is unreliable or not available, as is often the case, this study recommends mortality-based vaccination priorities.

Immunogenicity and efficacy of a chimpanzee adenovirus-vectored Rift Valley fever vaccine in mice.

OpenAIRE

Warimwe, GM; Lorenzo, G; Lopez-Gil, E; Reyes-Sandoval, A; Cottingham, MG; Spencer, AJ; Collins, KA; Dicks, MD; Milicic, A; Lall, A; Furze, J; Turner, AV; Hill, AV; Brun, A; Gilbert, SC

2013-01-01

BACKGROUND: Rift Valley Fever (RVF) is a viral zoonosis that historically affects livestock production and human health in sub-Saharan Africa, though epizootics have also occurred in the Arabian Peninsula. Whilst an effective live-attenuated vaccine is available for livestock, there is currently no licensed human RVF vaccine. Replication-deficient chimpanzee adenovirus (ChAd) vectors are an ideal platform for development of a human RVF vaccine, given the low prevalence of neutralizing antibod...

Vaccine prophylaxis: achievements, problems, perspectives of development

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Mavrutenkov V.V.

2016-09-01

Full Text Available The article presents medical and social aspects of immune prophylaxis of infectious diseases; the history of vaccines and vaccination is presented, as well as perspectives of development of vaccine prophylaxis.

Viral aetiology influenza like illnesses in Santa Cruz, Bolivia (2010–2012)

Science.gov (United States)

2014-01-01

Background Acute respiratory infections represent a serious public health issue worldwide but virological aetiologies of Influenza Like Illnesses (ILIs) remain largely unknown in developing countries. This study represents the first attempt to characterise viral aetiologies of ILIs in Bolivia. Methods It was performed in Santa Cruz city from January 2010 to September 2012, based on 564 naso-pharyngeal swabs collected in a National Reference Laboratory and real-time PCR techniques, viral cultures and phylogenetic analyses. Results 50.2% of samples were positive for at least one virus with influenza viruses (Flu A: ~15%; Flu B: ~9%), rhinoviruses (~8%), coronaviruses (~5%) and hRSV (~4%) being the most frequently identified. The pattern of viral infections varied according to age groups. The elucidation rate was the highest (>60%) amongst patients under 10 yo and the lowest (Bolivia in the study period, originating from Central and North America, Europe, Asia and Australia. Conclusion Our results emphasise the requirement for a reinforced epidemiological and genetic follow-up of influenza and other ILIs in Bolivia to further inform the preparation of vaccines used in the region, guide vaccination campaigns and improve the medical management of patients. PMID:24564892

A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates.

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Karthik Mallilankaraman

2011-01-01

Full Text Available Chikungunya virus (CHIKV is an emerging mosquito-borne alphavirus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgias, conjunctivitis, rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity, and no licensed vaccines or therapeutics are currently available for the pathogen. While the Aedes aegypti mosquito is its primary vector, recent evidence suggests that other carriers can transmit CHIKV thus raising concerns about its spread outside of natural endemic areas to new countries including the U.S. and Europe. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective counter measures against CHIKV. In this study, we isolated a new CHIKV virus from an acutely infected human patient and developed a defined viral challenge stock in mice that allowed us to study viral pathogenesis and develop a viral neutralization assay. We then constructed a synthetic DNA vaccine delivered by in vivo electroporation (EP that expresses a component of the CHIKV envelope glycoprotein and used this model to evaluate its efficacy. Vaccination induced robust antigen-specific cellular and humoral immune responses, which individually were capable of providing protection against CHIKV challenge in mice. Furthermore, vaccine studies in rhesus macaques demonstrated induction of nAb responses, which mimicked those induced in convalescent human patient sera. These data suggest a protective role for nAb against CHIKV disease and support further study of envelope-based CHIKV DNA vaccines.

Vaccination with experimental feline immunodeficiency virus vaccines, based on autologous infected cells, elicits enhancement of homologous challenge infection

NARCIS (Netherlands)

J.A. Karlas (Jos); C.H.J. Siebelink (Kees); M.A. Peer; W. Huisman (Willem); A.M. Cuisinier; G.F. Rimmelzwaan (Guus); A.D.M.E. Osterhaus (Albert)

1999-01-01

textabstractCats were vaccinated with fixed autologous feline immunodeficiency virus (FIV)-infected cells in order to present viral proteins to the immune system of individual cats in an MHC-matched fashion. Upon vaccination, a humoral response against Gag was induced. Furthermore,

Zika Vaccine Development: Flavivirus Foils

Science.gov (United States)

2016-09-01

Martins, Bavari, Zika Vaccine Development 1 Zika Vaccine Development: Flavivirus Foils Martins KAO, Bavari S. The current Zika virus...States government. The rapid response to Zika is perhaps the first of its kind, and it undoubtedly has been made possible by the lessons learned from...the response to the 2014 Ebola virus outbreak in West Africa. However, Zika virus is not Ebola virus. As of February 2016 there were only 296

Global Vaccine and Immunization Research Forum: Opportunities and challenges in vaccine discovery, development, and delivery.

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Ford, Andrew Q; Touchette, Nancy; Hall, B Fenton; Hwang, Angela; Hombach, Joachim

2016-03-18

The World Health Organization, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation convened the first Global Vaccine and Immunization Research Forum (GVIRF) in March 2014. This first GVIRF aimed to track recent progress of the Global Vaccine Action Plan research and development agenda, identify opportunities and challenges, promote partnerships in vaccine research, and facilitate the inclusion of all stakeholders in vaccine research and development. Leading scientists, vaccine developers, and public health officials from around the world discussed scientific and technical challenges in vaccine development, research to improve the impact of immunization, and regulatory issues. This report summarizes the discussions and conclusions from the forum participants. Copyright © 2016. Published by Elsevier Ltd.. All rights reserved.

Development and trial of vaccines against Brucella.

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Lalsiamthara, Jonathan; Lee, John Hwa

2017-08-31

The search for ideal brucellosis vaccines remains active today. Currently, no licensed human or canine anti-brucellosis vaccines are available. In bovines, the most successful vaccine (S19) is only used in calves, as adult vaccination results in orchitis in male, prolonged infection, and possible abortion complications in pregnant female cattle. Another widely deployed vaccine (RB51) has a low protective efficacy. An ideal vaccine should exhibit a safe profile as well as enhance protective efficacy. However, currently available vaccines exhibit one or more major drawbacks. Smooth live attenuated vaccines suffer shortcomings such as residual virulence and serodiagnostic interference. Inactivated vaccines, in general, confer relatively low levels of protection. Recent developments to improve brucellosis vaccines include generation of knockout mutants by targeting genes involved in metabolism, virulence, and the lipopolysaccharide synthesis pathway, as well as generation of DNA vaccines, mucosal vaccines, and live vectored vaccines, have all produced varying degrees of success. Herein, we briefly review the bacteriology, pathogenesis, immunological implications, candidate vaccines, vaccinations, and models related to Brucella .

The Immunoproteasome and Viral Infection: A Complex Regulator of Inflammation

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Mary Katherine McCarthy

2015-01-01

Full Text Available During viral infection, proper regulation of immune responses is necessary to ensure successful viral clearance with minimal host tissue damage. Proteasomes play a crucial role in the generation of antigenic peptides for presentation on MHC class I molecules, and thus activation of CD8 T cells, as well as activation of the NF-kB pathway. A specialized type of proteasome called the immunoproteasome is constitutively expressed in hematopoietic cells and induced in nonimmune cells during viral infection by interferon (IFN signaling. The immunoproteasome regulates CD8 T cell responses to many viral epitopes during infection. Accumulating evidence suggests that the immunoproteasome may also contribute to regulation of proinflammatory cytokine production, activation of the NF-kB pathway, and management of oxidative stress. Many viruses have mechanisms of interfering with immunoproteasome function, including prevention of transcriptional upregulation of immunoproteasome components as well as direct interaction of viral proteins with immunoproteasome subunits. A better understanding of the role of the immunoproteasome in different cell types, tissues, and hosts has the potential to improve vaccine design and facilitate the development of effective treatment strategies for viral infections.

Bacterial Artificial Chromosome Clones of Viruses Comprising the Towne Cytomegalovirus Vaccine

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Xiaohong Cui

2012-01-01

Full Text Available Bacterial artificial chromosome (BAC clones have proven invaluable for genetic manipulation of herpesvirus genomes. BAC cloning can also be useful for capturing representative genomes that comprise a viral stock or mixture. The Towne live attenuated cytomegalovirus vaccine was developed in the 1970s by serial passage in cultured fibroblasts. Although its safety, immunogenicity, and efficacy have been evaluated in nearly a thousand human subjects, the vaccine itself has been little studied. Instead, genetic composition and in vitro growth properties have been inferred from studies of laboratory stocks that may not always accurately represent the viruses that comprise the vaccine. Here we describe the use of BAC cloning to define the genotypic and phenotypic properties of viruses from the Towne vaccine. Given the extensive safety history of the Towne vaccine, these BACs provide a logical starting point for the development of next-generation rationally engineered cytomegalovirus vaccines.

Bacterial artificial chromosome clones of viruses comprising the towne cytomegalovirus vaccine.

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Cui, Xiaohong; Adler, Stuart P; Davison, Andrew J; Smith, Larry; Habib, El-Sayed E; McVoy, Michael A

2012-01-01

Bacterial artificial chromosome (BAC) clones have proven invaluable for genetic manipulation of herpesvirus genomes. BAC cloning can also be useful for capturing representative genomes that comprise a viral stock or mixture. The Towne live attenuated cytomegalovirus vaccine was developed in the 1970s by serial passage in cultured fibroblasts. Although its safety, immunogenicity, and efficacy have been evaluated in nearly a thousand human subjects, the vaccine itself has been little studied. Instead, genetic composition and in vitro growth properties have been inferred from studies of laboratory stocks that may not always accurately represent the viruses that comprise the vaccine. Here we describe the use of BAC cloning to define the genotypic and phenotypic properties of viruses from the Towne vaccine. Given the extensive safety history of the Towne vaccine, these BACs provide a logical starting point for the development of next-generation rationally engineered cytomegalovirus vaccines.

A Reverse Genetics Approach for the Design of Methyltransferase-Defective Live Attenuated Avian Metapneumovirus Vaccines.

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Zhang, Yu; Sun, Jing; Wei, Yongwei; Li, Jianrong

2016-01-01

Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is the causative agent of turkey rhinotracheitis and is associated with swollen head syndrome in chickens. aMPV belongs to the family Paramyxoviridae which includes many important human pathogens such as human respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and human parainfluenza virus type 3 (PIV3). The family also includes highly lethal emerging pathogens such as Nipah virus and Hendra virus, as well as agriculturally important viruses such as Newcastle disease virus (NDV). For many of these viruses, there is no effective vaccine. Here, we describe a reverse genetics approach to develop live attenuated aMPV vaccines by inhibiting the viral mRNA cap methyltransferase. The viral mRNA cap methyltransferase is an excellent target for the attenuation of paramyxoviruses because it plays essential roles in mRNA stability, efficient viral protein translation and innate immunity. We have described in detail the materials and methods used to generate recombinant aMPVs that lack viral mRNA cap methyltransferase activity. We have also provided methods to evaluate the genetic stability, pathogenesis, and immunogenicity of live aMPV vaccine candidates in turkeys.

Reversion to virulence of a subtype B avian metapneumovirus vaccine: is it time for regulators to require availability of vaccine progenitors?

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Cecchinato, M; Catelli, E; Lupini, C; Ricchizzi, E; Prosperi, S; Naylor, C J

2014-08-06

Empirically derived live avian metapneumovirus (AMPV) vaccines developed during the late 80s and early 90s have generally performed well in controlling turkey rhinotracheitis. Nonetheless, unstable attenuation was previously demonstrated in an AMPV subtype A vaccine. Until now this had not been investigated in subtype B vaccines due to lack of any similar availability of a vaccine progenitor or its sequence. The publication of the full genome sequence for the VCO3 vaccine progenitor facilitated a conclusive investigation of two AMPVs isolated from poults on a farm which had been vaccinated with VCO3 derived vaccine. Full genome sequencing of the isolates and their comparison to sequences of the vaccine and its progenitor, confirmed their vaccine origin. After determining the absence of extraneous infectious agents, one of these virus isolates was inoculated into 1-day-old turkeys in disease secure isolators and shown to cause disease with a severity similar to that caused by virulent field virus. This suggests that instability in live AMPV vaccines may be generalized and highlights the need for availability of vaccine progenitor sequences for the field assessment of all live viral vaccines. Copyright © 2014 Elsevier Ltd. All rights reserved.

Heterosybtypic T-cell immunity to influenza in humans: challenges for universal T-cell influenza vaccines

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Saranya eSridhar

2016-05-01

Full Text Available Influenza A virus (IAV remains a significant global health issue causing annual epidemics, pandemics and sporadic human infections with highly pathogenic avian or swine influenza viruses. Current inactivated and live vaccines are the mainstay of the public health response to influenza although vaccine efficacy is lower against antigenically distinct viral strains. The first pandemic of the 21st century underlined the urgent need to develop new vaccines capable of protection against a broad range of influenza strains. Such universal influenza vaccines are based on the idea of heterosubtypic immunity wherein immune responses to epitopes conserved across IAV strains can confer protection against subsequent infection and disease. T-cells recognising conserved antigens are a key contributor to reducing viral load and limiting disease severity during heterosubtypic infection in animal models. Recent studies undertaken during the 2009 H1N1 pandemic provided key insights into the role of cross-reactive T-cells in mediating heterosubtypic protection in humans. This review focuses on human influenza to discuss the epidemiological observations that underpin cross-protective immunity, the role of T-cells as key players in mediating heterosubtypic immunity including recent data from natural history cohort studies and the ongoing clinical development of T-cell inducing universal influenza vaccines. The challenges and knowledge gaps for developing vaccines to generate long-lived protective T-cell responses is discussed.

Interference of an ERM-vaccine with a VHS-DNA vaccine in rainbow trout

DEFF Research Database (Denmark)

Lorenzen, Ellen; Einer-Jensen, Katja; Rasmussen, Jesper Skou

Simultaneous vaccination of fish against several diseases is often desirable in order to minimise cost and handling of the fish. Intramuscular DNA-vaccination of rainbow trout against viral haemorrhagic septicaemia virus (VHSV) has proved to provide very good protection. However, preliminary...... results showed that intraperitoneal injection of a commercial vaccine against Enteric Redmouth Disease (ERM) based on formalin-killed bacteria in oil adjuvant immediately followed by intramuscular injection of an experimental DNA-vaccine against VHSV, decreased the protective effect of the DNA......-vaccine against challenge with VHSV 11 weeks post vaccination (pv). This experiment was performed with rainbow trout of 30 g injected with 0.5 g VHS-DNA vaccine. The experiment was later repeated with smaller fish (2.5g) and using two different doses of DNA-vaccine, 1 g and 0.05 g. Both doses provided good...

Arbovirus vaccines: opportunities for the baculovirus-insect cell expression system

NARCIS (Netherlands)

Metz, S.W.H.; Pijlman, G.P.

2011-01-01

The baculovirus-insect cell expression system is a well-established technology for the production of heterologous viral (glyco)proteins in cultured cells, applicable for basic scientific research as well as for the development and production of vaccines and diagnostics. Arboviruses form an emerging

Development of a vaccine-challenge model for avian metapneumovirus subtype C in turkeys.

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Velayudhan, Binu T; Noll, Sally L; Thachil, Anil J; Shaw, Daniel P; Goyal, Sagar M; Halvorson, David A; Nagaraja, Kakambi V

2007-02-26

The objective of this study was to evaluate different preparations of avian metapneumovirus (aMPV) subtype C as vaccine challenge in turkeys. Two aMPV isolates and their respective nasal turbinate homogenates after propagation in turkeys were used in the study. Significantly higher clinical sign scores were recorded in birds inoculated with 20 or 2% turbinate homogenate of recent isolate. Birds in the above groups showed more pronounced histopathological lesions, and a higher percentage of birds showed viral RNA and antigen in tissues. The data demonstrated that nasal turbinate homogenate of recent isolate produced severe clinical signs and lesions in turkeys and could be an ideal candidate for vaccine-challenge studies.

Potential Cost-Effectiveness of RSV Vaccination of Infants and Pregnant Women in Turkey : An Illustration Based on Bursa Data

NARCIS (Netherlands)

Pouwels, Koen B.; Bozdemir, Sefika E.; Yegenoglu, Selen; Celebi, Solmaz; McIntosh, E. David; Unal, Serhat; Postma, Maarten J.; Hacimustafaoglu, Mustafa

2016-01-01

Background Worldwide, respiratory syncytial virus (RSV) is considered to be the most important viral cause of respiratory morbidity and mortality among infants and young children. Although no active vaccine is available on the market yet, there are several active vaccine development programs in

Mumps vaccine virus genome is present in throat swabs obtained from uncomplicated healthy recipients.

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Nagai, T; Nakayama, T

2001-01-08

Seven children were followed for up to 42 days post-vaccination with live mumps vaccine and 37 throat swabs were obtained serially. Viral genomic RNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) in the phosphoprotein (P) and hemagglutinin-neuraminidase (HN) regions. Virus isolation was also attempted. Genomic differentiation of detected mumps virus genome was performed by sequence analysis and/or restriction fragment length polymorphism (RFLP). No adverse reaction was observed in these children. Although mumps virus was not isolated from any of the samples, viral RNA was detected in four samples from three vaccine recipients, 18, 18 and 26, and 7 days after vaccination, respectively. Detected viral RNA was identified as the vaccine strain. Our data suggests that vaccine virus inoculated replicates in the parotid glands but the incidence of virus transmission from recipients to other susceptible subjects should be low.

Tularemia vaccine development: paralysis or progress?

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Sunagar R

2016-05-01

Full Text Available Raju Sunagar, Sudeep Kumar, Brian J Franz, Edmund J Gosselin Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA Abstract: Francisella tularensis (Ft is a gram-negative intercellular pathogen and category A biothreat agent. However, despite 15 years of strong government investment and intense research focused on the development of a US Food and Drug Administration-approved vaccine against Ft, the primary goal remains elusive. This article reviews research efforts focused on developing an Ft vaccine, as well as a number of important factors, some only recently recognized as such, which can significantly impact the development and evaluation of Ft vaccine efficacy. Finally, an assessment is provided as to whether a US Food and Drug Administration-approved Ft vaccine is likely to be forthcoming and the potential means by which this might be achieved. Keywords: Sex bias, media impact, differential protection, cellular immunity, humoral immunity

Update on the current status of cytomegalovirus vaccines.

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Sung, Heungsup; Schleiss, Mark R

2010-11-01

Human cytomegalovirus (HCMV) is ubiquitous in all populations, and is the most commonly recognized cause of congenital viral infection in developed countries. On the basis of the economic costs saved and the improvement in quality of life that could potentially be conferred by a successful vaccine for prevention of congenital HCMV infection, the Institute of Medicine has identified HCMV vaccine development as a major public health priority. An effective vaccine could potentially also be beneficial in preventing or ameliorating HCMV disease in immunocompromised individuals. Although there are no licensed HCMV vaccines currently available, enormous progress has been made in the last decade, as evidenced by the recently reported results of a Phase II trial of a glycoprotein B vaccine for the prevention of HCMV infection in seronegative women of childbearing age. HCMV vaccines currently in clinical trials include: glycoprotein B subunit vaccines; alphavirus replicon particle vaccines; DNA vaccines; and live-attenuated vaccines. A variety of vaccine strategies are also being examined in preclinical systems and animal models of infection. These include: recombinant vesicular stomatitis virus vaccines; recombinant modified vaccinia virus Ankara; replication-deficient adenovirus-vectored vaccines; and recombinant live-attenuated virus vaccines generated by mutagenesis of cloned rodent CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli. In this article, we provide an overview of the current state of clinical trials and preclinical development of vaccines against HCMV, with an emphasis on studies that have been conducted in the past 5 years. We also summarize a number of recent advances in the study of the biology of HCMV, particularly with respect to epithelial and endothelial cell entry of the virus, which have implications for future vaccine design.

Temperature effects on vaccine induced immunity to viruses in fish

DEFF Research Database (Denmark)

Lorenzen, Niels; Lorenzen, Ellen; Rasmussen, Jesper Skou

a problem in terms of inducing a protective immune response by vaccination in aquaculture, since it is often desirable to vaccinate fish during autumn, winter, or spring. In experimental vaccination trials with rainbow trout (Oncorhynchus mykiss) using a DNA-vaccine encoding the viral glycoprotein of viral...... haemorrhagic septicaemia virus (VHSV), non-specific as well as specific immune mechanisms seemed to be delayed at low temperature. At five weeks post vaccination fish kept at 5C had no detectable response of neutralising antibodies while two thirds of the fish kept at 15C had sero-converted. While protective...... immunity was still established at both temperatures, specificity analysis suggested that protection at the lower temperature was mainly due to non-specific innate antiviral mechanisms, which appeared to last longer at low temperature. This was presumably related to a prolonged persistence of the vaccine...

Vaccine procurement and self-sufficiency in developing countries.

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Woodle, D

2000-06-01

This paper discusses the movement toward self-sufficiency in vaccine supply in developing countries (and countries in transition to new economic and political systems) and explains special supply concerns about vaccine as a product class. It traces some history of donor support and programmes aimed at self-financing, then continues with a discussion about self-sufficiency in terms of institutional capacity building. A number of deficiencies commonly found in vaccine procurement and supply in low- and middle-income countries are characterized, and institutional strengthening with procurement technical assistance is described. The paper also provides information about a vaccine procurement manual being developed by the United States Agency for International Development (USAID) and the World Health Organization (WHO) for use in this environment. Two brief case studies are included to illustrate the spectrum of existing capabilities and different approaches to technical assistance aimed at developing or improving vaccine procurement capability. In conclusion, the paper discusses the special nature of vaccine and issues surrounding potential integration and decentralization of vaccine supply systems as part of health sector reform.

Reproductive toxicity testing of vaccines

International Nuclear Information System (INIS)

Verdier, Francois; Barrow, Paul C.; Burge, Joeelle

2003-01-01

Vaccines play a major role in the prevention of human birth defects by protecting the pregnant woman from teratogenic or otherwise harmful infections. Until now, it has not been common practice to perform preclinical developmental toxicity tests for new vaccines. Despite the excellent safety record of vaccines, increased attention is now being given to the feasibility of screening new vaccines for developmental hazards in animals before their use in humans. Contrary to previous assumptions, many vaccines are now given to potentially pregnant women. Any new components of the vaccine formulation (adjuvants, excipients, stabilisers, preservatives, etc...) could also be tested for influences on development, although based on past experience the risks are limited by the very low dosages used. The conferred immunity following vaccination lasts for several years. Therefore, the developing conceptus may theoretically be exposed to the induced antibodies and/or sensitised T-cells, even if the pregnant woman was last vaccinated during childhood (particularly if she encounters the antigen during pregnancy through exposure to infection). However, it should be kept in mind that viral or bacterial infections represent a higher risk for a pregnant woman than the potential adverse effects related to vaccination or the associated immune response. Non-clinical safety studies may be employed as an aid for hazard identification. In these studies interactions of the vaccine with the maternal immune system or with the developmental systems of the offspring are considered. Post-natal examinations are necessary to detect all possible manifestations of developmental toxicity, such as effects on the immune system. Species selection for the preclinical studies is based on immunogenicity to the vaccine and the relative timing and rate of transfer of maternal antibodies to the offspring. A single study design is proposed for the pre- and post-natal developmental assessments of vaccines in

Influenza Vaccination Strategies: Comparing Inactivated and Live Attenuated Influenza Vaccines

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Saranya Sridhar

2015-04-01

Full Text Available Influenza is a major respiratory pathogen causing annual outbreaks and occasional pandemics. Influenza vaccination is the major method of prophylaxis. Currently annual influenza vaccination is recommended for groups at high risk of complications from influenza infection such as pregnant women, young children, people with underlying disease and the elderly, along with occupational groups such a healthcare workers and farm workers. There are two main types of vaccines available: the parenteral inactivated influenza vaccine and the intranasal live attenuated influenza vaccine. The inactivated vaccines are licensed from 6 months of age and have been used for more than 50 years with a good safety profile. Inactivated vaccines are standardized according to the presence of the viral major surface glycoprotein hemagglutinin and protection is mediated by the induction of vaccine strain specific antibody responses. In contrast, the live attenuated vaccines are licensed in Europe for children from 2–17 years of age and provide a multifaceted immune response with local and systemic antibody and T cell responses but with no clear correlate of protection. Here we discuss the immunological immune responses elicited by the two vaccines and discuss future work to better define correlates of protection.

Research progress of therapeutic vaccines for treating chronic hepatitis B.

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Li, Jianqiang; Bao, Mengru; Ge, Jun; Ren, Sulin; Zhou, Tong; Qi, Fengchun; Pu, Xiuying; Dou, Jia

2017-05-04

Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.

Rhabdoviruses as vaccine platforms for infectious disease and cancer.

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Zemp, Franz; Rajwani, Jahanara; Mahoney, Douglas J

2018-05-21

The family Rhabdoviridae (RV) comprises a large, genetically diverse collection of single-stranded, negative sense RNA viruses from the order Mononegavirales. Several RV members are being developed as live-attenuated vaccine vectors for the prevention or treatment of infectious disease and cancer. These include the prototype recombinant Vesicular Stomatitis Virus (rVSV) and the more recently developed recombinant Maraba Virus, both species within the genus Vesiculoviridae. A relatively strong safety profile in humans, robust immunogenicity and genetic malleability are key features that make the RV family attractive vaccine platforms. Currently, the rVSV vector is in preclinical development for vaccination against numerous high-priority infectious diseases, with clinical evaluation underway for HIV/AIDS and Ebola virus disease. Indeed, the success of the rVSV-ZEBOV vaccine during the 2014-15 Ebola virus outbreak in West Africa highlights the therapeutic potential of rVSV as a vaccine vector for acute, life-threatening viral illnesses. The rVSV and rMaraba platforms are also being tested as 'oncolytic' cancer vaccines in a series of phase 1-2 clinical trials, after being proven effective at eliciting immune-mediated tumour regression in preclinical mouse models. In this review, we discuss the biological and genetic features that make RVs attractive vaccine platforms and the development and ongoing testing of rVSV and rMaraba strains as vaccine vectors for infectious disease and cancer.

HIV vaccine development: would more (public) money bring quicker results?

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Winsbury, R

1999-01-01

Globally, $200-250 million/year are devoted to HIV vaccine research. Most of those funds pay for basic research rather than product development. Moreover, most of the funds are aimed at the HIV strain commonly found in the US and Europe, and not at the strains common to Africa and other developing countries. While US President Bill Clinton set in 1997 a 10-year target for the development of an HIV vaccine, that target date is looking increasingly unlikely. International vaccine and pharmaceutical companies typically drive vaccine research and development. However, concern over the ultimate profitability of developing and marketing an HIV vaccine, and the fear of major litigation should an eventual vaccine go awry have caused such firms to shy away from investing large amounts of money into HIV vaccine development. These companies somehow have to be attracted back into the field. A World Bank special task force is slated to present its report by mid-1999 on possible funding mechanisms to promote HIV vaccine development. It remains to be resolved whether public funds could and should be used, perhaps through a pooled international vaccine development fund. 2 new International AIDS Vaccine Initiative projects are described.

Successes and failures in human tuberculosis vaccine development.

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Zenteno-Cuevas, Roberto

2017-12-01

Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis. In 2016, the WHO estimated 10.5 million new cases and 1.8 million deaths, making this disease the leading cause of death by an infectious agent. The current and projected TB situation necessitates the development of new vaccines with improved attributes compared to the traditional BCG method. Areas covered: In this review, the authors describe the most promising candidate vaccines against TB and discuss additional key elements in vaccine development, such as animal models, new adjuvants and immunization routes and new strategies for the identification of candidate vaccines. Expert opinion: At present, around 13 candidate vaccines for TB are in the clinical phase of evaluation; however, there is still no substitute for the BCG vaccine. One major impediment to developing an effective vaccine is our lack of understanding of several of the mechanisms associated with infection and the immune response against TB. However, the recent implementation of an entirely new set of technological advances will facilitate the proposal of new candidates. Finally, development of a new vaccine will require a major coordination of effort in order to achieve its effective administration to the people most in need of it.

Interferon Response and Viral Evasion by Members of the Family Rhabdoviridae

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Matthias J. Schnell

2009-11-01

Full Text Available Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV and rabies virus (RABV. Despite their structural similarities, VSV and RABV have completely different mechanisms by which they avert the host immune response. VSV relies on the matrix protein to interfere with host gene transcription and nuclear export of anti-viral mRNAs. Alternatively, RABV uses its phosphoprotein to interfere with IRF-3 phosphorylation and STAT1 signaling. Understanding the virus-cell interactions and viral proteins necessary to evade the immune response is important in developing effective vaccines and therapeutics for this viral family.

The human immunodeficiency virus preventive vaccine research at the French National Agency for acquired immunodeficiency syndrome research

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Elizabeth Fischer

2005-02-01

Full Text Available The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS epidemic is of unprecedented gravity and is spreading rapidly, notably in the most disadvantaged regions of the world. The search for a preventive vaccine is thus an absolute priority. For over 10 years the French National Agency for AIDS research (ANRS has been committed to an original program combining basic science and clinical research. The HIV preventive vaccine research program run by the ANRS covers upstream research for the definition of immunogens, animal models, and clinical research to evaluate candidate vaccines. Most researchers in 2004 believe that it should be possible to obtain partial vaccine protection through the induction of a strong and multiepitopic cellular response. Since 1992, the ANRS has set up 15 phases I and II clinical trials in order to evaluate the safety and the capacity of the candidate vaccines for inducing cellular immune responses. The tested candidate vaccines were increasingly complex recombinant canarypox viruses (Alvac containing sequences coding for certain viral proteins, utilized alone or combined with other immunogens (whole or truncated envelope proteins. ANRS has also been developing an original strategy based on the utilization of lipopeptides. These comprise synthetic fragments of viral proteins associated with lipids that facilitate the induction of a cellular immune response. These approaches promptly allowed the assessment of a prime-boost strategy combining a viral vector and lipopeptides.

Universal Influenza Vaccines, a Dream to Be Realized Soon

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Han Zhang

2014-04-01

Full Text Available Due to frequent viral antigenic change, current influenza vaccines need to be re-formulated annually to match the circulating strains for battling seasonal influenza epidemics. These vaccines are also ineffective in preventing occasional outbreaks of new influenza pandemic viruses. All these challenges call for the development of universal influenza vaccines capable of conferring broad cross-protection against multiple subtypes of influenza A viruses. Facilitated by the advancement in modern molecular biology, delicate antigen design becomes one of the most effective factors for fulfilling such goals. Conserved epitopes residing in virus surface proteins including influenza matrix protein 2 and the stalk domain of the hemagglutinin draw general interest for improved antigen design. The present review summarizes the recent progress in such endeavors and also covers the encouraging progress in integrated antigen/adjuvant delivery and controlled release technology that facilitate the development of an affordable universal influenza vaccine.

Measles vaccination in children with neurological disorders

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S. P. Kaplina

2012-01-01

Full Text Available The data on the current vaccination process and specific antibody in 212 children with pathology of nervous systems in age from 1 year to 6 years old, vaccinated against measles. The comparison group consisted of 36 children without neurological disease. 86 children (40,6% were vaccinated measles – mumps vaccine, and 126 children (59,4% only measles vaccine. Post-vaccination period in 77,8% immunized against measles, was uneventful, layering intercurrent infections was noted in 22,2% of vaccine’s, and demonstrated the development of viral respiratory infections, bronchitis, otitis media and exacerbation of underlying disease. It is shown that the level of specific antibody to measles in children with pathology of nervous systems at 30 days after vaccination was 5,04±0,16 log 2, which did not differ from the comparison group (5,88±0,31 log 2. No significant differences in the level of antibody in a smooth and complicated course of vaccination period were found. Immunization of children with disorders of the nervous system of live vaccines is quite effective and leads to the formation of protective antibody titers in all vaccinated.

Vaccine instability in the cold chain: mechanisms, analysis and formulation strategies.

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Kumru, Ozan S; Joshi, Sangeeta B; Smith, Dawn E; Middaugh, C Russell; Prusik, Ted; Volkin, David B

2014-09-01

Instability of vaccines often emerges as a key challenge during clinical development (lab to clinic) as well as commercial distribution (factory to patient). To yield stable, efficacious vaccine dosage forms for human use, successful formulation strategies must address a combination of interrelated topics including stabilization of antigens, selection of appropriate adjuvants, and development of stability-indicating analytical methods. This review covers key concepts in understanding the causes and mechanisms of vaccine instability including (1) the complex and delicate nature of antigen structures (e.g., viruses, proteins, carbohydrates, protein-carbohydrate conjugates, etc.), (2) use of adjuvants to further enhance immune responses, (3) development of physicochemical and biological assays to assess vaccine integrity and potency, and (4) stabilization strategies to protect vaccine antigens and adjuvants (and their interactions) during storage. Despite these challenges, vaccines can usually be sufficiently stabilized for use as medicines through a combination of formulation approaches combined with maintenance of an efficient cold chain (manufacturing, distribution, storage and administration). Several illustrative case studies are described regarding mechanisms of vaccine instability along with formulation approaches for stabilization within the vaccine cold chain. These include live, attenuated (measles, polio) and inactivated (influenza, polio) viral vaccines as well as recombinant protein (hepatitis B) vaccines. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

DNA fusion gene vaccines

DEFF Research Database (Denmark)

Holst, Peter Johannes; Bassi, Maria Rosaria; Thomsen, Allan Randrup

2010-01-01

DNA vaccines are versatile and safe, but limited immunogenicity has prevented their use in the clinical setting. Experimentally, immunogenicity may be enhanced by the use of new delivery technologies, by coadministration of cytokines and pathogen-associated molecular patterns, or by fusion...... of antigens into molecular domains that enhance antigen presentation. More specifically, the immunogenicity of DNA vaccines may benefit from increased protein synthesis, increased T-cell help and MHC class I presentation, and the addition of a range of specific cytokines and pathogen-associated molecular...... with viral-vectored vaccines, various synergistic components may need to be incorporated into DNA vaccines. From the perspective of the future clinical use of DNA vaccines, it has been suggested that antigen presentation should be improved and cytokine coadministration attempted. However, even...

MMR (measles, mumps, and rubella) vaccine - what you need to know

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... taken in its entirety from the CDC MMR (Measles, Mumps, & Rubella) Vaccine Information Statement (VIS): www.cdc. ... Why get vaccinated? Measles, mumps, and rubella are viral diseases that can ... Before vaccines, these diseases were very common in ...

Evidence of pestivirus RNA in human virus vaccines.

Science.gov (United States)

Harasawa, R; Tomiyama, T

1994-01-01

We examined live virus vaccines against measles, mumps, and rubella for the presence of pestivirus RNA or of pestiviruses by reverse transcription PCR. Pestivirus RNA was detected in two measles-mumps-rubella combined vaccines and in two monovalent vaccines against mumps and rubella. Nucleotide sequence analysis of the PCR products indicated that a modified live vaccine strain used for immunization of cattle against bovine viral diarrhea is not responsible for the contamination of the vaccines. Images PMID:8077414

Antibody Persistence in Adults Two Years after Vaccination with an H1N1 2009 Pandemic Influenza Virus-Like Particle Vaccine.

Directory of Open Access Journals (Sweden)

Nuriban Valero-Pacheco

Full Text Available The influenza virus is a human pathogen that causes epidemics every year, as well as potential pandemic outbreaks, as occurred in 2009. Vaccination has proven to be sufficient in the prevention and containment of viral spreading. In addition to the current egg-based vaccines, new and promising vaccine platforms, such as cell culture-derived vaccines that include virus-like particles (VLPs, have been developed. VLPs have been shown to be both safe and immunogenic against influenza infections. Although antibody persistence has been studied in traditional egg-based influenza vaccines, studies on antibody response durations induced by VLP influenza vaccines in humans are scarce. Here, we show that subjects vaccinated with an insect cell-derived VLP vaccine, in the midst of the 2009 H1N1 influenza pandemic outbreak in Mexico City, showed antibody persistence up to 24 months post-vaccination. Additionally, we found that subjects that reported being revaccinated with a subsequent inactivated influenza virus vaccine showed higher antibody titres to the pandemic influenza virus than those who were not revaccinated. These findings provide insights into the duration of the antibody responses elicited by an insect cell-derived pandemic influenza VLP vaccine and the possible effects of subsequent influenza vaccination on antibody persistence induced by this VLP vaccine in humans.

Ebola virus vaccines: an overview of current approaches

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Marzi, Andrea; Feldmann, Heinz

2016-01-01

Ebola hemorrhagic fever is one of the most fatal viral diseases worldwide affecting humans and nonhuman primates. Although infections only occur frequently in Central Africa, the virus has the potential to spread globally and is classified as a category A pathogen that could be misused as a bioterrorism agent. As of today there is no vaccine or treatment licensed to counteract Ebola virus infections. DNA, subunit and several viral vector approaches, replicating and non-replicating, have been tested as potential vaccine platforms and their protective efficacy has been evaluated in nonhuman primate models for Ebola virus infections, which closely resemble disease progression in humans. Though these vaccine platforms seem to confer protection through different mechanisms, several of them are efficacious against lethal disease in nonhuman primates attesting that vaccination against Ebola virus infections is feasible. PMID:24575870

Transmission of the L-Zagreb mumps vaccine virus, Croatia, 2005-2008.

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Kaic, B; Gjenero-Margan, I; Aleraj, B; Ljubin-Sternak, S; Vilibic-Cavlek, T; Kilvain, S; Pavic, I; Stojanovic, D; Ilic, A

2008-04-17

We report on three cases of symptomatic transmission of the L-Zagreb mumps vaccine virus from three vaccinated children to five adult contacts. The five contact cases were parents of the vaccinated children and presented with parotitis and in one case also with aseptic meningitis. The etiology of the contacts' illness was determined by viral culture, genomic sequencing, serology and epidemiological linking. Two of the vaccinated children developed vaccine associated parotitis as an adverse event three weeks following immunization. Symptoms in contact cases developed five to seven weeks after the vaccination of the children. The five contact cases, as well as the three children with adverse events recovered completely. The children had been vaccinated with MMR vaccine produced by the Institute of Immunology Zagreb, each of them with a different lot. One of the possible explanations for these adverse events is that the very low levels of wild mumps virus circulation in the last decade, combined with waning immunity in those who received one dose of vaccine or suffered from mumps in childhood, resulted in susceptible young adults and that this unique epidemiological situation allows us to detect horizontal transmission of mumps vaccine virus.

Protective effect of enterovirus‑71 (EV71) virus‑like particle vaccine against lethal EV71 infection in a neonatal mouse model.

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Cao, Lei; Mao, Fengfeng; Pang, Zheng; Yi, Yao; Qiu, Feng; Tian, Ruiguang; Meng, Qingling; Jia, Zhiyuan; Bi, Shengli

2015-08-01

Enterovirus-71 (EV71) is a viral pathogen that causes severe cases of hand, foot and mouth disease (HFMD) among young children, with significant mortality. Effective vaccines against HFMD are urgently required. Several EV71 virus-like particle (VLP) vaccine candidates were found to be protective in the neonatal mouse EV71 challenge model. However, to what extent the VLP vaccine protects susceptible organs against EV71 infection in vivo has remained elusive. In the present study, the comprehensive immunogenicity of a potential EV71 vaccine candidate based on VLPs was evaluated in a neonatal mouse model. Despite lower levels of neutralizing antibodies to EV71 in the sera of VLP-immunized mice compared with those in mice vaccinated with inactivated EV71, the VLP-based vaccine was shown to be able to induce immunoglobulin (Ig)G and IgA memory-associated cellular immune responses to EV71. Of note, the EV71 VLP vaccine candidate was capable of inhibiting viral proliferation in cardiac muscle, skeletal muscle, lung and intestine of immunized mice and provided effective protection against the pathological damage caused by viral attack. In particular, the VLP vaccine was able to inhibit the transportation of EV71 from the central nervous system to the muscle tissue and greatly protected muscle tissue from infection, along with recovery from the viral infection. This led to nearly 100% immunoprotective efficacy, enabling neonatal mice delivered by VLP-immunized female adult mice to survive and grow with good health. The present study provided valuable additional knowledge of the specific protective efficacy of the EV71 VLP vaccine in vivo, which also indicated that it is a promising potential candidate for being developed into an EV71 vaccine.

Classical swine fever vaccines-State-of-the-art.

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Blome, Sandra; Moß, Claudia; Reimann, Ilona; König, Patricia; Beer, Martin

2017-07-01

Due to its impact on animal health and pig industry, classical swine fever (CSF) is still one of the most important viral diseases of pigs. To control the disease, safe and highly efficacious live attenuated vaccines exist for decades. These vaccines have usually outstanding efficacy and safety but lack differentiability of infected from vaccinated animals (DIVA or marker strategy). In contrast, the first generation of E2 subunit marker vaccines shows constraints in efficacy, application, and production. To overcome these limitations, new generations of marker vaccines are developed. A wide range of approaches have been tried including recombinant vaccines, recombinant inactivated vaccines or subunit vaccines, vector vaccines, and DNA/RNA vaccines. During the last years, especially attenuated deletion vaccines or chimeric constructs have shown potential. At present, especially two new constructs have been intensively tested, the adenovirus-delivered, Semliki Forest virus replicon-vectored marker vaccine candidate "rAdV-SFV-E2" and the pestivirus chimera "CP7_E2alf". The later was recently licensed by the European Medicines Agency. Under field conditions, all marker vaccines have to be accompanied by a potent test system. Particularly this point shows still weaknesses and it is important to embed vaccination in a well-established vaccination strategy and a suitable diagnostic workflow. In summary, conventional vaccines are a standard in terms of efficacy. However, only vaccines with DIVA will allow improved eradication strategies e.g. also under emergency vaccination conditions in free regions. To answer this demand, new generations of marker vaccines have been developed and add now to the tool box of CSF control. Copyright © 2017 Elsevier B.V. All rights reserved.

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases.

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Mao, Qunying; Wang, Yiping; Bian, Lianlian; Xu, Miao; Liang, Zhenglun

2016-07-20

Enteroviruses (EVs) are the most common viral agents in humans. Although most infections are mild or asymptomatic, there is a wide spectrum of clinical manifestations that may be caused by EV infections with varying degrees of severity. Among these viruses, EV-A71 and coxsackievirus (CV) CV-A16 from group A EVs attract the most attention because they are responsible for hand, foot and mouth disease (HFMD). Other EV-A viruses such as CV-A6 and CV-A10 were also reported to cause HFMD outbreaks in several countries or regions. Group B EVs such as CV-B3, CV-B5 and echovirus 30 were reported to be the main pathogens responsible for myocarditis and encephalitis epidemics and were also detected in HFMD patients. Vaccines are the best tools to control infectious diseases. In December 2015, China's Food and Drug Administration approved two inactivated EV-A71 vaccines for preventing severe HFMD.The CV-A16 vaccine and the EV-A71-CV-A16 bivalent vaccine showed substantial efficacy against HFMD in pre-clinical animal models. Previously, research on EV-B group vaccines was mainly focused on CV-B3 vaccine development. Because the HFMD pathogen spectrum has changed, and the threat from EV-B virus-associated severe diseases has gradually increased, it is necessary to develop multivalent HFMD vaccines. This study summarizes the clinical symptoms of diseases caused by EVs, such as HFMD, myocarditis and encephalitis, and the related EV vaccine development progress. In conclusion, developing multivalent EV vaccines should be strongly recommended to prevent HFMD, myocarditis, encephalitis and other severe diseases.

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.

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Hensel, Michael T; Marshall, Jason D; Dorwart, Michael R; Heeke, Darren S; Rao, Eileen; Tummala, Padmaja; Yu, Li; Cohen, Gary H; Eisenberg, Roselyn J; Sloan, Derek D

2017-05-01

Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses. IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors

Development of an influenza virus vaccine using the baculovirus-insect cell expression system : implications for pandemic preparedness

NARCIS (Netherlands)

Cox, M.M.J.

2009-01-01

Key word

Influenza, rHA, vaccine, baculovirus, insect cells, production, pandemic preparedness

Influenza (or flu) is a highly contagious, acute viral respiratory disease that occurs seasonally in most parts of the world and is caused by influenza viruses. Influenza

The use of an in vitro microneutralization assay to evaluate the potential of recombinant VP5 protein as an antigen for vaccinating against Grass carp reovirus

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Xu Dan

2011-03-01

Full Text Available Abstract Background Grass carp reovirus (GCRV is the causative pathogen of grass carp hemorrhagic disease, one of the major diseases damaging grass carp Ctenopharyngon idellus breeding industry in China. Prevention and control of the disease is impeded largely due to the lack of research in economic subunit vaccine development. This study aimed to evaluate the potential of viral outer shell protein VP5 as subunit vaccine. Methods The vp5 gene was isolated from the viral genome through RT-PCR and genetically engineered to express the recombinant VP5 protein in E coli. The viral origin of the recombinant protein was confirmed by Western blot analysis with a monoclonal antibody against viral VP5 protein. Polyclonal antibody against the recombinant VP5 protein was prepared from mice. A microneutralization assay was developed to test its neutralizing ability against GCRV infection in cell culture. Results The GST-VP5 fusion protein (rVP5 was produced from E. Coli with expected molecular weight of 90 kDa. The protein was purified and employed to prepare anti-VP5 polyclonal antibody from mice. The anti-VP5 antibody was found to neutralize GCRV through in vitro microneutralization assay and viral progeny quantification analysis. Conclusions The present study showed that the viral VP5 protein was involved in viral infection and bacterially-expressed VP5 could be suitable for developing subunit vaccine for the control of GCRV infection.

Gold nanorod vaccine for respiratory syncytial virus

International Nuclear Information System (INIS)

Stone, John W; Thornburg, Natalie J; Blum, David L; Kuhn, Sam J; Crowe Jr, James E; Wright, David W

2013-01-01

Respiratory syncytial virus (RSV) is a major cause of pneumonia and wheezing in infants and the elderly, but to date there is no licensed vaccine. We developed a gold nanorod construct that displayed the major protective antigen of the virus, the fusion protein (F). Nanorods conjugated to RSV F were formulated as a candidate vaccine preparation by covalent attachment of viral protein using a layer-by-layer approach. In vitro studies using ELISA, electron microscopy and circular dichroism revealed that conformation-dependent epitopes were maintained during conjugation, and transmission electron microscopy studies showed that a dispersed population of particles could be achieved. Human dendritic cells treated with the vaccine induced immune responses in primary human T cells. These results suggest that this vaccine approach may be a potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response. (paper)

Microsurgeon Hirudo medicinalis as a Natural Bioshuttle for Spontaneous Mass Vaccination against Influenza A Virus

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Sajjad Khani

2011-09-01

Full Text Available Introduction: Recent report on existence of a stem region of hemagglutinin has arisen new hopes for vaccination of influenza A as it consist of a conserve fusion peptide shared across several influenza subtypes and can be targeted by human immune system. Methods: Given that traditional vaccination based on live attenuated viruses often fails to surpass such viral infection, a great deal of attention has been devoted to develop a safe yet efficient system for vaccination influenza A. We believe that a natural bioshuttle can be recruited for spontaneous mass vaccination. Results: Thus, here, we hypothesize that a bioengineered transgenic Hirudo medicinalis can be considered as an alive bioshuttle for in-situ vaccination against influenza A virus. By introducing the designated gene(s encoding the target fragment (i.e., stem region of hemagglutinin, this microsurgeon can act as a rapid microproducer of viral proteins for in-house mass vaccination through imparting the necessary proteins such as those, naturally presented in leech's saliva. Conclusion: This peculiar bioshuttle can be easily exploited as a medical modality choice at home resulting in greater patient compliance.

Challenges to the development of vaccines to hepatitis C virus that elicit neutralizing antibodies.

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Heidi Edelgard Drummer

2014-07-01

Full Text Available Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. Hepatitis C virus encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor B class I. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of neutralizing antibodies to prevent HCV infection, the targets of the neutralizing antibody response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.

[History of viral hepatitis].

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Fonseca, José Carlos Ferraz da

2010-01-01

The history of viral hepatitis goes back thousands of years and is a fascinating one. When humans were first infected by such agents, a natural repetitive cycle began, with the capacity to infect billions of humans, thus decimating the population and causing sequelae in thousands of lives. This article reviews the available scientific information on the history of viral hepatitis. All the information was obtained through extensive bibliographic review, including original and review articles and consultations on the internet. There are reports on outbreaks of jaundice epidemics in China 5,000 years ago and in Babylon more than 2,500 years ago. The catastrophic history of great jaundice epidemics and pandemics is well known and generally associated with major wars. In the American Civil War, 40,000 cases occurred among Union troops. In 1885, an outbreak of catarrhal jaundice affected 191 workers at the Bremen shipyard (Germany) after vaccination against smallpox. In 1942, 28,585 soldiers became infected with hepatitis after inoculation with the yellow fever vaccine. The number of cases of hepatitis during the Second World War was estimated to be 16 million. Only in the twentieth century were the main agents causing viral hepatitis identified. The hepatitis B virus was the first to be discovered. In this paper, through reviewing the history of major epidemics caused by hepatitis viruses and the history of discovery of these agents, singular peculiarities were revealed. Examples of this include the accidental or chance discovery of the hepatitis B and D viruses.

Protein-energy malnutrition alters IgA responses to rotavirus vaccination and infection but does not impair vaccine efficacy in mice.

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Maier, Elizabeth A; Weage, Kristina J; Guedes, Marjorie M; Denson, Lee A; McNeal, Monica M; Bernstein, David I; Moore, Sean R

2013-12-17

Conflicting evidence links malnutrition to the reduced efficacy of rotavirus vaccines in developing countries, where diarrhea and undernutrition remain leading causes of child deaths. Here, we adapted mouse models of rotavirus vaccination (rhesus rotavirus, RRV), rotavirus infection (EDIM), and protein-energy malnutrition (PEM) to test the hypothesis that undernutrition reduces rotavirus vaccine immunogenicity and efficacy. We randomized wild type Balb/C dams with 3-day-old pups to a control diet (CD) or an isocaloric, multideficient regional basic diet (RBD) that produces PEM. At 3 weeks of age, we weaned CD and RBD pups to their dams' diet and subrandomized weanlings to receive a single dose of either live oral rotavirus vaccine (RRV) or PBS. At 6 weeks of age, we orally challenged all groups with murine rotavirus (EDIM). Serum and stool specimens were collected before and after RRV and EDIM administration to measure viral shedding and antibody responses by ELISA. RBD pups and weanlings exhibited significant failure to thrive compared to age-matched CD mice (Pvaccination induced higher levels of serum anti-RV IgA responses in RBD vs. CD mice (PVaccination protected CD and RBD mice equally against EDIM infection, as measured by viral shedding. In unvaccinated RBD mice, EDIM shedding peaked 1 day earlier (Pvaccination (Pvaccination mitigated stool IgA responses to EDIM more in CD vs. RBD mice (Pvaccination and infection, undernutrition does not impair rotavirus vaccine efficacy nor exacerbate infection in this mouse model of protein-energy malnutrition. Alternative models are needed to elucidate host-pathogen factors undermining rotavirus vaccine effectiveness in high-risk global settings. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Protection of macaques with diverse MHC genotypes against a heterologous SIV by vaccination with a deglycosylated live-attenuated SIV.

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Chie Sugimoto

Full Text Available HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc, following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a

Progress towards development of an HIV vaccine: report of the AIDS Vaccine 2009 Conference.

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Ross, Anna Laura; Bråve, Andreas; Scarlatti, Gabriella; Manrique, Amapola; Buonaguro, Luigi

2010-05-01

The search for an HIV/AIDS vaccine is steadily moving ahead, generating and validating new concepts in terms of novel vectors for antigen delivery and presentation, new vaccine and adjuvant strategies, alternative approaches to design HIV-1 antigens for eliciting protective cross-neutralising antibodies, and identification of key mechanisms in HIV infection and modulation of the immune system. All these different perspectives are contributing to the unprecedented challenge of developing a protective HIV-1 vaccine. The high scientific value of this massive effort is its great impact on vaccinology as a whole, providing invaluable scientific information for the current and future development of new preventive vaccine as well as therapeutic knowledge-based infectious-disease and cancer vaccines. Copyright 2010 Elsevier Ltd. All rights reserved.

Varicella and herpes zoster vaccine development: lessons learned.

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Warren-Gash, Charlotte; Forbes, Harriet; Breuer, Judith

2017-12-01

Before vaccination, varicella zoster virus (VZV), which is endemic worldwide, led to almost universal infection. This neurotropic virus persists lifelong by establishing latency in sensory ganglia, where its reactivation is controlled by VZV-specific T-cell immunity. Lifetime risk of VZV reactivation (zoster) is around 30%. Vaccine development was galvanised by the economic and societal burden of VZV, including debilitating zoster complications that largely affect older individuals. Areas covered: We describe the story of development, licensing and implementation of live attenuated vaccines against varicella and zoster. We consider the complex backdrop of VZV virology, pathogenesis and immune responses in the absence of suitable animal models and examine the changing epidemiology of VZV disease. We review the vaccines' efficacy, safety, effectiveness and coverage using evidence from trials, observational studies from large routine health datasets and clinical post-marketing surveillance studies and outline newer developments in subunit and inactivated vaccines. Expert commentary: Safe and effective, varicella and zoster vaccines have already made major inroads into reducing the burden of VZV disease globally. As these live vaccines have the potential to reactivate and cause clinical disease, developing alternatives that do not establish latency is an attractive prospect but will require better understanding of latency mechanisms.

Malnutrition and vaccination in developing countries

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Prendergast, Andrew J.

2015-01-01

Malnutrition contributes to an estimated 45% of deaths among children under 5 years of age in developing countries, predominantly due to infections. Malnourished children therefore stand to benefit hugely from vaccination, but malnutrition has been described as the most common immunodeficiency globally, suggesting that they may not be able to respond effectively to vaccines. The immunology of malnutrition remains poorly characterized, but is associated with impairments in mucosal barrier integrity, and innate and adaptive immune dysfunction. Despite this, the majority of malnourished children can mount a protective immune response following vaccination, although the timing, quality and duration of responses may be impaired. This paper reviews the evidence for vaccine immunogenicity in malnourished children, discusses the importance of vaccination in prevention of malnutrition and highlights evidence gaps in our current knowledge. PMID:25964453

Fowl adenovirus serotype 9 vectored vaccine for protection of avian influenza virus

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A fowl adenovirus serotype 9, a non-pathogenic large double stranded DNA virus, was developed as a viral vector to express influenza genes as a potential vaccine. Two separate constructs were developed that expressed either the hemagglutinin gene of A/Chicken/Jalisco/2012 (H7) or A/ Chicken/Iowa/20...

Newer Vaccines against Mosquito-borne Diseases.

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Aggarwal, Anju; Garg, Neha

2018-02-01

Mosquitos are responsible for a number of protozoal and viral diseases. Malaria, dengue, Japanese encephalitis (JE) and chikungunya epidemics occur commonly all over the world, leading to marked mortality and morbidity in children. Zika, Yellow fever and West Nile fever are others requiring prevention. Environmental control and mosquito bite prevention are useful in decreasing the burden of disease but vaccination has been found to be most cost-effective and is the need of the hour. RTS,S/AS01 vaccine is the first malaria vaccine being licensed for use against P. falciparum malaria. Dengvaxia (CYD-TDV) against dengue was licensed first in Mexico in 2015. A Vero-cell derived, inactivated and alum-adjuvanted JE vaccine based on the SA14-14-2 strain was approved in 2009 in North America, Australia and various European countries. It can be used from 2 mo of age. In India, immunization is carried out in endemic regions at 1 y of age. Another inactivated Vero-cell culture derived Kolar strain, 821564XY, JE vaccine is being used in India. Candidate vaccines against dengue, chikungunya and West Nile fever are been discussed. A continued research and development of new vaccines are required for controlling these mosquito-borne diseases.

DNA/MVA Vaccines for HIV/AIDS

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Smita S. Iyer

2014-02-01

Full Text Available Since the initial proof-of-concept studies examining the ability of antigen-encoded plasmid DNA to serve as an immunogen, DNA vaccines have evolved as a clinically safe and effective platform for priming HIV-specific cellular and humoral responses in heterologous “prime-boost” vaccination regimens. Direct injection of plasmid DNA into the muscle induces T- and B-cell responses against foreign antigens. However, the insufficient magnitude of this response has led to the development of approaches for enhancing the immunogenicity of DNA vaccines. The last two decades have seen significant progress in the DNA-based vaccine platform with optimized plasmid constructs, improved delivery methods, such as electroporation, the use of molecular adjuvants and novel strategies combining DNA with viral vectors and subunit proteins. These innovations are paving the way for the clinical application of DNA-based HIV vaccines. Here, we review preclinical studies on the DNA-prime/modified vaccinia Ankara (MVA-boost vaccine modality for HIV. There is a great deal of interest in enhancing the immunogenicity of DNA by engineering DNA vaccines to co-express immune modulatory adjuvants. Some of these adjuvants have demonstrated encouraging results in preclinical and clinical studies, and these data will be examined, as well.

Rapid host immune response and viral dynamics in herpes simplex virus-2 infection

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Schiffer, Joshua T; Corey, Lawrence

2014-01-01

Herpes Simplex Virus-2 (HSV-2) is episodically shed throughout the human genital tract. While high viral load correlates with development of genital ulcers, shedding also commonly occurs even when ulcers are not present, allowing for silent transmission during coitus and contributing to high seroprevalence of HSV-2 worldwide. Frequent viral reactivation occurs despite diverse and complementary host and viral mechanisms within ganglionic tissue that predispose towards latency, suggesting that viral replication may be constantly occurring in a small minority of neurons within the ganglia. Within genital mucosa, the in vivo expansion and clearance rates of HSV-2 are extremely rapid. Resident dendritic cells and memory HSV-specific T cells persist at prior sites of genital tract reactivation, and in conjunction with prompt innate recognition of infected cells, lead to rapid containment of infected cells. Shedding episodes vary greatly in duration and severity within a single person over time: this heterogeneity appears best explained by variation in the densities of host immunity across the genital tract. The fact that immune responses usually control viral replication in genital skin prior to development of lesions provides optimism that enhancing such responses could lead to effective vaccines and immunotherapies. PMID:23467247

A history of the development of Brucella vaccines.

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Avila-Calderón, Eric Daniel; Lopez-Merino, Ahidé; Sriranganathan, Nammalwar; Boyle, Stephen M; Contreras-Rodríguez, Araceli

2013-01-01

Brucellosis is a worldwide zoonosis affecting animal and human health. In the last several decades, much research has been performed to develop safer Brucella vaccines to control the disease mainly in animals. Till now, no effective human vaccine is available. The aim of this paper is to review and discuss the importance of methodologies used to develop Brucella vaccines in pursuing this challenge.

Viral gastroenteritis in daily pediatric practice

International Nuclear Information System (INIS)

Kracmarova, R.; Plisek, S.

2011-01-01

Diarrhoeal disease is one of the most common causes of an acute examination and hospitalisation of a child. Portion of a viral etiology of intestinal diseases is increasing in connection with an improvement of social and economical conditions. The most common viral agents are rotaviruses, caliciviruses, adenoviruses and astroviruses, but also other viruses cause an intestinal disease. The most severe clinical course is expected from the rotaviral and noroviral infection. The dehydratation, which could be less or more severe, often complicated the infection. The treatment is symptomatic. The most important role for the prevention of rotavirus disease is played by the vaccination. (author)

Regulatory T cell frequencies and phenotypes following anti-viral vaccination

NARCIS (Netherlands)

de Wolf, A Charlotte M T; van Aalst, Susan; Ludwig, Irene S; Bodinham, Caroline L; Lewis, David J; van der Zee, Ruurd; van Eden, Willem; Broere, Femke

2017-01-01

Regulatory T cells (Treg) function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays

In vitro neutralization against HoBi-like viruses by antiobodies in serum of cattle immunized with inactivated or modified live vaccines of bovine viral diarrhea virus 1 and 2

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HoBi-like viruses are an emerging species of pestiviruses with genetic and antigenic similarities to bovine viral diarrhea viruses 1 and 2 (BVDV1 and BVDV2). These viruses have been detected associated with respiratory and/or reproductive disease in cattle in Italy and Brazil. Vaccines for HoBi-like...

Dengue viral infections

OpenAIRE

Malavige, G; Fernando, S; Fernando, D; Seneviratne, S

2004-01-01

Dengue viral infections are one of the most important mosquito borne diseases in the world. They may be asymptomatic or may give rise to undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF), or dengue shock syndrome. Annually, 100 million cases of dengue fever and half a million cases of DHF occur worldwide. Ninety percent of DHF subjects are children less than 15 years of age. At present, dengue is endemic in 112 countries in the world. No vaccine is available for preventing...

Role of viral coinfections in asthma development.

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Maria Luz Garcia-Garcia

Full Text Available Viral respiratory infections, especially acute bronchiolitis, play a key role in the development of asthma in childhood. However, most studies have focused on respiratory syncytial virus or rhinovirus infections and none of them have compared the long-term evolution of single versus double or multiple viral infections.Our aim was to compare the frequency of asthma development at 6-8 years in children with previous admission for bronchiolitis associated with single versus double or multiple viral infection.A cross-sectional study was performed in 244 children currently aged 6-8 years, previously admitted due to bronchiolitis between September 2008 and December 2011. A structured clinical interview and the ISAAC questionnaire for asthma symptoms for 6-7-year-old children, were answered by parents by telephone. Specimens of nasopharyngeal aspirate for virological study (polymerase chain reaction and clinical data were prospectively taken during admission for bronchiolitis.Median current age at follow-up was 7.3 years (IQR: 6.7-8.1. The rate of recurrent wheezing was 82.7% in the coinfection group and 69.7% in the single-infection group, p = 0.06. The number of wheezing-related admissions was twice as high in coinfections than in single infections, p = 0.004. Regarding the ISAAC questionnaire, 30.8% of coinfections versus 15% of single infections, p = 0.01, presented "wheezing in the last 12 months", data that strongly correlate with current prevalence of asthma. "Dry cough at night" was also reported more frequently in coinfections than in single infections, p = 0.02. The strongest independent risk factors for asthma at 6-8 years of age were: age > 9 months at admission for bronchiolitis (OR: 3.484; CI95%: 1.459-8.317, p:0.005, allergic rhinitis (OR: 5.910; 95%CI: 2.622-13.318, p<0.001, and viral coinfection-bronchiolitis (OR: 3.374; CI95%: 1.542-7.386, p:0.01.Asthma at 6-8 years is more frequent and severe in those children previously hospitalized

Cervical screening in HPV-vaccinated populations.

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Canfell, K

2018-06-01

Cervical screening with cytology has been the basis for substantial reductions in cervical cancer incidence and mortality in most high-income countries over the last few decades. More recently, there have been two key, parallel developments which have prompted a major re-consideration of cervical screening. The first is the emergence of evidence on the improved sensitivity of human papillomavirus (HPV) DNA testing compared to cytology, and the second is the large-scale deployment of prophylactic vaccination against HPV. A key challenge to be overcome before HPV screening could be introduced into national cervical screening programs was the specificity of an infection, for detection of precancerous lesions. This has been done in three ways: (1) by considering the appropriate age for starting HPV screening (30 years in unvaccinated populations and 25 years in populations with mature vaccination programs and high vaccine uptake) and the appropriate screening interval; (2) via development of clinical HPV tests, which are (by design) not as sensitive to low viral loads; and (3) by introducing effective triaging for HPV-positive women, which further risk-stratifies women before referral for diagnostic evaluation. This review discusses these major developments and describes how the benefits of HPV screening are being optimized in both unvaccinated and vaccinated populations.

Plant-made vaccine antigens and biopharmaceuticals.

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Daniell, Henry; Singh, Nameirakpam D; Mason, Hugh; Streatfield, Stephen J

2009-12-01

Plant cells are ideal bioreactors for the production and oral delivery of vaccines and biopharmaceuticals, eliminating the need for expensive fermentation, purification, cold storage, transportation and sterile delivery. Plant-made vaccines have been developed for two decades but none has advanced beyond Phase I. However, two plant-made biopharmaceuticals are now advancing through Phase II and Phase III human clinical trials. In this review, we evaluate the advantages and disadvantages of different plant expression systems (stable nuclear and chloroplast or transient viral) and their current limitations or challenges. We provide suggestions for advancing this valuable concept for clinical applications and conclude that greater research emphasis is needed on large-scale production, purification, functional characterization, oral delivery and preclinical evaluation.

A History of the Development of Brucella Vaccines

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Eric Daniel Avila-Calderón

2013-01-01

Full Text Available Brucellosis is a worldwide zoonosis affecting animal and human health. In the last several decades, much research has been performed to develop safer Brucella vaccines to control the disease mainly in animals. Till now, no effective human vaccine is available. The aim of this paper is to review and discuss the importance of methodologies used to develop Brucella vaccines in pursuing this challenge.

The development of flavivirus vaccines | Pulmanausahakul | African ...

African Journals Online (AJOL)

Vaccine development to eliminate flaviviral infections has been marked by uneven progress and a large number of setbacks. To date, no single approach has proved successful in leading to vaccine development against a wide range of flaviviruses, but the application of modern techniques to the problem is opening up new ...

Guiding dengue vaccine development using knowledge gained from the success of the yellow fever vaccine.

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Liang, Huabin; Lee, Min; Jin, Xia

2016-01-01

Flaviviruses comprise approximately 70 closely related RNA viruses. These include several mosquito-borne pathogens, such as yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), which can cause significant human diseases and thus are of great medical importance. Vaccines against both YFV and JEV have been used successfully in humans for decades; however, the development of a DENV vaccine has encountered considerable obstacles. Here, we review the protective immune responses elicited by the vaccine against YFV to provide some insights into the development of a protective DENV vaccine.

Constrained pattern of viral evolution in acute and early HCV infection limits viral plasticity.

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Katja Pfafferott

2011-02-01

Full Text Available Cellular immune responses during acute Hepatitis C virus (HCV and HIV infection are a known correlate of infection outcome. Viral adaptation to these responses via mutation(s within CD8+ T-cell epitopes allows these viruses to subvert host immune control. This study examined HCV evolution in 21 HCV genotype 1-infected subjects to characterise the level of viral adaptation during acute and early HCV infection. Of the total mutations observed 25% were within described CD8+ T-cell epitopes or at viral adaptation sites. Most mutations were maintained into the chronic phase of HCV infection (75%. The lack of reversion of adaptations and high proportion of silent substitutions suggests that HCV has structural and functional limitations that constrain evolution. These results were compared to the pattern of viral evolution observed in 98 subjects during a similar phase in HIV infection from a previous study. In contrast to HCV, evolution during acute HIV infection is marked by high levels of amino acid change relative to silent substitutions, including a higher proportion of adaptations, likely reflecting strong and continued CD8+ T-cell pressure combined with greater plasticity of the virus. Understanding viral escape dynamics for these two viruses is important for effective T cell vaccine design.

Establishing Correlates of Protection for Vaccine Development: Considerations for the Respiratory Syncytial Virus Vaccine Field.

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Kulkarni, Prasad S; Hurwitz, Julia L; Simões, Eric A F; Piedra, Pedro A

2018-03-01

Correlates of protection (CoPs) can play a significant role in vaccine development by assisting the selection of vaccine candidates for clinical trials, supporting clinical trial design and implementation, and simplifying tests of vaccine modifications. Because of this important role in vaccine development, it is essential that CoPs be defined by well-designed immunogenicity and efficacy studies, with attention paid to benefits and limitations. The respiratory syncytial virus (RSV) field is unique in that a great deal of information about the humoral response is available from basic research and clinical studies. Polyclonal and monoclonal antibodies have been used routinely in the clinic to protect vulnerable infants from infection, providing a wealth of information about correlations between neutralizing antibodies and disease prevention. Considerations for the establishment of future CoPs to support RSV vaccine development in different populations are therefore discussed.

[Respiratory viral infections in a cohort of children during the first year of life and their role in the development of wheezing].

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Calvo, Cristina; Aguado, Isabel; García-García, María Luz; Ruiz-Chercoles, Esther; Díaz-Martinez, Eloisa; Albañil, Rosa María; Campelo, Olga; Olivas, Antonio; Muñóz-Gonzalez, Luisa; Pozo, Francisco; Fernandez-Arroyo, Rosa; Fernandez-Rincón, Adelaida; Calderon, Ana; Casas, Inmaculada

2017-08-01

It is known that infants with viral respiratory infections severe enough to require hospital admission have a high risk of developing recurrent wheezing. Few data have been published on unselected populations. The main aim of this study was to analyse symptomatic and asymptomatic respiratory viral infections during the first year of life in a cohort of infants, recruited at birth, and the development of recurrent wheezing. A total of 302 newborns were recruited. A nasopharyngeal aspirate was taken when the patients had a respiratory infection, as well as in the visits for vaccination at 2, 4, 6, and 12 months. RT-nested PCR assays were performed to detect 16 viruses. A total of 1,293 samples were analysed (1,005 healthy controls and 288 respiratory infections). Samples taken during routine check-ups were positive in 30.8% of cases, while those with respiratory infection were positive in 77.8%, P<.001 (OR: 3, 95% CI: 2.4-3.8). A total of 239 (79%) infants had at least 1 positive respiratory viral infection detected. The most frequent virus (71%) was rhinovirus (RV). Recurrent wheezing was found in 27 (11%) children during their first year of life (1.2 episodes, SD 2.9). Recurrent wheezing was present in 58.3% of patients admitted to hospital during their first viral infection, vs. 8.6% of infants when the first infection was mild or who had asymptomatic viral detection, P<.001 (OR: 2.18; 95% CI: 1.05-4.5). In our series, severe respiratory infections leading to hospitalisation in the first months of life are risk factors for developing wheezing, but not in the case of mild RV infections. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

The yellow fever 17D virus as a platform for new live attenuated vaccines.

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Bonaldo, Myrna C; Sequeira, Patrícia C; Galler, Ricardo

2014-01-01

The live-attenuated yellow fever 17D virus is one of the most outstanding human vaccines ever developed. It induces efficacious immune responses at a low production cost with a well-established manufacture process. These advantages make the YF17D virus attractive as a vector for the development of new vaccines. At the beginning of vector development studies, YF17D was genetically manipulated to express other flavivirus prM and E proteins, components of the viral envelope. While these 17D recombinants are based on the substitution of equivalent YF17D genes, other antigens from unrelated pathogens have also been successfully expressed and delivered by recombinant YF17D viruses employing alternative strategies for genetic manipulation of the YF17D genome. Herein, we discuss these strategies in terms of possibilities of single epitope or larger sequence expression and the main properties of these replication-competent viral platforms.

Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge.

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Junji Sashihara

2011-10-01

Full Text Available Epstein-Barr virus (EBV is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350 or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]. No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a soluble rhesus LCV gp350, (b virus-like replicon particles (VRPs expressing rhesus LCV gp350, (c VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with

DIVA vaccine properties of the live chimeric pestivirus strain CP7_E2gif.

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von Rosen, Tanya; Rangelova, Desislava; Nielsen, Jens; Rasmussen, Thomas Bruun; Uttenthal, Åse

2014-06-04

Live modified vaccines to protect against classical swine fever virus (CSFV), based on chimeric pestiviruses, have been developed to enable serological Differentiation of Infected from Vaccinated Animals (DIVA). In this context, the chimeric virus CP7_E2gif vaccine candidate is unique as it does not include any CSFV components. In the present study, the DIVA vaccine properties of CP7_E2gif were evaluated in comparison to the conventional live attenuated Riemser C-strain vaccine. Sera and tonsil samples obtained from pigs immunised with these two vaccines were analysed. No viral RNA was found in serum after vaccination with CP7_E2gif, whereas some serum samples from C-strain vaccinated animals were positive. In both vaccinated groups, individual viral RNA-positive tonsil samples were detected in animals euthanised between 7 and 21 days post vaccination. Furthermore, serum samples from these animals, together with archival samples from pigs vaccinated with CP7_E2gif and subsequently CSFV challenged, were analysed for specific antibodies using ELISAs and for homologous neutralising antibodies. In animals vaccinated with CP7_E2gif, neutralising antibodies were detected from day 10. However, the sera remained negative for anti-CSFV E2-specific antibodies whereas pigs vaccinated with C-strain seroconverted against CSFV by 14 days after vaccination, as determined by a CSFV-E2 specific blocking ELISA. One week after subsequent CSFV challenge, a strong anti-CSFV E2 reaction was detected in CP7_E2gif vaccinated pigs and anti-E(rns) antibodies were detected from 10 days after infection. In conclusion, CP7_E2gif has the potential to be used as a DIVA vaccine in combination with detection of anti-CSFV E2-specific antibodies. Copyright © 2014 Elsevier B.V. All rights reserved.

Can VHS virus bypass the protective immunity induced by DNA vaccination in rainbow trout?

DEFF Research Database (Denmark)

Sepúlveda, Dagoberto; Lorenzen, Niels

2016-01-01

DNA vaccines encoding viral glycoproteins have been very successful for induction of protective immunity against diseases caused by rhabdoviruses in cultured fish species. However, the vaccine concept is based on a single viral gene and since RNA viruses are known to possess high variability...... and adaptation capacity, this work aimed at evaluating whether viral haemorrhagic septicaemia virus (VHSV), an RNA virus and member of Rhabdoviridae family, was able to evade the protective immune response induced by the DNA vaccination of rainbow trout. The experiments comprised repeated passages of a highly...... pathogenic VHSV isolate in a fish cell line in the presence of neutralizing fish serum (in vitro approach), and in rainbow trout immunized with the VHS DNA vaccine (in vivo approach). For the in vitro approach, the virus collected from the last passage (passaged virus) was as sensitive as the parental virus...

Malaria Vaccine Development: The Need for Novel Approach-es: A Review Article

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Shima MAHMOUDI

2018-03-01

Full Text Available Background: Although rigorous efforts have substantially decreased the malaria burden through decades, it still threatens the lives of millions of children. Development of an effective vaccine can provide important approach in malaria control strategies. Unfortunately, development of an effective vaccine for falciparum malaria has been hindered by the extreme complexity of malaria parasite biology, complex and diverse parasite genomes, and immune evasion by the parasites as well as the intricate nature of the parasites infection cycle. The aim of this review was to discuss the different approaches to malaria vaccine development until now.Methods: Scientific databases, including MEDLINE (via PubMed and SCOPUS were searched up to 30 Jan 2017 and the articles regarding malaria vaccine development were taken into examination.Results: Several strategies for malaria vaccine development including pre-erythrocytic vaccines, antibody-based subunit vaccines, vectored vaccines, whole sporozoite vaccines, genetically Attenuated parasites and sporozoite subunit vaccine, erythrocytic vaccines, sexual stage vaccine, transmission-blocking vaccine as well as synthetic peptides and conjugate vaccine has been introduced. However, the success has been limited thus far.Conclusion: Although development of malaria vaccine over the past 70 year has been continued, the discovery, development, and licensing of a malaria vaccine formulation, which meets safety, affordability, accessibility, applicability, and efficacy has not yet been achieved.

Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease

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Xiao-Xin Wu

2015-11-01

Full Text Available Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD in humans and non-human primates (NHPs. Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs, vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirus∆VP30, recombinant cytomegalovirus (CMV-based vaccines, recombinant rabies virus (RABV-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD.

Current status, challenges and perspectives in the development of vaccines against yellow fever, dengue, Zika and chikungunya viruses.

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Silva, José V J; Lopes, Thaísa R R; Oliveira-Filho, Edmilson F de; Oliveira, Renato A S; Durães-Carvalho, Ricardo; Gil, Laura H V G

2018-06-01

Emerging and re-emerging viral infections transmitted by insect vectors (arthopode-borne viruses, arbovirus) are a serious threat to global public health. Among them, yellow fever (YFV), dengue (DENV), chikungunya (CHIKV) and Zika (ZIKV) viruses are particularly important in tropical and subtropical regions. Although vector control is one of the most used prophylactic measures against arboviruses, it often faces obstacles, such as vector diversity, uncontrolled urbanization and increasing resistance to insecticides. In this context, vaccines may be the best control strategy for arboviral diseases. Here, we provide a general overview about licensed vaccines and the most advanced vaccine candidates against YFV, DENV, CHIKV and ZIKV. In particular, we highlight vaccine difficulties, the current status of the most advanced strategies and discuss how the molecular characteristics of each virus can influence the choice of the different vaccine formulations. Copyright © 2018 Elsevier B.V. All rights reserved.

Topical herpes simplex virus 2 (HSV-2) vaccination with human papillomavirus vectors expressing gB/gD ectodomains induces genital-tissue-resident memory CD8+ T cells and reduces genital disease and viral shedding after HSV-2 challenge.

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Çuburu, Nicolas; Wang, Kening; Goodman, Kyle N; Pang, Yuk Ying; Thompson, Cynthia D; Lowy, Douglas R; Cohen, Jeffrey I; Schiller, John T

2015-01-01

No herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8(+) T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8(+) T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection. Genital herpes is a highly prevalent chronic disease caused by

Deep insight into white spot syndrome virus vaccines: A review

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MA Badhul Haq

2012-02-01

Full Text Available White spot syndrome virus (WSSV, the causative virus of the disease, is found in most shrimp farming areas of the world, where it causes large economic losses to the shrimp farming industry. The potentially fatal virus has been found to be a threat not only to all shrimp species, but also to other marine and freshwater crustaceans, such as crab and crayfish. To date, no effective prophylactic treatment measures are available for viral infections in shrimp and other crustaceans. Due to current aquaculture practices and the broad host range of WSSV, intervention strategies including vaccination against this virus would be pivotal to save and protect shrimp farming. Several achievements have been attained in the search of novel vaccines for WSSV. DNA vaccination, recombinant vaccines, oral vaccination techniques and gene therapy are some of the thrust areas of focus for scientists and researchers. This review article highlights the recent trends in the development of WSSV vaccines either as DNA vaccines or recombinant vaccines and their functioning strategies as suggested by the researchers worldwide.

An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants.

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Rose, N F; Marx, P A; Luckay, A; Nixon, D F; Moretto, W J; Donahoe, S M; Montefiori, D; Roberts, A; Buonocore, L; Rose, J K

2001-09-07

We developed an AIDS vaccine based on attenuated VSV vectors expressing env and gag genes and tested it in rhesus monkeys. Boosting was accomplished using vectors with glycoproteins from different VSV serotypes. Animals were challenged with a pathogenic AIDS virus (SHIV89.6P). Control monkeys showed a severe loss of CD4+ T cells and high viral loads, and 7/8 progressed to AIDS with an average time of 148 days. All seven vaccinees were initially infected with SHIV89.6P but have remained healthy for up to 14 months after challenge with low or undetectable viral loads. Protection from AIDS was highly significant (p = 0.001). VSV vectors are promising candidates for human AIDS vaccine trials because they propagate to high titers and can be delivered without injection.

The effect of vaccination on the evolution and population dynamics of avian paramyxovirus-1.

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Yee Ling Chong

2010-04-01

Full Text Available Newcastle Disease Virus (NDV is a pathogenic strain of avian paramyxovirus (aPMV-1 that is among the most serious of disease threats to the poultry industry worldwide. Viral diversity is high in aPMV-1; eight genotypes are recognized based on phylogenetic reconstruction of gene sequences. Modified live vaccines have been developed to decrease the economic losses caused by this virus. Vaccines derived from avirulent genotype II strains were developed in the 1950s and are in use globally, whereas Australian strains belonging to genotype I were developed as vaccines in the 1970s and are used mainly in Asia. In this study, we evaluated the consequences of attenuated live virus vaccination on the evolution of aPMV-1 genotypes. There was phylogenetic incongruence among trees based on individual genes and complete coding region of 54 full length aPMV-1 genomes, suggesting that recombinant sequences were present in the data set. Subsequently, five recombinant genomes were identified, four of which contained sequences from either genotype I or II. The population history of vaccine-related genotype II strains was distinct from other aPMV-1 genotypes; genotype II emerged in the late 19(th century and is evolving more slowly than other genotypes, which emerged in the 1960s. Despite vaccination efforts, genotype II viruses have experienced constant population growth to the present. In contrast, other contemporary genotypes showed population declines in the late 1990s. Additionally, genotype I and II viruses, which are circulating in the presence of homotypic vaccine pressure, have unique selection profiles compared to nonvaccine-related strains. Collectively, these data show that vaccination with live attenuated viruses has changed the evolution of aPMV-1 by maintaining a large effective population size of a vaccine-related genotype, allowing for coinfection and recombination of vaccine and wild type strains, and by applying unique selective pressures on

Development of Burkholderia mallei and pseudomallei vaccines

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Silva, Ediane B.; Dow, Steven W.

2013-01-01

Burkholderia mallei and Burkholderia pseudomallei are Gram-negative bacteria that cause glanders and melioidosis, respectively. Inhalational infection with either organism can result in severe and rapidly fatal pneumonia. Inoculation by the oral and cutaneous routes can also produce infection. Chronic infection may develop after recovery from acute infection with both agents, and control of infection with antibiotics requires prolonged treatment. Symptoms for both meliodosis and glanders are non-specific, making diagnosis difficult. B. pseudomallei can be located in the environment, but in the host, B. mallei and B. psedomallei are intracellular organisms, and infection results in similar immune responses to both agents. Effective early innate immune responses are critical to controlling the early phase of the infection. Innate immune signaling molecules such as TLR, NOD, MyD88, and pro-inflammatory cytokines such as IFN-γ and TNF-α play key roles in regulating control of infection. Neutrophils and monocytes are critical cells in the early infection for both microorganisms. Both monocytes and macrophages are necessary for limiting dissemination of B. pseudomallei. In contrast, the role of adaptive immune responses in controlling Burkholderia infection is less well understood. However, T cell responses are critical for vaccine protection from Burkholderia infection. At present, effective vaccines for prevention of glanders or meliodosis have not been developed, although recently development of Burkholderia vaccines has received renewed attention. This review will summarize current and past approaches to develop B. mallei and B. pseudomalllei vaccines, with emphasis on immune mechanisms of protection and the challenges facing the field. At present, immunization with live attenuated bacteria provides the most effective and durable immunity, and it is important therefore to understand the immune correlates of protection induced by live attenuated vaccines. Subunit

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery.

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Bahadoran, Azadeh; Moeini, Hassan; Bejo, Mohd Hair; Hussein, Mohd Zobir; Omar, Abdul Rahman

In order to enhance cellular uptake and to facilitate transdermal delivery of DNA vaccine, polyamidoamine (PAMAM) dendrimers conjugated with HIV transactivator of transcription (TAT) was developed. First, the plasmid DNA (pIRES-H5/GFP) nanoparticle was formulated using PAMAM dendrimer and TAT peptide and then characterized for surface charge, particle size, DNA encapsulation and protection of the pIRES-H5/GFP DNA plasmid to enzymatic digestion. Subsequently, the potency of the TAT-conjugated dendrimer for gene delivery was evaluated through in vitro transfection into Vero cells followed by gene expression analysis including western blotting, fluorescent microscopy and PCR. The effect of the TAT peptide on cellular uptake of DNA vaccine was studied by qRT-PCR and flow cytometry. Finally, the ability of TAT-conjugated PAMAM dendrimer for transdermal delivery of the DNA plasmid was assessed through artificial membranes followed by qRT-PCR and flow cytometry. TAT-conjugated PAMAM dendrimer showed the ability to form a compact and nanometre-sized polyplexes with the plasmid DNA, having the size range of 105 to 115 nm and a positive charge of +42 to +45 mV over the N/P ratio of 6:1(+/-).  In vitro transfection analysis into Vero cells confirms the high potency of TAT-conjugated PAMAM dendrimer to enhance the cellular uptake of DNA vaccine.  The permeability value assay through artificial membranes reveals that TAT-conjugated PAMAM has more capacity for transdermal delivery of the DNA compared to unmodified PAMAM dendrimer (Pdendrimer is a promising non-viral vector for transdermal use.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Envelope exchange for the generation of live-attenuated arenavirus vaccines.

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Andreas Bergthaler

2006-06-01

Full Text Available Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.

Envelope Exchange for the Generation of Live-Attenuated Arenavirus Vaccines.

Directory of Open Access Journals (Sweden)

2006-06-01

Full Text Available Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.

Characterization of foot-and-mouth disease virus's viral peptides with LC-ESI-MS

International Nuclear Information System (INIS)

Pzdemir, Z.O.; Bulut, E.K.; Mustafeva, Z.; Karahan, M.

2010-01-01

Peptides and proteins play a central role in numerous biological and physiological processes in living organisms. Viral capsid peptides are part of the viruses' outer shell of genetic materials. Viruses are recognized by immune system via capsid peptides. Depending on this property of capsid peptides, prototypes synthetic peptide-based vaccine can be developed. In this work, we synthesized three different viral peptide sequences of foot-and-mouth disease virus with microwave enhanced solid phase synthesis method. These peptides were characterized by using liquid chromatography electro spray interface mass spectrometry (LC-ESI-MS) with electro spray ionization. We briefly describe the essential facts for peptide characterization. (author)

Development of a Vaccine for Eradicating Contagious Bovine ...

International Development Research Centre (IDRC) Digital Library (Canada)

Since eventual success depends on the vaccine's acceptability by livestock keepers, the project involves them in field-testing and assesses their willingness to pay for the vaccine. The project also ... Outputs. Studies. Developing vaccines for animals, the case of Contagious Bovine Pleuropneumonia (CBPP) in Africa. 53232.

Nucleic acid-based vaccines targeting respiratory syncytial virus: Delivering the goods.

Science.gov (United States)

Smith, Trevor R F; Schultheis, Katherine; Broderick, Kate E

2017-11-02

Respiratory syncytial virus (RSV) is a massive medical burden on a global scale. Infants, children and the elderly represent the vulnerable populations. Currently there is no approved vaccine to protect against the disease. Vaccine development has been hindered by several factors including vaccine enhanced disease (VED) associated with formalin-inactivated RSV vaccines, inability of target populations to raise protective immune responses after vaccination or natural viral infection, and a lack of consensus concerning the most appropriate virus-associated target antigen. However, with recent advances in the molecular understanding of the virus, and design of highly characterized vaccines with enhanced immunogenicity there is new belief a RSV vaccine is possible. One promising approach is nucleic acid-based vaccinology. Both DNA and mRNA RSV vaccines are showing promising results in clinically relevant animal models, supporting their transition into humans. Here we will discuss this strategy to target RSV, and the ongoing studies to advance the nucleic acid vaccine platform as a viable option to protect vulnerable populations from this important disease.

Is a multivalent hand, foot, and mouth disease vaccine feasible?

Science.gov (United States)

Klein, Michel; Chong, Pele

2015-01-01

Enterovirus A infections are the primary cause of hand, foot and mouth disease (HFMD) in infants and young children. Although enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are the predominant causes of HFMD epidemics worldwide, EV-A71 has emerged as a major neurovirulent virus responsible for severe neurological complications and fatal outcomes. HFMD is a serious health threat and economic burden across the Asia-Pacific region. Inactivated EV-A71 vaccines have elicited protection against EV-A71 but not against CV-A16 infections in large efficacy trials. The current development of a bivalent inactivated EV-A71/CV-A16 vaccine is the next step toward that of multivalent HFMD vaccines. These vaccines should ultimately include other prevalent pathogenic coxsackieviruses A (CV-A6 and CV-A10), coxsackieviruses B (B3 and B5) and echovirus 30 that often co-circulate during HFMD epidemics and can cause severe HFMD, aseptic meningitis and acute viral myocarditis. The prospect and challenges for the development of such multivalent vaccines are discussed. PMID:26009802

Status of vaccine research and development for Shigella.

Science.gov (United States)

Mani, Sachin; Wierzba, Thomas; Walker, Richard I

2016-06-03

Shigella are gram-negative bacteria that cause severe diarrhea and dysentery. In 2013, Shigella infections caused an estimated 34,400 deaths in children less than five years old and, in 2010, an estimated 40,000 deaths in persons older than five years globally. New disease burden estimates from newly deployed molecular diagnostic assays with increased sensitivity suggest that Shigella-associated morbidity may be much greater than previous disease estimates from culture-based methods. Primary prevention of this disease should be based on universal provision of potable water and sanitation methods and improved personal and food hygiene. However, an efficacious and low-cost vaccine would complement and accelerate disease reduction while waiting for universal access to water, sanitation, and hygiene improvements. This review article provides a landscape of Shigella vaccine development efforts. No vaccine is yet available, but human and animal challenge-rechallenge trials with virulent Shigella as well as observational studies in Shigella-endemic areas have shown that the incidence of disease decreases following Shigella infection, pointing to biological feasibility of a vaccine. Immunity to Shigella appears to be strain-specific, so a vaccine that covers the most commonly detected strains (i.e., S. flexneri 2a, 3a, 6, and S. sonnei) or a vaccine using cross-species conserved antigens would likely be most effective. Vaccine development and testing may be accelerated by use of animal models, such as the guinea pig keratoconjunctivitis or murine pneumonia models. Because there is no correlate of protection, however, human studies will be necessary to evaluate vaccine efficacy prior to deployment. A diversity of Shigella vaccine constructs are under development, including live attenuated, formalin-killed whole-cell, glycoconjugate, subunit, and novel antigen vaccines (e.g., Type III secretion system and outer membrane proteins). Copyright © 2016 World Health Organization

A Functional Food Mixture “Protector” Reinforces the Protective Immune Parameters against Viral Flu Infection in Mice

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Kenza A. Mansoor

2018-06-01

Full Text Available Background: Viral influenza infection causes serious health issues especially when an outbreak occurs. Although influenza virus vaccines are available and each year manufactures modify the vaccine depending on the expected mutated strain, it is still far from satisfactory, mainly in young children and older adults. Therefore, a product that can support and shape the immune system to protect against viral flu infections is highly essential. Methods: A functional food water-soluble mixture of pomegranate, red grape, dates, olive fruit, figs, and ginger extracts, termed herein “Protector”, was prepared and tested in stimulating/modulating the production of specific cytokines, and hemagglutinin inhibition (HAI antibodies following viral flu vaccination in mice. Results: A single intraperitoneal or multiple oral administration for 1–7 days of “Protector” significantly increased the production of interferon (IFN-γ and interleukin (IL-12 in blood, spleen, and lungs of mice. When “Protector” was orally administered for one week following a single vaccine injection (primary immunization or for two weeks (one week apart following double vaccine injections (secondary immunization, mice significantly produced higher titers of HAI antibodies. This increase in HAI antibodies was associated with Pillow-inducing significant and different changes in vaccine-induced IFN-γ, IL-12, IL-6 and IL-22 following primary and secondary immunizations. Conclusions: “Protector” administration reinforces the protective immune parameters against viral flu infection. Therefore, after performing preclinical toxicology studies and ensuring its safety, “Protector” should be considered a potential product to be tested in clinical trials to conclude its efficacy in reducing the devastating effects of flu infection in humans and its outbreaks.