WorldWideScience

Sample records for malaria vaccine design

  1. Potency assay design for adjuvanted recombinant proteins as malaria vaccines.

    Science.gov (United States)

    Giersing, Birgitte K; Dubovsky, Filip; Saul, Allan; Denamur, Francoise; Minor, Philip; Meade, Bruce

    2006-05-15

    Many licensed vaccines are composed of live, attenuated or inactivated whole-cell microorganisms, or they comprise purified components from whole-cell extracts or culture supernatants. For some diseases, pathology is fairly well understood, and there may be known correlates of protection that provide obvious parameters for assessment of vaccine potency. However, this is not always the case, and some effective vaccines are routinely used even though the mechanisms or correlates of protection are unknown. Some more modern vaccine approaches employ purified recombinant proteins, based on molecules that appear on the surface of the pathogen. This is one of the strategies that has been adopted in the quest to develop a malaria vaccine. Use of these parasite antigens as vaccine candidates is supported by substantial epidemiological data, and some have demonstrated the ability to elicit protective responses in animal models of malaria infection. However, there is as yet no immunological correlate of protection and no functional assays or animal models that have demonstrated the ability to predict efficacy in humans. There is little precedence for the most appropriate and practical method for assessing potency of vaccines based on these recombinant molecules for malaria vaccines. This is likely because the majority of malaria vaccine candidates have only recently entered clinical evaluation. The PATH Malaria Vaccine Initiative (MVI) convened a panel with expertise in potency assay design from industry, governmental institutions, and regulatory bodies to discuss and review the rationale, available methods, and best approaches for assessing the potency of recombinant proteins, specifically for their use as malarial vaccines. The aim of this meeting was to produce a discussion document on the practical potency assessment of recombinant protein malaria vaccines, focusing on early phase potency assay development.

  2. Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design.

    Science.gov (United States)

    Flanagan, Katie L; Wilson, Kirsty L; Plebanski, Magdalena

    2016-01-01

    The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes.

  3. MALARIA VACCINE: MYTH OR REALITY?

    African Journals Online (AJOL)

    Femi Olaleye

    Malaria currently remains the highest killer disease nationwide despite existing control measures. Malaria vaccine ... that malaria could be eliminated or at least controlled. However, because of changes in vector behaviour, drug resistance, manpower constraints for public ..... Although animal host models are different from ...

  4. A research agenda for malaria eradication: vaccines.

    NARCIS (Netherlands)

    Abdulla, S.; Agre, P.; Alonso, P.L.; Arevalo-Herrera, M.; Bassat, Q.; Binka, F.; Chitnis, C.; Corradin, G.; Cowman, A. F.; Culpepper, J.; Portillo, H. del; Dinglasan, R.R.; Duffy, P.; Gargallo, D.; Greenwood, B.; Guinovart, C.; Hall, B.F.; Herrera, S.; Hoffman, S.; Lanzavecchia, A.; Leroy, O.; Levine, M.M.; Loucq, C.; Mendis, K.; Milman, J.; Moorthy, V.S.; Pleuschke, G.; Plowe, C.V.; Reed, S.; Sauerwein, R.W.; Saul, A.; Schofield, L.; Sinden, R.R.; Stubbs, J.; Villafana, T.; Wirth, D.; Yadav, P.; Ballou, R.; Brown, G.; Birkett, A.; Brandt, W.; Brooks, A.; Carter, T.; Golden, A.; Lee, C.; Nunes, J.; Puijalon, O.; Raphael, T.; Richards, H.; Warren, C.; Woods, C.

    2011-01-01

    Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if

  5. Advances and challenges in malaria vaccine development.

    Science.gov (United States)

    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.

  6. Towards A Malaria Vaccine?

    Directory of Open Access Journals (Sweden)

    B S GARG

    1990-12-01

    Full Text Available The last few years have seen a marked change in the understanding of malaria mmunology.We have very little knowledge on immunity of Malaria based on experiments in humanbeings due to ethical reasons. Whatsoever our knowledge exists at present is based onexperimentas in mice and monkey. However it is clear that it is sporzoite or merozoitewhich is directly exposed to our immune system in the life cycle of Malaria parasite. On thebasis of human experiments we can draw inference that immunity to malaria is species.specific (on cross immunity, stage specific and strain specific as well acquired in the response to surface antigen and relapsed antigen although the parasite also demonstrates escape machanism to immune system.So the host system kills or elimi nate the parasite by means of (a Antbody to extracell~ular form of parasite with the help of mechanism of Block invasion, Agglutination or opsonization and/or (b Cellular machanism-either by phago-cytosis of parasite or by antibody dependent cellular cytotoxicity ABCC (? or by effects of mediators like tumor necrosis fJ.ctor (TNF in cerebaral malaria or crisis forming factor as found in sudan or by possible role of lysis mechanism.However, inspite of all these theories the parasite has been able to invade the immunesystem by virtue of its intracellular development stage specificity, sequestration in capillaries and also by its unusual characteristics of antigenic diversity and antigenic variation.

  7. Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

    Science.gov (United States)

    Carey, John B.; Pearson, Frances E.; Vrdoljak, Anto; McGrath, Marie G.; Crean, Abina M.; Walsh, Patrick T.; Doody, Timothy; O'Mahony, Conor; Hill, Adrian V. S.; Moore, Anne C.

    2011-01-01

    Background Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8+ T cell responses to a malaria antigen induced by a live vaccine. Methodology and Findings Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. Conclusions/Significance This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction

  8. Microneedle array design determines the induction of protective memory CD8+ T cell responses induced by a recombinant live malaria vaccine in mice.

    Directory of Open Access Journals (Sweden)

    John B Carey

    Full Text Available Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC, must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8(+ T cell responses to a malaria antigen induced by a live vaccine.Recombinant modified vaccinia virus Ankara (MVA expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes.This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8(+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids

  9. Malaria vaccines: immunity, models and monoclonal antibodies

    DEFF Research Database (Denmark)

    Hviid, Lars; Barfod, Lea

    2008-01-01

    Although experts in the field have agreed on the malaria vaccine technology roadmap that should be followed (http://www.malariavaccineroadmap.net/), the path towards an effective malaria vaccine remains littered with intellectual and practical pot-holes. The animal models that are currently...

  10. Important advances in malaria vaccine research

    Directory of Open Access Journals (Sweden)

    Priyanka Jadhav

    2012-01-01

    Full Text Available Malaria is one of the most widespread parasitic infection in Asian countries affecting the poor of the poor. In an effort to develop an effective vaccine for the treatment of malaria, various attempts are being made worldwide. If successful, such a vaccine can be effective for treatment of both Plasmodium vivax and Plasmodium falciparum. This would also be able to avoid complications such as drug resistance, resistance to insecticides, nonadherence to the treatment schedule, and eventually high cost of treatment in the resource-limited settings. In the current compilation, the details from the literature were collected by using PubMed and Medline as search engines and searched for terms such as malaria, vaccine, and malaria treatment. This review collates and provides glimpses of the information on the recent malaria vaccine development. The reader will be taken through the historical perspective followed by the approaches to the malaria vaccine development from pre-erythrocytic stage vaccines, asexual stage vaccines, transmission blocking vaccines, etc. Looking at the current scenario of the malaria and treatment strategies, it is an absolute need of an hour that an effective malaria vaccine should be developed. This would bring a revolutionary breakthrough in the treatment modalities especially when there is increasing emergence of resistance to existing drug therapy. It would be of great purpose to serve those living in malaria endemic region and also for travelers which are nonimmune and coming to malaria endemic region. As infection by P. vivax is more prevalent in India and other Asian subcontinent and is often prominent in areas where elimination is being attempted, special consideration is required of the role of vaccines in blocking transmission, regardless of the stages being targeted. Development of vaccines is feasible but with the support of private sector and government organization in terms of regulatory and most importantly

  11. Molecular Vaccines for Malaria

    Science.gov (United States)

    2010-01-01

    Removing inhibitory plasm ids from the cock- with the radiation-attenuated sporozoite (RAS) vaccine36•37 (see tail restored the immunogenicity of the...relative increased in vitro growth inhibitory activity against homologous to the P. folciparum antigen expressing plasm ids alone, and none parasites...25nm and have a molecular weight of 14.8 kDa. (C) Transmission electron microscopy image of P4c-Mal nanoparticles at 242 OOOx. The sample was

  12. Steady progress toward a malaria vaccine.

    Science.gov (United States)

    Lyke, Kirsten E

    2017-10-01

    Great progress has been made in reducing malaria morbidity and mortality, yet the parasite continues to cause a startling 200 million infections and 500 000 deaths annually. Malaria vaccine development is pushing new boundaries by steady advancement toward a licensed product. Despite 50 years of research, the complexity of Plasmoidum falciparum confounds all attempts to eradicate the organism. This very complexity has pushed the boundaries of vaccine development to new heights, yet it remains to be seen if an affordable vaccine can provide durable and high-level protection. Novel vaccines such as RTS,S/AS01E are on the edge of licensure, but old techniques have resurged with the ability to deliver vialed, whole organism vaccines. Novel adjuvants, multistage/multiantigen approaches and transmission blocking vaccines all contribute to a multipronged battle plan to conquer malaria. Vaccines are the most cost-effective tools to control infectious diseases, yet the complexity of malaria has frustrated all attempts to develop an effective product. This review concentrates on recent advances in malaria vaccine development that lend hope that a vaccine can be produced and malaria eradicated.

  13. Recent advances in recombinant protein-based malaria vaccines

    DEFF Research Database (Denmark)

    Draper, Simon J; Angov, Evelina; Horii, Toshihiro

    2015-01-01

    Plasmodium parasites are the causative agent of human malaria, and the development of a highly effective vaccine against infection, disease and transmission remains a key priority. It is widely established that multiple stages of the parasite's complex lifecycle within the human host and mosquito...... vector are susceptible to vaccine-induced antibodies. The mainstay approach to antibody induction by subunit vaccination has been the delivery of protein antigen formulated in adjuvant. Extensive efforts have been made in this endeavor with respect to malaria vaccine development, especially with regard......, with the prospects for the development of a highly effective multi-component/multi-stage/multi-antigen formulation seeming ever more likely. This review will focus on recent progress in protein vaccine design, development and/or clinical testing for a number of leading malaria antigens from the sporozoite...

  14. Shape of Key Malaria Protein Could Help Improve Vaccine Efficacy

    Science.gov (United States)

    ... Featured Diseases & Conditions Food Allergy HIV/AIDS Influenza Malaria Respiratory Syncytial Virus (RSV) Tuberculosis Zika Virus Find ... To Volunteer for Vaccine Research Studies Volunteer for Malaria Vaccine Research Volunteer Profiles Q&A: Vaccine Clinical ...

  15. Immunoinformatics of Placental Malaria Vaccine Development

    DEFF Research Database (Denmark)

    Jessen, Leon Eyrich

    Malaria is an infectious disease caused by a protozoan parasite of the genus Plasmodium, which is transferred by female Anopheles mosquitos. WHO estimates that in 2012 there were 207 million cases of malaria, of which 627,000 were fatal. People living in malaria-endemic areas, gradually acquire...... immunity with multiple infections. Placental malaria (PM) is caused by P. falciparum sequestering in the placenta of pregnant women due to the presence of novel receptors in the placenta. An estimated 200,000 infants die a year as a result of PM. In 2004 the specific protein responsible...... and development in the field of placental malaria vaccine development....

  16. Optimal control for Malaria disease through vaccination

    Science.gov (United States)

    Munzir, Said; Nasir, Muhammad; Ramli, Marwan

    2018-01-01

    Malaria is a disease caused by an amoeba (single-celled animal) type of plasmodium where anopheles mosquito serves as the carrier. This study examines the optimal control problem of malaria disease spread based on Aron and May (1982) SIR type models and seeks the optimal solution by minimizing the prevention of the spreading of malaria by vaccine. The aim is to investigate optimal control strategies on preventing the spread of malaria by vaccination. The problem in this research is solved using analytical approach. The analytical method uses the Pontryagin Minimum Principle with the symbolic help of MATLAB software to obtain optimal control result and to analyse the spread of malaria with vaccination control.

  17. Malaria vaccine offers hope. International / Africa.

    Science.gov (United States)

    1995-03-13

    Colombian professor Manuel Patarroyo developed a new malaria vaccine (SPF66). In February 1995, WHO and the Colombian government agreed to establish a manufacturing plant in Colombia for mass production of SPF66. This vaccine is likely to be available to persons in Africa, where 90% of all annual global cases live. In fact, Africa witnesses one million of 1.5 million annual malaria cases. Many children die from malaria. An extensive clinical trial of the SPF66 vaccine in Colombia achieved a 22-77% protection rate. The young and the very old had the high protection rates. A series of human clinical trials in the Gambia and Tanzania indicate that SPF66 produces a strong immune response against malaria without any harmful side effects. The results of field tests in the Gambia and Thailand and of trials in Colombia are expected in 1995. If the vaccine could reduce the incidence of malaria by just 50%, the lives of as many as 500,000 African children could be saved. SPF66 contains a combination of synthetic peptides (=or 2 amino acids). Mass production would make it affordable (estimated $5/injection). At least five other malaria vaccines hold promise and are ready for human testing in endemic countries. SPF66 is approximately three years ahead of all other promising malaria vaccines. 20 more vaccines are in the development stage. The large scale production of SPF66 in Colombia could begin within three years. Professor Patarroyo has financed his 12-year-old research himself because he wants to protect the lives of persons in developing countries. In 1992, the Congo's president petitioned the international community at the WHO summit in Amsterdam to join the fight against malaria since it is now in a position to defeat malaria since it finished the cold war.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  19. Review Article: Vaccine for Malaria – How Far? | Oyeyinka | African ...

    African Journals Online (AJOL)

    This is a review of the progress made so far in the effort to produce a malaria vaccine. The problems that have made it impossible to get an effective vaccine for malaria are discussed. Also examined are the current efforts to produce the vaccine and the prospects for an effective vaccine in the future. Key words: Vaccine ...

  20. Malaria vaccines: lessons from field trials

    Directory of Open Access Journals (Sweden)

    Claudio J. Struchiner

    1994-07-01

    Full Text Available Malaria vaccine candidates have already been tested and new trials are being carried out. We present a brief description of specific issues of validity that are relevant when assessing vaccine efficacy in the field and illustrate how the application of these principles might improve our interpretation of the data being gathered in actual malaria vaccine field trials. Our discussion assumes that vaccine evaluation shares the same general principles of validity with epidemiologic causal inference, i.e., the process of drawing inferences from epidemiologic data aiming at the identification of causes of diseases. Judicious exercise of these principles indicates that, for meaningful interpretation, measures of vaccine efficacy require definitions based upon arguments conditional on the amount of exposure to infection, and specification of the initial and final states in which one believes the effect of interest takes place.

  1. Vaccines for preventing malaria (blood-stage).

    Science.gov (United States)

    Graves, P; Gelband, H

    2006-10-18

    A malaria vaccine is needed because of the heavy burden of mortality and morbidity due to this disease. This review describes the results of trials of blood (asexual)-stage vaccines. Several are under development, but only one (MSP/RESA, also known as Combination B) has been tested in randomized controlled trials. To assess the effect of blood-stage malaria vaccines in preventing infection, disease, and death. In March 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 1), MEDLINE, EMBASE, LILACS, and the Science Citation Index. We also searched conference proceedings and reference lists of articles, and contacted organizations and researchers in the field. Randomized controlled trials comparing blood-stage vaccines (other than SPf66) against P. falciparum, P. vivax, P. malariae, or P. ovale with placebo, control vaccine, or routine antimalarial control measures in people of any age receiving a challenge malaria infection. Both authors independently assessed trial quality and extracted data. Results for dichotomous data were expressed as relative risks (RR) with 95% confidence intervals (CI). Five trials of MSP/RESA vaccine with 217 participants were included; all five reported on safety, and two on efficacy. No severe or systemic adverse effects were reported at doses of 13 to 15 microg of each antigen (39 to 45 microg total). One small efficacy trial with 17 non-immune participants with blood-stage parasites showed no reduction or delay in parasite growth rates after artificial challenge. In the second efficacy trial in 120 children aged five to nine years in Papua New Guinea, episodes of clinical malaria were not reduced, but MSP/RESA significantly reduced parasite density only in children who had not been pretreated with an antimalarial drug (sulfadoxine-pyrimethamine). Infections with the 3D7 parasite subtype of MSP2 (the variant included in the vaccine) were reduced (RR 0.38, 95% CI 0.26 to

  2. [Vaccinations and malaria prophylaxis for international travelers].

    Science.gov (United States)

    Alberer, Martin; Löscher, Thomas

    2015-05-01

    The prevention of infectious diseases by vaccination and by counselling about malaria prophylaxis is a central aspect of travel medicine. Besides mandatory vaccinations required for entry to certain countries various vaccinations may be indicated depending on destination and type of travel as well as on individual risks of the traveler. In addition, pre-travel counselling should always include a check-up of standard vaccinations. Protection against mosquito bites is the basis of malaria prophylaxis. The addition of chemoprophylaxis is warranted in high risk areas. When regular chemoprophylaxis is not applied it is recommended to carry an appropriate antimalarial drug which can be used for emergency stand-by treatment in case of unexplained fever and when medical attention is not available within 24 hours. Travelers should realize that self-treatment is a first-aid measure and that they should still seek medical advice as soon as possible. © Georg Thieme Verlag KG Stuttgart · New York.

  3. Secreted HSP Vaccine for Malaria Prophylaxis

    Science.gov (United States)

    2017-10-01

    burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing...thereby stimulating an avid, antigen specific, cytotoxic CD8 T cell response. Here we developed malaria vaccine that relies on secreted gp96-Ig... stimulating multi-epitope specific cytotoxic T cells. In the proposed studies, we will adapt this vaccine approach to stimulate cytotoxic T cells

  4. Stakeholders' opinions and questions regarding the anticipated malaria vaccine in Tanzania.

    Science.gov (United States)

    Mtenga, Sally; Kimweri, Angela; Romore, Idda; Ali, Ali; Exavery, Amon; Sicuri, Elisa; Tanner, Marcel; Abdulla, Salim; Lusingu, John; Kafuruki, Shubi

    2016-04-05

    Within the context of combined interventions, malaria vaccine may provide additional value in malaria prevention. Stakeholders' perspectives are thus critical for informed recommendation of the vaccine in Tanzania. This paper presents the views of stakeholders with regards to malaria vaccine in 12 Tanzanian districts. Quantitative and qualitative methods were employed. A structured questionnaire was administered to 2123 mothers of under five children. Forty-six in-depth interviews and 12 focus group discussions were conducted with teachers, religious leaders, community health workers, health care professionals, and scientists. Quantitative data analysis involved frequency distributions and cross tabulations using Chi square test to determine the association between malaria vaccine acceptability and independent variables. Qualitative data were analysed thematically. Overall, 84.2% of the mothers had perfect acceptance of malaria vaccine. Acceptance varied significantly according to religion, occupation, tribe and region (p Stakeholders had high acceptance and positive opinions towards the combined use of the anticipated malaria vaccine and ITNs, and that their acceptance remains high even when the vaccine may not provide full protection, this is a crucial finding for malaria vaccine policy decisions in Tanzania. An inclusive communication strategy should be designed to address the stakeholders' questions through a process that should engage and be implemented by communities and health care professionals. Social cultural aspects associated with vaccine acceptance should be integrated in the communication strategy.

  5. Review Article: Prospect and Progress of Malaria Vaccine ...

    African Journals Online (AJOL)

    Malaria kills one child every 30 seconds in Africa. The development of a safe vaccine remains an urgent unmet need which could greatly control and even lead to the eradication of the disease. The success recorded in the recent vaccine trials have given some ray of hope that a safe and effective vaccine against malaria will ...

  6. Update on the Clinical Development of Candidate Malaria Vaccines

    National Research Council Canada - National Science Library

    Ballou, W. R; Arevalo-Herrera, Myriam; Carucci, Daniel; Richie, Thomas L; Corradin, Giampietro; Diggs, Carter; Druilhe, Pierre; Giersing, Birgitte K; Saul, Allan; Heppner, D. G

    2004-01-01

    ... powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure...

  7. APPROACHING THE TARGET: THE PATH TOWARDS AN EFFECTIVE MALARIA VACCINE

    Directory of Open Access Journals (Sweden)

    Alberto L. García-Basteiro

    2012-01-01

    Full Text Available Eliciting an effective malaria vaccine has been the goal of the scientific community for many years. A malaria vaccine, added to existing tools and strategies, would further prevent and decrease the unacceptable malaria morbidity and mortality burden. Great progress has been made over the last decade, with some vaccine candidates in the clinical phases of development. The RTS,S malaria vaccine candidate, based on a recombinant P. falciparum protein, is the most advanced of such candidates, currently undergoing a large phase III trial. RTS,S has consistently shown an efficacy of around 50% against the first clinical episode of malaria, with protection in some cases extending up to 4 years of duration. Thus, it is hoped that this candidate vaccine will eventually become the first licensed malaria vaccine. This first vaccine against a human parasite is a groundbreaking achievement, but improved malaria vaccines conferring higher protection will be needed if the aspiration of malaria eradication is to be achieved

  8. The dog that did not bark: malaria vaccines without antibodies.

    NARCIS (Netherlands)

    Heppner, D.G.; Schwenk, R.J.; Arnot, D.; Sauerwein, R.W.; Luty, A.J.F.

    2007-01-01

    To date, the only pre-blood stage vaccine to confer protection against malaria in field trials elicits both antigen-specific antibody and T-cell responses. Recent clinical trials of new heterologous prime-boost malaria vaccine regimens using DNA, fowlpox or MVA, have chiefly elicited T-cell

  9. A multilateral effort to develop DNA vaccines against falciparum malaria.

    Science.gov (United States)

    Kumar, Sanjai; Epstein, Judith E; Richie, Thomas L; Nkrumah, Francis K; Soisson, Lorraine; Carucci, Daniel J; Hoffman, Stephen L

    2002-03-01

    Scientists from several organizations worldwide are working together to develop a multistage, multigene DNA-based vaccine against Plasmodium falciparum malaria. This collaborative vaccine development effort is named Multi-Stage DNA-based Malaria Vaccine Operation. An advisory board of international experts in vaccinology, malariology and field trials provides the scientific oversight to support the operation. This article discusses the rationale for the approach, underlying concepts and the pre-clinical development process, and provides a brief outline of the plans for the clinical testing of a multistage, multiantigen malaria vaccine based on DNA plasmid immunization technology.

  10. Development of replication-deficient adenovirus malaria vaccines.

    Science.gov (United States)

    Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith

    2017-03-01

    Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.

  11. Overview of Plant-Made Vaccine Antigens against Malaria

    Directory of Open Access Journals (Sweden)

    Marina Clemente

    2012-01-01

    Full Text Available This paper is an overview of vaccine antigens against malaria produced in plants. Plant-based expression systems represent an interesting production platform due to their reduced manufacturing costs and high scalability. At present, different Plasmodium antigens and expression strategies have been optimized in plants. Furthermore, malaria antigens are one of the few examples of eukaryotic proteins with vaccine value expressed in plants, making plant-derived malaria antigens an interesting model to analyze. Up to now, malaria antigen expression in plants has allowed the complete synthesis of these vaccine antigens, which have been able to induce an active immune response in mice. Therefore, plant production platforms offer wonderful prospects for improving the access to malaria vaccines.

  12. Clinical development of placental malaria vaccines and immunoassays harmonization

    DEFF Research Database (Denmark)

    Chêne, Arnaud; Houard, Sophie; Nielsen, Morten A

    2016-01-01

    Placental malaria caused by Plasmodium falciparum infection constitutes a major health problem manifesting as severe disease and anaemia in the mother, impaired fetal development, low birth weight or spontaneous abortion. Prevention of placental malaria currently relies on two key strategies...... that are losing efficacy due to spread of resistance: long-lasting insecticide-treated nets and intermittent preventive treatment during pregnancy. A placental malaria vaccine would be an attractive, cost-effective complement to the existing control tools. Two placental malaria vaccine candidates are currently...... in Phase Ia/b clinical trials. During two workshops hosted by the European Vaccine Initiative, one in Paris in April 2014 and the other in Brussels in November 2014, the main actors in placental malaria vaccine research discussed the harmonization of clinical development plans and of the immunoassays...

  13. Malaria vaccines and their potential role in the elimination of malaria

    Directory of Open Access Journals (Sweden)

    Greenwood Brian M

    2008-12-01

    Full Text Available Abstract Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely. The feature of the life-cycles of human malarias that presents the greatest challenge to an elimination programme is the persistence of parasites as asymptomatic infections. These are an important source from which transmission to mosquitoes can occur. Consequently, an elimination strategy requires a community-based approach covering all individuals and not just those who are susceptible to clinical malaria. The progress that has been made in development of candidate malaria vaccines is reviewed. It is unlikely that many of these will have the efficacy required for complete elimination of parasites, though they may have an important role to play as part of future integrated control programmes. Vaccines for elimination must have a high level of efficacy in order to stop transmission to mosquitoes. This might be achieved with some pre-erythrocytic stage candidate vaccines or by targeting the sexual stages directly with transmission-blocking vaccines. An expanded malaria vaccine programme with such objectives is now a priority.

  14. Perception and acceptability of malaria vaccine among maternal ...

    African Journals Online (AJOL)

    Perception and acceptability of malaria vaccine among maternal and child health clinic ... Journal of Community Medicine and Primary Health Care ... used for data collection from maternal and child health clinic attendees in Calabar, Nigeria.

  15. RTS,S/AS01 malaria vaccine and child mortality

    DEFF Research Database (Denmark)

    Aaby, Peter; Rodrigues, Amabelia; Kofoed, Poul-Erik

    2015-01-01

    Comment on Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. [Lancet. 2015]......Comment on Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. [Lancet. 2015]...

  16. Community perceptions of malaria and vaccines in two districts of Mozambique

    Directory of Open Access Journals (Sweden)

    Bingham Allison

    2012-11-01

    Full Text Available Abstract Background Malaria is a leading cause of mortality and morbidity in Mozambique, with nearly three-quarters of the country’s malaria-related deaths occurring in children younger than five years. A malaria vaccine is not yet available, but planning is underway for a possible introduction, as soon as one becomes available. In an effort to inform the planning process, this study explored sociocultural and health communications issues among individuals at the community level who are both responsible for decisions about vaccine use and who are likely to influence decisions about vaccine use. Methods Researchers conducted a qualitative study in two malaria-endemic districts in southern Mozambique. Using criterion-based sampling, they conducted 23 focus group discussions and 26 in-depth interviews. Implementation was guided by the engagement of community stakeholders. Results Community members recognize that malaria contributes to high death rates and affects the workforce, school attendance, and the economy. Vaccines are seen as a means to reduce the threat of childhood illnesses and to keep children and the rest of the community healthy. Perceived constraints to accessing vaccine services include long queues, staff shortages, and a lack of resources at health care facilities. Local leaders play a significant role in motivating caregivers to have their children vaccinated. Participants generally felt that a vaccine could help to prevent malaria, although some voiced concern that the focus was only on young children and not on older children, pregnant women, and the elderly. Probed on their understanding of vaccine efficacy, participants voiced various views, including the perception that while some vaccines did not fully prevent disease they still had important benefits. Overall, it would be essential for local leaders to be involved in the design of specific messages for a future malaria vaccine communications strategy, and for those

  17. Novel approaches to identify protective malaria vaccine candidates

    Directory of Open Access Journals (Sweden)

    Wan Ni eChia

    2014-11-01

    Full Text Available Efforts to develop vaccines against malaria have been the focus of substantial research activities for decades. Several categories of candidate vaccines are currently being developed for protection against malaria, based on antigens corresponding to the pre-erythrocytic, blood-stage or sexual stages of the parasite. Long lasting sterile protection from Plasmodium falciparum sporozoite challenge has been observed in human following vaccination with whole parasite formulations, clearly demonstrating that a protective immune response targeting predominantly the pre-erythrocytic stages can develop against malaria. However, most of vaccine candidates currently being investigated, which are mostly subunits vaccines, have not been able to induce substantial (>50% protection thus far. This is due to the fact that the antigens responsible for protection against the different parasite stages are still yet to be known and relevant correlates of protection have remained elusive. For a vaccine to be developed in a timely manner, novel approaches are required. In this article, we review the novel approaches that have been developed to identify the antigens for the development of an effective malaria vaccine.

  18. Simulation of the cost-effectiveness of malaria vaccines

    Directory of Open Access Journals (Sweden)

    Tediosi Fabrizio

    2009-06-01

    Full Text Available Abstract Background A wide range of possible malaria vaccines is being considered and there is a need to identify which vaccines should be prioritized for clinical development. An important element of the information needed for this prioritization is a prediction of the cost-effectiveness of potential vaccines in the transmission settings in which they are likely to be deployed. This analysis needs to consider a range of delivery modalities to ensure that clinical development plans can be aligned with the most appropriate deployment strategies. Methods The simulations are based on a previously published individual-based stochastic model for the natural history and epidemiology of Plasmodium falciparum malaria. Three different vaccine types: pre-erythrocytic vaccines (PEV, blood stage vaccines (BSV, mosquito-stage transmission-blocking vaccines (MSTBV, and combinations of these, are considered each delivered via a range of delivery modalities (Expanded Programme of Immunization – EPI-, EPI with booster, and mass vaccination combined with EPI. The cost-effectiveness ratios presented are calculated for four health outcomes, for assumed vaccine prices of US$ 2 or US$ 10 per dose, projected over a 10-year period. Results The simulations suggest that PEV will be more cost-effective in low transmission settings, while BSV at higher transmission settings. Combinations of BSV and PEV are more efficient than PEV, especially in moderate to high transmission settings, while compared to BSV they are more cost-effective in moderate to low transmission settings. Combinations of MSTBV and PEV or PEV and BSV improve the effectiveness and the cost-effectiveness compared to PEV and BSV alone only when applied with EPI and mass vaccinations. Adding booster doses to the EPI is unlikely to be a cost-effective alternative to delivering vaccines via the EPI for any vaccine, while mass vaccination improves effectiveness, especially in low transmission settings, and is

  19. Willingness to pay for three hypothetical malaria vaccines in Nigeria.

    Science.gov (United States)

    Udezi, Waka Anthony; Usifoh, Cyril Odianose; Ihimekpen, Omoyeme Oluwatosin

    2010-08-01

    Unlike some African countries that have reported a approximately 50% reduction in malaria deaths in recent years, Nigeria has shown no evidence of a systematic decline in malaria burden. An important and sustainable reduction in malaria burden cannot be achieved unless an effective and inexpensive malaria vaccine becomes available. The goals of this study were to determine the willingness to pay (WTP) for 3 hypothetical malaria vaccines with different levels of protection (in years), effectiveness, and adverse effects; and to identify factors that influence the price that people are willing to pay in Nigeria. With the aid of a questionnaire, a contingent valuation method using payment cards was used to elicit WTP values for 3 hypothetical malaria vaccines. Payment cards contained both a description of the features of the vaccine being evaluated and price options. The 3 hypothetical vaccines had the following characteristics: vaccine A was 75% effective, protected for 3 years, and was well tolerated; vaccine B was 85% effective, protected for 6 years, and was less well tolerated than vaccine A; and vaccine C was 95% effective and protected for 12 years, but was the least well tolerated. Participants consisted of a convenience sample of individuals who were at the pharmacy waiting area of the state-owned hospitals located in Benin City and Warri, Nigeria. Every third patient or caregiver who was in the pharmacy to fill a prescription was asked to take part in the study as they waited to see the pharmacist. If consent was not granted, the next person in line was approached to be interviewed. Linear multiple regression analysis and nonparametric Kruskal-Wallis, Mann-Whitney, or chi(2) test was applied in inferential analysis, where necessary, to investigate the effects of sociodemographic factors on WTP. Prices on payment cards were expressed in Nigerian naira (NGN 150.00 approximately US $1.00), but study results were expressed in US dollars. A total of 359

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Malaria vaccines: the case for a whole-organism approach.

    Science.gov (United States)

    Pinzon-Charry, Alberto; Good, Michael F

    2008-04-01

    Malaria is a significant health problem causing morbidity and mortality worldwide. Vaccine development has been an imperative for decades. However, the intricacy of the parasite's lifecycle coupled with the lack of evidence for robust infection-induced immunity has made vaccine development exceptionally difficult. To review some of the key advances in the field and discuss potential ways forward for a whole-organism vaccine. The authors searched PubMed using the words 'malaria and vaccine'. We searched for manuscripts detailing antigen characterisation and vaccine strategies with emphasis on subunit versus whole-parasite approaches. Abstracts were selected and relevant articles are discussed. The searches were not restricted by language or date. The early cloning of malaria antigens has fuelled rapid development of subunit vaccines. However, the disappointing results of clinical trials have resulted in reappraisal of current strategies. Whole-parasite approaches have re-emerged as an alternative strategy. Immunization using radiation or genetically attenuated sporozoites has been shown to result in sterile immunity and immunization with blood-stage parasites curtailed by antimalarials has demonstrated delayed parasitemia in rodent models as well as in human malaria.

  2. Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination

    DEFF Research Database (Denmark)

    Theander, Thor Grundtvig; Lusingu, John Peter Andrea

    2014-01-01

    BACKGROUND: A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission. METHODS AND FINDINGS: 6,537 infants aged 6......-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p... after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants...

  3. Quantitative PCR evaluation of cellular immune responses in Kenyan children vaccinated with a candidate malaria vaccine.

    Directory of Open Access Journals (Sweden)

    Jedidah Mwacharo

    2009-12-01

    Full Text Available The T-cell mediated immune response plays a central role in the control of malaria after natural infection or vaccination. There is increasing evidence that T-cell responses are heterogeneous and that both the quality of the immune response and the balance between pro-inflammatory and regulatory T-cells determines the outcome of an infection. As Malaria parasites have been shown to induce immunosuppressive responses to the parasite and non-related antigens this study examined T-cell mediated pro-inflammatory and regulatory immune responses induced by malaria vaccination in children in an endemic area to determine if these responses were associated with vaccine immunogenicity.Using real-time RT- PCR we profiled the expression of a panel of key markers of immunogenecity at different time points after vaccination with two viral vector vaccines expressing the malaria TRAP antigen (FP9-TRAP and MVA-TRAP or following rabies vaccination as a control.The vaccine induced modest levels of IFN-gamma mRNA one week after vaccination. There was also an increase in FoxP3 mRNA expression in both TRAP stimulated and media stimulated cells in the FFM ME-TRAP vaccine group; however, this may have been driven by natural exposure to parasite rather than by vaccination.Quantitative PCR is a useful method for evaluating vaccine induced cell mediated immune responses in frozen PBMC from children in a malaria endemic country. Future studies should seek to use vaccine vectors that increase the magnitude and quality of the IFN-gamma immune response in naturally exposed populations and should monitor the induction of a regulatory T cell response.

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

    Directory of Open Access Journals (Sweden)

    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

  5. A nonintegrative lentiviral vector-based vaccine provides long-term sterile protection against malaria.

    Directory of Open Access Journals (Sweden)

    Frédéric Coutant

    Full Text Available Trials testing the RTS,S candidate malaria vaccine and radiation-attenuated sporozoites (RAS have shown that protective immunity against malaria can be induced and that an effective vaccine is not out of reach. However, longer-term protection and higher protection rates are required to eradicate malaria from the endemic regions. It implies that there is still a need to explore new vaccine strategies. Lentiviral vectors are very potent at inducing strong immunological memory. However their integrative status challenges their safety profile. Eliminating the integration step obviates the risk of insertional oncogenesis. Providing they confer sterile immunity, nonintegrative lentiviral vectors (NILV hold promise as mass pediatric vaccine by meeting high safety standards. In this study, we have assessed the protective efficacy of NILV against malaria in a robust pre-clinical model. Mice were immunized with NILV encoding Plasmodium yoelii Circumsporozoite Protein (Py CSP and challenged with sporozoites one month later. In two independent protective efficacy studies, 50% (37.5-62.5 of the animals were fully protected (p = 0.0072 and p = 0.0008 respectively when compared to naive mice. The remaining mice with detectable parasitized red blood cells exhibited a prolonged patency and reduced parasitemia. Moreover, protection was long-lasting with 42.8% sterile protection six months after the last immunization (p = 0.0042. Post-challenge CD8+ T cells to CSP, in contrast to anti-CSP antibodies, were associated with protection (r = -0.6615 and p = 0.0004 between the frequency of IFN-g secreting specific T cells in spleen and parasitemia. However, while NILV and RAS immunizations elicited comparable immunity to CSP, only RAS conferred 100% of sterile protection. Given that a better protection can be anticipated from a multi-antigen vaccine and an optimized vector design, NILV appear as a promising malaria vaccine.

  6. The Feasibility of Gamma Irradiation for Developing Malaria Vaccine

    International Nuclear Information System (INIS)

    Syaifudin, M.; Tetriana, D.; Darlina; Nurhayati, S.

    2011-01-01

    Malaria, a plasmodial disease, causes more than one million deaths per year and has a significant public health impact. Improved access to prompt treatment with effective antimalarial drugs need to be conducted for prevention of infection in high risk groups. However, the parasite as causal agent has exhibited a potential danger of wide-spread resistances. This warning has directed attention to the study of alternative methods of protection against the disease, among them is to do the immunization. A deeper understanding of the nature and regulation of protective immune mechanisms against this parasite will facilitate the development of much needed vaccines. Developing a malaria vaccine remains an enormous scientific, technical, and financial challenge. Currently a vaccine is not fully available. Among the practical applications of radiobiological techniques that may be of considerable interest for public health is the use of ionizing radiation in the preparation of vaccines. Convincing data were reported that sporozoites of Plasmodium berghei irradiated with X- or gamma-rays, provide an antigenic stimulus effective to induce a protective immune response in mice and rats against subsequent sporozoite infection. Irradiated parasites are better immunogens than killed ones and although non-infective they are still metabolically active, as shown by continued protein and nucleic acid synthesis. There is a substantial number of data from human studies demonstrating that sporozoites attenuated by radiation are potent inducer of protective immunity and that they are safe and do not give rise to the asexual erythrocytic infections that cause malaria. This vaccine is relatively inexpensive to produce, easy to store, and transportable without refrigeration. A long-term effort and commitment to providing resources must be maintained and increased to achieve the goal of a malaria vaccine candidate where ionizing radiation as a tool to prepare is seemingly feasible. (author)

  7. Towards a vaccine against pregnancy-associated malaria

    Directory of Open Access Journals (Sweden)

    Tuikue Ndam N.

    2008-09-01

    Full Text Available The consequences of pregnancy-associated malaria on pregnant women (anaemia, their babies (birth weight reduction, and infants (increased morbidity and mortality are well documented. Field observations during the last decade have underlined the key role of the interactions between P. falciparum variable surface antigens expressed on infected erythrocytes and a novel receptor: chondroitin sulfate A (CSA for the placental sequestration of infected erythrocytes. Identification of a distinct P. falciparum erythrocyte membrane protein 1 (PfEMP1 variant, VAR2CSA, as the dominant variant surface antigen and as a clinically important target for protective immune response to pregnancy-associated malaria has raised hope for developing a new preventive strategy based on inducing these immune responses by vaccination. However, despite particular structure and interclonal conservation of VAR2CSA among other PfEMP1, significant challenges still exist concerning the development of a VAR2CSA-based vaccine with profound efficacy.

  8. Potential public health impact of RTS,S malaria candidate vaccine in sub-Saharan Africa: a modelling study.

    Science.gov (United States)

    Sauboin, Christophe J; Van Bellinghen, Laure-Anne; Van De Velde, Nicolas; Van Vlaenderen, Ilse

    2015-12-23

    Adding malaria vaccination to existing interventions could help to reduce the health burden due to malaria. This study modelled the potential public health impact of the RTS,S candidate malaria vaccine in 42 malaria-endemic countries in sub-Saharan Africa. An individual-based Markov cohort model was constructed with three categories of malaria transmission intensity and six successive malaria immunity levels. The cycle time was 5 days. Vaccination was assumed to reduce the risk of infection, with no other effects. Vaccine efficacy was assumed to wane exponentially over time. Malaria incidence and vaccine efficacy data were taken from a Phase III trial of the RTS,S vaccine with 18 months of follow-up (NCT00866619). The model was calibrated to reproduce the malaria incidence in the control arm of the trial in each transmission category and published age distribution data. Individual-level heterogeneity in malaria exposure and vaccine protection was accounted for. Parameter uncertainty and variability were captured by using stochastic model transitions. The model followed a cohort from birth to 10 years of age without malaria vaccination, or with RTS,S malaria vaccination administered at age 6, 10 and 14 weeks or at age 6, 7-and-a-half and 9 months. Median and 95% confidence intervals were calculated for the number of clinical malaria cases, severe cases, malaria hospitalizations and malaria deaths expected to be averted by each vaccination strategy. Univariate sensitivity analysis was conducted by varying the values of key input parameters. Vaccination assuming the coverage of diphtheria-tetanus-pertussis (DTP3) at age 6, 10 and 14 weeks is estimated to avert over five million clinical malaria cases, 119,000 severe malaria cases, 98,600 malaria hospitalizations and 31,000 malaria deaths in the 42 countries over the 10-year period. Vaccination at age 6, 7-and-a-half and 9 months with 75% of DTP3 coverage is estimated to avert almost 12.5 million clinical malaria cases

  9. The Malaria Vaccine Candidate GMZ2 Elicits Functional Antibodies in Individuals From Malaria Endemic and Non-Endemic Areas

    DEFF Research Database (Denmark)

    Jepsen, Micha Phill Grønholm; Jogdand, Prajakta S; Singh, Susheel K

    2013-01-01

    against Plasmodium falciparum. Results. We showed that the maximum level of immunoglobulin G (IgG) antibodies obtained by GMZ2 vaccination is independent of ethnicity, time under malaria-exposure, and vaccine dose and that GMZ2 elicits high levels of functionally active IgG antibodies. Both, malaria......-naive adults and malaria-exposed preschool children elicit vaccine-specific antibodies with broad inhibitory activity against geographically diverse P. falciparum isolates. Peptide-mapping studies of IgG subclass responses identified IgG3 against a peptide derived from MSP3 as the strongest predictor...

  10. RTS,S malaria vaccine development: progress and considerations for postapproval introduction

    Directory of Open Access Journals (Sweden)

    Asante KP

    2016-06-01

    Full Text Available Kwaku Poku Asante, George Adjei, Yeetey Enuameh, Seth Owusu-Agyei Kintampo Health Research Centre, Kintampo, Brong Ahafo Region, Ghana Abstract: Though the burden of malaria has decreased in the last decade in some sub-Saharan African countries, it is still high in others, and there is no malaria vaccine in use. The development of malaria vaccines in combination with current control programs could be effective in reducing the malaria burden. In this paper, we review and discuss the progress made in the RTS,S malaria vaccine development and considerations for its postapproval process. We conclude that the development of malaria vaccines has been a long process confronted with challenges of funding, difficulty in identifying malaria antigens that correlate with protection, and development of adjuvant systems among others. The scientific approval of the vaccine by the European Medicines Agency in July 2015 and subsequent recommendations for pilot implementation studies by the World Health Organization made history as the first human parasite vaccine. It is also a major public health achievement as the vaccine has the potential to prevent thousands of malaria cases. However, there are implementation challenges such as cold chain systems, community acceptance, and monitoring of adverse events post-licensure that need to be carefully addressed. Keywords: malaria, vaccines, challenges, introduction, Africa, implementation considerations 

  11. Application of a scalable plant transient gene expression platform for malaria vaccine development

    Directory of Open Access Journals (Sweden)

    Holger eSpiegel

    2015-12-01

    Full Text Available Despite decades of intensive research efforts there is currently no vaccine that provides sustained sterile immunity against malaria. In this context, a large number of targets from the different stages of the Plasmodium falciparum life cycle have been evaluated as vaccine candidates. None of these candidates has fulfilled expectations, and as long as we lack a single target that induces strain-transcending protective immune responses, combining key antigens from different life cycle stages seems to be the most promising route towards the development of efficacious malaria vaccines. After the identification of potential targets using approaches such as omics-based technology and reverse immunology, the rapid expression, purification and characterization of these proteins, as well as the generation and analysis of fusion constructs combining different promising antigens or antigen domains before committing to expensive and time consuming clinical development, represents one of the bottlenecks in the vaccine development pipeline. The production of recombinant proteins by transient gene expression in plants is a robust and versatile alternative to cell-based microbial and eukaryotic production platforms. The transfection of plant tissues and/or whole plants using Agrobacterium tumefaciens offers a low technical entry barrier, low costs and a high degree of flexibility embedded within a rapid and scalable workflow. Recombinant proteins can easily be targeted to different subcellular compartments according to their physicochemical requirements, including post-translational modifications, to ensure optimal yields of high quality product, and to support simple and economical downstream processing. Here we demonstrate the use of a plant transient expression platform based on transfection with A. tumefaciens as essential component of a malaria vaccine development workflow involving screens for expression, solubility and stability using fluorescent fusion

  12. Pre-clinical and clinical development of the first placental malaria vaccine

    DEFF Research Database (Denmark)

    Pehrson, Caroline; Salanti, Ali; Theander, Thor G

    2017-01-01

    the condition.  Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical...... vaccine development. However, all papers from these searches were not systematically included.  Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy...

  13. Novel Plasmodium falciparum malaria vaccines: evidence-based searching for variant surface antigens as candidates for vaccination against pregnancy-associated malaria

    DEFF Research Database (Denmark)

    Staalsoe, Trine; Jensen, Anja T R; Theander, Thor G

    2002-01-01

    Malaria vaccine development has traditionally concentrated on careful molecular, biochemical, and immunological characterisation of candidate antigens. In contrast, evidence of the importance of identified antigens in immunity to human infection and disease has generally been limited to statistic......Malaria vaccine development has traditionally concentrated on careful molecular, biochemical, and immunological characterisation of candidate antigens. In contrast, evidence of the importance of identified antigens in immunity to human infection and disease has generally been limited...... to statistically significant co-variation with protection rather than on demonstration of causal relationships. We have studied the relationship between variant surface antigen-specific antibodies and clinical protection from Plasmodium falciparum malaria in general, and from pregnancy-associated malaria (PAM......) in particular, to provide robust evidence of a causal link between the two in order to allow efficient and evidence-based identification of candidate antigens for malaria vaccine development....

  14. Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine

    DEFF Research Database (Denmark)

    Neafsey, Daniel E; Juraska, Michal; Bedford, Trevor

    2015-01-01

    Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the c......Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes...... protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. Results In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.......3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine...

  15. Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria.

    Science.gov (United States)

    Hoffman, Stephen L; Billingsley, Peter F; James, Eric; Richman, Adam; Loyevsky, Mark; Li, Tao; Chakravarty, Sumana; Gunasekera, Anusha; Chattopadhyay, Rana; Li, Minglin; Stafford, Richard; Ahumada, Adriana; Epstein, Judith E; Sedegah, Martha; Reyes, Sharina; Richie, Thomas L; Lyke, Kirsten E; Edelman, Robert; Laurens, Matthew B; Plowe, Christopher V; Sim, B Kim Lee

    2010-01-01

    Immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated Plasmodium falciparum sporozoites protects greater than 90% of such volunteers against malaria, if adequate numbers of immunizing biting sessions and sporozoite-infected mosquitoes are used. Nonetheless, until recently it was considered impossible to develop, license and commercialize a live, whole parasite P. falciparum sporozoite (PfSPZ) vaccine. In 2003 Sanaria scientists reappraised the potential impact of a metabolically active, non-replicating PfSPZ vaccine, and outlined the challenges to producing such a vaccine. Six years later, significant progress has been made in overcoming these challenges. This progress has enabled the manufacture and release of multiple clinical lots of a 1(st) generation metabolically active, non-replicating PfSPZ vaccine, the Sanaria PfSPZ Vaccine, submission of a successful Investigational New Drug application to the US Food and Drug Administration, and initiation of safety, immunogenicity and protective efficacy studies in volunteers in MD, US. Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the vaccine to the primary target population of African children in the shortest possible period of time. This will require implementation of a systematic, efficient clinical development plan. Short term challenges include optimizing the (1) efficiency and scale up of the manufacturing process and quality control assays, (2) dosage regimen and method of administration, (3) potency of the vaccine, and (4) logistics of delivering the vaccine to those who need it most, and finalizing the methods for vaccine stabilization and attenuation. A medium term goal is to design and build a facility for manufacturing highly potent and stable vaccine for pivotal Phase 3 studies and commercial launch.

  16. Malaria transmission dynamics at a site in northern Ghana proposed for testing malaria vaccines.

    Science.gov (United States)

    Appawu, Maxwell; Owusu-Agyei, Seth; Dadzie, Samuel; Asoala, Victor; Anto, Francis; Koram, Kwadwo; Rogers, William; Nkrumah, Francis; Hoffman, Stephen L; Fryauff, David J

    2004-01-01

    We studied the malaria transmission dynamics in Kassena Nankana district (KND), a site in northern Ghana proposed for testing malaria vaccines. Intensive mosquito sampling for 1 year using human landing catches in three micro-ecological sites (irrigated, lowland and rocky highland) yielded 18 228 mosquitoes. Anopheles gambiae s.l. and Anopheles funestus constituted 94.3% of the total collection with 76.8% captured from the irrigated communities. Other species collected but in relatively few numbers were Anopheles pharoensis (5.4%) and Anopheles rufipes (0.3%). Molecular analysis of 728 An. gambiae.s.l. identified Anopheles gambiae s.s. as the most dominant sibling species (97.7%) of the An. gambiae complex from the three ecological sites. Biting rates of the vectors (36.7 bites per man per night) were significantly higher (P<0.05) in the irrigated area than in the non-irrigated lowland (5.2) and rocky highlands (5.9). Plasmodium falciparum sporozoite rates of 7.2% (295/4075) and 7.1% (269/3773) were estimated for An. gambiae s.s. and An. funestus, respectively. Transmission was highly seasonal, and the heaviest transmission occurred from June to October. The intensity of transmission was higher for people in the irrigated communities than the non-irrigated ones. An overall annual entomological inoculation rate (EIR) of 418 infective bites was estimated in KND. There were micro-ecological variations in the EIRs, with values of 228 infective bites in the rocky highlands, 360 in the lowlands and 630 in the irrigated area. Approximately 60% of malaria transmission in KND occurred indoors during the second half of the night, peaking at daybreak between 04.00 and 06.00 hours. Vaccine trials could be conducted in this district, with timing dependent on the seasonal patterns and intensity of transmission taking into consideration the micro-geographical differences and vaccine trial objectives.

  17. malaria

    African Journals Online (AJOL)

    children who presented with malaria symptoms at the same clinic and tested positive or ... phagocytes immunity and induce anti-inflammatory immune response ...... treatment gap, Malawi will be ready to submit a validation request for virtual .... Conclusions. Vaccination and quarantine are the important disease preventive.

  18. Increased immunogenicity of recombinant Ad35-based malaria vaccine through formulation with aluminium phosphate adjuvant

    NARCIS (Netherlands)

    Ophorst, Olga J. A. E.; Radosevic, Katarina; Klap, Jaco M.; Sijtsma, Jeroen; Gillissen, Gert; Mintardjo, Ratna; van Ooij, Mark J. M.; Holterman, Lennart; Companjen, Arjen; Goudsmit, Jaap; Havenga, Menzo J. E.

    2007-01-01

    Previously, we have shown the potency of recombinant Adenovirus serotype 35 viral vaccines (rAd35) to induce strong immune response against the circumsporozoite protein (CS) of the plasmodium parasite. To further optimize immunogenicity of Ad35-based malaria vaccines we formulated rAd35.CS vaccine

  19. On the efficacy of malaria DNA vaccination with magnetic gene vectors.

    Science.gov (United States)

    Nawwab Al-Deen, Fatin; Ma, Charles; Xiang, Sue D; Selomulya, Cordelia; Plebanski, Magdalena; Coppel, Ross L

    2013-05-28

    We investigated the efficacy and types of immune responses from plasmid malaria DNA vaccine encoding VR1020-PyMSP119 condensed on the surface of polyethyleneimine (PEI)-coated SPIONs. In vivo mouse studies were done firstly to determine the optimum magnetic vector composition, and then to observe immune responses elicited when magnetic vectors were introduced via different administration routes. Higher serum antibody titers against PyMSP119 were observed with intraperitoneal and intramuscular injections than subcutaneous and intradermal injections. Robust IgG2a and IgG1 responses were observed for intraperitoneal administration, which could be due to the physiology of peritoneum as a major reservoir of macrophages and dendritic cells. Heterologous DNA prime followed by single protein boost vaccination regime also enhanced IgG2a, IgG1, and IgG2b responses, indicating the induction of appropriate memory immunity that can be elicited by protein on recall. These outcomes support the possibility to design superparamagnetic nanoparticle-based DNA vaccines to optimally evoke desired antibody responses, useful for a variety of diseases including malaria. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. New gorilla adenovirus vaccine vectors induce potent immune responses and protection in a mouse malaria model.

    Science.gov (United States)

    Limbach, Keith; Stefaniak, Maureen; Chen, Ping; Patterson, Noelle B; Liao, Grant; Weng, Shaojie; Krepkiy, Svetlana; Ekberg, Greg; Torano, Holly; Ettyreddy, Damodar; Gowda, Kalpana; Sonawane, Sharvari; Belmonte, Arnel; Abot, Esteban; Sedegah, Martha; Hollingdale, Michael R; Moormann, Ann; Vulule, John; Villasante, Eileen; Richie, Thomas L; Brough, Douglas E; Bruder, Joseph T

    2017-07-03

    A DNA-human Ad5 (HuAd5) prime-boost malaria vaccine has been shown to protect volunteers against a controlled human malaria infection. The potency of this vaccine, however, appeared to be affected by the presence of pre-existing immunity against the HuAd5 vector. Since HuAd5 seroprevalence is very high in malaria-endemic areas of the world, HuAd5 may not be the most appropriate malaria vaccine vector. This report describes the evaluation of the seroprevalence, immunogenicity and efficacy of three newly identified gorilla adenoviruses, GC44, GC45 and GC46, as potential malaria vaccine vectors. The seroprevalence of GC44, GC45 and GC46 is very low, and the three vectors are not efficiently neutralized by human sera from Kenya and Ghana, two countries where malaria is endemic. In mice, a single administration of GC44, GC45 and GC46 vectors expressing a murine malaria gene, Plasmodium yoelii circumsporozoite protein (PyCSP), induced robust PyCSP-specific T cell and antibody responses that were at least as high as a comparable HuAd5-PyCSP vector. Efficacy studies in a murine malaria model indicated that a prime-boost regimen with DNA-PyCSP and GC-PyCSP vectors can protect mice against a malaria challenge. Moreover, these studies indicated that a DNA-GC46-PyCSP vaccine regimen was significantly more efficacious than a DNA-HuAd5-PyCSP regimen. These data suggest that these gorilla-based adenovectors have key performance characteristics for an effective malaria vaccine. The superior performance of GC46 over HuAd5 highlights its potential for clinical development.

  1. 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...

  2. Comparison of functional assays used in the clinical development of a placental malaria vaccine

    DEFF Research Database (Denmark)

    Pehrson, Caroline; Heno, Kristine Klysner; Adams, Yvonne

    2017-01-01

    BACKGROUND: Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria...

  3. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants

    DEFF Research Database (Denmark)

    Agnandji, Selidji Todagbe; Lell, Bertrand; Fernandes, José Francisco

    2012-01-01

    The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial....

  4. Stable malaria incidence despite scaling up control strategies in a malaria vaccine-testing site in Mali.

    Science.gov (United States)

    Coulibaly, Drissa; Travassos, Mark A; Kone, Abdoulaye K; Tolo, Youssouf; Laurens, Matthew B; Traore, Karim; Diarra, Issa; Niangaly, Amadou; Daou, Modibo; Dembele, Ahmadou; Sissoko, Mody; Guindo, Bouréima; Douyon, Raymond; Guindo, Aldiouma; Kouriba, Bourema; Sissoko, Mahamadou S; Sagara, Issaka; Plowe, Christopher V; Doumbo, Ogobara K; Thera, Mahamadou A

    2014-09-19

    The recent decline in malaria incidence in many African countries has been attributed to the provision of prompt and effective anti-malarial treatment using artemisinin-based combination therapy (ACT) and to the widespread distribution of long-lasting, insecticide-treated bed nets (LLINs). At a malaria vaccine-testing site in Bandiagara, Mali, ACT was introduced in 2004, and LLINs have been distributed free of charge since 2007 to infants after they complete the Expanded Programme of Immunization (EPI) schedule and to pregnant women receiving antenatal care. These strategies may have an impact on malaria incidence. To document malaria incidence, a cohort of 400 children aged 0 to 14 years was followed for three to four years up to July 2013. Monthly cross-sectional surveys were done to measure the prevalence of malaria infection and anaemia. Clinical disease was measured both actively and passively through continuous availability of primary medical care. Measured outcomes included asymptomatic Plasmodium infection, anaemia and clinical malaria episodes. The incidence rate of clinical malaria varied significantly from June 2009 to July 2013 without a clear downward trend. A sharp seasonality in malaria illness incidence was observed with higher clinical malaria incidence rates during the rainy season. Parasite and anaemia point prevalence also showed seasonal variation with much higher prevalence rates during rainy seasons compared to dry seasons. Despite the scaling up of malaria prevention and treatment, including the widespread use of bed nets, better diagnosis and wider availability of ACT, malaria incidence did not decrease in Bandiagara during the study period.

  5. The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi.

    Directory of Open Access Journals (Sweden)

    Victoria C Barclay

    Full Text Available Malaria vaccine developers are concerned that antigenic escape will erode vaccine efficacy. Evolutionary theorists have raised the possibility that some types of vaccine could also create conditions favoring the evolution of more virulent pathogens. Such evolution would put unvaccinated people at greater risk of severe disease. Here we test the impact of vaccination with a single highly purified antigen on the malaria parasite Plasmodium chabaudi evolving in laboratory mice. The antigen we used, AMA-1, is a component of several candidate malaria vaccines currently in various stages of trials in humans. We first found that a more virulent clone was less readily controlled by AMA-1-induced immunity than its less virulent progenitor. Replicated parasites were then serially passaged through control or AMA-1 vaccinated mice and evaluated after 10 and 21 rounds of selection. We found no evidence of evolution at the ama-1 locus. Instead, virulence evolved; AMA-1-selected parasites induced greater anemia in naïve mice than both control and ancestral parasites. Our data suggest that recombinant blood stage malaria vaccines can drive the evolution of more virulent malaria parasites.

  6. Malaria chemoprophylaxis and the serologic response to measles and diphtheria-tetanus-whole-cell pertussis vaccines

    Directory of Open Access Journals (Sweden)

    Saliou Pierre

    2005-11-01

    Full Text Available Abstract Background Acute malaria has been associated with a decreased antibody response to tetanus and diphtheria toxoids, meningococcal, salmonella, and Hib vaccines. Interest in giving malaria drug therapy and prevention at the time of childhood immunizations has increased greatly following recent trials of intermittent preventive therapy during infancy (IPTi, stimulating this re-analysis of unpublished data. The effect of malaria chemoprophylaxis on vaccine response was studied following administration of measles vaccines and diphtheria-tetanus-whole cell pertussis (DTP vaccines. Methods In 1975, six villages divided into two groups of children ≤74 months of age from Burkina Faso, were assigned to receive amodiaquine hydrochloride chemoprophylaxis (CH+ every two weeks for seven months or no chemoprophylaxis (CH-. After five months, children in each group received either one dose of measles or two doses of DTP vaccines. Results For recipients of the measles vaccine, the seroconversion rates in CH+ and CH- children, respectively, were 93% and 96% (P > 0.05. The seroresponse rates in CH+ and CH- children respectively, were 73% and 86% for diphtheria (P > 0.05 and 77% and 91% for tetanus toxoid (P > 0.05. In a subset analysis, in which only children who strictly adhered to chemoprophylaxis criteria were included, there were, likewise, no significant differences in seroconversion or seroresponse for measles, diphtheria, or tetanus vaccines (P > 0.05. While analysis for pertussis showed a 43% (CH+ and 67% (CH- response (P Conclusion Malaria chemoprophylaxis prior to vaccination in malaria endemic settings did not improve or impair immunogenicity of DTP and measles vaccines. This is the first human study to look at the association between malaria chemoprophylaxis and the serologic response to whole-cell pertussis vaccine.

  7. Malaria in pregnancy: the relevance of animal models for vaccine development.

    Science.gov (United States)

    Doritchamou, Justin; Teo, Andrew; Fried, Michal; Duffy, Patrick E

    2017-10-06

    Malaria during pregnancy due to Plasmodium falciparum or P. vivax is a major public health problem in endemic areas, with P. falciparum causing the greatest burden of disease. Increasing resistance of parasites and mosquitoes to existing tools, such as preventive antimalarial treatments and insecticide-treated bed nets respectively, is eroding the partial protection that they offer to pregnant women. Thus, development of effective vaccines against malaria during pregnancy is an urgent priority. Relevant animal models that recapitulate key features of the pathophysiology and immunology of malaria in pregnant women could be used to accelerate vaccine development. This review summarizes available rodent and nonhuman primate models of malaria in pregnancy, and discusses their suitability for studies of biologics intended to prevent or treat malaria in this vulnerable population.

  8. Development of vaccines against Plasmodium falciparum malaria: taking lessons from naturally acquired protective immunity

    DEFF Research Database (Denmark)

    Hviid, Lars

    2007-01-01

    The acquisition of substantial anti-malarial protection in people naturally exposed to P. falciparum is often cited as evidence that malaria vaccines can be developed, but is rarely used to guide the development. We are pursuing the development of vaccines based on antigens and immune responses...

  9. Avances más recientes en el desarrollo de vacunas contra la malaria The most recent advances in developing vaccines against malaria

    Directory of Open Access Journals (Sweden)

    Lázara Rojas Rivero

    2005-02-01

    Full Text Available According to reports of the Pan American Health Organization, malaria transmission continues to occur in 21 countries of the Americas. Of the 835 million inhabitants of the Region of the Americas, 293 million live in areas with some possibility of transmission of the disease. The most advanced of the candidate vaccines that have been designed based on the sequences of the circumsporozoite protein, is one based on the RTS,S/AS02A polypeptides of Plasmodium falciparum. A test of that vaccine was conducted in Mozambique with children from 1 to 4 years old. The test proved the vaccine to be safe, well tolerated, and immunogenic, but the level of protection reached was still low. However, the advantages that the RTS,S/AS02A vaccine offers to people who live in malaria-endemic areas justifies its being tested in the Americas in order to evaluate its effectiveness in the clinical and epidemiological conditions specific to the Region.

  10. Plasmodium falciparum CS protein - prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation

    Directory of Open Access Journals (Sweden)

    Denise L. Doolan

    1992-01-01

    Full Text Available Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by citotoxic T lymphocytes (CTL specific for epitopes within the circumsporozoite (CS protein. Humans, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans ralies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL. against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.

  11. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children

    DEFF Research Database (Denmark)

    Agnandji, Selidji Todagbe; Lell, Bertrand; Soulanoudjingar, Solange Solmeheim

    2011-01-01

    An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries.......An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries....

  12. A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria.

    Science.gov (United States)

    Lozano, José Manuel; Varela, Yahson; Silva, Yolanda; Ardila, Karen; Forero, Martha; Guasca, Laura; Guerrero, Yuly; Bermudez, Adriana; Alba, Patricia; Vanegas, Magnolia; Patarroyo, Manuel Elkin

    2017-11-01

    Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of Pf CSP, STARP; MSA1 and Pf 155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei -ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

  13. A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria

    Directory of Open Access Journals (Sweden)

    José Manuel Lozano

    2017-11-01

    Full Text Available Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of PfCSP, STARP; MSA1 and Pf155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei-ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

  14. Induction and maintenance of protective CD8+ T cells against malaria liver stages: implications for vaccine development

    Directory of Open Access Journals (Sweden)

    Sze-Wah Tse

    2011-08-01

    Full Text Available CD8+ T cells against malaria liver stages represent a major protective immune mechanism against infection. Following induction in the peripheral lymph nodes by dendritic cells (DCs, these CD8+ T cells migrate to the liver and eliminate parasite infected hepatocytes. The processing and presentation of sporozoite antigen requires TAP mediated transport of major histocompatibility complex class I epitopes to the endoplasmic reticulum. Importantly, in DCs this process is also dependent on endosome-mediated cross presentation while this mechanism is not required for epitope presentation on hepatocytes. Protective CD8+ T cell responses are strongly dependent on the presence of CD4+ T cells and the capacity of sporozoite antigen to persist for a prolonged period of time. While human trials with subunit vaccines capable of inducing antibodies and CD4+ T cell responses have yielded encouraging results, an effective anti-malaria vaccine will likely require vaccine constructs designed to induce protective CD8+ T cells against malaria liver stages.

  15. Structure-activity-based design of a synthetic malaria peptide eliciting sporozoite inhibitory antibodies in a virosomal formulation.

    NARCIS (Netherlands)

    Okitsu, S.L.; Kienzl, U.; Moehle, K.; Silvie, O.; Peduzzi, E.; Mueller, M.S.; Sauerwein, R.W.; Matile, H.; Zurbriggen, R.; Mazier, D.; Robinson, J.A.; Pluschke, G.

    2007-01-01

    The circumsporozoite protein (CSP) of Plasmodium falciparum is a leading candidate antigen for inclusion in a malaria subunit vaccine. We describe here the design of a conformationally constrained synthetic peptide, designated UK-39, which has structural and antigenic similarity to the NPNA-repeat

  16. Clinical development of a VAR2CSA-based placental malaria vaccine PAMVAC

    DEFF Research Database (Denmark)

    Gbédandé, Komi; Fievet, Nadine; Viwami, Firmine

    2017-01-01

    Background  The antigen VAR2CSA plays a pivotal role in the pathophysiology of pregnancy-associated malaria (PAM) caused by Plasmodium falciparum. A VAR2CSA-based vaccine candidate, PAMVAC, is under development by an EU-funded multi-country consortium (PlacMalVac project). As part of PAMVAC...

  17. Development of malaria transmission-blocking vaccines: from concept to product.

    Science.gov (United States)

    Wu, Yimin; Sinden, Robert E; Churcher, Thomas S; Tsuboi, Takafumi; Yusibov, Vidadi

    2015-06-01

    Despite decades of effort battling against malaria, the disease is still a major cause of morbidity and mortality. Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. In the 1950s, Huff et al. first demonstrated the induction of transmission-blocking immunity in chickens by repeated immunizations with Plasmodium gallinaceum-infected red blood cells. Since then, significant progress has been made in identification of parasite antigens responsible for transmission-blocking activity. Recombinant technologies accelerated evaluation of these antigens as vaccine candidates, and it is possible to induce effective transmission-blocking immunity in humans both by natural infection and now by immunization with recombinant vaccines. This chapter reviews the efforts to produce TBVs, summarizes the current status and advances and discusses the remaining challenges and approaches. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. A malaria vaccine that elicits in humans antibodies able to kill Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available BACKGROUND: Plasmodium falciparum merozoite surface protein 3 is a malaria vaccine candidate that was identified, characterised, and developed based on a unique immuno-clinical approach. The vaccine construct was derived from regions fully conserved among various strains and containing B cell epitopes targeted by human antibodies (from malaria-immune adults that are able to mediate a monocyte-dependent parasite killing effect. The corresponding long synthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 as adjuvant. METHODS AND FINDINGS: Both formulations induced cellular and humoral immune responses. With alum, the responses lasted up to 12 mo. The vaccine-induced antibodies were predominantly of cytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced an inhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, which was in most instances as high as or greater than that induced by natural antibodies from immune African adults. In vivo transfer of the volunteers' sera into P. falciparum-infected humanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effects were related to the antibody reactivity with the parasite native protein, which was seen in 60% of the volunteers, and remained in samples taken 12 mo postimmunisation. CONCLUSION: This is the first malaria vaccine clinical trial to clearly demonstrate antiparasitic activity by vaccine-induced antibodies by both in vitro and in vivo methods. The results, showing the induction of long-lasting antibodies directed to a fully conserved polypeptide, also challenge current concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity, and poor induction of immune memory.

  19. A malaria vaccine that elicits in humans antibodies able to kill Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Pierre Druilhe

    2005-11-01

    Full Text Available Plasmodium falciparum merozoite surface protein 3 is a malaria vaccine candidate that was identified, characterised, and developed based on a unique immuno-clinical approach. The vaccine construct was derived from regions fully conserved among various strains and containing B cell epitopes targeted by human antibodies (from malaria-immune adults that are able to mediate a monocyte-dependent parasite killing effect. The corresponding long synthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 as adjuvant.Both formulations induced cellular and humoral immune responses. With alum, the responses lasted up to 12 mo. The vaccine-induced antibodies were predominantly of cytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced an inhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, which was in most instances as high as or greater than that induced by natural antibodies from immune African adults. In vivo transfer of the volunteers' sera into P. falciparum-infected humanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effects were related to the antibody reactivity with the parasite native protein, which was seen in 60% of the volunteers, and remained in samples taken 12 mo postimmunisation.This is the first malaria vaccine clinical trial to clearly demonstrate antiparasitic activity by vaccine-induced antibodies by both in vitro and in vivo methods. The results, showing the induction of long-lasting antibodies directed to a fully conserved polypeptide, also challenge current concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity, and poor induction of immune memory.

  20. N-Terminal Plasmodium vivax Merozoite Surface Protein-1, a Potential Subunit for Malaria Vivax Vaccine

    Directory of Open Access Journals (Sweden)

    Fernanda G. Versiani

    2013-01-01

    Full Text Available The human malaria is widely distributed in the Middle East, Asia, the western Pacific, and Central and South America. Plasmodium vivax started to have the attention of many researchers since it is causing diseases to millions of people and several reports of severe malaria cases have been noticed in the last few years. The lack of in vitro cultures for P. vivax represents a major delay in developing a functional malaria vaccine. One of the major candidates to antimalarial vaccine is the merozoite surface protein-1 (MSP1, which is expressed abundantly on the merozoite surface and capable of activating the host protective immunity. Studies have shown that MSP-1 possesses highly immunogenic fragments, capable of generating immune response and protection in natural infection in endemic regions. This paper shows humoral immune response to different proteins of PvMSP1 and the statement of N-terminal to be added to the list of potential candidates for malaria vivax vaccine.

  1. Evidence for globally shared, cross-reacting polymorphic epitopes in the pregnancy-associated malaria vaccine candidate VAR2CSA

    DEFF Research Database (Denmark)

    Avril, Marion; Kulasekara, Bridget R; Gose, Severin O

    2008-01-01

    Pregnancy-associated malaria (PAM) is characterized by the placental sequestration of Plasmodium falciparum-infected erythrocytes (IEs) with the ability to bind to chondroitin sulfate A (CSA). VAR2CSA is a leading candidate for a pregnancy malaria vaccine, but its large size ( approximately 350 k...

  2. Comparative decline in funding of European Commission malaria vaccine projects: what next for the European scientists working in this field?

    Directory of Open Access Journals (Sweden)

    Imoukhuede Egeruan B

    2011-09-01

    Full Text Available Abstract Since 2000, under the Fifth and subsequent Framework Programmes, the European Commission has funded research to spur the development of a malaria vaccine. This funding has contributed to the promotion of an integrated infrastructure consisting of European basic, applied and clinical scientists in academia and small and medium enterprises, together with partners in Africa. Research has added basic understanding of what is required of a malaria vaccine, allowing selected candidates to be prioritized and some to be moved forward into clinical trials. To end the health burden of malaria, and its economic and social impact on development, the international community has now essentially committed itself to the eventual eradication of malaria. Given the current tentative advances towards elimination or eradication of malaria in many endemic areas, malaria vaccines constitute an additional and almost certainly essential component of any strategic plan to interrupt transmission of malaria. However, funding for malaria vaccines has been substantially reduced in the Seventh Framework Programme compared with earlier Framework Programmes, and without further support the gains made by earlier European investment will be lost.

  3. Comparative decline in funding of European Commission malaria vaccine projects: what next for the European scientists working in this field?

    DEFF Research Database (Denmark)

    Thøgersen, Regitze L; Holder, Anthony A; Hill, Adrian Vs

    2011-01-01

    scientists in academia and small and medium enterprises, together with partners in Africa. Research has added basic understanding of what is required of a malaria vaccine, allowing selected candidates to be prioritized and some to be moved forward into clinical trials. To end the health burden of malaria...

  4. A randomized controlled Phase Ib trial of the malaria vaccine candidate GMZ2 in African children

    DEFF Research Database (Denmark)

    Bélard, Sabine; Issifou, Saadou; Hounkpatin, Aurore B

    2011-01-01

    GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP) that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese ...... adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials....

  5. Phase 1 trial of malaria transmission blocking vaccine candidates Pfs25 and Pvs25 formulated with montanide ISA 51.

    Directory of Open Access Journals (Sweden)

    Yimin Wu

    2008-07-01

    Full Text Available Pfs25 and Pvs25, surface proteins of mosquito stage of the malaria parasites P. falciparum and P. vivax, respectively, are leading candidates for vaccines preventing malaria transmission by mosquitoes. This single blinded, dose escalating, controlled Phase 1 study assessed the safety and immunogenicity of recombinant Pfs25 and Pvs25 formulated with Montanide ISA 51, a water-in-oil emulsion.The trial was conducted at The Johns Hopkins Center for Immunization Research, Washington DC, USA, between May 16, 2005-April 30, 2007. The trial was designed to enroll 72 healthy male and non-pregnant female volunteers into 1 group to receive adjuvant control and 6 groups to receive escalating doses of the vaccines. Due to unexpected reactogenicity, the vaccination was halted and only 36 volunteers were enrolled into 4 groups: 3 groups of 10 volunteers each were immunized with 5 microg of Pfs25/ISA 51, 5 microg of Pvs25/ISA 51, or 20 microg of Pvs25/ISA 51, respectively. A fourth group of 6 volunteers received adjuvant control (PBS/ISA 51. Frequent local reactogenicity was observed. Systemic adverse events included two cases of erythema nodosum considered to be probably related to the combination of the antigen and the adjuvant. Significant antibody responses were detected in volunteers who completed the lowest scheduled doses of Pfs25/ISA 51. Serum anti-Pfs25 levels correlated with transmission blocking activity.It is feasible to induce transmission blocking immunity in humans using the Pfs25/ISA 51 vaccine, but these vaccines are unexpectedly reactogenic for further development. This is the first report that the formulation is associated with systemic adverse events including erythema nodosum.ClinicalTrials.gov NCT00295581.

  6. Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine.

    Directory of Open Access Journals (Sweden)

    Matthew B Laurens

    Full Text Available The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1 and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90 (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02. From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001. In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364 and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials

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

    Directory of Open Access Journals (Sweden)

    Mahamadou A Thera

    2008-01-01

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

  8. Factors likely to affect community acceptance of a malaria vaccine in two districts of Ghana: a qualitative study.

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    Arantza Meñaca

    Full Text Available Malaria is a leading cause of morbidity and mortality among children in Ghana. As part of the effort to inform local and national decision-making in preparation for possible malaria vaccine introduction, this qualitative study explored community-level factors that could affect vaccine acceptance in Ghana and provides recommendations for a health communications strategy. The study was conducted in two purposively selected districts: the Ashanti and Upper East Regions. A total of 25 focus group discussions, 107 in-depth interviews, and 21 semi-structured observations at Child Welfare Clinics were conducted. Malaria was acknowledged to be one of the most common health problems among children. While mosquitoes were linked to the cause and bed nets were considered to be the main preventive method, participants acknowledged that no single measure prevented malaria. The communities highly valued vaccines and cited vaccination as the main motivation for taking children to Child Welfare Clinics. Nevertheless, knowledge of specific vaccines and what they do was limited. While communities accepted the idea of minor vaccine side effects, other side effects perceived to be more serious could deter families from taking children for vaccination, especially during vaccination campaigns. Attendance at Child Welfare Clinics after age nine months was limited. Observations at clinics revealed that while two different opportunities for counseling were offered, little attention was given to addressing mothers' specific concerns and to answering questions related to child immunization. Positive community attitudes toward vaccines and the understanding that malaria prevention requires a comprehensive approach would support the introduction of a malaria vaccine. These attitudes are bolstered by a well-established child welfare program and the availability in Ghana of active, flexible structures for conveying health information to communities. At the same time, it would

  9. Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care.

    Science.gov (United States)

    Vekemans, Johan; Marsh, Kevin; Greenwood, Brian; Leach, Amanda; Kabore, William; Soulanoudjingar, Solange; Asante, Kwaku Poku; Ansong, Daniel; Evans, Jennifer; Sacarlal, Jahit; Bejon, Philip; Kamthunzi, Portia; Salim, Nahya; Njuguna, Patricia; Hamel, Mary J; Otieno, Walter; Gesase, Samwel; Schellenberg, David

    2011-08-04

    An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children

  10. Multiple Antigen Peptide Vaccines against Plasmodium falciparum Malaria

    Science.gov (United States)

    2010-01-01

    Robert A. Boykins/ Victoria Majam,l Hong Zheng,1 Rana Chattopadhyay,l Patricia de Ia Vcga,3 J. Kathleen Moch ,J J. David Hayncs,3 Igor M. Belyakov,2...K. Moch , and D. S. Smoot. 2002. Erythroc-ytic malaria growth or invasion inhibition assays with emphasis on suspension culture GIA. Methods Mol. Med

  11. Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production.

    Science.gov (United States)

    Oyarzún, Patricio; Kobe, Bostjan

    2016-03-03

    Novel vaccination approaches based on rational design of B- and T-cell epitopes - epitope-based vaccines - are making progress in the clinical trial pipeline. The epitope-focused recombinant protein-based malaria vaccine (termed RTS,S) is a next-generation approach that successfully reached phase-III trials, and will potentially become the first commercial vaccine against a human parasitic disease. Progress made on methods such as recombinant DNA technology, advanced cell-culture techniques, immunoinformatics and rational design of immunogens are driving the development of these novel concepts. Synthetic recombinant proteins comprising both B- and T-cell epitopes can be efficiently produced through modern biotechnology and bioprocessing methods, and can enable the induction of large repertoires of immune specificities. In particular, the inclusion of appropriate CD4+ T-cell epitopes is increasingly considered a key vaccine component to elicit robust immune responses, as suggested by results coming from HIV-1 clinical trials. In silico strategies for vaccine design are under active development to address genetic variation in pathogens and several broadly protective "universal" influenza and HIV-1 vaccines are currently at different stages of clinical trials. Other methods focus on improving population coverage in target populations by rationally considering specificity and prevalence of the HLA proteins, though a proof-of-concept in humans has not been demonstrated yet. Overall, we expect immunoinformatics and bioprocessing methods to become a central part of the next-generation epitope-based vaccine development and production process.

  12. Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: further results from a phase IIb trial in Mozambican children.

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    Caterina Guinovart

    Full Text Available The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S.The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1 and infection (cohort 2. Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase and over the following 12 months (single-blind phase, and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029 over the double-blind phase and of 9.0% (-30.6-36.6; p = 0.609 during the single-blind phase.Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia

  13. Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children.

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    John Lusingu

    2010-11-01

    Full Text Available The malaria vaccine candidate, RTS,S/AS01(E, showed promising protective efficacy in a trial of Kenyan and Tanzanian children aged 5 to 17 months. Here we report on the vaccine's safety and tolerability. The experimental design was a Phase 2b, two-centre, double-blind (observer- and participant-blind, randomised (1∶1 ratio controlled trial. Three doses of study or control (rabies vaccines were administered intramuscularly at 1 month intervals. Solicited adverse events (AEs were collected for 7 days after each vaccination. There was surveillance and reporting for unsolicited adverse events for 30 days after each vaccination. Serious adverse events (SAEs were recorded throughout the study period which lasted for 14 months after dose 1 in Korogwe, Tanzania and an average of 18 months post-dose 1 in Kilifi, Kenya. Blood samples for safety monitoring of haematological, renal and hepatic functions were taken at baseline, 3, 10 and 14 months after dose 1. A total of 894 children received RTS,S/AS01(E or rabies vaccine between March and August 2007. Overall, children vaccinated with RTS,S/AS01(E had fewer SAEs (51/447 than children in the control group (88/447. One SAE episode in a RTS,S/AS01(E recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01(E group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently reported unsolicited AE. Fever was the most frequently observed solicited AE and was recorded after 11% of RTS,S/AS01(E doses compared to 31% of doses of rabies vaccine. The candidate vaccine RTS,S/AS01(E showed an acceptable safety profile in children living in a malaria-endemic area in East Africa. More data on the safety of RTS,S/AS01(E will become available from the Phase 3 programme.

  14. Antingens for a Vaccine that Prevents Severe Malaria

    Science.gov (United States)

    2009-03-01

    3,210,682 220,620 sum 6,076,570 4,845,314 Table 3: Number of sequencing reads for uninfected blood and blood with cultured parasites o determine if the...Trends Parasitol, 22(3):99-101 2. Kappe SHI, Duffy PE. 2006. Malaria liver stage culture : in Hyg, 74(5):706-7 3. Duffy PE, Muta 367(9528):2037-9. 4...classified as the short (S) allele. SNPs that flanked the dinucleotide repeat region and that varied in frequency between Caucasian and Yoruba

  15. Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

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    Mahamadou A Thera

    2010-02-01

    Full Text Available The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02(A in children exposed to seasonal falciparum malaria.A Phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02(A is a recombinant protein (FMP2.1 based on apical membrane antigen 1 (AMA1 from the 3D7 clone of P. falciparum, formulated in the Adjuvant System AS02(A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert. One hundred healthy Malian children aged 1-6 years were recruited into 3 cohorts and randomized to receive either 10 microg FMP2.1 in 0.1 mL AS02(A, or 25 microg FMP2.1 in 0.25 mL AS02(A, or 50 microg FMP2.1 50 microg in 0.5 mL AS02(A, or rabies vaccine. Three doses of vaccine were given at 0, 1 and 2 months, and children were followed for 1 year. Solicited symptoms were assessed for 7 days and unsolicited symptoms for 30 days after each vaccination. Serious adverse events were assessed throughout the study. Transient local pain and swelling were common and more frequent in all malaria vaccine dosage groups than in the comparator group, but were acceptable to parents of participants. Levels of anti-AMA1 antibodies measured by ELISA increased significantly (at least 100-fold compared to baseline in all 3 malaria vaccine groups, and remained high during the year of follow up.The FMP2.1/AS02(A vaccine had a good safety profile, was well-tolerated, and induced high and sustained antibody levels in malaria-exposed children. This malaria vaccine is being evaluated in a Phase 2 efficacy trial in children at this site.ClinicalTrials.gov NCT00358332 [NCT00358332].

  16. Malaria.

    Science.gov (United States)

    Dupasquier, Isabelle

    1989-01-01

    Malaria, the greatest pandemia in the world, claims an estimated one million lives each year in Africa alone. While it may still be said that for the most part malaria is found in what is known as the world's poverty belt, cases are now frequently diagnosed in western countries. Due to resistant strains of malaria which have developed because of…

  17. Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: randomized phase 1b trial in semi-immune adults & children.

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    Patrick Georges Cech

    Full Text Available This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.No serious or severe adverse events (AEs related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014. In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29-0.88], p = 0.02.These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.ClinicalTrials.gov NCT00513669.

  18. Prospects and Pitfalls of Pregnancy-Associated Malaria Vaccination Based on the Natural Immune Response to Plasmodium falciparum VAR2CSA-Expressing Parasites

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    Elizabeth G. Kane

    2011-01-01

    Full Text Available Pregnancy-associated malaria, a manifestation of severe malaria, is the cause of up to 200,000 infant deaths a year, through the effects of placental insufficiency leading to growth restriction and preterm delivery. Development of a vaccine is one strategy for control. Plasmodium falciparum-infected red blood cells accumulate in the placenta through specific binding of pregnancy-associated parasite variants that express the VAR2CSA antigen to chondroitin sulphate A on the surface of syncytiotrophoblast cells. Parasite accumulation, accompanied by an inflammatory infiltrate, disrupts the cytokine balance of pregnancy with the potential to cause placental damage and compromise foetal growth. Multigravid women develop immunity towards VAR2CSA-expressing parasites in a gravidity-dependent manner which prevents unfavourable pregnancy outcomes. Although current vaccine design, targeting VAR2CSA antigens, has succeeded in inducing antibodies artificially, this candidate may not provide protection during the first trimester and may only protect those women living in areas endemic for malaria. It is concluded that while insufficient information about placental-parasite interactions is presently available to produce an effective vaccine, incremental progress is being made towards achieving this goal.

  19. A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children

    DEFF Research Database (Denmark)

    Sirima, Sodiomon B; Mordmüller, Benjamin; Milligan, Paul

    2016-01-01

    randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL. RESULTS: A cohort of 1849...... in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). CONCLUSIONS: GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially...

  20. Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12–24 months

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    Segeja Method D

    2009-07-01

    Full Text Available Abstract Background Development and deployment of an effective malaria vaccine would complement existing malaria control measures. A blood stage malaria vaccine candidate, Merozoite Surface Protein-3 (MSP3, produced as a long synthetic peptide, has been shown to be safe in non-immune and semi-immune adults. A phase Ib dose-escalating study was conducted to assess the vaccine's safety and immunogenicity in children aged 12 to 24 months in Korogwe, Tanzania (ClinicalTrials.gov number: NCT00469651. Methods This was a double-blind, randomized, controlled, dose escalation phase Ib trial, in which children were given one of two different doses of the MSP3 antigen (15 μg or 30 μg or a control vaccine (Engerix B. Children were randomly allocated either to the MSP3 candidate malaria vaccine or the control vaccine administered at a schedule of 0, 1, and 2 months. Immunization with lower and higher doses was staggered for safety reasons starting with the lower dose. The primary endpoint was safety and reactogenicity within 28 days post-vaccination. Blood samples were obtained at different time points to measure immunological responses. Results are presented up to 84 days post-vaccination. Results A total of 45 children were enrolled, 15 in each of the two MSP3 dose groups and 15 in the Engerix B group. There were no important differences in reactogenicity between the two MSP3 groups and Engerix B. Grade 3 adverse events were infrequent; only five were detected throughout the study, all of which were transient and resolved without sequelae. No serious adverse event reported was considered to be related to MSP3 vaccine. Both MSP3 dose regimens elicited strong cytophilic IgG responses (subclasses IgG1 and IgG3, the isotypes involved in the monocyte-dependant mechanism of Plasmodium falciparum parasite-killing. The titers reached are similar to those from African adults having reached a state of premunition. Furthermore, vaccination induced seroconversion in

  1. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa

    DEFF Research Database (Denmark)

    Theander, Thor Grundtvig; Lusingu, John Peter Andrea

    2015-01-01

    and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through......, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative....

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

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    Jason W Bennett

    2016-02-01

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

  3. Multilaboratory approach to preclinical evaluation of vaccine immunogens for placental malaria

    DEFF Research Database (Denmark)

    Fried, Michal; Avril, Marion; Chaturvedi, Richa

    2013-01-01

    a vaccine targeting individual Duffy binding-like (DBL) domains. In this study, a consortium of laboratories under the Pregnancy Malaria Initiative compared the functional activity of antiadhesion antibodies elicited by different VAR2CSA domains and variants produced in prokaryotic and eukaryotic expression...... systems. Antisera were initially tested against laboratory lines of maternal parasites, and the most promising reagents were evaluated in the field against fresh placental parasite samples. Recombinant proteins expressed in Escherichia coli elicited antibody levels similar to those expressed in eukaryotic...

  4. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age

    DEFF Research Database (Denmark)

    Bejon, Philip; Lusingu, John; Olotu, Ally

    2008-01-01

    . We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS: We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi...... vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy...... rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; Prabies vaccine, with an adjusted rate of efficacy...

  5. Sterile protection against Plasmodium knowlesi in rhesus monkeys from a malaria vaccine: comparison of heterologous prime boost strategies.

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    George Jiang

    Full Text Available Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA, alphavirus replicons (VRP, attenuated adenovirus serotype 5 (Ad, or attenuated poxvirus (Pox. These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost.

  6. Efficacy of RTS,S/AS01E Vaccine against Malaria in Children 5 to 17 Months of Age

    Science.gov (United States)

    Bejon, Philip; Lusingu, John; Olotu, Ally; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Mshamu, Salum; Lang, Trudie; Gould, Jayne; Dubois, Marie-Claude; Demoitié, Marie-Ange; Stallaert, Jean-Francois; Vansadia, Preeti; Carter, Terrell; Njuguna, Patricia; Awuondo, Ken O.; Malabeja, Anangisye; Abdul, Omar; Gesase, Samwel; Mturi, Neema; Drakeley, Chris J.; Savarese, Barbara; Villafana, Tonya; Ballou, W. Ripley; Cohen, Joe; Riley, Eleanor M.; Lemnge, Martha M.; Marsh, Kevin; von Seidlein, Lorenz

    2009-01-01

    BACKGROUND Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P<0.001) on the basis of Cox regression. Overall, there were 38 episodes of clinical malaria among recipients of RTS,S/AS01E, as compared with 86 episodes among recipients of the rabies vaccine, with an adjusted rate of efficacy against all malarial episodes of 56% (95% CI, 31 to 72; P<0.001). All 894 children were included in the intention-to-treat analysis, which showed an unadjusted efficacy rate of 49% (95% CI, 26 to 65; P<0.001). There were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only due to a difference in the number of admissions directly attributable to malaria. CONCLUSIONS RTS,S/AS01E shows promise as a candidate malaria vaccine. (ClinicalTrials.gov number, NCT

  7. Phase 1 study in malaria naïve adults of BSAM2/Alhydrogel®+CPG 7909, a blood stage vaccine against P. falciparum malaria.

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    Ruth D Ellis

    Full Text Available A Phase 1 dose escalating study was conducted in malaria naïve adults to assess the safety, reactogenicity, and immunogenicity of the blood stage malaria vaccine BSAM2/Alhydrogel®+ CPG 7909. BSAM2 is a combination of the FVO and 3D7 alleles of recombinant AMA1 and MSP1(42, with equal amounts by weight of each of the four proteins mixed, bound to Alhydrogel®, and administered with the adjuvant CPG 7909. Thirty (30 volunteers were enrolled in two dose groups, with 15 volunteers receiving up to three doses of 40 µg total protein at Days 0, 56, and 180, and 15 volunteers receiving up to three doses of 160 µg protein on the same schedule. Most related adverse events were mild or moderate, but 4 volunteers experienced severe systemic reactions and two were withdrawn from vaccinations due to adverse events. Geometric mean antibody levels after two vaccinations with the high dose formulation were 136 µg/ml for AMA1 and 78 µg/ml for MSP1(42. Antibody responses were not significantly different in the high dose versus low dose groups and did not further increase after third vaccination. In vitro growth inhibition was demonstrated and was closely correlated with anti-AMA1 antibody responses. A Phase 1b trial in malaria-exposed adults is being conducted.Clinicaltrials.gov NCT00889616.

  8. Ensemble modeling of the likely public health impact of a pre-erythrocytic malaria vaccine.

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    Thomas Smith

    2012-01-01

    Full Text Available BACKGROUND: The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure. METHODS AND FINDINGS: An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations, supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage. CONCLUSIONS: In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the

  9. The case for PfEMP1-based vaccines to protect pregnant women against Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, Lars

    2011-01-01

    , as well as knowledge regarding the protective immune response that is acquired in response to placental P. falciparum infection. Nevertheless, it remains controversial in some quarters whether such a vaccine would have the desired impact, or indeed whether the strategy is meaningful. This article......Vaccines are very cost-effective tools in combating infectious disease mortality and morbidity. Unfortunately, vaccines efficiently protecting against infection with malaria parasites are not available and are not likely to appear in the near future. An alternative strategy would be vaccines...... protecting against the disease and its consequences rather than against infection per se, by accelerating the development of the protective immunity that is normally acquired after years of exposure to malaria parasites in areas of stable transmission. This latter strategy is being energetically pursued...

  10. Designing a sustainable strategy for malaria control?

    Directory of Open Access Journals (Sweden)

    Mharakurwa Sungano

    2011-08-01

    Full Text Available Abstract Malaria in the 21st century is showing signs of declining over much of its distribution, including several countries in Africa where previously this was not thought to be feasible. Yet for the most part the strategies to attack the infection are similar to those of the 1950s. Three major Journals have recently drawn attention to the situation, stressing the importance of research, describing the successes and defining semantics related to control. But there is a need to stress the importance of local sustainability, and consider somewhat urgently how individual endemic countries can plan and implement the programmes that are currently financed, for the most part, by donor institutions. On an immediate basis research should be more focused on a data driven approach to control. This will entail new thinking on the role of local infrastructure and in training of local scientists in local universities in epidemiology and field malariology so that expanded control programmes can become operational. Donor agencies should encourage and facilitate development of career opportunities for such personnel so that local expertise is available to contribute appropriately.

  11. Molecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25.

    Science.gov (United States)

    Scally, Stephen W; McLeod, Brandon; Bosch, Alexandre; Miura, Kazutoyo; Liang, Qi; Carroll, Sean; Reponen, Sini; Nguyen, Ngan; Giladi, Eldar; Rämisch, Sebastian; Yusibov, Vidadi; Bradley, Allan; Lemiale, Franck; Schief, William R; Emerling, Daniel; Kellam, Paul; King, C Richter; Julien, Jean-Philippe

    2017-11-16

    The Plasmodium falciparum Pfs25 protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen. Pfs25 vaccination is intended to elicit antibodies that inhibit parasite development when ingested by Anopheles mosquitoes during blood meals. The Pfs25 three-dimensional structure has remained elusive, hampering a molecular understanding of its function and limiting immunogen design. We report six crystal structures of Pfs25 in complex with antibodies elicited by immunization via Pfs25 virus-like particles in human immunoglobulin loci transgenic mice. Our structural findings reveal the fine specificities associated with two distinct immunogenic sites on Pfs25. Importantly, one of these sites broadly overlaps with the epitope of the well-known 4B7 mouse antibody, which can be targeted simultaneously by antibodies that target a non-overlapping site to additively increase parasite inhibition. Our molecular characterization of inhibitory antibodies informs on the natural disposition of Pfs25 on the surface of ookinetes and provides the structural blueprints to design next-generation immunogens.

  12. Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccine.

    Science.gov (United States)

    Moon, James J; Suh, Heikyung; Polhemus, Mark E; Ockenhouse, Christian F; Yadava, Anjali; Irvine, Darrell J

    2012-01-01

    The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) "enveloped" by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.

  13. Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccine.

    Directory of Open Access Journals (Sweden)

    James J Moon

    Full Text Available The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide acid (PLGA "enveloped" by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA, was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs. Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.

  14. Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children

    DEFF Research Database (Denmark)

    Lusingu, John; Olotu, Ally; Leach, Amanda

    2010-01-01

    ) recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01(E) group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently...

  15. Malaria

    Science.gov (United States)

    ... less than the risk of catching this infection. Chloroquine has been the drug of choice for protecting against malaria. But because of resistance, it is now only suggested for use in areas where Plasmodium vivax , P. oval , and ...

  16. Malaria

    Science.gov (United States)

    ... bites you, the parasite can get into your blood. The parasite lays eggs, which develop into more parasites. They ... cells until you get very sick. Because the parasites live in the blood, malaria can also be spread through other ways. ...

  17. Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris.

    Science.gov (United States)

    Avril, Marion; Hathaway, Marianne J; Cartwright, Megan M; Gose, Severin O; Narum, David L; Smith, Joseph D

    2009-06-29

    VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.

  18. Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris

    Directory of Open Access Journals (Sweden)

    Narum David L

    2009-06-01

    Full Text Available Abstract Background VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. Methods VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. Results From a total of 42 different VAR2CSA constructs, 15 proteins (36% were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. Conclusion These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.

  19. Assessing the economic benefits of vaccines based on the health investment life course framework: a review of a broader approach to evaluate malaria vaccination.

    Science.gov (United States)

    Constenla, Dagna

    2015-03-24

    Economic evaluations have routinely understated the net benefits of vaccination by not including the full range of economic benefits that accrue over the lifetime of a vaccinated person. Broader approaches for evaluating benefits of vaccination can be used to more accurately calculate the value of vaccination. This paper reflects on the methodology of one such approach - the health investment life course approach - that looks at the impact of vaccine investment on lifetime returns. The role of this approach on vaccine decision-making will be assessed using the malaria health investment life course model example. We describe a framework that measures the impact of a health policy decision on government accounts over many generations. The methodological issues emerging from this approach are illustrated with an example from a recently completed health investment life course analysis of malaria vaccination in Ghana. Beyond the results, various conceptual and practical challenges of applying this framework to Ghana are discussed in this paper. The current framework seeks to understand how disease and available technologies can impact a range of economic parameters such as labour force participation, education, healthcare consumption, productivity, wages or economic growth, and taxation following their introduction. The framework is unique amongst previous economic models in malaria because it considers future tax revenue for governments. The framework is complementary to cost-effectiveness and budget impact analysis. The intent of this paper is to stimulate discussion on how existing and new methodology can add to knowledge regarding the benefits from investing in new and underutilized vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Plasmodium falciparum incidence relative to entomologic inoculation rates at a site proposed for testing malaria vaccines in western Kenya.

    Science.gov (United States)

    Beier, J C; Oster, C N; Onyango, F K; Bales, J D; Sherwood, J A; Perkins, P V; Chumo, D K; Koech, D V; Whitmire, R E; Roberts, C R

    1994-05-01

    Relationships between Plasmodium falciparum incidence and entomologic inoculation rates (EIRs) were determined for a 21-month period in Saradidi, western Kenya, in preparation for malaria vaccine field trials. Children, ranging in age from six months to six years and treated to clear malaria parasites, were monitored daily for up to 12 weeks to detect new malaria infections. Overall, new P. falciparum infections were detected in 77% of 809 children. The percentage of children that developed infections per two-week period averaged 34.7%, ranging from 7.3% to 90.9%. Transmission by vector populations was detected in 86.4% (38 of 44) of the two-week periods, with daily EIRs averaging 0.75 infective bites per person. Periods of intense transmission during April to August, and from November to January, coincided with seasonal rains. Relationships between daily malaria attack rates and EIRs indicated that an average of only 7.5% (1 in 13) of the sporozoite inoculations produced new infections in children. Regression analysis demonstrated that EIRs accounted for 74% of the variation in attack rates. One of the components of the EIR, the human-biting rate, alone accounted for 68% of the variation in attack rates. Thus, measurements of either the EIR or the human-biting rate can be used to predict corresponding attack rates in children. These baseline epidemiologic studies indicate that the intense transmission patterns of P. falciparum in Saradidi will provide excellent conditions for evaluating malaria vaccine efficacy.

  1. How well are malaria maps used to design and finance malaria control in Africa?

    Directory of Open Access Journals (Sweden)

    Judy A Omumbo

    Full Text Available Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed.An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated.91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control.The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be necessary to guide appropriate

  2. How well are malaria maps used to design and finance malaria control in Africa?

    Science.gov (United States)

    Omumbo, Judy A; Noor, Abdisalan M; Fall, Ibrahima S; Snow, Robert W

    2013-01-01

    Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed. An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated. 91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control. The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be necessary to guide appropriate financing for malaria

  3. How Well Are Malaria Maps Used to Design and Finance Malaria Control in Africa?

    Science.gov (United States)

    Omumbo, Judy A.; Noor, Abdisalan M.; Fall, Ibrahima S.; Snow, Robert W.

    2013-01-01

    Introduction Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed. Materials and Methods An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated. Results 91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control. Conclusion The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be

  4. ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans.

    Science.gov (United States)

    Sheehy, Susanne H; Duncan, Christopher J A; Elias, Sean C; Choudhary, Prateek; Biswas, Sumi; Halstead, Fenella D; Collins, Katharine A; Edwards, Nick J; Douglas, Alexander D; Anagnostou, Nicholas A; Ewer, Katie J; Havelock, Tom; Mahungu, Tabitha; Bliss, Carly M; Miura, Kazutoyo; Poulton, Ian D; Lillie, Patrick J; Antrobus, Richard D; Berrie, Eleanor; Moyle, Sarah; Gantlett, Katherine; Colloca, Stefano; Cortese, Riccardo; Long, Carole A; Sinden, Robert E; Gilbert, Sarah C; Lawrie, Alison M; Doherty, Tom; Faust, Saul N; Nicosia, Alfredo; Hill, Adrian V S; Draper, Simon J

    2012-12-01

    The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

  5. A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA.

    Directory of Open Access Journals (Sweden)

    Susan Thrane

    Full Text Available Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP based vaccines (e.g., the licensed human papillomavirus vaccines have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of

  6. Cell biological characterization of the malaria vaccine candidate trophozoite exported protein 1.

    Directory of Open Access Journals (Sweden)

    Caroline Kulangara

    Full Text Available In a genome-wide screen for alpha-helical coiled coil motifs aiming at structurally defined vaccine candidates we identified PFF0165c. This protein is exported in the trophozoite stage and was named accordingly Trophozoite exported protein 1 (Tex1. In an extensive preclinical evaluation of its coiled coil peptides Tex1 was identified as promising novel malaria vaccine candidate providing the rational for a comprehensive cell biological characterization of Tex1. Antibodies generated against an intrinsically unstructured N-terminal region of Tex1 and against a coiled coil domain were used to investigate cytological localization, solubility and expression profile. Co-localization experiments revealed that Tex1 is exported across the parasitophorous vacuole membrane and located to Maurer's clefts. Change in location is accompanied by a change in solubility: from a soluble state within the parasite to a membrane-associated state after export to Maurer's clefts. No classical export motifs such as PEXEL, signal sequence/anchor or transmembrane domain was identified for Tex1.

  7. A Glycolipid Adjuvant, 7DW8-5, Enhances CD8+ T Cell Responses Induced by an Adenovirus-Vectored Malaria Vaccine in Non-Human Primates

    OpenAIRE

    Padte, Neal N.; Boente-Carrera, Mar; Andrews, Chasity D.; McManus, Jenny; Grasperge, Brooke F.; Gettie, Agegnehu; Coelho-dos-Reis, Jordana G.; Li, Xiangming; Wu, Douglass; Bruder, Joseph T.; Sedegah, Martha; Patterson, Noelle; Richie, Thomas L.; Wong, Chi-Huey; Ho, David D.

    2013-01-01

    A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent ad...

  8. Malaria

    Science.gov (United States)

    2011-06-01

    dividing and are far more noticeable than the small amount of clear cyto- plasm surrounding them (Figs 10.6a & 10.6b). Mature schizonts contain 8...edema Same as P. vivax 16 10 • Topics on The paThology of proTozoan and invasive arThropod diseases Figure 10.38 Transmission electron micrograph of...mesangiopathic glo- merulonephropathy caused by quartan malaria, deposition of immune complexes may be demonstrated by electron or immunofluorescence microscopy

  9. Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Bernhards R Ogutu

    Full Text Available The antigen, falciparum malaria protein 1 (FMP1, represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1 of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System, it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg or Rabipur(R rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE was measured over a six-month period following third vaccinations.374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42 antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7.FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42 vaccine development should focus on other formulations and antigen constructs

  10. Comparative testing of six antigen-based malaria vaccine candidates directed toward merozoite-stage Plasmodium falciparum

    DEFF Research Database (Denmark)

    Arnot, David E; Cavanagh, David R; Remarque, Edmond J

    2008-01-01

    Immunogenicity testing of Plasmodium falciparum antigens being considered as malaria vaccine candidates was undertaken in rabbits. The antigens compared were recombinant baculovirus MSP-1(19) and five Pichia pastoris candidates, including two versions of MSP-1(19), AMA-1 (domains I and II), AMA-1......G concentrations. The two P. pastoris-produced MSP-1(19)-induced IgGs conferred the lowest growth inhibition. Comparative analysis of immunogenicity of vaccine antigens can be used to prioritize candidates before moving to expensive GMP production and clinical testing. The assays used have given discriminating...

  11. malERA: An updated research agenda for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication.

    Science.gov (United States)

    2017-11-01

    Since the turn of the century, a remarkable expansion has been achieved in the range and effectiveness of products and strategies available to prevent, treat, and control malaria, including advances in diagnostics, drugs, vaccines, and vector control. These advances have once again put malaria elimination on the agenda. However, it is clear that even with the means available today, malaria control and elimination pose a formidable challenge in many settings. Thus, currently available resources must be used more effectively, and new products and approaches likely to achieve these goals must be developed. This paper considers tools (both those available and others that may be required) to achieve and maintain malaria elimination. New diagnostics are needed to direct treatment and detect transmission potential; new drugs and vaccines to overcome existing resistance and protect against clinical and severe disease, as well as block transmission and prevent relapses; and new vector control measures to overcome insecticide resistance and more powerfully interrupt transmission. It is also essential that strategies for combining new and existing approaches are developed for different settings to maximise their longevity and effectiveness in areas with continuing transmission and receptivity. For areas where local elimination has been recently achieved, understanding which measures are needed to maintain elimination is necessary to prevent rebound and the reestablishment of transmission. This becomes increasingly important as more countries move towards elimination.

  12. Simulation of the Costs and Consequences of Potential Vaccines for Plasmodium Falciparum Malaria

    OpenAIRE

    Tediosi, Fabrizio

    2010-01-01

    Malaria is one of the major public health problems for low income countries, a major global health priority, and it has also a dramatic economic impact. Funding for malaria control is on the rise and both international donors and governments of malaria endemic countries need tools and evidence to assess which are the best and most efficient strategies to control malaria. Standard tools traditionally used to assess the public health and economic impact of malaria control inte...

  13. Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine.

    Science.gov (United States)

    Pearson, Frances E; O'Mahony, Conor; Moore, Anne C; Hill, Adrian V S

    2015-06-22

    There is an urgent need for improvements in vaccine delivery technologies. This is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. Microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. Here, we aimed to investigate immunity induced by the recombinant simian adenovirus-vectored vaccine ChAd63.ME-TRAP; currently undergoing clinical assessment as a candidate malaria vaccine, when delivered percutaneously by silicon microneedle arrays. In mice, we demonstrate that microneedle-mediated delivery of ChAd63.ME-TRAP induced similar numbers of transgene-specific CD8(+) T cells compared to intradermal (ID) administration with needle-and-syringe, following a single immunisation and after a ChAd63/MVA heterologous prime-boost schedule. When mice immunised with ChAd63/MVA were challenged with live Plasmodium berghei sporozoites, microneedle-mediated ChAd63.ME-TRAP priming demonstrated equivalent protective efficacy as did ID immunisation. Furthermore, responses following ChAd63/MVA immunisation correlated with a specific design parameter of the array used ('total array volume'). The level of transgene expression at the immunisation site and skin-draining lymph node (dLN) was also linked to total array volume. These findings have implications for defining silicon microneedle array design for use with live, vectored vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. A randomized placebo-controlled phase Ia malaria vaccine trial of two virosome-formulated synthetic peptides in healthy adult volunteers.

    Directory of Open Access Journals (Sweden)

    Blaise Genton

    2007-10-01

    Full Text Available Influenza virosomes represent an innovative human-compatible antigen delivery system that has already proven its suitability for subunit vaccine design. The aim of the study was to proof the concept that virosomes can also be used to elicit high titers of antibodies against synthetic peptides. The specific objective was to demonstrate the safety and immunogenicity of two virosome-formulated P. falciparum protein derived synthetic peptide antigens given in two different doses alone or in combination.The design was a single blind, randomized, placebo controlled, dose-escalating study involving 46 healthy Caucasian volunteers aged 18-45 years. Five groups of 8 subjects received virosomal formulations containing 10 microg or 50 microg of AMA 49-CPE, an apical membrane antigen-1 (AMA-1 derived synthetic phospatidylethanolamine (PE-peptide conjugate or 10 ug or 50 ug of UK39, a circumsporozoite protein (CSP derived synthetic PE-peptide conjugate or 50 ug of both antigens each. A control group of 6 subjects received unmodified virosomes. Virosomal formulations of the antigens (designated PEV301 and PEV302 for the AMA-1 and the CSP virosomal vaccine, respectively or unmodified virosomes were injected i. m. on days 0, 60 and 180. In terms of safety, no serious or severe adverse events (AEs related to the vaccine were observed. 11/46 study participants reported 16 vaccine related local AEs. Of these 16 events, all being pain, 4 occurred after the 1(st, 7 after the 2(nd and 5 after the 3(rd vaccination. 6 systemic AEs probably related to the study vaccine were reported after the 1(st injection, 10 after the 2(nd and 6 after the 3(rd. Generally, no difference in the distribution of the systemic AEs between either the doses applied (10 respectively 50 microg or the synthetic antigen vaccines (PEV301 and PEV302 used for immunization was found. In terms of immunogenicity, both PEV301 and PEV302 elicited already after two injections a synthetic peptide

  15. Identification of pre-erythrocytic malaria antigens that target hepatocytes for killing in vivo and contribute to protection elicited by whole-parasite vaccination.

    Directory of Open Access Journals (Sweden)

    Lin Chen

    Full Text Available Pre-erythrocytic malaria vaccines, including those based on whole-parasite approaches, have shown protective efficacy in animal and human studies. However few pre-erythocytic antigens other than the immunodominant circumsporozoite protein (CSP have been studied in depth with the goal of developing potent subunit malaria vaccines that are suited for use in endemic areas. Here we describe a novel technique to identify pre-erythrocytic malaria antigens that contribute to protection elicited by whole-parasite vaccination in the mouse model. Our approach combines immunization with genetically attenuated parasites and challenge with DNA plasmids encoding for potential protective pre-erythrocytic malaria antigens as luciferase fusions by hydrodynamic tail vein injection. After optimizing the technique, we first showed that immunization with Pyfabb/f-, a P. yoelii genetically attenuated parasite, induces killing of CSP-presenting hepatocytes. Depletion of CD8+ but not CD4+ T cells diminished the killing of CSP-expressing hepatocytes, indicating that killing is CD8+ T cell-dependent. Finally we showed that the use of heterologous prime/boost immunization strategies that use genetically attenuated parasites and DNA vaccines enabled the characterization of a novel pre-erythrocytic antigen, Tmp21, as a contributor to Pyfabb/f- induced protection. This technique will be valuable for identification of potentially protective liver stage antigens and has the potential to contribute to the understanding of immunity elicited by whole parasite vaccination, as well as the development of effective subunit malaria vaccines.

  16. Mother-Newborn Pairs in Malawi Have Similar Antibody Repertoires to Diverse Malaria Antigens.

    Science.gov (United States)

    Boudová, Sarah; Walldorf, Jenny A; Bailey, Jason A; Divala, Titus; Mungwira, Randy; Mawindo, Patricia; Pablo, Jozelyn; Jasinskas, Algis; Nakajima, Rie; Ouattara, Amed; Adams, Matthew; Felgner, Philip L; Plowe, Christopher V; Travassos, Mark A; Laufer, Miriam K

    2017-10-01

    Maternal antibodies may play a role in protecting newborns against malaria disease. Plasmodium falciparum parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria-specific antibodies have been shown to cross the placenta, the extent to which antibodies that respond to the full repertoire of diverse antigens are transferred from the mother to the infant has not been explored. Understanding the breadth of maternal antibody responses and to what extent these antibodies are transferred to the child can inform vaccine design and evaluation. We probed plasma from cord blood and serum from mothers at delivery using a customized protein microarray that included variants of malaria vaccine target antigens to assess the intensity and breadth of seroreactivity to three malaria vaccine candidate antigens in mother-newborn pairs in Malawi. Among the 33 paired specimens that were assessed, mothers and newborns had similar intensity and repertoire of seroreactivity. Maternal antibody levels against vaccine candidate antigens were the strongest predictors of infant antibody levels. Placental malaria did not significantly impair transplacental antibody transfer. However, mothers with placental malaria had significantly higher antibody levels against these blood-stage antigens than mothers without placental malaria. The repertoire and levels of infant antibodies against a wide range of malaria vaccine candidate antigen variants closely mirror maternal levels in breadth and magnitude regardless of evidence of placental malaria. Vaccinating mothers with an effective malaria vaccine during pregnancy may induce high and potentially protective antibody repertoires in newborns. Copyright © 2017 American Society for Microbiology.

  17. Effect of the pre-erythrocytic candidate malaria vaccine RTS,S/AS01E on blood stage immunity in young children

    DEFF Research Database (Denmark)

    Bejon, Philip; Cook, Jackie; Bergmann-Leitner, Elke

    2011-01-01

    (See the article by Greenhouse et al, on pages 19-26.) Background. RTS,S/AS01(E) is the lead candidate malaria vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage malaria parasites after natural infection. Methods. We measured, by enzyme......, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical malaria. Conclusions. Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus......-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-1(42), EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01(E) or a control vaccine. Results. Antibody...

  18. Humoral immune responses to a single allele PfAMA1 vaccine in healthy malaria-naïve adults.

    Directory of Open Access Journals (Sweden)

    Edmond J Remarque

    Full Text Available Plasmodium falciparum: apical membrane antigen 1 (AMA1 is a candidate malaria vaccine antigen expressed on merozoites and sporozoites. The polymorphic nature of AMA1 may compromise vaccine induced protection. The humoral response induced by two dosages (10 and 50 µg of a single allele AMA1 antigen (FVO formulated with Alhydrogel, Montanide ISA 720 or AS02 was investigated in 47 malaria-naïve adult volunteers. Volunteers were vaccinated 3 times at 4 weekly intervals and serum samples obtained four weeks after the third immunization were analysed for (i Antibody responses to various allelic variants, (ii Domain specificity, (iii Avidity, (iv IgG subclass levels, by ELISA and (v functionality of antibody responses by Growth Inhibition Assay (GIA. About half of the antibodies induced by vaccination cross reacted with heterologous AMA1 alleles. The choice of adjuvant determined the magnitude of the antibody response, but had only a marginal influence on specificity, avidity, domain recognition or subclass responses. The highest antibody responses were observed for AMA1 formulated with AS02. The Growth Inhibition Assay activity of the antibodies was proportional to the amount of antigen specific IgG and the functional capacity of the antibodies was similar for heterologous AMA1-expressing laboratory strains.ClinicalTrials.gov NCT00730782.

  19. Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa

    Directory of Open Access Journals (Sweden)

    Essack Zaynab

    2010-03-01

    Full Text Available Abstract Background Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. Methods In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Results Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. Conclusion The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields.

  20. Convergent ethical issues in HIV/AIDS, tuberculosis and malaria vaccine trials in Africa: Report from the WHO/UNAIDS African AIDS Vaccine Programme's Ethics, Law and Human Rights Collaborating Centre consultation, 10-11 February 2009, Durban, South Africa.

    Science.gov (United States)

    Mamotte, Nicole; Wassenaar, Douglas; Koen, Jennifer; Essack, Zaynab

    2010-03-09

    Africa continues to bear a disproportionate share of the global HIV/AIDS, tuberculosis (TB) and malaria burden. The development and distribution of safe, effective and affordable vaccines is critical to reduce these epidemics. However, conducting HIV/AIDS, TB, and/or malaria vaccine trials simultaneously in developing countries, or in populations affected by all three diseases, is likely to result in numerous ethical challenges. In order to explore convergent ethical issues in HIV/AIDS, TB and malaria vaccine trials in Africa, the Ethics, Law and Human Rights Collaborating Centre of the WHO/UNAIDS African AIDS Vaccine Programme hosted a consultation on the Convergent Ethical Issues in HIV/AIDS, TB and Malaria Vaccine Trials in Africa in Durban, South Africa on the 10-11 February 2009. Key cross cutting ethical issues were prioritized during the consultation as community engagement; ancillary care obligations; care and treatment; informed consent; and resource sharing. The consultation revealed that while there have been few attempts to find convergence on ethical issues between HIV/AIDS, TB and malaria vaccine trial fields to date, there is much common ground and scope for convergence work between stakeholders in the three fields.

  1. Impact on malaria parasite multiplication rates in infected volunteers of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909.

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    Christopher J A Duncan

    Full Text Available Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria.In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes.A significant correlation was observed between parasite multiplication rate in 48 hours (PMR and both vaccine-induced growth-inhibitory activity (Pearson r = -0.93 [95% CI: -1.0, -0.27] P = 0.02 and AMA1 antibody titres in the vaccine group (Pearson r = -0.93 [95% CI: -0.99, -0.25] P = 0.02. However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70. Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5-9], control group median 9 days [range 7-9].Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers.ClinicalTrials.gov [NCT00984763].

  2. The synthetic Plasmodium falciparum circumsporozoite peptide PfCS102 as a malaria vaccine candidate: a randomized controlled phase I trial.

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    Régine Audran

    Full Text Available BACKGROUND: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102 in malaria naive adults. METHODOLOGY AND PRINCIPAL FINDINGS: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity was based on the frequency of adverse events (AE and of abnormal biological safety tests; secondary-end point (immunogenicity on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema. After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+ T cell responses. Responses were only marginally boosted after the 3(rd vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma responses than Montanide formulations. CONCLUSIONS/SIGNIFICANCE: PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential

  3. Malaria resistance | Iyabo | Nigerian Medical Practitioner

    African Journals Online (AJOL)

    Age and puberty have been found to contribute to malaria resistance. It is expected that knowledge of natural resistance to malaria may aid in developing Vaccines against this deadly disease. Keywords: malaria resistance, puberty, malaria economy, malaria vaccine. Nigerian Medical Practitioner Vol. 49(5) 2006: 133-142 ...

  4. Chloroplast-derived vaccine antigens confer dual immunity against cholera and malaria by oral or injectable delivery.

    Science.gov (United States)

    Davoodi-Semiromi, Abdoreza; Schreiber, Melissa; Nalapalli, Samson; Verma, Dheeraj; Singh, Nameirakpam D; Banks, Robert K; Chakrabarti, Debopam; Daniell, Henry

    2010-02-01

    Cholera and malaria are major diseases causing high mortality. The only licensed cholera vaccine is expensive; immunity is lost in children within 3 years and adults are not fully protected. No vaccine is yet available for malaria. Therefore, in this study, the cholera toxin-B subunit (CTB) of Vibrio cholerae fused to malarial vaccine antigens apical membrane antigen-1 (AMA1) and merozoite surface protein-1 (MSP1) was expressed in lettuce and tobacco chloroplasts. Southern blot analysis confirmed homoplasmy and stable integration of transgenes. CTB-AMA1 and CTB-MSP1 fusion proteins accumulated up to 13.17% and 10.11% (total soluble protein, TSP) in tobacco and up to 7.3% and 6.1% (TSP) in lettuce, respectively. Nine groups of mice (n = 10/group) were immunized subcutaneously (SQV) or orally (ORV) with purified antigens or transplastomic tobacco leaves. Significant levels of antigen-specific antibody titres of immunized mice completely inhibited proliferation of the malarial parasite and cross-reacted with the native parasite proteins in immunoblots and immunofluorescence studies. Protection against cholera toxin challenge in both ORV (100%) and SQV (89%) mice correlated with CTB-specific titres of intestinal, serum IgA and IgG1 in ORV and only IgG1 in SQV mice, but no other immunoglobulin. Increasing numbers of interleukin-10(+) T cell but not Foxp3(+) regulatory T cells, suppression of interferon-gamma and absence of interleukin-17 were observed in protected mice, suggesting that immunity is conferred via the Tr1/Th2 immune response. Dual immunity against two major infectious diseases provided by chloroplast-derived vaccine antigens for long-term (>300 days, 50% of mouse life span) offers a realistic platform for low cost vaccines and insight into mucosal and systemic immunity.

  5. Development of behaviour change communication strategy for a vaccination-linked malaria control tool in southern Tanzania

    Directory of Open Access Journals (Sweden)

    Mshinda Hassan

    2008-09-01

    Full Text Available Abstract Background Intermittent preventive treatment of malaria in infants (IPTi using sulphadoxine-pyrimethamine and linked to the expanded programme on immunization (EPI is a promising strategy for malaria control in young children. As evidence grows on the efficacy of IPTi as public health strategy, information is needed so that this novel control tool can be put into practice promptly, once a policy recommendation is made to implement it. This paper describes the development of a behaviour change communication strategy to support implementation of IPTi by the routine health services in southern Tanzania, in the context of a five-year research programme evaluating the community effectiveness of IPTi. Methods Mixed methods including a rapid qualitative assessment and quantitative health facility survey were used to investigate communities' and providers' knowledge and practices relating to malaria, EPI, sulphadoxine-pyrimethamine and existing health posters. Results were applied to develop an appropriate behaviour change communication strategy for IPTi involving personal communication between mothers and health staff, supported by a brand name and two posters. Results Malaria in young children was considered to be a nuisance because it causes sleepless nights. Vaccination services were well accepted and their use was considered the mother's responsibility. Babies were generally taken for vaccination despite complaints about fevers and swellings after the injections. Sulphadoxine-pyrimethamine was widely used for malaria treatment and intermittent preventive treatment of malaria in pregnancy, despite widespread rumours of adverse reactions based on hearsay and newspaper reports. Almost all health providers said that they or their spouse were ready to take SP in pregnancy (96%, 223/242. A brand name, key messages and images were developed and pre-tested as behaviour change communication materials. The posters contained public health messages

  6. A full-length Plasmodium falciparum recombinant circumsporozoite protein expressed by Pseudomonas fluorescens platform as a malaria vaccine candidate.

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    Amy R Noe

    Full Text Available The circumsporozoite protein (CSP of Plasmodium falciparum is a major surface protein, which forms a dense coat on the sporozoite's surface. Preclinical research on CSP and clinical evaluation of a CSP fragment-based RTS, S/AS01 vaccine have demonstrated a modest degree of protection against P. falciparum, mediated in part by humoral immunity and in part by cell-mediated immunity. Given the partial protective efficacy of the RTS, S/AS01 vaccine in a recent Phase 3 trial, further improvement of CSP-based vaccines is crucial. In this report, we describe the preclinical development of a full-length, recombinant CSP (rCSP-based vaccine candidate against P. falciparum malaria suitable for current Good Manufacturing Practice (cGMP production. Utilizing a novel high-throughput Pseudomonas fluorescens expression platform, we demonstrated greater efficacy of full-length rCSP as compared to N-terminally truncated versions, rapidly down-selected a promising lead vaccine candidate, and developed a high-yield purification process to express immunologically active, intact antigen for clinical trial material production. The rCSP, when formulated with various adjuvants, induced antigen-specific antibody responses as measured by enzyme-linked immunosorbent assay (ELISA and immunofluorescence assay (IFA, as well as CD4+ T-cell responses as determined by ELISpot. The adjuvanted rCSP vaccine conferred protection in mice when challenged with transgenic P. berghei sporozoites containing the P. falciparum repeat region of CSP. Furthermore, heterologous prime/boost regimens with adjuvanted rCSP and an adenovirus type 35-vectored CSP (Ad35CS showed modest improvements in eliciting CSP-specific T-cell responses and anti-malarial protection, depending on the order of vaccine delivery. Collectively, these data support the importance of further clinical development of adjuvanted rCSP, either as a stand-alone product or as one of the components in a heterologous prime

  7. Proof of principle for epitope-focused vaccine design

    Science.gov (United States)

    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.

  8. Rational design of gene-based vaccines.

    Science.gov (United States)

    Barouch, Dan H

    2006-01-01

    Vaccine development has traditionally been an empirical discipline. Classical vaccine strategies include the development of attenuated organisms, whole killed organisms, and protein subunits, followed by empirical optimization and iterative improvements. While these strategies have been remarkably successful for a wide variety of viruses and bacteria, these approaches have proven more limited for pathogens that require cellular immune responses for their control. In this review, current strategies to develop and optimize gene-based vaccines are described, with an emphasis on novel approaches to improve plasmid DNA vaccines and recombinant adenovirus vector-based vaccines. Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  9. Adversomics: a new paradigm for vaccine safety and design.

    Science.gov (United States)

    Whitaker, Jennifer A; Ovsyannikova, Inna G; Poland, Gregory A

    2015-07-01

    Despite the enormous population benefits of routine vaccination, vaccine adverse events (AEs) and reactions, whether real or perceived, have posed one of the greatest barriers to vaccine acceptance--and thus to infectious disease prevention--worldwide. A truly integrated clinical, translational, and basic science approach is required to understand the mechanisms behind vaccine AEs, predict them, and then apply this knowledge to new vaccine design approaches that decrease, or avoid, these events. The term 'adversomics' was first introduced in 2009 and refers to the study of vaccine adverse reactions using immunogenomics and systems biology approaches. In this review, we present the current state of adversomics research, review known associations and mechanisms of vaccine AEs/reactions, and outline a plan for the further development of this emerging research field.

  10. Mathematical model for optimal use of sulfadoxine-pyrimethamine as a temporary malaria vaccine.

    Science.gov (United States)

    Dembele, Bassidy; Friedman, Avner; Yakubu, Abdul-Aziz

    2010-05-01

    In this paper, we introduce a deterministic malaria model for determining the drug administration protocol that leads to the smallest first malaria episodes during the wet season. To explore the effects of administering the malaria drug on different days during the wet season while minimizing the potential harmful effects of drug overdose, we define 40 drug administration protocols. Our results fit well with the clinical studies of Coulibaly et al. at a site in Mali. In addition, we provide protocols that lead to smaller number of first malaria episodes during the wet season than the protocol of Coulibaly et al.

  11. Catalase epitopes vaccine design for Helicobacter pylori : A ...

    African Journals Online (AJOL)

    Catalase, an important enzyme in the virulence of H. pylori, could be a suitable candidate for vaccine design because it is highly conserved, which is important for the survival of H. pylori; it is expressed in high level and it is exposed on the surface of the bacteria. In this study, we designed epitope-based vaccine for catalase ...

  12. Using simulation to aid trial design: Ring-vaccination trials.

    Directory of Open Access Journals (Sweden)

    Matt David Thomas Hitchings

    2017-03-01

    Full Text Available The 2014-6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination.We present a stochastic, compartmental model for a ring vaccination trial. After identification of an index case, a ring of contacts is recruited and either vaccinated immediately or after 21 days. The primary outcome of the trial is total vaccine effect, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. Simulation results are used to calculate necessary sample size and estimated vaccine effect. Under baseline assumptions about vaccine properties, monthly incidence in unvaccinated rings and trial design, a standard sample-size calculation neglecting dynamic effects estimated that 7,100 participants would be needed to achieve 80% power to detect a difference in attack rate between arms, while incorporating dynamic considerations in the model increased the estimate to 8,900. This approach replaces assumptions about parameters at the ring level with assumptions about disease dynamics and vaccine characteristics at the individual level, so within this framework we were able to describe the sensitivity of the trial power and estimated effect to various parameters. We found that both of these quantities are sensitive to properties of the vaccine, to setting-specific parameters over which investigators have little control, and to parameters that are determined by the study design.Incorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the

  13. Re-designing the Mozambique vaccine supply chain to improve access to vaccines.

    Science.gov (United States)

    Lee, Bruce Y; Haidari, Leila A; Prosser, Wendy; Connor, Diana L; Bechtel, Ruth; Dipuve, Amelia; Kassim, Hidayat; Khanlawia, Balbina; Brown, Shawn T

    2016-09-22

    Populations and routine childhood vaccine regimens have changed substantially since supply chains were designed in the 1980s, and introducing new vaccines during the "Decade of Vaccine" may exacerbate existing bottlenecks, further inhibiting the flow of all vaccines. Working with the Mozambique Ministry of Health, our team implemented a new process that integrated HERMES computational simulation modeling and on-the-ground implementers to evaluate and improve the Mozambique vaccine supply chain using a system-re-design that integrated new supply chain structures, information technology, equipment, personnel, and policies. The alternative system design raised vaccine availability (from 66% to 93% in Gaza; from 76% to 84% in Cabo Delgado) and reduced the logistics cost per dose administered (from $0.53 to $0.32 in Gaza; from $0.38 to $0.24 in Cabo Delgado) as compared to the multi-tiered system under the current EPI. The alternative system also produced higher availability at lower costs after new vaccine introductions. Since reviewing scenarios modeling deliveries every two months in the north of Gaza, the provincial directorate has decided to pilot this approach diverging from decades of policies dictating monthly deliveries. Re-design improved not only supply chain efficacy but also efficiency, important since resources to deliver vaccines are limited. The Mozambique experience and process can serve as a model for other countries during the Decade of Vaccines. For the Decade of Vaccines, getting vaccines at affordable prices to the market is not enough. Vaccines must reach the population to be successful. Copyright © 2016. Published by Elsevier Ltd.

  14. Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route

    OpenAIRE

    Carey, John B.; Vrdoljak, Anto; O'Mahony, Conor; Hill, Adrian V. S.; Draper, Simon J.; Moore, Anne C.

    2014-01-01

    Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP142, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delive...

  15. Towards clinical development of a Pfs48/45-based transmission blocking malaria vaccine

    NARCIS (Netherlands)

    Theisen, M.; Jore, M.M.; Sauerwein, R.

    2017-01-01

    INTRODUCTION: Malaria is a devastating vector-borne disease caused by the Plasmodium parasite, resulting in almost 0.5 million casualties per year. The parasite has a complex life-cycle that includes asexual replication in human red blood cells, causing symptomatic malaria, and sexual stages which

  16. The GMZ2 malaria vaccine: from concept to efficacy in humans

    DEFF Research Database (Denmark)

    Theisen, Michael; Adu, Bright; Mordmueller, Benjamin

    2017-01-01

    Introduction: GMZ2 is a recombinant protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of Plasmodium falciparum, and is designed with the aim of mimicking naturally acquired anti-malarial immunity. The rationale for combining these two antigens is based...... to review the progress and future prospects for clinical development of GMZ2 sub-unit vaccine. We will focus on discovery, naturally acquired immunity, functional activity of specific antibodies, sequence diversity, production, pre-clinical and clinical studies. Expert commentary: GMZ2 is well tolerated...

  17. Vaccine efficacy against malaria by the combination of porcine parvovirus-like particles and vaccinia virus vectors expressing CS of Plasmodium.

    Directory of Open Access Journals (Sweden)

    Dolores Rodríguez

    Full Text Available With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs carrying the CD8(+ T cell epitope (SYVPSAEQI of the circumsporozoite (CS protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS, and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8(+ T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV vectors from the Western Reserve (WR and modified virus Ankara (MVA strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria.

  18. Vaccine efficacy against malaria by the combination of porcine parvovirus-like particles and vaccinia virus vectors expressing CS of Plasmodium.

    Science.gov (United States)

    Rodríguez, Dolores; González-Aseguinolaza, Gloria; Rodríguez, Juan R; Vijayan, Aneesh; Gherardi, Magdalena; Rueda, Paloma; Casal, J Ignacio; Esteban, Mariano

    2012-01-01

    With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8(+) T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8(+) T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV-PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria.

  19. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial

    DEFF Research Database (Denmark)

    Olotu, Ally; Lusingu, John; Leach, Amanda

    2011-01-01

    RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.......RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up....

  20. Pathogen-mimicking vaccine delivery system designed with a bioactive polymer (inulin acetate) for robust humoral and cellular immune responses.

    Science.gov (United States)

    Kumar, Sunny; Kesharwani, Siddharth S; Kuppast, Bhimanna; Bakkari, Mohammed Ali; Tummala, Hemachand

    2017-09-10

    New and improved vaccines are needed against challenging diseases such as malaria, tuberculosis, Ebola, influenza, AIDS, and cancer. The majority of existing vaccine adjuvants lack the ability to significantly stimulate the cellular immune response, which is required to prevent the aforementioned diseases. This study designed a novel particulate based pathogen-mimicking vaccine delivery system (PMVDS) to target antigen-presenting-cells (APCs) such as dendritic cells. The uniqueness of PMVDS is that the polymer used to prepare the delivery system, Inulin Acetate (InAc), activates the innate immune system. InAc was synthesized from the plant polysaccharide, inulin. PMVDS provided improved and persistent antigen delivery to APCs as an efficient vaccine delivery system, and simultaneously, activated Toll-Like Receptor-4 (TLR-4) on APCs to release chemokine's/cytokines as an immune-adjuvant. Through this dual mechanism, PMVDS robustly stimulated both the humoral (>32 times of IgG1 levels vs alum) and the cell-mediated immune responses against the encapsulated antigen (ovalbumin) in mice. More importantly, PMVDS stimulated both cytotoxic T cells and natural killer cells of cell-mediated immunity to provide tumor (B16-ova-Melanoma) protection in around 40% of vaccinated mice and significantly delayed tumor progression in rest of the mice. PMVDS is a unique bio-active vaccine delivery technology with broader applications for vaccines against cancer and several intracellular pathogens, where both humoral and cellular immune responses are desired. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Immunogenicity of a virosomally-formulated Plasmodium falciparum GLURP-MSP3 chimeric protein-based malaria vaccine candidate in comparison to adjuvanted formulations

    DEFF Research Database (Denmark)

    Tamborrini, Marco; Stoffel, Sabine A; Westerfeld, Nicole

    2011-01-01

    In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs) have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant ...... fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP....

  2. Improving the malaria transmission-blocking activity of a Plasmodium falciparum 48/45 based vaccine antigen by SpyTag/SpyCatcher mediated virus-like display

    DEFF Research Database (Denmark)

    Singh, Susheel K; Thrane, Susan; Janitzek, Christoph M

    2017-01-01

    Malaria is a devastating disease caused by Plasmodium parasites, resulting in almost 0.5 million deaths per year. The Pfs48/45 protein exposed on the P. falciparum sexual stages is one of the most advanced antigen candidates for a transmission-blocking (TB) vaccine in the clinical pipeline. However...

  3. Considerations for the rational design of a Chlamydia vaccine.

    Science.gov (United States)

    Liang, Steven; Bulir, David; Kaushic, Charu; Mahony, James

    2017-04-03

    Chlamydia trachomatis is the leading cause of preventable blindness and the most common bacterial sexually transmitted infection. Remarkable progress in vaccine research over the past six decades has led to the advancement of novel C. trachomatis vaccine candidates into clinical trials. However, many questions regarding the role of specific cellular populations and molecular mechanisms in protective immunity against human C. trachomatis genital tract infections remain unanswered. Biomarkers of vaccine induced protective immunity are elusive in humans, while a cautionary message on the translatability of data obtained from current animal models has emanated from vaccine research and development efforts against other important human pathogens. In this commentary, we highlight recent advances in Chlamydia vaccine development and discuss their implications in the context of a rational approach to the design of a human C. trachomatis vaccine.

  4. A glycolipid adjuvant, 7DW8-5, enhances CD8+ T cell responses induced by an adenovirus-vectored malaria vaccine in non-human primates.

    Science.gov (United States)

    Padte, Neal N; Boente-Carrera, Mar; Andrews, Chasity D; McManus, Jenny; Grasperge, Brooke F; Gettie, Agegnehu; Coelho-dos-Reis, Jordana G; Li, Xiangming; Wu, Douglass; Bruder, Joseph T; Sedegah, Martha; Patterson, Noelle; Richie, Thomas L; Wong, Chi-Huey; Ho, David D; Vasan, Sandhya; Tsuji, Moriya

    2013-01-01

    A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP) model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA), consists of two non-replicating recombinant adenoviral (Ad) vectors, one expressing the circumsporozoite protein (CSP) and another expressing the apical membrane antigen-1 (AMA1) of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM) immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold) in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.

  5. A glycolipid adjuvant, 7DW8-5, enhances CD8+ T cell responses induced by an adenovirus-vectored malaria vaccine in non-human primates.

    Directory of Open Access Journals (Sweden)

    Neal N Padte

    Full Text Available A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer, enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA, consists of two non-replicating recombinant adenoviral (Ad vectors, one expressing the circumsporozoite protein (CSP and another expressing the apical membrane antigen-1 (AMA1 of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.

  6. Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso

    DEFF Research Database (Denmark)

    Diarra, Amidou; Nebie, Issa; Tiono, Alfred

    2012-01-01

    ABSTRACT: BACKGROUND: Patient immune status is thought to affect the efficacy of anti-malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment...... of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. METHODS: Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml) was obtained from each child...... to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. RESULTS: IgG levels to MSP3 were always higher in the successfully treated...

  7. Is maternal education a social vaccine for childhood malaria infection? A cross-sectional study from war-torn Democratic Republic of Congo.

    Science.gov (United States)

    Ma, Cary; Claude, Kasereka Masumbuko; Kibendelwa, Zacharie Tsongo; Brooks, Hannah; Zheng, Xiaonan; Hawkes, Michael

    2017-03-01

    In zones of violent conflict in the tropics, social disruption leads to elevated child mortality, of which malaria is the leading cause. Understanding the social determinants of malaria transmission may be helpful to optimize malaria control efforts. We conducted a cross-sectional study of healthy children aged 2 months to 5 years attending well-child and/or immunization visits in the Democratic Republic of Congo (DRC). Six hundred and forty-seven children were tested for malaria antigenemia by rapid diagnostic test and the accompanying parent or legal guardian simultaneously completed a survey questionnaire related to demographics, socioeconomic status, maternal education, as well as bednet use and recent febrile illness. We examined the associations between variables using multivariable logistic regression analysis, chi-squared statistic, Fisher's exact test, and Spearman's rank correlation, as appropriate. One hundred and twenty-three out of the 647 (19%) children in the study tested positive for malaria. Higher levels of maternal education were associated with a lower risk of malaria in their children. The prevalence of malaria in children of mothers with no education, primary school, and beyond primary was 41/138 (30%), 41/241 (17%), and 39/262 (15%), respectively (p = 0.001). In a multivariable logistic regression model adjusting for the effect of a child's age and study site, the following remained significant predictors of malaria antigenemia: maternal education, number of children under five per household, and HIV serostatus. Higher maternal education, through several putative causal pathways, was associated with lower malaria prevalence among children in the DRC. Our findings suggest that maternal education might be an effective 'social vaccine' against malaria in the DRC and globally.

  8. Analysis of a Multi-component Multi-stage Malaria Vaccine Candidate--Tackling the Cocktail Challenge.

    Directory of Open Access Journals (Sweden)

    Alexander Boes

    Full Text Available Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission of the disease. To investigate the potential of such an approach we combined proteins and domains (11 in total from the pre-erythrocytic, blood and sexual stages of P. falciparum into a cocktail of four different components recombinantly produced in plants. After immunization of rabbits we determined the domain-specific antibody titers as well as component-specific antibody concentrations and correlated them with stage specific in vitro efficacy. Using purified rabbit immune IgG we observed strong inhibition in functional in vitro assays addressing the pre-erythrocytic (up to 80%, blood (up to 90% and sexual parasite stages (100%. Based on the component-specific antibody concentrations we calculated the IC50 values for the pre-erythrocytic stage (17-25 μg/ml, the blood stage (40-60 μg/ml and the sexual stage (1.75 μg/ml. While the results underline the feasibility of a multi-stage vaccine cocktail, the analysis of component-specific efficacy indicates significant differences in IC50 requirements for stage-specific antibody concentrations providing valuable insights into this complex scenario and will thereby improve future approaches towards malaria vaccine cocktail development regarding the selection of suitable antigens and the ratios of components, to fine tune overall and stage-specific efficacy.

  9. Protection of Rhesus Monkeys by a DNA Prime/Poxvirus Boost Malaria Vaccine Depends on Optimal DNA Priming and Inclusion of Blood Stage Antigens

    Science.gov (United States)

    Weiss, Walter R.; Kumar, Anita; Jiang, George; Williams, Jackie; Bostick, Anthony; Conteh, Solomon; Fryauff, David; Aguiar, Joao; Singh, Manmohan; O'Hagan, Derek T.; Ulmer, Jeffery B.; Richie, Thomas L.

    2007-01-01

    Background We have previously described a four antigen malaria vaccine consisting of DNA plasmids boosted by recombinant poxviruses which protects a high percentage of rhesus monkeys against Plasmodium knowlesi (Pk) malaria. This is a multi-stage vaccine that includes two pre-erythrocytic antigens, PkCSP and PkSSP2(TRAP), and two erythrocytic antigens, PkAMA-1 and PkMSP-1(42kD). The present study reports three further experiments where we investigate the effects of DNA dose, timing, and formulation. We also compare vaccines utilizing only the pre-erythrocytic antigens with the four antigen vaccine. Methodology In three experiments, rhesus monkeys were immunized with malaria vaccines using DNA plasmid injections followed by boosting with poxvirus vaccine. A variety of parameters were tested, including formulation of DNA on poly-lactic co-glycolide (PLG) particles, varying the number of DNA injections and the amount of DNA, varying the interval between the last DNA injection to the poxvirus boost from 7 to 21 weeks, and using vaccines with from one to four malaria antigens. Monkeys were challenged with Pk sporozoites given iv 2 to 4 weeks after the poxvirus injection, and parasitemia was measured by daily Giemsa stained blood films. Immune responses in venous blood samples taken after each vaccine injection were measured by ELIspot production of interferon-γ, and by ELISA. Conclusions 1) the number of DNA injections, the formulation of the DNA plasmids, and the interval between the last DNA injection and the poxvirus injection are critical to vaccine efficacy. However, the total dose used for DNA priming is not as important; 2) the blood stage antigens PkAMA-1 and PkMSP-1 were able to protect against high parasitemias as part of a genetic vaccine where antigen folding is not well defined; 3) immunization with PkSSP2 DNA inhibited immune responses to PkCSP DNA even when vaccinations were given into separate legs; and 4) in a counter-intuitive result, higher

  10. Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route.

    Science.gov (United States)

    Carey, John B; Vrdoljak, Anto; O'Mahony, Conor; Hill, Adrian V S; Draper, Simon J; Moore, Anne C

    2014-08-21

    Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP1₄₂, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP1₄₂ also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP1₄₂ using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies.

  11. Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route

    Science.gov (United States)

    Carey, John B.; Vrdoljak, Anto; O'Mahony, Conor; Hill, Adrian V. S.; Draper, Simon J.; Moore, Anne C.

    2014-01-01

    Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP142, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP142 also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP142 using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies. PMID:25142082

  12. Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Gregory E D Mullen

    2008-08-01

    Full Text Available Apical Membrane Antigen 1 (AMA1, a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. This is the first reported use in humans of an investigational vaccine, AMA1-C1/Alhydrogel, with the novel adjuvant CPG 7909.A phase 1 trial was conducted at the University of Rochester with 75 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine. Participants were sequentially enrolled and randomized within dose escalating cohorts to receive three vaccinations on days 0, 28 and 56 of either 20 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 15, 80 microg of AMA1-C1/Alhydrogel (n = 30, or 80 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 30.Local and systemic adverse events were significantly more likely to be of higher severity with the addition of CPG 7909. Anti-AMA1 immunoglobulin G (IgG were detected by enzyme-linked immunosorbent assay (ELISA, and the immune sera of volunteers that received 20 microg or 80 microg of AMA1-C1/Alhydrogel+CPG 7909 had up to 14 fold significant increases in anti-AMA1 antibody concentration compared to 80 microg of AMA1-C1/Alhydrogel alone. The addition of CPG 7909 to the AMA1-C1/Alhydrogel vaccine in humans also elicited AMA1 specific immune IgG that significantly and dramatically increased the in vitro growth inhibition of homologous parasites to levels as high as 96% inhibition.The safety profile of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine is acceptable, given the significant increase in immunogenicity observed. Further clinical development is ongoing.ClinicalTrials.gov NCT00344539.

  13. Designing Peptide-Based HIV Vaccine for Chinese

    Science.gov (United States)

    Fan, Xiaojuan

    2014-01-01

    CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese. PMID:25136573

  14. The Ethics of Health Care Delivery in a Pediatric Malaria Vaccine Trial: The Perspectives of Stakeholders From Ghana and Tanzania.

    Science.gov (United States)

    Ward, Claire Leonie; Shaw, David; Anane-Sarpong, Evelyn; Sankoh, Osman; Tanner, Marcel; Elger, Bernice

    2018-02-01

    This study explores ethical issues raised in providing medical care to participants and communities of low-resource settings involved in a Phase II/III pediatric malaria vaccine trial (PMVT). We conducted 52 key informant interviews with major stakeholders of an international multi-center PMVT (GSK/PATH-MVI RTS,S) (NCT00866619) in Ghana and Tanzania. Based on their stakeholder experiences, the responses fell into three main themes: (a) undue inducement, (b) community disparities, and (c) broad therapeutic misconceptions. The study identified the critical ethical aspects, from the perspectives of stakeholders, of delivering health care during a PMVT. The study showed that integrating research into health care services needs to be addressed in a manner that upholds the favorable risk-benefit ratio of research and attends to the health needs of local populations. The implementation of research should aim to improve local standards of care through building a collaborative agenda with local institutions and systems of health.

  15. A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine.

    Directory of Open Access Journals (Sweden)

    Jairo Andres Fonseca

    Full Text Available A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions (HVR of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity

  16. Examination on the protein profiles of salivary glands of P. berghei infected anopheles Sp. post gamma irradiation using SDS-PAGE technique for developing malaria vaccine

    International Nuclear Information System (INIS)

    Tetriana, D.; Syaifudin, M.

    2014-01-01

    Sporozoite is a step of malaria parasitic live cycle that is most invasive and appropriate vaccine candidate. Result of experiments showed that malaria vaccine created by attenuating Plasmodium sp sporozoites with gamma rays was proven more effective. Study on the effects of irradiation to the profiles of protein in vaccine development is also important. The aim of this research was to examine the protein profile of salivary glands in sporozoite infected Anopheles sp post gamma irradiation using Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) technique. Examination covered the infection of Anopheles sp with Plasmodium sp, maintenance of infected mosquitoes for 14-16 days to obtain sporozoites, in vivo - in vitro irradiation of mosquitoes, preparation of salivary glands, electrophoresis on 10% SDS-PAGE, and Commassie blue staining. Results showed a different protein profile of infected and non infected salivary glands of Anopheles sp. There was additional protein band numbers at higher dose of irradiation (200 Gy) from sporozoite protein of P. berghei (MW 62 kDa). However, no difference of the profiles of circumsporozoite protein (CSP) observed among gamma irradiation doses of 150, 175 and 200 Gy. These results provide basic information that would lead to further study on the role of sporozoite proteins in malaria vaccine development. (author)

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

    Directory of Open Access Journals (Sweden)

    Matthew B Laurens

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

  18. Detection of Malaria parasite species based on 18S rRNA and assessment of its resistance to the drug for DHPS gene to support the development of irradiation Malaria vaccine

    International Nuclear Information System (INIS)

    Mukh Syaifudin; Darlina; Siti Nurhayati

    2016-01-01

    Malaria remains a major public health problem because it causes 1-2 million mortality per year. Therefore the development of its vaccine, including vaccine created by ionizing radiation, is urgently needed to control the disease. Aim of this research was to determine the species of malaria parasite infecting the blood of malaria suspected patients and its resistance to sulfadoxine-pyrimethamine (SP). The number of samples used were 10 blood specimens that obtained from Dok II Hospital in Jayapura. Microscopic examination on thin blood smear was done according to standard procedure, followed by Polymerase Chain Reaction (PCR) based diagnosis to further confirm the parasite using 18S rRNA gene on deoxyribonucleic acid extract. The presence of mutation in the dhps (dihydropteroate synthetase) gene related to SP drugs was examined using restriction fragment length polymorphism (RFLP) method. Results showed that 9 samples were infected with Plasmodium falciparum and 1 infected with P. vivax. Allelic mutants of dhps gene at codon K540E were detected in 3 (33.3%) samples. Even though only in very limited number of samples analyzed, the information obtained will be a great value in additional knowledge for vaccine development with irradiation. (author)

  19. Vaccination with lipid core peptides fails to induce epitope-specific T cell responses but confers non-specific protective immunity in a malaria model.

    Directory of Open Access Journals (Sweden)

    Simon H Apte

    Full Text Available Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4(+ and/or CD8(+ T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8(+ T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8(+ T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.

  20. Computational study of a magnetic design to improve the diagnosis of malaria: 2D model

    International Nuclear Information System (INIS)

    Vyas, Siddharth; Genis, Vladimir; Friedman, Gary

    2017-01-01

    This paper investigates the feasibility of a cost effective high gradient magnetic separation based device for the detection and identification of malaria parasites in a blood sample. The design utilizes magnetic properties of hemozoin present in malaria-infected red blood cells (mRBCs) in order to separate and concentrate them inside a microfluidic channel slide for easier examination under the microscope. The design consists of a rectangular microfluidic channel with multiple magnetic wires positioned on top of and underneath it along the length of the channel at a small angle with respect to the channel axis. Strong magnetic field gradients, produced by the wires, exert sufficient magnetic forces on the mRBCs in order to separate and concentrate them in a specific region small enough to fit within the microscope field of view at magnifications typically required to identify the malaria parasite type. The feasibility of the device is studied using a model where the trajectories of the mRBCs inside the channel are determined using first-order ordinary differential equations (ODEs) solved numerically using a multistep ODE solver available within MATLAB. The mRBCs trajectories reveal that it is possible to separate and concentrate the mRBCs in less than 5 min, even in cases of very low parasitemia (1–10 parasites/µL of blood) using blood sample volumes of around 3 µL employed today. - Highlights: • A simple and cost-effective design is presented to improve the diagnosis of malaria. • The design is studied using a computational model. • It is possible to concentrate malaria-infected cells in a small area. • This can improve slide-examination and the efficiency of microscopists. • This can improve diagnosis of low-parasitemia and asymptomatic malaria.

  1. Computational study of a magnetic design to improve the diagnosis of malaria: 2D model

    Energy Technology Data Exchange (ETDEWEB)

    Vyas, Siddharth, E-mail: svyas76@gmail.com [Department of Electrical and Computer Engineering, Drexel University, Philadelphia, PA 19104 (United States); Department of Engineering Technology, Drexel University, Philadelphia, PA 19104 (United States); Genis, Vladimir [Department of Engineering Technology, Drexel University, Philadelphia, PA 19104 (United States); Friedman, Gary [Department of Electrical and Computer Engineering, Drexel University, Philadelphia, PA 19104 (United States)

    2017-02-01

    This paper investigates the feasibility of a cost effective high gradient magnetic separation based device for the detection and identification of malaria parasites in a blood sample. The design utilizes magnetic properties of hemozoin present in malaria-infected red blood cells (mRBCs) in order to separate and concentrate them inside a microfluidic channel slide for easier examination under the microscope. The design consists of a rectangular microfluidic channel with multiple magnetic wires positioned on top of and underneath it along the length of the channel at a small angle with respect to the channel axis. Strong magnetic field gradients, produced by the wires, exert sufficient magnetic forces on the mRBCs in order to separate and concentrate them in a specific region small enough to fit within the microscope field of view at magnifications typically required to identify the malaria parasite type. The feasibility of the device is studied using a model where the trajectories of the mRBCs inside the channel are determined using first-order ordinary differential equations (ODEs) solved numerically using a multistep ODE solver available within MATLAB. The mRBCs trajectories reveal that it is possible to separate and concentrate the mRBCs in less than 5 min, even in cases of very low parasitemia (1–10 parasites/µL of blood) using blood sample volumes of around 3 µL employed today. - Highlights: • A simple and cost-effective design is presented to improve the diagnosis of malaria. • The design is studied using a computational model. • It is possible to concentrate malaria-infected cells in a small area. • This can improve slide-examination and the efficiency of microscopists. • This can improve diagnosis of low-parasitemia and asymptomatic malaria.

  2. Safety and immunogenicity of a malaria vaccine, Plasmodium falciparum AMA-1/MSP-1 chimeric protein formulated in montanide ISA 720 in healthy adults.

    Directory of Open Access Journals (Sweden)

    Jinhong Hu

    Full Text Available BACKGROUND: The P. falciparum chimeric protein 2.9 (PfCP-2.9 consisting of the sequences of MSP1-19 and AMA-1 (III is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 microg respectively, and 1 placebo group of 12 participants receiving the adjuvant only. METHODS AND FINDINGS: The vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1:10,000 of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA. CONCLUSION: This study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity. TRIAL REGISTRATION: Chinese State Food and Drug Administration (SFDA 2002SL0046; Controlled

  3. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1 administered in adjuvant system AS01B or AS02A.

    Directory of Open Access Journals (Sweden)

    Michele D Spring

    Full Text Available This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1 representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems.After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 microg/0.5 mL of AMA-1/AS01B (n = 15 or AMA-1/AS02A (n = 15, followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs with 95% Confidence Intervals (CIs were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL, full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA, against homologous but not against heterologous (FVO parasites as well as demonstrable interferon-gamma (IFN-gamma responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR. However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements.All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite

  4. Safety and Immunogenicity of Pfs25-EPA/Alhydrogel®, a Transmission Blocking Vaccine against Plasmodium falciparum: An Open Label Study in Malaria Naïve Adults.

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    Kawsar R Talaat

    Full Text Available Transmission-blocking vaccines (TBVs that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®. Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147 μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population.

  5. Differential induction of functional IgG using the Plasmodium falciparum placental malaria vaccine candidate VAR2CSA

    DEFF Research Database (Denmark)

    Pinto, Vera V; Ditlev, Sisse B; Jensen, Kamilla E

    2011-01-01

    In Plasmodium falciparum malaria endemic areas placental malaria (PM) is an important complication of malaria. The recurrence of malaria in primigravidae women irrespective of acquired protection during childhood is caused by the interaction between the parasite-expressed VAR2CSA antigen and chon...

  6. Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013.

    Science.gov (United States)

    Genito, Christopher J; Beck, Zoltan; Phares, Timothy W; Kalle, Fanta; Limbach, Keith J; Stefaniak, Maureen E; Patterson, Noelle B; Bergmann-Leitner, Elke S; Waters, Norman C; Matyas, Gary R; Alving, Carl R; Dutta, Sheetij

    2017-07-05

    Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4 + T-cells and a T H 1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI

  7. 42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

    Science.gov (United States)

    2010-10-01

    ... safe, potent, and pure yellow fever vaccine. Medical facilities of Federal agencies are authorized to obtain yellow fever vaccine without being designated as a yellow fever vaccination center by the Director..., storage, and administration of yellow fever vaccine. If a designated center fails to comply with such...

  8. Challenges in malaria control in sub-Saharan Africa: the vaccine perspective

    DEFF Research Database (Denmark)

    Lusingu, John P A; Von Seidlein, Lorenz

    2008-01-01

    of these interventions. The emergence of resistance against drugs and insecticides requires in response a steady stream of new interventions. Up to the beginning of this millennium, most sub-Saharan African countries have been using chloroquine (CQ) as the first-line antimalarial drug, which had to be replaced...... malaria control measures have been applied such as environmental improvements, use of insecticide impregnated nets, residual indoor spraying, early case detection and treatment with effective antimalarial drugs. However, the adaptation of vector and parasite has so far limited the effect...... with sulphadoxine-pyrimethamine (SP) after resistant parasites had rendered CQ ineffective. Currently the first line treatment of malaria consists of combination therapy which includes an artemisinin derivative. The current approach appears robust but history has taught us to be alert and to expect resistance...

  9. A retrospective evaluation of the role of T cells in the development of malaria vaccine

    OpenAIRE

    Tsuji, Moriya

    2009-01-01

    Due to the fact that the life cycle of malaria parasites is complex, undergoing both an extracellular and intracellular phases in its host, the human immune system has to mobilize both the humoral and cellular arms of immune responses to fight against this parasitic infection. Whereas humoral immunity is directed toward the extra-cellular stages which include sporozoite, erythrocytic and sexual stages, cell-mediated immunity (CMI), in which T cells play a major role, targets intracellular sta...

  10. Design of clinical trials for therapeutic cancer vaccines development.

    Science.gov (United States)

    Mackiewicz, Jacek; Mackiewicz, Andrzej

    2009-12-25

    Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

  11. RTS,S/AS01E Malaria Vaccine Induces Memory and Polyfunctional T Cell Responses in a Pediatric African Phase III Trial

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    Gemma Moncunill

    2017-08-01

    Full Text Available Comprehensive assessment of cellular responses to the RTS,S/AS01E vaccine is needed to understand potential correlates and ultimately mechanisms of protection against malaria disease. Cellular responses recognizing the RTS,S/AS01E-containing circumsporozoite protein (CSP and Hepatitis B surface antigen (HBsAg were assessed before and 1 month after primary vaccination by intracellular cytokine staining and 16-color flow cytometry in 105 RTS,S/AS01-vaccinated and 74 rabies-vaccinated participants (controls in a pediatric phase III trial in Africa. RTS,S/AS01E-vaccinated children had significantly higher frequencies of CSP- and HBsAg-specific CD4+ T cells producing IL-2, TNF-α, and CD40L and HBsAg-specific CD4+ T producing IFN-γ and IL-17 than baseline and the control group. Vaccine-induced responses were identified in both central and effector memory (EM compartments. EM CD4+ T cells expressing IL-4 and IL-21 were detected recognizing both vaccine antigens. Consistently higher response rates to both antigens in RTS,S/AS01E-vaccinated than comparator-vaccinated children were observed. RTS,S/AS01E induced polyfunctional CSP- and HBsAg-specific CD4+ T cells, with a greater degree of polyfunctionality in HBsAg responses. In conclusion, RTS,S/AS01E vaccine induces T cells of higher functional heterogeneity and polyfunctionality than previously characterized. Responses detected in memory CD4+ T cell compartments may provide correlates of RTS,S/AS01-induced immunity and duration of protection in future correlates of immunity studies.

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

    Directory of Open Access Journals (Sweden)

    Bertrand Lell

    2009-10-01

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

  13. The test-negative design for estimating influenza vaccine effectiveness.

    Science.gov (United States)

    Jackson, Michael L; Nelson, Jennifer C

    2013-04-19

    The test-negative design has emerged in recent years as the preferred method for estimating influenza vaccine effectiveness (VE) in observational studies. However, the methodologic basis of this design has not been formally developed. In this paper we develop the rationale and underlying assumptions of the test-negative study. Under the test-negative design for influenza VE, study subjects are all persons who seek care for an acute respiratory illness (ARI). All subjects are tested for influenza infection. Influenza VE is estimated from the ratio of the odds of vaccination among subjects testing positive for influenza to the odds of vaccination among subjects testing negative. With the assumptions that (a) the distribution of non-influenza causes of ARI does not vary by influenza vaccination status, and (b) VE does not vary by health care-seeking behavior, the VE estimate from the sample can generalized to the full source population that gave rise to the study sample. Based on our derivation of this design, we show that test-negative studies of influenza VE can produce biased VE estimates if they include persons seeking care for ARI when influenza is not circulating or do not adjust for calendar time. The test-negative design is less susceptible to bias due to misclassification of infection and to confounding by health care-seeking behavior, relative to traditional case-control or cohort studies. The cost of the test-negative design is the additional, difficult-to-test assumptions that incidence of non-influenza respiratory infections is similar between vaccinated and unvaccinated groups within any stratum of care-seeking behavior, and that influenza VE does not vary across care-seeking strata. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Towards clinical development of a Pfs48/45-based transmission blocking malaria vaccine

    DEFF Research Database (Denmark)

    Theisen, Michael; Jore, Matthijs M; Sauerwein, Robert

    2017-01-01

    : PubMed was searched to review the progress and future prospects for clinical development of a Pfs48/45-based subunit vaccine. We will focus on biological function, naturally acquired immunity, functional activity of specific antibodies, sequence diversity, production of recombinant protein...

  15. Principles underlying rational design of live attenuated influenza vaccines

    Science.gov (United States)

    Jang, Yo Han

    2012-01-01

    Despite recent innovative advances in molecular virology and the developments of vaccines, influenza virus remains a serious burden for human health. Vaccination has been considered a primary countermeasure for prevention of influenza infection. Live attenuated influenza vaccines (LAIVs) are particularly attracting attention as an effective strategy due to several advantages over inactivated vaccines. Cold-adaptation, as a classical means for attenuating viral virulence, has been successfully used for generating safe and effective donor strains of LAIVs against seasonal epidemics and occasional pandemics. Recently, the advent of reverse genetics technique expedited a variety of rational strategies to broaden the pool of LAIVs. Considering the breadth of antigenic diversity of influenza virus, the pool of LAIVs is likely to equip us with better options for controlling influenza pandemics. With a brief reflection on classical attenuating strategies used at the initial stage of development of LAIVs, especially on the principles underlying the development of cold-adapted LAIVs, we further discuss and outline other attenuation strategies especially with respect to the rationales for attenuation, and their practicality for mass production. Finally, we propose important considerations for a rational vaccine design, which will provide us with practical guidelines for improving the safety and effectiveness of LAIVs. PMID:23596576

  16. Malaria drives T cells to exhaustion

    Directory of Open Access Journals (Sweden)

    Michelle N Wykes

    2014-05-01

    Full Text Available Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp.. Recent research on malaria, has investigated the Programmed cell death-1 (PD-1 pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4+ T cells and an unappreciated role for CD8+ T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8+ T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria.

  17. Vaccine Containing the Three Allelic Variants of the Plasmodium vivax Circumsporozoite Antigen Induces Protection in Mice after Challenge with a Transgenic Rodent Malaria Parasite

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    Alba Marina Gimenez

    2017-10-01

    Full Text Available Plasmodium vivax is the most common species that cause malaria outside of the African continent. The development of an efficacious vaccine would contribute greatly to control malaria. Recently, using bacterial and adenoviral recombinant proteins based on the P. vivax circumsporozoite protein (CSP, we demonstrated the possibility of eliciting strong antibody-mediated immune responses to each of the three allelic forms of P. vivax CSP (PvCSP. In the present study, recombinant proteins representing the PvCSP alleles (VK210, VK247, and P. vivax-like, as well as a hybrid polypeptide, named PvCSP-All epitopes, were generated. This hybrid containing the conserved C-terminal of the PvCSP and the three variant repeat domains in tandem were successfully produced in the yeast Pichia pastoris. After purification and biochemical characterization, they were used for the experimental immunization of C57BL/6 mice in a vaccine formulation containing the adjuvant Poly(I:C. Immunization with a recombinant protein expressing all three different allelic forms in fusion elicited high IgG antibody titers reacting with all three different allelic variants of PvCSP. The antibodies targeted both the C-terminal and repeat domains of PvCSP and recognized the native protein on the surface of P. vivax sporozoites. More importantly, mice that received the vaccine formulation were protected after challenge with chimeric Plasmodium berghei sporozoites expressing CSP repeats of P. vivax sporozoites (Pb/PvVK210. Our results suggest that it is possible to elicit protective immunity against one of the most common PvCSP alleles using soluble recombinant proteins expressed by P. pastoris. These recombinant proteins are promising candidates for clinical trials aiming to develop a multiallele vaccine against P. vivax malaria.

  18. Enhanced vaccine-induced CD8+ T cell responses to malaria antigen ME-TRAP by fusion to MHC class ii invariant chain.

    Directory of Open Access Journals (Sweden)

    Alexandra J Spencer

    Full Text Available The orthodox role of the invariant chain (CD74; Ii is in antigen presentation to CD4+ T cells, but enhanced CD8+ T cells responses have been reported after vaccination with vectored viral vaccines encoding a fusion of Ii to the antigen of interest. In this study we assessed whether fusion of the malarial antigen, ME-TRAP, to Ii could increase the vaccine-induced CD8+ T cell response. Following single or heterologous prime-boost vaccination of mice with a recombinant chimpanzee adenovirus vector, ChAd63, or recombinant modified vaccinia virus Ankara (MVA, higher frequencies of antigen-specific CD4+ and CD8+ T cells were observed, with the largest increases observed following a ChAd63-MVA heterologous prime-boost regimen. Studies in non-human primates confirmed the ability of Ii-fusion to augment the T cell response, where a 4-fold increase was maintained up to 11 weeks after the MVA boost. Of the numerous different approaches explored to increase vectored vaccine induced immunogenicity over the years, fusion to the invariant chain showed a consistent enhancement in CD8+ T cell responses across different animal species and may therefore find application in the development of vaccines against human malaria and other diseases where high levels of cell-mediated immunity are required.

  19. DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity.

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    Ilin Chuang

    Full Text Available BACKGROUND: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. METHODOLOGY/PRINCIPAL FINDINGS: The vaccine regimen was three monthly doses of two DNA plasmids (DNA followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad. The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP and apical membrane antigen-1 (AMA1. The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea, possibly related to immunization, was severe (Grade 3, preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27% were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44-817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5-102 and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13-408; AMA1 348, range 88-1270 and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019. Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. SIGNIFICANCE: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%. Protection

  20. Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso

    Directory of Open Access Journals (Sweden)

    Diarra Amidou

    2012-03-01

    Full Text Available Abstract Background Patient immune status is thought to affect the efficacy of anti-malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. Methods Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml was obtained from each child to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. Results IgG levels to MSP3 were always higher in the successfully treated group than in the group with treatment failure. The same observation was made for GLURP but the reverse observation was noticed for MSP1-19. Cytophilic and non-cytophilic antibodies were significantly associated with protection against all three antigens, except for IgG4 to MSP1-19 and GLURP. Conclusion Acquired anti-malarial antibodies may play an important role in the efficacy of anti-malarial drugs in younger children more susceptible to the disease.

  1. Rational design of diagnostic and vaccination strategies for tuberculosis

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    Sibele Borsuk

    Full Text Available The development of diagnostic tests which can readily differentiate between vaccinated and tuberculosis-infected individuals is crucial for the wider utilization of bacillus Calmette-Guérin (BCG as vaccine in humans and animals. BCG_0092 is an antigen that elicits specific delayed type hypersensitivity reactions similar in size and morphological aspects to that elicited by purified protein derivative, in both animals and humans infected with the tubercle bacilli. We carried out bioinformatics analyses of the BCG_0092 and designed a diagnostic test by using the predicted MHC class I epitopes. In addition, we performed a knockout of this gene by homologous recombination in the BCG vaccine strain to allow differentiation of vaccinated from infected individuals. For that, the flanking sequences of the target gene (BCG_0092were cloned into a suicide vector. Spontaneous double crossovers, which result in wild type revertants or knockouts were selected using SacB. BCG_0092 is present only in members of the Mycobacterium tuberculosis complex. Eight predicted MHC class I epitopes with potential for immunological diagnosis were defined, allowing the design of a specific diagnostic test. The strategy used to delete the (BCG_0092 gene from BCG was successful. The knockout genotype was confirmed by PCR and by Southern blot. The mutant BCG strain has the potential of inducing protection against tuberculosis without interfering with the diagnostic test based on the use of selected epitopes from BCG_0092.

  2. Structure and Computation in Immunoreagent Design: From Diagnostics to Vaccines.

    Science.gov (United States)

    Gourlay, Louise; Peri, Claudio; Bolognesi, Martino; Colombo, Giorgio

    2017-12-01

    Novel immunological tools for efficient diagnosis and treatment of emerging infections are urgently required. Advances in the diagnostic and vaccine development fields are continuously progressing, with reverse vaccinology and structural vaccinology (SV) methods for antigen identification and structure-based antigen (re)design playing increasingly relevant roles. SV, in particular, is predicted to be the front-runner in the future development of diagnostics and vaccines targeting challenging diseases such as AIDS and cancer. We review state-of-the-art methodologies for structure-based epitope identification and antigen design, with specific applicative examples. We highlight the implications of such methods for the engineering of biomolecules with improved immunological properties, potential diagnostic and/or therapeutic uses, and discuss the perspectives of structure-based rational design for the production of advanced immunoreagents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Evaluation of two formulations of adjuvanted RTS, S malaria vaccine in children aged 3 to 5 years living in a malaria-endemic region of Mozambique: a Phase I/IIb randomized double-blind bridging trial

    Directory of Open Access Journals (Sweden)

    Mandomando Inacio

    2007-03-01

    Full Text Available Abstract Background Previous trials of the RTS, S malaria candidate vaccine have shown that this vaccine is safe, tolerated and immunogenic. The development plan for this vaccine aims at administering it in the first year of life through the Expanded Program on Immunization (EPI. The objective was to evaluate the safety and reactogenicity of RTS, S/AS02D (0.5 ml dose, a pediatric formulation of GlaxoSmithKline Biologicals' current malaria candidate vaccine RTS, S/AS02A (0.25 ml dose. A 0.5 ml dose of AS02D is composed of the same active ingredients in the same quantities as in a 0.25 ml dose of AS02A and has been developed to be easily introduced into routine EPI practices. Methods We performed a phase I/IIb randomized double-blind bridging study in a malaria-endemic region of Mozambique, to compare the safety and immunogenicity of both candidate vaccines with the aim of replacing RTS, S/AS02A with RTS, S/AS02D as the candidate pediatric vaccine. 200 Mozambican children aged 3 to 5 years were randomized 1:1 to receive one of the 2 vaccines according to a 0, 1, 2 month schedule. Results Both vaccines were safe and had similar reactogenicity profiles. All subjects with paired pre and post-vaccination samples showed a vaccine response with respect to anti-circumsporozoite (CS antibodies irrespective of initial anti-CS serostatus. Geometric mean titers (GMTs were 191 EU/ml (95% CI 150–242 in recipients of RTS, S/AS02D compared to 180 EU/ml (95% CI 146–221 in recipients of RTS, S/AS02A. For the anti-hepatitis B surface antigen (HBsAg, all subjects were seroprotected at day 90, and the GMTs were 23978 mIU/ml (95% CI 17896–32127 in RTS, S/AS02D recipients and 17410 mIU/ml (95% CI 13322–22752 in RTS, S/AS02A recipients. There was a decrease in anti-CS GMTs between months 3 and 14 in both groups (191 vs 22 EU/mL in RTS, S/AS02D group and 180 vs 29 EU/mL in RTS, S/AS02A group. Conclusion Our data show that the RTS, S/AS02D is safe, well tolerated

  4. Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya.

    Directory of Open Access Journals (Sweden)

    Philip Bejon

    2007-08-01

    Full Text Available "FFM ME-TRAP" is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara delivering the pre-erythrocytic malaria antigen ME-TRAP. Over nine months follow-up in our original study, there was no evidence that FFM ME-TRAP provided protection against malaria. The incidence of malaria was slightly higher in children who received FFM ME-TRAP, but this was not statistically significant (hazard ratio 1.5, 95% CI 1.0-2.3. Although the study was unblinded, another nine months follow-up was planned to monitor the incidence of malaria and other serious adverse events.405 children aged 1-6 yrs were initially randomized to vaccination with either FFM ME-TRAP or control (rabies vaccine. 380 children were still available for follow-up after the first nine months. Children were seen weekly and whenever they were unwell for nine months monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to parasitaemia >2,500/microl. During the second nine months monitoring, 49 events met the primary endpoint (febrile malaria with parasites >2,500/microl in the Intention To Treat (ITT group. 23 events occurred among the 189 children in the FFM ME-TRAP group, and 26 among the 194 children in the control group. In the full 18 months of monitoring, there were 63 events in the FFM ME-TRAP group and 60 in the control group (HR = 1.2, CI 0.84-1.73, p = 0.35. There was no evidence that the HR changed over the 18 months (test for interaction between time and vaccination p = 0.11.Vaccination with FFM ME-TRAP was not protective against malaria in this study. Malaria incidence during 18 months of surveillance was similar in both vaccine groups.Controlled-Trials.com ISRCTN88335123.

  5. Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naïve and Vaccinated Hosts.

    Directory of Open Access Journals (Sweden)

    Thomas S Churcher

    2017-01-01

    Full Text Available Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP, and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.

  6. Functional characterization of Plasmodium berghei PSOP25 during ookinete development and as a malaria transmission-blocking vaccine candidate.

    Science.gov (United States)

    Zheng, Wenqi; Liu, Fei; He, Yiwen; Liu, Qingyang; Humphreys, Gregory B; Tsuboi, Takafumi; Fan, Qi; Luo, Enjie; Cao, Yaming; Cui, Liwang

    2017-01-05

    Plasmodium ookinete surface proteins as post-fertilization target antigens are potential malaria transmission-blocking vaccine (TBV) candidates. Putative secreted ookinete protein 25 (PSOP25) is a highly conserved ookinete surface protein, and has been shown to be a promising novel TBV target. Here, we further investigated the TBV activities of the full-length recombinant PSOP25 (rPSOP25) protein in Plasmodium berghei, and characterized the potential functions of PSOP25 during the P. berghei life-cycle. We expressed the full-length P. berghei PSOP25 protein in a prokaryotic expression system, and developed polyclonal mouse antisera and a monoclonal antibody (mAb) against the recombinant protein. Indirect immunofluorescence assay (IFA) and Western blot were used to test the specificity of antibodies. The transmission-blocking (TB) activities of antibodies were evaluated by the in vitro ookinete conversion assay and by direct mosquito feeding assay (DFA). Finally, the function of PSOP25 during Plasmodium development was studied by deleting the psop25 gene. Both polyclonal mouse antisera and anti-rPSOP25 mAb recognized the PSOP25 proteins in the parasites, and IFA showed the preferential expression of PSOP25 on the surface of zygotes, retorts and mature ookinetes. In vitro, these antibodies significantly inhibited ookinetes formation in an antibody concentration-dependent manner. In DFA, mice immunized with the rPSOP25 and those receiving passive transfer of the anti-rPSOP25 mAb reduced the prevalence of mosquito infection by 31.2 and 26.1%, and oocyst density by 66.3 and 63.3%, respectively. Genetic knockout of the psop25 gene did not have a detectable impact on the asexual growth of P. berghei, but significantly affected the maturation of ookinetes and the formation of midgut oocysts. The full-length rPSOP25 could elicit strong antibody response in mice. Polyclonal and monoclonal antibodies against PSOP25 could effectively block the formation of ookinetes in vitro

  7. Phase 1b randomized trial and follow-up study in Uganda of the blood-stage malaria vaccine candidate BK-SE36.

    Science.gov (United States)

    Palacpac, Nirianne Marie Q; Ntege, Edward; Yeka, Adoke; Balikagala, Betty; Suzuki, Nahoko; Shirai, Hiroki; Yagi, Masanori; Ito, Kazuya; Fukushima, Wakaba; Hirota, Yoshio; Nsereko, Christopher; Okada, Takuya; Kanoi, Bernard N; Tetsutani, Kohhei; Arisue, Nobuko; Itagaki, Sawako; Tougan, Takahiro; Ishii, Ken J; Ueda, Shigeharu; Egwang, Thomas G; Horii, Toshihiro

    2013-01-01

    Up to now a malaria vaccine remains elusive. The Plasmodium falciparum serine repeat antigen-5 formulated with aluminum hydroxyl gel (BK-SE36) is a blood-stage malaria vaccine candidate that has undergone phase 1a trial in malaria-naive Japanese adults. We have now assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda. We performed a two-stage, randomized, single-blinded, placebo-controlled phase 1b trial (Current Controlled trials ISRCTN71619711). A computer-generated sequence randomized healthy subjects for 2 subcutaneous injections at 21-day intervals in Stage1 (21-40 year-olds) to 1-mL BK-SE36 (BKSE1.0) (n = 36) or saline (n = 20) and in Stage2 (6-20 year-olds) to BKSE1.0 (n = 33), 0.5-mL BK-SE36 (BKSE0.5) (n = 33), or saline (n = 18). Subjects and laboratory personnel were blinded. Safety and antibody responses 21-days post-second vaccination (Day42) were assessed. Post-trial, to compare the risk of malaria episodes 130-365 days post-second vaccination, Stage2 subjects were age-matched to 50 control individuals. Nearly all subjects who received BK-SE36 had induration (Stage1, n = 33, 92%; Stage2, n = 63, 96%) as a local adverse event. No serious adverse event related to BK-SE36 was reported. Pre-existing anti-SE36 antibody titers negatively correlated with vaccination-induced antibody response. At Day42, change in antibody titers was significant for seronegative adults (1.95-fold higher than baseline [95% CI, 1.56-2.43], p = 0.004) and 6-10 year-olds (5.71-fold [95% CI, 2.38-13.72], p = 0.002) vaccinated with BKSE1.0. Immunogenicity response to BKSE0.5 was low and not significant (1.55-fold [95% CI, 1.24-1.94], p = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/µL was 7 cases/33 subjects in BKSE1.0 and 10 cases/33 subjects in BKSE0.5 vs. 29 cases/66 subjects in the control group. Risk ratio for BKSE1.0 was 0.48 (95% CI, 0

  8. Tailoring DNA vaccines: designing strategies against HER2 positive cancers

    Directory of Open Access Journals (Sweden)

    Cristina eMarchini

    2013-05-01

    Full Text Available The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing phase I clinical trial (EudraCT 2011-001104-34.

  9. randomised trial of alternative malaria chemoprophylaxis strategies

    African Journals Online (AJOL)

    hi-tech

    2000-02-02

    Feb 2, 2000 ... randomisation produced comparable intervention and comparison groups with balanced characteristics. Specific results of the baseline studies are presented in the companion paper. ... strategies for protecting pregnant women against malaria. ..... from malaria vaccine trial conducted among Tanzanian.

  10. Humoral immune response to Plasmodium falciparum vaccine candidate GMZ2 and its components in populations naturally exposed to seasonal malaria in Ethiopia

    DEFF Research Database (Denmark)

    Mamo, Hassen; Esen, Meral; Ajua, Anthony

    2013-01-01

    for malaria infection microscopically and by the rapid diagnostic test (RDT). Sera were tested by using enzyme-linked immunosorbent assay (ELISA) for total immunoglobulin (Ig) G against P. falciparum blood-stage vaccine candidate GMZ2 and its subunits (Glutamate-rich protein (GLURP-R0), merozoite surface...... transmission in the two localities and/or genetic differences between the two populations in their response to the antigens. In both study sites, IgG subclass levels to GLURP-R0 were significantly higher than that to MSP3 for all corresponding subclasses in most individuals, indicating the higher relative...

  11. Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study.

    Directory of Open Access Journals (Sweden)

    Kwadwo A Koram

    Full Text Available The erythrocyte binding antigen region II (EBA-175 RII is a Plasmodium falciparum ligand that mediates erythrocyte invasion and is considered an important malaria vaccine candidate. A phase Ia trial in malaria naïve adults living in the United States found the recombinant non-glycosylated vaccine antigen, EBA-175 RII-NG adjuvanted with aluminium phosphate to be safe, immunogenic and capable of inducing biologically active antibodies that can inhibit parasite growth in vitro. The aim of the current study was to assess the safety and immunogenicity of this vaccine in malaria exposed semi-immune healthy adults living in a malaria endemic country, Ghana. In this double-blinded, placebo controlled, dose escalation phase I trial, eighteen subjects per group received ascending dose concentrations (5 μg, 20 μg or 80 μg of the vaccine intramuscularly at 0, 1 and 6 months, while 6 subjects received placebo (normal saline. The primary end point was the number of subjects experiencing Grade 3 systemic or local adverse events within 14 days post-vaccination. Serious adverse events were assessed throughout the study period. Blood samples for immunological analyses were collected at days 0, 14, 28, 42, 180 and 194. A total of 52 subjects received three doses of the vaccine in the respective groups. No serious adverse events were reported. The majority of all adverse events reported were mild to moderate in severity, with local pain and tenderness being the most common. All adverse events, irrespective of severity, resolved without any sequelae. Subjects who received any of the EBA-175 RII-NG doses had high immunoglobulin G levels which moderately inhibited P. falciparum growth in vitro, compared to those in the placebo group. In conclusion, the EBA-175 RII-NG vaccine was safe, well tolerated and immunogenic in malaria semi-immune Ghanaian adults. Its further development is recommended.ClinicalTrials.gov. Identifier: NCT01026246.

  12. Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study.

    Science.gov (United States)

    Koram, Kwadwo A; Adu, Bright; Ocran, Josephine; Karikari, Yaa S; Adu-Amankwah, Susan; Ntiri, Michael; Abuaku, Benjamin; Dodoo, Daniel; Gyan, Ben; Kronmann, Karl C; Nkrumah, Francis

    2016-01-01

    The erythrocyte binding antigen region II (EBA-175 RII) is a Plasmodium falciparum ligand that mediates erythrocyte invasion and is considered an important malaria vaccine candidate. A phase Ia trial in malaria naïve adults living in the United States found the recombinant non-glycosylated vaccine antigen, EBA-175 RII-NG adjuvanted with aluminium phosphate to be safe, immunogenic and capable of inducing biologically active antibodies that can inhibit parasite growth in vitro. The aim of the current study was to assess the safety and immunogenicity of this vaccine in malaria exposed semi-immune healthy adults living in a malaria endemic country, Ghana. In this double-blinded, placebo controlled, dose escalation phase I trial, eighteen subjects per group received ascending dose concentrations (5 μg, 20 μg or 80 μg) of the vaccine intramuscularly at 0, 1 and 6 months, while 6 subjects received placebo (normal saline). The primary end point was the number of subjects experiencing Grade 3 systemic or local adverse events within 14 days post-vaccination. Serious adverse events were assessed throughout the study period. Blood samples for immunological analyses were collected at days 0, 14, 28, 42, 180 and 194. A total of 52 subjects received three doses of the vaccine in the respective groups. No serious adverse events were reported. The majority of all adverse events reported were mild to moderate in severity, with local pain and tenderness being the most common. All adverse events, irrespective of severity, resolved without any sequelae. Subjects who received any of the EBA-175 RII-NG doses had high immunoglobulin G levels which moderately inhibited P. falciparum growth in vitro, compared to those in the placebo group. In conclusion, the EBA-175 RII-NG vaccine was safe, well tolerated and immunogenic in malaria semi-immune Ghanaian adults. Its further development is recommended. ClinicalTrials.gov. Identifier: NCT01026246.

  13. Design of Epidemia - an Ecohealth Informatics System for Integrated Forecasting of Malaria Epidemics

    Science.gov (United States)

    Wimberly, M. C.; Bayabil, E.; Beyane, B.; Bishaw, M.; Henebry, G. M.; Lemma, A.; Liu, Y.; Merkord, C. L.; Mihretie, A.; Senay, G. B.; Yalew, W.

    2014-12-01

    Early warning of the timing and locations of malaria epidemics can facilitate the targeting of resources for prevention and emergency response. In response to this need, we are developing the Epidemic Prognosis Incorporating Disease and Environmental Monitoring for Integrated Assessment (EPIDEMIA) computer system. The system incorporates software for capturing, processing, and integrating environmental and epidemiological data from multiple sources; data assimilation techniques that continually update models and forecasts; and a web-based interface that makes the resulting information available to public health decision makers. This technology will enable forecasts based on lagged responses to environmental risk factors as well as information about recent trends in malaria cases. Environmental driving variables will include a variety of remote-sensed hydrological indicators. EPIDEMIA will be implemented and tested in the Amhara Region of Ethiopia in collaboration with local stakeholders. We conducted an initial co-design workshop in July 2014 that included environmental scientists, software engineers, and participants from the NGO, academic, and public health sectors in Ethiopia. A prototype of the EPIDEMIA web interface was presented and a requirements analysis was conducted to characterize the main use cases for the public health community, identify the critical data requirements for malaria risk modeling, and develop of a list of baseline features for the public health interface. Several critical system features were identified, including a secure web-based interface for uploading and validating surveillance data; a flexible query system to allow retrieval of environmental and epidemiological data summaries as tables, charts, and maps; and an alert system to provide automatic warnings in response to environmental and epidemiological risk factors for malaria. Future system development will involve a cycle of implementation, training, usability testing, and

  14. 3D analysis of the TCR/pMHCII complex formation in monkeys vaccinated with the first peptide inducing sterilizing immunity against human malaria.

    Directory of Open Access Journals (Sweden)

    Manuel A Patarroyo

    Full Text Available T-cell receptor gene rearrangements were studied in Aotus monkeys developing high antibody titers and sterilizing immunity against the Plasmodium falciparum malaria parasite upon vaccination with the modified synthetic peptide 24112, which was identified in the Merozoite Surface Protein 2 (MSP-2 and is known to bind to HLA-DRbeta1*0403 molecules with high capacity. Spectratyping analysis showed a preferential usage of Vbeta12 and Vbeta6 TCR gene families in 67% of HLA-DRbeta1*0403-like genotyped monkeys. Docking of peptide 24112 into the HLA-DRbeta1*0401-HA peptide-HA1.7TCR complex containing the VDJ rearrangements identified in fully protected monkeys showed a different structural signature compared to nonprotected monkeys. These striking results show the exquisite specificity of the TCR/pMHCII complex formation needed for inducing sterilizing immunity and provide important hints for a logical and rational methodology to develop multiepitopic, minimal subunit-based synthetic vaccines against infectious diseases, among them malaria.

  15. Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite.

    Science.gov (United States)

    Mistarz, Ulrik H; Singh, Susheel K; Nguyen, Tam T T N; Roeffen, Will; Yang, Fen; Lissau, Casper; Madsen, Søren M; Vrang, Astrid; Tiendrebeogo, Régis W; Kana, Ikhlaq H; Sauerwein, Robert W; Theisen, Michael; Rand, Kasper D

    2017-09-01

    Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability was analysed by RP-HPLC, SEC-HPLC, 2-site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins encompassing similar parts of Pfs48/45. GMZ2'.10C, combining GMZ2' and correctly-folded Pfs48/45 can be produced by the Lactoccus lactis P170 based expression system in purity and quality for pharmaceutical development and elicit high level of TB antibodies. The cysteine connectivity for the 10C region of Pfs48/45 was revealed experimentally, providing an important guideline for employing the Pfs48/45 antigen in vaccine design.

  16. Monitoring selective components of primary health care: methodology and community assessment of vaccination, diarrhoea, and malaria practices in Conakry, Guinea. ACSI-CCCD team.

    Science.gov (United States)

    Dabis, F; Breman, J G; Roisin, A J; Haba, F

    1989-01-01

    The Africa Child Survival Initiative-Combatting Childhood Communicable Diseases (ACSI-CCCD) Project is a primary health care activity that focuses on antenatal care, immunization, diarrhoeal disease control, and malaria control in children under 5 years of age. In order to gauge progress made in the project, a community-based health interview survey to measure simultaneously several prevention and treatment indicators was carried out in 1986 in Conakry, Guinea. A sample of 1415 caretakers and their 2048 children aged under 5 years was visited using a cluster sampling technique. The survey documented the levels of literacy and health education awareness of the caretakers, measured the vaccination coverage levels for children and women of childbearing age, and determined treatment practices for diarrhoea and malaria. Of the 637 women who reported having given birth in the previous 12 months, 96% had visited an antenatal clinic, but only 49% had had two or more doses of tetanus toxoid, and 13% took weekly chemoprophylaxis against malaria. The vaccination coverage for measles was 16% for children aged 12-23 months. Oral rehydration therapy (ORT) was given to 16% of children with diarrhoea; however, only 43% of those who were administered ORT at home were treated according to standard guidelines. Of children with diarrhoea, 51% were given antidiarrhoeal or antimicrobial drugs by caretakers. Fever was treated at home for 79% of the febrile children, and 43% of those with fever also visited health units. The use of injectable antimalarials and prolonged treatments with chloroquine were common. Combining findings from a population-based community study with an assessment of practices in health facilities can provide reliable information for the implementation and monitoring of selective components of primary health care.

  17. Project MEDSAT: The design of a remote sensing platform for malaria research and control

    Science.gov (United States)

    1991-04-01

    Project MEDSAT was proposed with the specific goal of designing a satellite to remotely sense pertinent information useful in establishing strategies to control malaria. The 340 kg MEDSAT satellite is to be inserted into circular earth orbit aboard the Pegasus Air-Launched Space Booster at an inclination of 21 degrees and an altitude of 473 km. It is equipped with a synthetic aperture radar and a visible thermal/infrared sensor to remotely sense conditions at the target area of Chiapas, Mexico. The orbit is designed so that MEDSAT will pass over the target site twice each day. The data from each scan will be downlinked to Hawaii for processing, resulting in maps indicating areas of high malaria risk. These will be distributed to health officials at the target site. A relatively inexpensive launch by Pegasus and a design using mainly proven, off-the-shelf technology permit a low mission cost, while innovations in the satellite controls and the scientific instruments allow a fairly complex mission.

  18.   A rationally designed tyrosine hydroxylase DNA vaccine induces specific antineuroblastoma immunity

    DEFF Research Database (Denmark)

    Huebener, Nicole; Fest, Stefan; Strandsby, Anne Bystrup

    2008-01-01

    Therapeutic vaccination against tumor antigens without induction of autoimmunity remains a major challenge in cancer immunotherapy. Here, we show for the first time effective therapeutic vaccination followed by suppression of established spontaneous neuroblastoma metastases using a tyrosine...... show effective therapeutic vaccination against neuroblastoma with a novel rationally designed TH minigene vaccine without induction of autoimmunity providing an important baseline for future clinical application of this strategy....

  19. The elderly, the young and the pregnant traveler -- A retrospective data analysis from a large Swiss Travel Center with a special focus on malaria prophylaxis and yellow fever vaccination.

    Science.gov (United States)

    Jaeger, Veronika K; Tschudi, Nadine; Rüegg, Rolanda; Hatz, Christoph; Bühler, Silja

    2015-01-01

    Vulnerable individuals such as elderly, children/adolescents and pregnant/breastfeeding women increasingly travel overseas. We describe the travel and vaccination patterns of these groups at the largest Travel Clinic in Switzerland especially focusing on travel to yellow fever and malaria-endemic countries, and yellow fever vaccination (YFV) and malaria medications. An analysis of pre-travel visits between 2010 and 2012 at the Travel Clinic of the University of Zurich, was performed assessing differences between the elderly, young and middle-aged travelers as well as between pregnant/breastfeeding and other female travelers. Overall, the vulnerable groups did not differ from other travelers regarding their travel patterns. YFV was the most often administered vaccine to elderly travelers; half of them received it for the first time. More than 30% of children/adolescents received YFV, but no child below six months was vaccinated. 80% of young travelers and a similar percentage of pregnant women went to malaria-endemic regions. Twenty-five pregnant/breastfeeding women traveled to YF endemic areas. Travel patterns of vulnerable travelers are comparable to those of other travelers. In view of the limited data on malaria medications and precautions against YFV during pregnancy and at the extreme ages of life, giving travel advice to these groups is challenging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-l) administered in adjuvant system AS01B or AS02A

    NARCIS (Netherlands)

    M.D. Spring (Michele Donna); J.F. Cummings (James); C.F. Ockenhouse (Christian); S. Dutta (Shantanu); R. Reidler (Randall); E. Angov (Evelina); E. Bergmann-Leitner (Elke); V.A. Stewart (Ann); S. Bittner (Stacey); L. Juompan (Laure); M.G. Kortepeter (Mark); R. Nielsen (Robin); U. Krzych (Urszula); E. Tierney (Ev); L.A. Ware (Lisa); M. Dowler (Megan); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake); O. Ofori-Anyinam (Opokua); D.E. Lanar (David); J.L. Williams (Jack); K.E. Kester (Kent); K. Tucker (Kathryn); M. Shi (Meng); E. Malkin (Elissa); C. Long (Carole); C.L. Diggs (Carter); L. Soisson (Lorraine Amory); M.C. Dubois; W.R. Ballou (Ripley); J. Cohen (Joe); D.G. Heppner (Gray)

    2009-01-01

    textabstractBackground: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A

  1. Vaccines and immunization

    African Journals Online (AJOL)

    Prof Ezechukwu

    vaccines for malaria and HIV infection. Despite the ... decades, effective vaccines against the major causes of ... challenge antibodies, specific helper and effector T lymphocytes ... materials to produced immunity to a disease. It was originally ...

  2. In silico-based vaccine design against Ebola virus glycoprotein

    Directory of Open Access Journals (Sweden)

    Dash R

    2017-03-01

    Full Text Available Raju Dash,1 Rasel Das,2 Md Junaid,3 Md Forhad Chowdhury Akash,4 Ashekul Islam,5 SM Zahid Hosen1 1Molecular Modeling and Drug Design Laboratory (MMDDL, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research (BCSIR, Chittagong, Bangladesh; 2Nanotechnology and Catalysis Research Center, University of Malaya, Kuala Lumpur, Malaysia; 3Department of Pharmaceutical Sciences, North South University, Dhaka, Bangladesh; 4Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh; 5Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh Abstract: Ebola virus (EBOV is one of the lethal viruses, causing more than 24 epidemic outbreaks to date. Despite having available molecular knowledge of this virus, no definite vaccine or other remedial agents have been developed yet for the management and avoidance of EBOV infections in humans. Disclosing this, the present study described an epitope-based peptide vaccine against EBOV, using a combination of B-cell and T-cell epitope predictions, followed by molecular docking and molecular dynamics simulation approach. Here, protein sequences of all glycoproteins of EBOV were collected and examined via in silico methods to determine the most immunogenic protein. From the identified antigenic protein, the peptide region ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154–162 were considered the most potential B-cell and T-cell epitopes, correspondingly. Moreover, this peptide (HKEGAFFLY interacted with HLA-A*32:15 with the highest binding energy and stability, and also a good conservancy of 83.85% with maximum population coverage. The results imply that the designed epitopes could manifest vigorous enduring defensive immunity against EBOV. Keywords: Ebola virus, epitope, glycoprotein, vaccine design

  3. Randomized controlled trial of RTS,S/AS02D and RTS,S/AS01E malaria candidate vaccines given according to different schedules in Ghanaian children.

    Directory of Open Access Journals (Sweden)

    Seth Owusu-Agyei

    2009-10-01

    Full Text Available The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic countries in Africa is the World Health Organisation Expanded Program on Immunization. As an Adjuvant System, age de-escalation and schedule selection step, this study assessed 3 schedules of RTS,S/AS01(E and RTS,S/AS02(D in infants and young children 5-17 months of age in Ghana.A Phase II, partially-blind randomized controlled study (blind to vaccine, not to schedule, of 19 months duration was conducted in two (2 centres in Ghana between August 2006 and May 2008. Subjects were allocated randomly (1:1:1:1:1:1 to one of six study groups at each study site, each defining which vaccine should be given and by which schedule (0,1-, 0,1,2- or 0,1,7-months. For the 0,1,2-month schedule participants received RTS,S/AS01(E or rabies vaccine at one center and RTS,S/AS01(E or RTS,S/AS02(D at the other. For the other schedules at both study sites, they received RTS,S/AS01(E or RTS,S/AS02(D. The primary outcome measure was the occurrence of serious adverse events until 10 months post dose 1.The number of serious adverse events reported across groups was balanced. One child had a simple febrile convulsion, which evolved favourably without sequelae, considered to be related to RTS,S/AS01(E vaccination. Low grade reactions occurred slightly more frequently in recipients of RTS,S/AS than rabies vaccines; grade 3 reactions were infrequent. Less local reactogenicity occurred with RTS,S/AS01(E than RTS,S/AS02(D. Both candidate vaccines were highly immunogenic for anti-circumsporozoite and anti-Hepatitis B Virus surface antigen antibodies. Recipients of RTS,S/AS01(E compared to RTS,S/AS02(D had higher peak anti-circumsporozoite antibody responses for all 3 schedules. Three dose schedules were more immunogenic than 2 dose schedules. Area under the curve analyses for anti-circumsporozoite antibodies were comparable between the 0,1,2- and 0,1,7-month RTS,S/AS01(E schedules.Both candidate

  4. Generation of genetically attenuated blood-stage malaria parasites; characterizing growth and virulence in a rodent model of malaria

    NARCIS (Netherlands)

    Lin, Jingwen

    2013-01-01

    Despite intense efforts over the past 50 years to develop a vaccine, there is currently no licensed malaria vaccine available. The limited success in inducing sufficient protection against malaria with subunit-vaccines has renewed an interest in whole-parasite vaccination strategies. While

  5. Immunogenicity of a virosomally-formulated Plasmodium falciparum GLURP-MSP3 chimeric protein-based malaria vaccine candidate in comparison to adjuvanted formulations

    Directory of Open Access Journals (Sweden)

    Tamborrini Marco

    2011-12-01

    Full Text Available Abstract Background In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP. Methods The highly purified recombinant protein GMZ2 was coupled to phosphatidylethanolamine and the conjugates incorporated into the membrane of IRIVs. The immunogenicity of this adjuvant-free virosomal formulation was compared to GMZ2 formulated with the adjuvants Montanide ISA 720 and Alum in three mouse strains with different genetic backgrounds. Results Intramuscular injections of all three candidate vaccine formulations induced GMZ2-specific antibody responses in all mice tested. In general, the humoral immune response in outbred NMRI mice was stronger than that in inbred BALB/c and C57BL/6 mice. ELISA with the recombinant antigens demonstrated immunodominance of the GLURP component over the MSP3 component. However, compared to the Al(OH3-adjuvanted formulation the two other formulations elicited in NMRI mice a larger proportion of anti-MSP3 antibodies. Analyses of the induced GMZ2-specific IgG subclass profiles showed for all three formulations a predominance of the IgG1 isotype. Immune sera against all three formulations exhibited cross-reactivity with in vitro cultivated blood-stage parasites. Immunofluorescence and immunoblot competition experiments showed that both components of the hybrid protein induced IgG cross-reactive with the corresponding native proteins. Conclusion A virosomal formulation of the chimeric protein GMZ2 induced P. falciparum blood stage parasite cross-reactive IgG responses specific for both MSP3 and GLURP. GMZ2 thus represents a candidate component suitable for inclusion into a multi-valent virosomal

  6. Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology.

    Science.gov (United States)

    Rodrigues, Ana F; Soares, Hugo R; Guerreiro, Miguel R; Alves, Paula M; Coroadinha, Ana S

    2015-09-01

    Vaccination is one of the most effective interventions in global health. The worldwide vaccination programs significantly reduced the number of deaths caused by infectious agents. A successful example was the eradication of smallpox in 1979 after two centuries of vaccination campaigns. Since the first variolation administrations until today, the knowledge on immunology has increased substantially. This knowledge combined with the introduction of cell culture and DNA recombinant technologies revolutionized vaccine design. This review will focus on vaccines against human viral pathogens, recent developments on vaccine design and cell substrates used for their manufacture. While the production of attenuated and inactivated vaccines requires the use of the respective permissible cell substrates, the production of recombinant antigens, virus-like particles, vectored vaccines and chimeric vaccines requires the use - and often the development - of specific cell lines. Indeed, the development of novel modern viral vaccine designs combined with, the stringent safety requirements for manufacture, and the better understanding on animal cell metabolism and physiology are increasing the awareness on the importance of cell line development and engineering areas. A new era of modern vaccinology is arriving, offering an extensive toolbox to materialize novel and creative ideas in vaccine design and its manufacture. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: a strategy for enhancing immunogenicity of malaria vaccine candidates

    OpenAIRE

    Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L.; Long, Carole A.; Miller, Louis H.; Saul, Allan

    2007-01-01

    Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) for blood stage vaccines and surface protein 25 (Pfs25) for mosquito stage vaccines, each was chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66 kD) relatively good i...

  8. A combinatorial approach to the design of vaccines.

    Science.gov (United States)

    Martínez, Luis; Milanič, Martin; Legarreta, Leire; Medvedev, Paul; Malaina, Iker; de la Fuente, Ildefonso M

    2015-05-01

    We present two new problems of combinatorial optimization and discuss their applications to the computational design of vaccines. In the shortest λ-superstring problem, given a family S1,...,S(k) of strings over a finite alphabet, a set Τ of "target" strings over that alphabet, and an integer λ, the task is to find a string of minimum length containing, for each i, at least λ target strings as substrings of S(i). In the shortest λ-cover superstring problem, given a collection X1,...,X(n) of finite sets of strings over a finite alphabet and an integer λ, the task is to find a string of minimum length containing, for each i, at least λ elements of X(i) as substrings. The two problems are polynomially equivalent, and the shortest λ-cover superstring problem is a common generalization of two well known combinatorial optimization problems, the shortest common superstring problem and the set cover problem. We present two approaches to obtain exact or approximate solutions to the shortest λ-superstring and λ-cover superstring problems: one based on integer programming, and a hill-climbing algorithm. An application is given to the computational design of vaccines and the algorithms are applied to experimental data taken from patients infected by H5N1 and HIV-1.

  9. Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design.

    Science.gov (United States)

    Schwartz, Lauren M; Halloran, M Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M; Victor, John C

    2017-01-03

    The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  10. Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design

    OpenAIRE

    Schwartz, Lauren M.; Halloran, M. Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M.; Victor, John C.

    2017-01-01

    Background The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. Methods This study builds upon prior methods to evaluate the use of the T...

  11. Design of therapeutic vaccines as a novel antibody therapy for cardiovascular diseases.

    Science.gov (United States)

    Nakagami, Hironori

    2017-09-01

    Vaccines are primarily used worldwide as a preventive medicine for infectious diseases and have recently been applied to cancer. We and others have developed therapeutic vaccines designed for cardiovascular diseases that are notably different from previous vaccines. In the case of cancer vaccines, a specific protein in cancer cells is a target antigen, and the activation of cytotoxic T cells (CTL) is required to kill and remove the antigen-presenting cancer cells. Our therapeutic vaccines work against hypertension by targeting angiotensin II (Ang II) as the antigen, which is an endogenous hormone. Therapeutic vaccines must avoid CTL activation and induce the blocking antibodies for Ang II. The goal of our therapeutic vaccine for cardiovascular diseases is to induce the specific antibody response toward the target protein without inducing T-cell or antibody-mediated inflammation through the careful selection of the target antigen, carrier protein and adjuvants. The goal of our therapeutic vaccine is similar to that of antibody therapy. Recently, multiple antibody-based drugs have been developed for cancer, immune-related diseases, and dyslipidemia, which are efficient but expensive. If the effect of a therapeutic vaccine is nearly equivalent to antibody therapy as an alternative approach, the lower medical cost and improvement in drug adherence can be advantages of therapeutic vaccines. In this review, we will describe our concept of therapeutic vaccines for cardiovascular diseases and the future directions of therapeutic vaccines as novel antibody therapies. Copyright © 2017. Published by Elsevier Ltd.

  12. A novel virus-like particle based vaccine platform displaying the placental malaria antigen VAR2CSA

    DEFF Research Database (Denmark)

    Thrane, Susan; Janitzek, Christoph M; Agerbæk, Mette Ø

    2015-01-01

    , this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA. This study demonstrates that the described Avi-L1 VLP-platform may serve as a versatile system for facilitating optimal VLP......SA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however...

  13. Development of standardized laboratory methods and quality processes for a phase III study of the RTS, S/AS01 candidate malaria vaccine

    Directory of Open Access Journals (Sweden)

    Carter Terrell

    2011-08-01

    Full Text Available Abstract Background A pivotal phase III study of the RTS,S/AS01 malaria candidate vaccine is ongoing in several research centres across Africa. The development and establishment of quality systems was a requirement for trial conduct to meet international regulatory standards, as well as providing an important capacity strengthening opportunity for study centres. Methods Standardized laboratory methods and quality assurance processes were implemented at each of the study centres, facilitated by funding partners. Results A robust protocol for determination of parasite density based on actual blood cell counts was set up in accordance with World Health Organization recommendations. Automated equipment including haematology and biochemistry analyzers were put in place with standard methods for bedside testing of glycaemia, base excess and lactacidaemia. Facilities for X-rays and basic microbiology testing were also provided or upgraded alongside health care infrastructure in some centres. External quality assurance assessment of all major laboratory methods was established and method qualification by each laboratory demonstrated. The resulting capacity strengthening has ensured laboratory evaluations are conducted locally to the high standards required in clinical trials. Conclusion Major efforts by study centres, together with support from collaborating parties, have allowed standardized methods and robust quality assurance processes to be put in place for the phase III evaluation of the RTS, S/AS01 malaria candidate vaccine. Extensive training programmes, coupled with continuous commitment from research centre staff, have been the key elements behind the successful implementation of quality processes. It is expected these activities will culminate in healthcare benefits for the subjects and communities participating in these trials. Trial registration Clinicaltrials.gov NCT00866619

  14. Solution structure of a Plasmodium falciparum AMA-1/MSP 1 chimeric protein vaccine candidate (PfCP-2.9 for malaria

    Directory of Open Access Journals (Sweden)

    Jin Changwen

    2010-03-01

    Full Text Available Abstract Background The Plasmodium falciparum chimeric protein PfCP-2.9 is a promising asexual-stage malaria vaccine evaluated in clinical trials. This chimeric protein consists of two cysteine-rich domains: domain III of the apical membrane antigen 1 (AMA-1 [III] and the C-terminal region of the merozoite surface protein 1 (MSP1-19. It has been reported that the fusion of these two antigens enhanced their immunogenicity and antibody-mediated inhibition of parasite growth in vitro. Methods The 15N-labeled and 13C/15N-labeled PfCP-2.9 was produced in Pichia pastoris for nuclear magnetic resonance (NMR structure analysis. The chemical shift assignments of PfCP-2.9 were compared with those previously reported for the individual domains (i.e., PfAMA-1(III or PfMSP 1-19. The two-dimensional spectra and transverse relaxation rates (R2 of the PfMSP1-19 alone were compared with that of the PfCP-2.9. Results Confident backbone assignments were obtained for 122 out of 241 residues of PfCP-2.9. The assigned residues in PfCP-2.9 were very similar to those previously reported for the individual domains. The conformation of the PfMSP1-19 in different constructs is essentially the same. Comparison of transverse relaxation rates (R2 strongly suggests no weak interaction between the domains. Conclusions These data indicate that the fusion of AMA-1(III and MSP1-19 as chimeric protein did not change their structures, supporting the use of the chimeric protein as a potential malaria vaccine.

  15. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial

    Science.gov (United States)

    Olotu, Ally; Lusingu, John; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Msham, Salum; Lang, Trudie; Gould, Jayne; Dubois, Marie-Claude; Jongert, Erik; Vansadia, Preeti; Carter, Terrell; Njuguna, Patricia; Awuondo, Ken O; Malabeja, Anangisye; Abdul, Omar; Gesase, Samwel; Mturi, Neema; Drakeley, Chris J; Savarese, Barbara; Villafana, Tonya; Lapierre, Didier; Ballou, W Ripley; Cohen, Joe; Lemnge, Martha M; Peshu, Norbert; Marsh, Kevin; Riley, Eleanor M; von Seidlein, Lorenz; Bejon, Philip

    2011-01-01

    Summary Background RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. Methods Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. Findings 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were

  16. Optimal designs for population pharmacokinetic studies of oral artesunate in patients with uncomplicated falciparum malaria

    Directory of Open Access Journals (Sweden)

    Lindegardh Niklas

    2011-07-01

    Full Text Available Abstract Background Currently, population pharmacokinetic (PK studies of anti-malarial drugs are designed primarily by the logistical and ethical constraints of taking blood samples from patients, and the statistical models that are fitted to the data are not formally considered. This could lead to imprecise estimates of the target PK parameters, and/or designs insufficient to estimate all of the parameters. Optimal design methodology has been developed to determine blood sampling schedules that will yield precise parameter estimates within the practical constraints of sampling the study populations. In this work optimal design methods were used to determine sampling designs for typical future population PK studies of dihydroartemisinin, the principal biologically active metabolite of oral artesunate. Methods Optimal designs were derived using freely available software and were based on appropriate structural PK models from an analysis of data or the literature and key sampling constraints identified in a questionnaire sent to active malaria researchers (3-4 samples per patient, at least 15 minutes between samples. The derived optimal designs were then evaluated via simulation-estimation. Results The derived optimal sampling windows were 17 to 29 minutes, 30 to 57 minutes, 2.5 to 3.7 hours and 5.8 to 6.6 hours for non-pregnant adults; 16 to 29 minutes, 31 minutes to 1 hour, 2.0 to 3.4 hours and 5.5 to 6.6 hours for designs with non-pregnant adults and children and 35 to 59 minutes, 1.2 to 3.4 hours, 3.4 to 4.9 hours and 6.0 to 8.0 hours for pregnant women. The optimal designs resulted in acceptable precision of the PK parameters. Conclusions The proposed sampling designs in this paper are robust and efficient and should be considered in future PK studies of oral artesunate where only three or four blood samples can be collected.

  17. The Cost of Cost-Sharing: The Impact of Medicaid Benefit Design on Influenza Vaccination Uptake

    Directory of Open Access Journals (Sweden)

    Charles Stoecker

    2017-03-01

    Full Text Available Prior research indicates that cost-sharing and lack of insurance coverage reduce preventive services use among low-income persons. State Medicaid policy may affect the uptake of recommended adult vaccinations. We examined the impact of three aspects of Medicaid benefit design (coverage for vaccines, prohibiting cost-sharing, and copayment amounts on vaccine uptake in the fee-for-service Medicaid population 19–64 years old. We combined previously published reports to obtain state Medicaid policy information from 2003 and 2012. Data on influenza vaccination uptake were taken from the Behavioral Risk Factor Surveillance System. We used a differences-in-differences framework, controlling for national trends and state differences, to estimate the effect of each benefit design factor on vaccination uptake in different Medicaid-eligible populations. Each additional dollar of copayment for vaccination decreased influenza vaccination coverage 1–6 percentage points. The effects of covering vaccines or prohibiting cost-sharing were mixed. Imposing copayments for vaccination is associated with lower vaccination coverage. These findings have implications for the implementation of Medicaid expansion in states that currently impose copayments.

  18. Safety, immunogenicity and duration of protection of the RTS,S/AS02(D malaria vaccine: one year follow-up of a randomized controlled phase I/IIb trial.

    Directory of Open Access Journals (Sweden)

    Pedro Aide

    2010-11-01

    Full Text Available The RTS,S/AS02(D vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001. We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D, remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076 over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003.The RTS,S/AS02(D malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028.

  19. Designing Vaccines for the Twenty-First Century Society

    OpenAIRE

    Finco, Oretta; Rappuoli, Rino

    2014-01-01

    The history of vaccination clearly demonstrates that vaccines have been highly successful in preventing infectious diseases, reducing significantly the incidence of childhood diseases and mortality. However, many infections are still not preventable with the currently available vaccines and they represent a major cause of mortality worldwide. In the twenty-first century, the innovation brought by novel technologies in antigen discovery and formulation together with a deeper knowledge of the h...

  20. Designing vaccines for the 21st century society

    OpenAIRE

    Oretta eFinco; Rino eRappuoli

    2014-01-01

    The history of vaccination clearly demonstrates that vaccines have been highly successful in preventing infectious diseases, reducing significantly the incidence of childhood diseases and mortality. However many infections are still not preventable with the currently available vaccines and they represent a major cause of mortality worldwide. In the 21st century, the innovation brought by novel technologies in antigen discovery and formulation together with a deeper knowledge of the human imm...

  1. Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls.

    Science.gov (United States)

    Verani, Jennifer R; Baqui, Abdullah H; Broome, Claire V; Cherian, Thomas; Cohen, Cheryl; Farrar, Jennifer L; Feikin, Daniel R; Groome, Michelle J; Hajjeh, Rana A; Johnson, Hope L; Madhi, Shabir A; Mulholland, Kim; O'Brien, Katherine L; Parashar, Umesh D; Patel, Manish M; Rodrigues, Laura C; Santosham, Mathuram; Scott, J Anthony; Smith, Peter G; Sommerfelt, Halvor; Tate, Jacqueline E; Victor, J Chris; Whitney, Cynthia G; Zaidi, Anita K; Zell, Elizabeth R

    2017-06-05

    Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential. Published by Elsevier Ltd.

  2. [VACCINES].

    Science.gov (United States)

    Bellver Capella, Vincente

    2015-10-01

    Vaccines are an extraordinary instrument of immunization of the population against infectious diseases. Around them there are many ethical issues. One of the most debated is what to do with certain groups opposition to vaccination of their children. States have managed in different ways the conflict between the duty of vaccination and the refusal to use vaccines: some impose the vaccination and others simply promote it. In this article we deal with which of these two approaches is the most suitable from an ethical and legal point of view. We stand up for the second option, which is the current one in Spain, and we propose some measures which should be kept in mind to improve immunization programs.

  3. Malaria infection and socioeconomic status of some residents of Port ...

    African Journals Online (AJOL)

    ADOWIE PERE

    public health interventions against malaria, such as insecticide spraying or ... prepared, air dried, stained and examined ... Port Harcourt metropolis is presented in Table 1. It showed that more ..... of effective vaccine for malaria prevention and.

  4. [The gentic principles for the design of live Salmonella vaccines].

    Science.gov (United States)

    Petrovskaia, V G; Marakusha, B I; Bondarenko, V M

    1996-01-01

    The presently known methods of obtaining Salmonella vaccine strains are characterized, their advantages and drawbacks are noted. Great importance of the genetic safety of Salmonella attenuated strains to be controlled is emphasized, taking into account that they are also used as carrier strains for obtaining hybrid and gene-engineering (vector) vaccines carrying immunogenicity factors of other species of pathogenic microorganisms.

  5. Evolution of rational vaccine designs for genital herpes immunotherapy.

    Science.gov (United States)

    Kaufmann, Johanna Katharina; Flechtner, Jessica Baker

    2016-04-01

    Immunotherapeutic vaccines have emerged as a novel treatment modality for genital herpes, a sexually transmitted disease mainly caused by herpes simplex virus type 2. The approaches to identify potential vaccine antigens have evolved from classic virus attenuation and characterization of antibody and T cell responses in exposed, but seronegative individuals, to systematic screens for novel T cell antigens. Combined with implementation of novel vaccine concepts revolving around immune evasion and local recruitment of immune effectors, the development of a safe and effective therapeutic vaccine is within reach. Here, we describe the vaccine approaches that currently show promise at clinical and pre-clinical stages and link them to the evolving scientific strategies that led to their identification. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Recent advances in the molecular design of synthetic vaccines

    Science.gov (United States)

    Jones, Lyn H.

    2015-12-01

    Vaccines have typically been prepared using whole organisms. These are normally either attenuated bacteria or viruses that are live but have been altered to reduce their virulence, or pathogens that have been inactivated and effectively killed through exposure to heat or formaldehyde. However, using whole organisms to elicit an immune response introduces the potential for infections arising from a reversion to a virulent form in live pathogens, unproductive reactions to vaccine components or batch-to-batch variability. Synthetic vaccines, in which a molecular antigen is conjugated to a carrier protein, offer the opportunity to circumvent these problems. This Perspective will highlight the progress that has been achieved in developing synthetic vaccines using a variety of molecular antigens. In particular, the different approaches used to develop conjugate vaccines using peptide/proteins, carbohydrates and other small molecule haptens as antigens are compared.

  7. New insight-guided approaches to detect, cure, prevent and eliminate malaria.

    Science.gov (United States)

    Kumar, Sushil; Kumari, Renu; Pandey, Richa

    2015-05-01

    New challenges posed by the development of resistance against artemisinin-based combination therapies (ACTs) as well as previous first-line therapies, and the continuing absence of vaccine, have given impetus to research in all areas of malaria control. This review portrays the ongoing progress in several directions of malaria research. The variants of RTS,S and apical membrane antigen 1 (AMA1) are being developed and test adapted as multicomponent and multistage malaria control vaccines, while many other vaccine candidates and methodologies to produce antigens are under experimentation. To track and prevent the spread of artemisinin resistance from Southeast Asia to other parts of the world, rolling circle-enhanced enzyme activity detection (REEAD), a time- and cost-effective malaria diagnosis in field conditions, and a DNA marker associated with artemisinin resistance have become available. Novel mosquito repellents and mosquito trapping and killing techniques much more effective than the prevalent ones are undergoing field testing. Mosquito lines stably infected with their symbiotic wild-type or genetically engineered bacteria that kill sympatric malaria parasites are being constructed and field tested for stopping malaria transmission. A complementary approach being pursued is the addition of ivermectin-like drug molecules to ACTs to cure malaria and kill mosquitoes. Experiments are in progress to eradicate malaria mosquito by making it genetically male sterile. High-throughput screening procedures are being developed and used to discover molecules that possess long in vivo half life and are active against liver and blood stages for the fast cure of malaria symptoms caused by simple or relapsing and drug-sensitive and drug-resistant types of varied malaria parasites, can stop gametocytogenesis and sporogony and could be given in one dose. Target-based antimalarial drug designing has begun. Some of the putative next-generation antimalarials that possess in their

  8. New approaches to design HIV-1 T-cell vaccines.

    Science.gov (United States)

    Perrin, Hélène; Canderan, Glenda; Sékaly, Rafick-Pierre; Trautmann, Lydie

    2010-09-01

    Following the evidence that T-cell responses are crucial in the control of HIV-1 infection, vaccines targeting T-cell responses were tested in recent clinical trials. However, these vaccines showed a lack of efficacy. This review attempts to define the qualitative and quantitative features that are desirable for T-cell-induced responses by vaccines. We also describe strategies that could lead to achievement of this goal. Using the yellow fever vaccine as a benchmark of an efficient vaccine, recent studies identified factors of immune protection and more importantly innate immune pathways needed for the establishment of long-term protective adaptive immunity. To prevent or control HIV-1 infection, a vaccine must induce efficient and persistent antigen-specific T cells endowed with mucosal homing capacity. Such cells should have the capability to counteract HIV-1 diversity and its rapid spread from the initial site of infection. To achieve this goal, the activation of a diversified innate immune response is critical. New systems biology approaches will provide more precise correlates of immune protection that will pave the way for new approaches in T-cell-based vaccines.

  9. Immunization with the Malaria Diversity-Covering Blood-Stage Vaccine Candidate Plasmodium falciparum Apical Membrane Antigen 1 DiCo in Complex with Its Natural Ligand PfRon2 Does Not Improve the In Vitro Efficacy

    Directory of Open Access Journals (Sweden)

    Holger Spiegel

    2017-06-01

    Full Text Available The blood-stage malaria vaccine candidate Plasmodium falciparum apical membrane antigen 1 (PfAMA1 can induce strong parasite growth-inhibitory antibody responses in animals but has not achieved the anticipated efficacy in clinical trials. Possible explanations in humans are the insufficient potency of the elicited antibody responses, as well as the high degree of sequence polymorphisms found in the field. Several strategies have been developed to improve the cross-strain coverage of PfAMA1-based vaccines, whereas innovative concepts to increase the potency of PfAMA1-specific IgG responses have received little attention even though this may be an essential requirement for protective efficacy. A previous study has demonstrated that immunization with a complex of PyAMA1 and PyRON2, a ligand with an essential functional role in erythrocyte invasion, leads to protection from lethal Plasmodium yoelli challenge in an animal model and suggested to extend this strategy toward improved strain coverage by using multiple PfAMA1 alleles in combination with PfRon2L. As an alternative approach along this line, we decided to use PfRon2L in combination with three PfAMA1 diversity covering variants (DiCo to investigate the potential of this complex to induce more potent parasite growth inhibitory immune response in combination with better cross-strain-specific efficacy. Within the limits of the study design, the ability of the PfAMA1 DiCo-Mix to induce cross-strain-specific antibodies was not affected in all immunization groups, but the DiCo–PfRon2L complexes did not improve the potency of PfAMA1-specific IgG responses.

  10. Catalase epitopes vaccine design for Helicobacter pylori: A ...

    African Journals Online (AJOL)

    Jane

    2011-08-15

    Aug 15, 2011 ... colored region and P1 anchor or the starting residue of each ..... score of MVNKDVKQTT; * 1, MVNKDVKQTT is a composition of two epitopes: MVNKDVKQT and .... Therapeutic efficacy of a multi-epitope vaccine against.

  11. A Randomized Longitudinal Factorial Design to Assess Malaria Vector Control and Disease Management Interventions in Rural Tanzania

    Directory of Open Access Journals (Sweden)

    Randall A. Kramer

    2014-05-01

    Full Text Available The optimization of malaria control strategies is complicated by constraints posed by local health systems, infrastructure, limited resources, and the complex interactions between infection, disease, and treatment. The purpose of this paper is to describe the protocol of a randomized factorial study designed to address this research gap. This project will evaluate two malaria control interventions in Mvomero District, Tanzania: (1 a disease management strategy involving early detection and treatment by community health workers using rapid diagnostic technology; and (2 vector control through community-supported larviciding. Six study villages were assigned to each of four groups (control, early detection and treatment, larviciding, and early detection and treatment plus larviciding. The primary endpoint of interest was change in malaria infection prevalence across the intervention groups measured during annual longitudinal cross-sectional surveys. Recurring entomological surveying, household surveying, and focus group discussions will provide additional valuable insights. At baseline, 962 households across all 24 villages participated in a household survey; 2,884 members from 720 of these households participated in subsequent malariometric surveying. The study design will allow us to estimate the effect sizes of different intervention mixtures. Careful documentation of our study protocol may also serve other researchers designing field-based intervention trials.

  12. A randomized longitudinal factorial design to assess malaria vector control and disease management interventions in rural Tanzania.

    Science.gov (United States)

    Kramer, Randall A; Mboera, Leonard E G; Senkoro, Kesheni; Lesser, Adriane; Shayo, Elizabeth H; Paul, Christopher J; Miranda, Marie Lynn

    2014-05-16

    The optimization of malaria control strategies is complicated by constraints posed by local health systems, infrastructure, limited resources, and the complex interactions between infection, disease, and treatment. The purpose of this paper is to describe the protocol of a randomized factorial study designed to address this research gap. This project will evaluate two malaria control interventions in Mvomero District, Tanzania: (1) a disease management strategy involving early detection and treatment by community health workers using rapid diagnostic technology; and (2) vector control through community-supported larviciding. Six study villages were assigned to each of four groups (control, early detection and treatment, larviciding, and early detection and treatment plus larviciding). The primary endpoint of interest was change in malaria infection prevalence across the intervention groups measured during annual longitudinal cross-sectional surveys. Recurring entomological surveying, household surveying, and focus group discussions will provide additional valuable insights. At baseline, 962 households across all 24 villages participated in a household survey; 2,884 members from 720 of these households participated in subsequent malariometric surveying. The study design will allow us to estimate the effect sizes of different intervention mixtures. Careful documentation of our study protocol may also serve other researchers designing field-based intervention trials.

  13. Considerations for the rational design of a Chlamydia vaccine

    OpenAIRE

    Liang, Steven; Bulir, David; Kaushic, Charu; Mahony, James

    2016-01-01

    ABSTRACT Chlamydia trachomatis is the leading cause of preventable blindness and the most common bacterial sexually transmitted infection. Remarkable progress in vaccine research over the past six?decades has led to the advancement of novel C. trachomatis vaccine candidates into clinical trials. However, many questions regarding the role of specific cellular populations and molecular mechanisms in protective immunity against human C. trachomatis genital tract infections remain unanswered. Bio...

  14. Mapping hypoendemic, seasonal malaria in rural Bandarban, Bangladesh: a prospective surveillance

    Directory of Open Access Journals (Sweden)

    Glass Gregory

    2011-05-01

    Full Text Available Abstract Background Until recently the Chittagong Hill tracts have been hyperendemic for malaria. A past cross-sectional RDT based survey in 2007 recorded rates of approximately 15%. This study was designed to understand the present epidemiology of malaria in this region, to monitor and facilitate the uptake of malaria intervention activities of the national malaria programme and to serve as an area for developing new and innovative control strategies for malaria. Methods This research field area was established in two rural unions of Bandarban District of Bangladesh north of Bandarban city, which are known to be endemic for malaria due to Plasmodium falciparum. The project included the following elements: a a demographic surveillance system including an initial census with updates every four months, b periodic surveys of knowledge attitude and practice, c a geographic information system, d weekly active and continuous passive surveillance for malaria infections using smears, rapid tests and PCR, f monthly mosquito surveillance, and e daily weather measures. The programme included both traditional and molecular methods for detecting malaria as well as lab methods for speciating mosquitoes and detecting mosquitoes infected with sporozoites. Results The demographic surveillance enumerated and mapped 20,563 people, 75% of which were tribal non-Bengali. The monthly mosquito surveys identified 22 Anopheles species, eight of which were positive by circumsporozoite ELISA. The annual rate of malaria was close to 1% with 85% of cases in the rainy months of May-October. Definitive clustering identified in the low transmission season persisted during the high transmission season. Conclusion This demographically and geographically defined area, near to the Myanmar border, which is also hypoendemic for malaria, will be useful for future studies of the epidemiology of malaria and for evaluation of strategies for malaria control including new drugs and

  15. About Malaria

    Science.gov (United States)

    ... Emergency Consultations, and General Public. Contact Us About Malaria Recommend on Facebook Tweet Share Compartir Malaria is ... from sub-Saharan Africa and South Asia. About Malaria Topics FAQs Frequently Asked Question, Incubation period, uncomplicated & ...

  16. An open source business model for malaria.

    Science.gov (United States)

    Årdal, Christine; Røttingen, John-Arne

    2015-01-01

    Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new malaria

  17. An open source business model for malaria.

    Directory of Open Access Journals (Sweden)

    Christine Årdal

    Full Text Available Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related

  18. T-cell responses in malaria

    DEFF Research Database (Denmark)

    Hviid, L; Jakobsen, P H; Abu-Zeid, Y A

    1992-01-01

    Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria...... vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information......, and discusses factors affecting the responses of T cells to malaria antigens....

  19. Rationally Designed TLR4 Ligands for Vaccine Adjuvant Discovery

    Directory of Open Access Journals (Sweden)

    Kelsey A. Gregg

    2017-05-01

    Full Text Available Adjuvant properties of bacterial cell wall components like MPLA (monophosphoryl lipid A are well described and have gained FDA approval for use in vaccines such as Cervarix. MPLA is the product of chemically modified lipooligosaccharide (LOS, altered to diminish toxic proinflammatory effects while retaining adequate immunogenicity. Despite the virtually unlimited number of potential sources among bacterial strains, the number of useable compounds within this promising class of adjuvants are few. We have developed bacterial enzymatic combinatorial chemistry (BECC as a method to generate rationally designed, functionally diverse lipid A. BECC removes endogenous or introduces exogenous lipid A-modifying enzymes to bacteria, effectively reprogramming the lipid A biosynthetic pathway. In this study, BECC is applied within an avirulent strain of Yersinia pestis to develop structurally distinct LOS molecules that elicit differential Toll-like receptor 4 (TLR4 activation. Using reporter cell lines that measure NF-κB activation, BECC-derived molecules were screened for the ability to induce a lower proinflammatory response than Escherichia coli LOS. Their structures exhibit varied, dose-dependent, TLR4-driven NF-κB activation with both human and mouse TLR4 complexes. Additional cytokine secretion screening identified molecules that induce levels of tumor necrosis factor alpha (TNF-α and interleukin-8 (IL-8 comparable to the levels induced by phosphorylated hexa-acyl disaccharide (PHAD. The lead candidates demonstrated potent immunostimulation in mouse splenocytes, human primary blood mononuclear cells (PBMCs, and human monocyte-derived dendritic cells (DCs. This newly described system allows directed programming of lipid A synthesis and has the potential to generate a diverse array of TLR4 agonist candidates.

  20. The effect of vitamin A supplementation and diphtheria-tetanus-pertussis vaccination on parasitaemia in an experimental murine malaria model

    DEFF Research Database (Denmark)

    Jørgensen, Mathias Jul; Hein-Kristensen, Line; Hempel, Casper

    2011-01-01

    infectious diseases when given with the diphtheria-tetanus-pertussis (DTP) vaccine. The immunological effects of combining the 2 treatments are unknown. Methods: We studied the effect of treating C57BL/6 mice with VAS and DTP, 1 week prior to infection with Plasmodium berghei ANKA. The progression of disease...

  1. Feline immunodeficiency virus model for designing HIV/AIDS vaccines.

    Science.gov (United States)

    Yamamoto, Janet K; Sanou, Missa P; Abbott, Jeffrey R; Coleman, James K

    2010-01-01

    Feline immunodeficiency virus (FIV) discovered in 1986 is a lentivirus that causes AIDS in domestic cats. FIV is classified into five subtypes (A-E), and all subtypes and circulating intersubtype recombinants have been identified throughout the world. A commercial FIV vaccine, consisting of inactivated subtype-A and -D viruses (Fel-O-Vax FIV, Fort Dodge Animal Health), was released in the United States in 2002. The United States Department of Agriculture approved the commercial release of Fel-O-Vax FIV based on two efficacy trials using 105 laboratory cats and a major safety trial performed on 689 pet cats. The prototype and commercial FIV vaccines had broad prophylactic efficacy against global FIV subtypes and circulating intersubtype recombinants. The mechanisms of cross-subtype efficacy are attributed to FIV-specific T-cell immunity. Findings from these studies are being used to define the prophylactic epitopes needed for an HIV-1 vaccine for humans.

  2. Naturally acquired immune responses to malaria vaccine candidate antigens MSP3 and GLURP in Guahibo and Piaroa indigenous communities of the Venezuelan Amazon

    DEFF Research Database (Denmark)

    Baumann, Andreas; Magris, Magda M; Urbaez, Marie-Luz

    2012-01-01

    ABSTRACT: BACKGROUND: Malaria transmission in most of Latin America can be considered as controlled. In such a scenario, parameters of baseline immunity to malaria antigens are of specific interest with respect to future malaria eradication efforts. METHODS: A cross-sectional study was carried ou...

  3. Design of Malaria Diagnostic Criteria for the Sysmex XE-2100 Hematology Analyzer

    Science.gov (United States)

    Campuzano-Zuluaga, Germán; Álvarez-Sánchez, Gonzalo; Escobar-Gallo, Gloria Elcy; Valencia-Zuluaga, Luz Marina; Ríos-Orrego, Alexandra Marcela; Pabón-Vidal, Adriana; Miranda-Arboleda, Andrés Felipe; Blair-Trujillo, Silvia; Campuzano-Maya, Germán

    2010-01-01

    Thick film, the standard diagnostic procedure for malaria, is not always ordered promptly. A failsafe diagnostic strategy using an XE-2100 analyzer is proposed, and for this strategy, malaria diagnostic models for the XE-2100 were developed and tested for accuracy. Two hundred eighty-one samples were distributed into Plasmodium vivax, P. falciparum, and acute febrile syndrome groups for model construction. Model validation was performed using 60% of malaria cases and a composite control group of samples from AFS and healthy participants from endemic and non-endemic regions. For P. vivax, two observer-dependent models (accuracy = 95.3–96.9%), one non–observer-dependent model using built-in variables (accuracy = 94.7%), and one non–observer-dependent model using new and built-in variables (accuracy = 96.8%) were developed. For P. falciparum, two non–observer-dependent models (accuracies = 85% and 89%) were developed. These models could be used by health personnel or be integrated as a malaria alarm for the XE-2100 to prompt early malaria microscopic diagnosis. PMID:20207864

  4. Using Hematology Data from Malaria Vaccine Research Trials in Humans and Rhesus Macaques (Macaca mulatta) To Guide Volume Limits for Blood Withdrawal.

    Science.gov (United States)

    Hegge, Sara R; Hickey, Bradley W; Mcgrath, Shannon M; Stewart, V Ann

    2016-12-01

    Guidelines on safe volume limits for blood collection from research participants in both humans and laboratory animals vary widely between institutions. The main adverse event that may be encountered in large blood volume withdrawal is iron-deficiency anemia. Monitoring various parameters in a standard blood panel may help to prevent this outcome. To this end, we analyzed the Hgb and MCV values from 43 humans and 46 macaques in malaria vaccine research trials. Although the percentage of blood volume removed was greater for macaques than humans, macaques demonstrated an overall increase of MCV over time, indicating the ability to respond appropriately to frequent volume withdrawals. In contrast, humans showed a consistent declining trend in MCV. These declines in human MCV and Hgb were significant from the beginning to end of the study despite withdrawals that were smaller than recommended volume limits. Limiting the volume withdrawn to no more than 12.5% seemed to be sufficient for macaques, and at 14% or more individual animals tended to fail to respond appropriately to large-volume blood loss, as demonstrated by a decrease in MCV. The overall positive erythropoietic response seen in macaques was likely due to the controlled, iron-fortified diet they received. The lack of erythropoietic response in the human subjects may warrant iron supplementation or reconsideration of current blood volume withdrawal guidelines.

  5. Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors

    Science.gov (United States)

    Anderson, Annaliesa S.; Miller, Alita A.; Donald, Robert G.K.; Scully, Ingrid L.; Nanra, Jasdeep S.; Cooper, David; Jansen, Kathrin U.

    2012-01-01

    Staphylococcus aureus is a major cause of healthcare-associated infections and is responsible for a substantial burden of disease in hospitalized patients. Despite increasingly rigorous infection control guidelines, the prevalence and corresponding negative impact of S. aureus infections remain considerable. Difficulties in controlling S. aureus infections as well as the associated treatment costs are exacerbated by increasing rates of resistance to available antibiotics. Despite ongoing efforts over the past 20 years, no licensed S. aureus vaccine is currently available. However, learnings from past clinical failures of vaccine candidates and a better understanding of the immunopathology of S. aureus colonization and infection have aided in the design of new vaccine candidates based on multiple important bacterial pathogenesis mechanisms. This review outlines important considerations in designing a vaccine for the prevention of S. aureus disease in healthcare settings. PMID:22922765

  6. Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: a strategy for enhancing immunogenicity of malaria vaccine candidates.

    Science.gov (United States)

    Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L; Long, Carole A; Miller, Louis H; Saul, Allan; Mullen, Gregory E D

    2007-05-16

    Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) to a blood stage vaccine candidate and surface protein 25 (Pfs25) a mosquito stage vaccine candidate, were each independently chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66kD) relatively good immunogen in mice; Pfs25 is a poorly immunogenic protein when presented on alum to mice. Mice were immunized on days 0 and 28 with AMA1- or Pfs25-rEPA conjugates or unconjugated AMA1 or Pfs25, all formulated on Alhydrogel. Remarkably, sera from mice 14 days after the second immunization with Pfs25-rEPA conjugates displayed over a 1000-fold higher antibody titers as compared to unconjugated Pfs25. In contrast, AMA1 conjugated under the same conditions induced only a three-fold increase in antibody titers. When tested for functional activity, antibodies elicited by the AMA1-rEPA inhibited invasion of erythrocytes by blood-stage parasites and antibodies elicited by the Pfs25-rEPA conjugates blocked the development of the sexual stage parasites in the mosquito midgut. These results demonstrate that conjugation to rEPA induces a marked improvement in the antibody titer in mice for the poor immunogen (Pfs25) and for the larger protein (AMA1). These conjugates now need to be tested in humans to determine if mice are predictive of the response in humans.

  7. Towards the intelligent design of a vaccine against Edwardsiella ictaluri

    Science.gov (United States)

    Edwardsiella ictaluri is the leading cause of disease loss in the catfish industry in the United States, accounting for an estimated 20.2 % loss in 2009. Previous work to establish live-attenuated vaccines for E. ictaluri demonstrated a relatively weak channel catfish immune response, with better im...

  8. Introducing rapid diagnostic tests for malaria into drug shops in Uganda: design and implementation of a cluster randomized trial.

    Science.gov (United States)

    Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare I R; Hansen, Kristian S; Lal, Sham; Cundill, Bonnie; Lynch, Caroline A; Clarke, Siân E

    2014-07-29

    An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop vendors and implemented supporting interventions to orientate local communities (patients) and the public sector (health facility staff and district officials) to the behavioral changes in diagnosis, treatment and referral being introduced in drug shops. The intervention was designed to be evaluated through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions on diagnosis and treatment of malaria at drug shops, and affordable prices for mRDTs and ACTs in order to inform the design of the intervention and implementation modalities. The intervention required careful design with the intention to be acceptable, sustainable and effective. Critical components of intervention were: community sensitization and creating awareness, training of drug shop vendors to diagnose malaria with mRDTs, treat and refer customers to formal health facilities, giving pre-referral rectal artesunate and improved record-keeping. The primary outcome was the proportion of patients receiving appropriately-targeted treatment with ACT, evaluated against microscopy on a research blood slide. Introducing mRDTs in drug shops may seem simple, but our experience of intervention design, conduct and evaluation showed this to be a complex process requiring multiple interventions and evaluation components drawing from a combination of epidemiological, social science and health economics methodologies. The trial was conducted in phases sequenced such that each benefited from the other. The main challenges

  9. Tapping the world wide web for designing vaccines for livestock diseases

    International Nuclear Information System (INIS)

    Deocaris, C.C.

    2005-01-01

    Post-genomic approaches in the development of new vaccines will fundamentally change how veterinarians prevent and treat diseases. One type of vaccine that has generated renewed interest is the subunit or synthetic vaccine, which has the advantage of rapid, safe and high-throughput production via chemical (as synthetic peptides) or recombinant approaches (as DNA, purified subunit or multigene vaccines). At the heart of such a vaccine are few but powerful epitopes that confer both the humoral and cell-mediated immune responses. Traditional biochemical assays have been used to map these epitopes; however, they are prohibitively labour and capital intensive. In contrast, in silico development of multivalent subunit vaccines is now possible through the availability of genomic information and the nascence of molecular immunoinformatics as a discipline. Algorithms are described in this paper to aid in identifying B and T cell epitopes for design of vaccines based on published available protein databases. From the mapped epitopes, synthetic mimotopes (or epitope-mimicking sequences) are concatenated using glycine bridges aimed at maintaining at least 90% of the secondary structures while minimizing steric hindrances between adjacent epitopes. (author)

  10. PD-1 Dependent Exhaustion of CD8+ T Cells Drives Chronic Malaria

    Directory of Open Access Journals (Sweden)

    Joshua M. Horne-Debets

    2013-12-01

    Full Text Available Malaria is a highly prevalent disease caused by infection by Plasmodium spp., which infect hepatocytes and erythrocytes. Blood-stage infections cause devastating symptoms and can persist for years. Antibodies and CD4+ T cells are thought to protect against blood-stage infections. However, there has been considerable difficulty in developing an efficacious malaria vaccine, highlighting our incomplete understanding of immunity against this disease. Here, we used an experimental rodent malaria model to show that PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8+ T cells. Furthermore, in contrast to widely held views, parasite-specific CD8+ T cells are required to control both acute and chronic blood-stage disease even when parasite-specific antibodies and CD4+ T cells are present. Our findings provide a molecular explanation for chronic malaria that will be relevant to future malaria-vaccine design and may need consideration when vaccine development for other infections is problematic.

  11. Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial

    DEFF Research Database (Denmark)

    Fröbert, Ole; Götberg, Matthias; Angerås, Oskar

    2017-01-01

    BACKGROUND: Registry studies and case-control studies have demonstrated that the risk of acute myocardial infarction (AMI) is increased following influenza infection. Small randomized trials, underpowered for clinical end points, indicate that future cardiovascular events can be reduced following...... influenza vaccination in patients with established cardiovascular disease. Influenza vaccination is recommended by international guidelines for patients with cardiovascular disease, but uptake is varying and vaccination is rarely prioritized during hospitalization for AMI. METHODS/DESIGN: The Influenza...... be assigned either to in-hospital influenza vaccination or to placebo. Baseline information is collected from national heart disease registries, and follow-up will be performed using both registries and a structured telephone interview. The primary end point is a composite of time to all-cause death, a new...

  12. User-Centered Design for Developing Interventions to Improve Clinician Recommendation of Human Papillomavirus Vaccination.

    Science.gov (United States)

    Henninger, Michelle L; Mcmullen, Carmit K; Firemark, Alison J; Naleway, Allison L; Henrikson, Nora B; Turcotte, Joseph A

    2017-01-01

    Human papillomavirus (HPV) is the most common sexually transmitted infection in the US and is associated with multiple types of cancer. Although effective HPV vaccines have been available since 2006, coverage rates in the US remain much lower than with other adolescent vaccinations. Prior research has shown that a strong recommendation from a clinician is a critical determinant in HPV vaccine uptake and coverage. However, few published studies to date have specifically addressed the issue of helping clinicians communicate more effectively with their patients about the HPV vaccine. To develop one or more novel interventions for helping clinicians make strong and effective recommendations for HPV vaccination. Using principles of user-centered design, we conducted qualitative interviews, interviews with persons from analogous industries, and a data synthesis workshop with multiple stakeholders. Five potential intervention strategies targeted at health care clinicians, youth, and their parents were developed. The two most popular choices to pursue were a values-based communication strategy and a puberty education workbook. User-centered design is a useful strategy for developing potential interventions to improve the rate and success of clinicians recommending the HPV vaccine. Further research is needed to test the effectiveness and acceptability of these interventions in clinical settings.

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

    Science.gov (United States)

    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.

  14. Development of a Preventive HIV Vaccine Requires Solving Inverse Problems Which Is Unattainable by Rational Vaccine Design

    Directory of Open Access Journals (Sweden)

    Marc H. V. Van Regenmortel

    2018-01-01

    Full Text Available Hypotheses and theories are essential constituents of the scientific method. Many vaccinologists are unaware that the problems they try to solve are mostly inverse problems that consist in imagining what could bring about a desired outcome. An inverse problem starts with the result and tries to guess what are the multiple causes that could have produced it. Compared to the usual direct scientific problems that start with the causes and derive or calculate the results using deductive reasoning and known mechanisms, solving an inverse problem uses a less reliable inductive approach and requires the development of a theoretical model that may have different solutions or none at all. Unsuccessful attempts to solve inverse problems in HIV vaccinology by reductionist methods, systems biology and structure-based reverse vaccinology are described. The popular strategy known as rational vaccine design is unable to solve the multiple inverse problems faced by HIV vaccine developers. The term “rational” is derived from “rational drug design” which uses the 3D structure of a biological target for designing molecules that will selectively bind to it and inhibit its biological activity. In vaccine design, however, the word “rational” simply means that the investigator is concentrating on parts of the system for which molecular information is available. The economist and Nobel laureate Herbert Simon introduced the concept of “bounded rationality” to explain why the complexity of the world economic system makes it impossible, for instance, to predict an event like the financial crash of 2007–2008. Humans always operate under unavoidable constraints such as insufficient information, a limited capacity to process huge amounts of data and a limited amount of time available to reach a decision. Such limitations always prevent us from achieving the complete understanding and optimization of a complex system that would be needed to achieve a truly

  15. Retinopathy in severe malaria in Ghanaian children - overlap between fundus changes in cerebral and non-cerebral malaria

    DEFF Research Database (Denmark)

    Essuman, Vera A; Ntim-Amponsah, Christine T; Astrup, Birgitte S

    2010-01-01

    diagnostic tool. This study was designed to determine the diagnostic usefulness of retinopathy on ophthalmoscopy in severe malaria syndromes: Cerebral malaria (CM) and non-cerebral severe malaria (non-CM), i.e. malaria with respiratory distress (RD) and malaria with severe anaemia (SA), in Ghanaian children...

  16. The Malaria Season Is Upon Us

    African Journals Online (AJOL)

    imported or Odyssean malaria from countries such as Swaziland,. Mozambique ... can be administered.⁵ The only .... Treatment. With the introduction of an effective vaccine for Southern Africa .... Being prepared for a malaria infection by packing ... sulfadoxine-pyrimethamine against Plasmodium falciparum in Yemen and.

  17. Population genomics diversity of Plasmodium falciparum in malaria ...

    African Journals Online (AJOL)

    Background: Plasmodium falciparum, the most dangerous malaria parasite species to ... tigen for subunit malaria vaccine.10 It comprises highly ... were also prepared for Giemsa staining as described by ... parasites with different alleles at a given locus and ranges ..... surface protein 1, immune evasion and vaccines against.

  18. Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant.

    Science.gov (United States)

    Li, Xiangming; Fujio, Masakazu; Imamura, Masakazu; Wu, Douglass; Vasan, Sandhya; Wong, Chi-Huey; Ho, David D; Tsuji, Moriya

    2010-07-20

    The glycolipid alpha-galactosylceramide (alpha-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, alpha-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNKT cells and dendritic cells and produce an adjuvant effect superior to alpha-GalCer, we performed step-wise screening assays on a focused library of 25 alpha-GalCer analogues. Assays included quantification of the magnitude of stimulatory activity against human iNKT cells in vitro, binding affinity to human and murine CD1d molecules, and binding affinity to the invariant t cell receptor of human iNKT cells. Through this rigorous and iterative screening process, we have identified a lead candidate glycolipid, 7DW8-5, that exhibits a superior adjuvant effect than alpha-GalCer on HIV and malaria vaccines in mice.

  19. Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial.

    Science.gov (United States)

    Otieno, Lucas; Oneko, Martina; Otieno, Walter; Abuodha, Joseph; Owino, Emmanuel; Odero, Chris; Mendoza, Yolanda Guerra; Andagalu, Ben; Awino, Norbert; Ivinson, Karen; Heerwegh, Dirk; Otsyula, Nekoye; Oziemkowska, Maria; Usuf, Effua Abigail; Otieno, Allan; Otieno, Kephas; Leboulleux, Didier; Leach, Amanda; Oyieko, Janet; Slutsker, Laurence; Lievens, Marc; Cowden, Jessica; Lapierre, Didier; Kariuki, Simon; Ogutu, Bernhards; Vekemans, Johan; Hamel, Mary J

    2016-10-01

    Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered

  20. 'He is now like a brother, I can even give him some blood'--relational ethics and material exchanges in a malaria vaccine 'trial community' in The Gambia.

    Science.gov (United States)

    Geissler, P Wenzel; Kelly, Ann; Imoukhuede, Babatunde; Pool, Robert

    2008-09-01

    This paper explores social relations within the 'trial community' (staff and volunteers) of a Malaria Vaccine Trial (MVT), implemented by the Medical Research Council (MRC) in The Gambia between 2001 and 2004. It situates ethical concerns with medical research within the everyday life of scientific fieldwork. Based upon discussions with volunteers and staff, we explore processes of mediation between scientific project and study population, and between formal ethics, local ethical debates and everyday practice. We observe that material contact and substantial transactions, notably of blood and medicine, are central to the construction of the MVT. These transactions are guided by a concrete and relational form of ethics, which contrasts with the abstract and vertical formal ethical principles underwriting the scientific study protocol. The success of the MVT owed much to these kinship-like ethics. One possible conclusion from these observations is that research ethics should be understood, not just as a quasi-legal frame but also as an open, searching movement, much in the same way that kinship is not merely a juridical institution and a prescriptive frame of rules, but a network made through relational work. However, this conclusion raises new problems: by contrasting formal, abstract principles to intimate, immediate relations, and economic justice to personal morality, we accept that the order of medical research is moved further out of the public and political, and into the domains of either quasi-legal claims or of private morality. Irrespective of the undeniable importance of clear-cut rules and of good face-to-face relations, a third essential foundation of medical research ethics is the democratically constituted public sphere, including equitable health services, and transparent institutions to facilitate open debate and regulate particular interests. Ultimately, the ethics of global science can rely neither on principles nor trust but requires citizenship

  1. Unusual antigen presentation offers new insight into HIV vaccine design.

    Science.gov (United States)

    McMichael, Andrew J; Picker, Louis J

    2017-06-01

    Recent findings with a rhesus monkey cytomegalovirus based simian immunodeficiency virus vaccine have identified strong CD8+ T cell responses that are restricted by MHC-E. Also mycobacteria specific CD8+ T cells, that are MHC-E restricted, have been identified. MHC-E therefore can present a wide range of epitope peptides to CD8+ T cells, alongside its well defined role in presenting a conserved MHC-class I signal peptide to the NKG2A/C-CD94 receptor on natural killer cells. Here we explore the antigen processing pathways involved in these atypical T cell responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. High-Throughput Testing of Antibody-Dependent Binding Inhibition of Placental Malaria Parasites

    DEFF Research Database (Denmark)

    Nielsen, Morten A; Salanti, Ali

    2015-01-01

    The particular virulence of Plasmodium falciparum manifests in diverse severe malaria syndromes as cerebral malaria, severe anemia and placental malaria. The cause of both the severity and the diversity of infection outcome, is the ability of the infected erythrocyte (IE) to bind a range......-throughput assay used in the preclinical and clinical development of a VAR2CSA based vaccine against placental malaria....

  3. 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

  4. Optimal vaccine stockpile design for an eradicated disease: application to polio.

    Science.gov (United States)

    Tebbens, Radboud J Duintjer; Pallansch, Mark A; Alexander, James P; Thompson, Kimberly M

    2010-06-11

    Eradication of a disease promises significant health and financial benefits. Preserving those benefits, hopefully in perpetuity, requires preparing for the possibility that the causal agent could re-emerge (unintentionally or intentionally). In the case of a vaccine-preventable disease, creation and planning for the use of a vaccine stockpile becomes a primary concern. Doing so requires consideration of the dynamics at different levels, including the stockpile supply chain and transmission of the causal agent. This paper develops a mathematical framework for determining the optimal management of a vaccine stockpile over time. We apply the framework to the polio vaccine stockpile for the post-eradication era and present examples of solutions to one possible framing of the optimization problem. We use the framework to discuss issues relevant to the development and use of the polio vaccine stockpile, including capacity constraints, production and filling delays, risks associated with the stockpile, dynamics and uncertainty of vaccine needs, issues of funding, location, and serotype dependent behavior, and the implications of likely changes over time that might occur. This framework serves as a helpful context for discussions and analyses related to the process of designing and maintaining a stockpile for an eradicated disease. (c) 2010 Elsevier Ltd. All rights reserved.

  5. Design and implementation of a children vaccination reminder system based on short message service

    Directory of Open Access Journals (Sweden)

    Marjan Ghazisaeedi

    2016-09-01

    Full Text Available Background: Most problems related to quality of care and patient safety are related to human negligence. One of the causes of these problems is forgetting to do something. This problem can be avoided with information technology in many cases. Some forgotten are very important. Among these is failure to comply with vaccination schedule by parents that can result in inappropriate outcomes. In this study, we developed and evaluated a SMS reminder system for regular and timely vaccination of children. Methods: In this developmental-applied research, firstly, a child vaccination reminder system was designed and implemented to help parents reduce the forgetfulness. This system based on the child's vaccination history and the date of birth, offer time and type of future vaccines. Then the parents of 27 children, that their vaccination was between 22 June and 21 August 2015, referred to Children's Medical Center, were sent text messages by using this system. We evaluated the accuracy of the system logic by using some scenarios. In addition, we evaluated parents' satisfaction with the system using a questionnaire. Results: In all cases but one, the system proposed the type and date of future children vaccines correctly. All the parents who have received text messages had good perception and satisfaction on the majority of questions (total mean score of 4.15 out of 5. Most parents (4.92 out of 5 stated that using the system to remind their visit for child immunization was helpful and willing to offer the system to their friends and other families. Conclusion: Using the short message system is beneficial for parents to remind their children’s vaccination time and increases their satisfaction. So, it can be considered as an important and essential tool in providing healthcare services. SMS is an easy, cheap and effective way to improve the quality of care services.

  6. Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia.

    Directory of Open Access Journals (Sweden)

    Rajan P Adhikari

    Full Text Available Staphylococcus aureus (S. aureus is a human pathogen associated with skin and soft tissue infections (SSTI and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC. Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection.

  7. Cancer vaccine development: Designing tumor cells for greater immunogenicity

    Science.gov (United States)

    Bozeman, Erica N.; Shashidharamurthy, Rangaiah; Paulos, Simon A.; Palaniappan, Ravi; D’Souza, Martin; Selvaraj, Periasamy

    2014-01-01

    Cancer vaccine development is one of the most hopeful and exhilarating areas in cancer research. For this reason, there has been a growing interest in the development and application of novel immunotherapies for the treatment of cancer with the focus being on stimulating the immune system to target tumor cells specifically while leaving normal cells unharmed. From such research has emerged a host of promising immunotherapies such as dendritic cell-based vaccines, cytokine therapies and gene transfer technology. These therapies seek to counteract the poor immunogenicity of tumors by augmenting the host’s immune system with a variety of immunostimulatory proteins such as cytokines and costimulatory molecules. While such therapies have proven effective in the induction of anti-tumor immunity in animal models, they are less than optimal and pose a high risk of clinical infeasibility. Herein, we further discuss these immunotherapies as well as a feasible and efficient alternative that, in pre-clinical animal models, allows for the expression of specific immunostimulatory molecules on the surface of tumor cells by a novel protein transfer technology. PMID:20036822

  8. Effect of ingested human antibodies induced by RTS, S/AS01 malaria vaccination in children on Plasmodium falciparum oocyst formation and sporogony in mosquitoes

    DEFF Research Database (Denmark)

    Miura, Kazutoyo; Jongert, Erik; Deng, Bingbing

    2014-01-01

    falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated. METHODS: Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted....... In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability...

  9. Evaluation of peptide selection approaches for epitope‐based vaccine design

    DEFF Research Database (Denmark)

    Schubert, B.; Lund, Ole; Nielsen, Morten

    2013-01-01

    A major challenge in epitope-based vaccine (EV) design stems from the vast genomic variation of pathogens and the diversity of the host cellular immune system. Several computational approaches have been published to assist the selection of potential T cell epitopes for EV design. So far, no thoro......A major challenge in epitope-based vaccine (EV) design stems from the vast genomic variation of pathogens and the diversity of the host cellular immune system. Several computational approaches have been published to assist the selection of potential T cell epitopes for EV design. So far...... in terms of in silico measurements simulating important vaccine properties like the ability of inducing protection against a multivariant pathogen in a population; the predicted immunogenicity; pathogen, allele, and population coverage; as well as the conservation of selected epitopes. Additionally, we...... evaluate the use of human leukocyte antigen (HLA) supertypes with regards to their applicability for population-spanning vaccine design. The results showed that in terms of induced protection methods that simultaneously aim to optimize pathogen and HLA coverage significantly outperform methods focusing...

  10. Effect of schistosoma infection on malaria immune response: A systematic review.

    Science.gov (United States)

    Yesuf, Elias Ali; Dejene, Tariku

    2011-01-01

    Background Worldwide an estimated 225 million cases and about 800, 000 deaths due to malaria were documented in 2009. Malaria vaccines have been developed as a malaria control strategy. Immune response to these vaccines might be affected by the blood fluke schistosoma which is often co-endemic with malaria in Sub-Saharan Africa where most of phase II and Phase III malaria vaccine trials were conducted.Objectives To systematically search, appraise and synthesize the best available evidence on the effect of schistosoma infection on the immune response to malaria antigens and provide direction to future malaria vaccination trials.Types of participants The review considered studies with above 5 year old individuals as participants.Phenomenon of interest The phenomenon of interest was the presence of schistosoma infectionTypes of outcomes Blood serum levels of Th1 and Th2 specific to Merozoite Surface Proteins 1, 2, and 3 of malaria were considered as primary outcomes. While blood serum levels of IgG1, IgG2, IgG3, IFN-γ, IL-10 and TGF-β directed against Merozoite Surface Proteins were considered as secondary outcomes.Types of studies Studies with any quantitative study designs were considered for inclusion.Search Strategy Any quantitative English language articles published between 1994 and April 2011 were sought using a comprehensive search strategy.Assessment of methodological quality It was done using Joanna Briggs Institutes' Meta Analysis of Statistical Assessment and Review Instrument critical appraisal tools.Data extraction Data extraction was carried out using the Joanna Briggs Institute Meta Analysis of Statistical Assessment and Review Instrument data extraction tool.Data synthesis Meta- analysis was conducted using random effects model with an inverse variance method with RevMan5 software. Heterogeneity between the studies was assessed using ξ test at a p-value of SMD (95% CI), 0.15 (-2.00, 2.31), p=0.89.Similarly a small and statistically not significant

  11. Malaria Research

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Malaria Go to Information for Researchers ► Credit: NIAID Colorized ... for the disease. Why Is the Study of Malaria a Priority for NIAID? Roughly 3.2 billion ...

  12. Serum protein profile of Malaria patients through SDS-PAGE method ...

    African Journals Online (AJOL)

    Serum protein profile of Malaria patients through SDS-PAGE method. ... reliable method in the diagnosis of antibodies produced against Plasmodium spps. ... of malaria patients may be undertaken for study to develop possible future vaccine.

  13. Influence of malaria on the serum levels of vitamin A, zinc and ...

    African Journals Online (AJOL)

    GREGO

    2007-04-02

    Apr 2, 2007 ... to usual anti-malaria drugs and insecticides (Müller and. Garenne, 1999). ... METHOD. Collection and preparation of sera ... consultation (for malaria) or vaccination (control) in the catholic medical .... are presented in Table 1.

  14. Designing and modeling of complex DNA vaccine based on tropomyosin protein of Boophilus genus tick.

    Science.gov (United States)

    Ranjbar, Mohamamd Mahdi; Gupta, Shishir K; Ghorban, Khodayar; Nabian, Sedigheh; Sazmand, Alireza; Taheri, Mohammad; Esfandyari, Sahar; Taheri, Maryam

    2015-01-01

    Boophilus tick is a bloodsucking ectoparasite that transfers some pathogens, reducing production and thus leading to economical losses in the cattle industry. Tropomyosin (TPM) protein is a salivary protein, has actin regulator activity, and plays an important role in immune reactions against parasites. In the current study, besides developing a safe, effective, and broad spectrum protective measure against Boophilus genus tick based on TPM protein, we attempted to minimize possible problems occurring in the design of polytopic vaccines. Briefly, the steps that were followed in the present study were as follows: retrieving sequences and finding the mutational/conservative regions, selecting consensus and high immunogenic epitopes of B and CD4(+) T cells by different approaches, three-dimensional structure (3D structure) prediction and representation of epitopes and highly variable/conserve regions, designing vaccinal construct by fusion of B and T cell epitopes by special patterns and improving immunogenicity, evaluation of the constructs' primary structure and posttranslational modification, calculation of hydrophobic regions, reverse translation, codon optimization, open reading frame checking, insertion of start/end codon, Kozak sequence, and finally constructing the DNA vaccine. Variation plot showed some shared epitopes among the ticks' and mites' species that some might be effective only in some species. Finally, by following the steps mentioned above, two constructs for B and T cells were achieved. Checking constructs revealed their reliability and efficacy for in vitro production and utilization. Successful in silico modeling is an essential step of designing vigorous vaccines. We developed a novel protective and therapeutic vaccine against Boophilus genus (based on TPM protein). At the next step, constructed DNA vaccine would be produced in vitro and administrated to cattle, and its potency to induction of immune response and protection against Boophilus

  15. Vaccines today, vaccines tomorrow: a perspective.

    Science.gov (United States)

    Loucq, Christian

    2013-01-01

    Vaccines are considered as one of the major contributions of the 20th century and one of the most cost effective public health interventions. The International Vaccine Institute has as a mission to discover, develop and deliver new and improved vaccines against infectious diseases that affects developing nations. If Louis Pasteur is known across the globe, vaccinologists like Maurice Hilleman, Jonas Salk and Charles Mérieux are known among experts only despite their contribution to global health. Thanks to a vaccine, smallpox has been eradicated, polio has nearly disappeared, Haemophilus influenzae B, measles and more recently meningitis A are controlled in many countries. While a malaria vaccine is undergoing phase 3, International Vaccine Institute, in collaboration with an Indian manufacturer has brought an oral inactivated cholera vaccine to pre-qualification. The field of vaccinology has undergone major changes thanks to philanthropists such as Bill and Melinda Gates, initiatives like the Decade of Vaccines and public private partnerships. Current researches on vaccines have more challenging targets like the dengue viruses, malaria, human immunodeficiency virus, the respiratory syncytial virus and nosocomial diseases. Exciting research is taking place on new adjuvants, nanoparticles, virus like particles and new route of administration. An overcrowded infant immunization program, anti-vaccine groups, immunizing a growing number of elderlies and delivering vaccines to difficult places are among challenges faced by vaccinologists and global health experts.

  16. A clinically parameterized mathematical model of Shigella immunity to inform vaccine design.

    Directory of Open Access Journals (Sweden)

    Courtney L Davis

    Full Text Available We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella's lipopolysaccharide (LPS and O-membrane proteins (OMP were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella's LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1 the rate that Shigella migrates into the lamina propria or epithelium, 2 the rate that memory B cells (BM differentiate into antibody-secreting cells (ASC, 3 the rate at which antibodies are produced by activated ASC, and 4 the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine.

  17. A clinically parameterized mathematical model of Shigella immunity to inform vaccine design.

    Science.gov (United States)

    Davis, Courtney L; Wahid, Rezwanul; Toapanta, Franklin R; Simon, Jakub K; Sztein, Marcelo B

    2018-01-01

    We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella's lipopolysaccharide (LPS) and O-membrane proteins (OMP) were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella's LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1) the rate that Shigella migrates into the lamina propria or epithelium, 2) the rate that memory B cells (BM) differentiate into antibody-secreting cells (ASC), 3) the rate at which antibodies are produced by activated ASC, and 4) the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine.

  18. Identificación y caracterización inmunológica preclínica de antígenos con potencial vacunal frente a la malaria en un modelo de malaria murina. Identification and preclinical immunological characterization of potential malaria vaccine antigens in a murine model of malaria

    OpenAIRE

    Kamai, Ali Naghi

    2012-01-01

    A pesar de los esfuerzos realizados durante más de un siglo en la investigación para suprimir la malaria, esta enfermedad sigue siendo una amenaza importante y creciente para la salud pública y el desarrollo económico de países en las regiones tropicales y subtropicales del mundo. La malaria humana está causada por la infección de parásitos intracelulares del género Plasmodium que se transmiten por mosquitos Anopheles. De las cinco especies de Plasmodium que infectan a seres humanos, las infe...

  19. Age-dependent association between IgG2 and IgG3 subclasses to Pf332-C231 antigen and protection from malaria, and induction of protective antibodies by sub-patent malaria infections, in Daraweesh

    DEFF Research Database (Denmark)

    Giha, Hayder A; Nasr, Amre; Iriemenam, Nnaemeka C

    2010-01-01

    The certainty of the protective role of acquired immunity in malaria is the major drive for malaria vaccine development. In this study, we measured the levels of total IgG and IgG subclasses to four candidate malaria vaccine antigens; MSP2-3D7, MSP2-FC27, AMA-1 and Pf332-C231, in plasma obtained ...

  20. Design and application of chitosan microspheres as oral and nasal vaccine carriers: an updated review

    Directory of Open Access Journals (Sweden)

    Islam MA

    2012-12-01

    Full Text Available Mohammad Ariful Islam,1–3,* Jannatul Firdous,1–3,* Yun-Jaie Choi,1 Cheol-Heui Yun,1–4 Chong-Su Cho1,21Department of Agricultural Biotechnology, 2Research Institute for Agriculture and Life Sciences, 3Center for Food and Bioconvergence, 4World Class University Biomodulation Program, Seoul National University, Seoul, South Korea*These authors contributed equally to this workAbstract: Chitosan, a natural biodegradable polymer, is of great interest in biomedical research due to its excellent properties including bioavailability, nontoxicity, high charge density, and mucoadhesivity, which creates immense potential for various pharmaceutical applications. It has gelling properties when it interacts with counterions such as sulfates or polyphosphates and when it crosslinks with glutaraldehyde. This characteristic facilitates its usefulness in the coating or entrapment of biochemicals, drugs, antigenic molecules as a vaccine candidate, and microorganisms. Therefore, chitosan together with the advance of nanotechnology can be effectively applied as a carrier system for vaccine delivery. In fact, chitosan microspheres have been studied as a promising carrier system for mucosal vaccination, especially via the oral and nasal route to induce enhanced immune responses. Moreover, the thiolated form of chitosan is of considerable interest due to its improved mucoadhesivity, permeability, stability, and controlled/extended release profile. This review describes the various methods used to design and synthesize chitosan microspheres and recent updates on their potential applications for oral and nasal delivery of vaccines. The potential use of thiolated chitosan microspheres as next-generation mucosal vaccine carriers is also discussed.Keywords: chitosan microspheres, oral, nasal, vaccine delivery, mucosal and systemic immune responses

  1. Designing and testing broadly-protective filoviral vaccines optimized for cytotoxic T-lymphocyte epitope coverage.

    Directory of Open Access Journals (Sweden)

    Paul W Fenimore

    Full Text Available We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1 but also appropriate for Hepatitis C virus (HCV and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.

  2. Designing and testing broadly-protective filoviral vaccines optimized for cytotoxic T-lymphocyte epitope coverage.

    Science.gov (United States)

    Fenimore, Paul W; Muhammad, Majidat A; Fischer, William M; Foley, Brian T; Bakken, Russell R; Thurmond, James R; Yusim, Karina; Yoon, Hyejin; Parker, Michael; Hart, Mary Kate; Dye, John M; Korber, Bette; Kuiken, Carla

    2012-01-01

    We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1) but also appropriate for Hepatitis C virus (HCV) and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL) epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.

  3. The role of vitamin D in malaria.

    Science.gov (United States)

    Lương, Khanh Vinh Quốc; Nguyễn, Lan Thi Hoàng

    2015-01-15

    An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus Calmette-Guerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed.

  4. Phase 1 trial of the Plasmodium falciparum blood stage vaccine MSP1(42-C1/Alhydrogel with and without CPG 7909 in malaria naïve adults.

    Directory of Open Access Journals (Sweden)

    Ruth D Ellis

    2010-01-01

    Full Text Available Merozoite surface protein 1(42 (MSP1(42 is a leading blood stage malaria vaccine candidate. In order to induce immune responses that cover the major antigenic polymorphisms, FVO and 3D7 recombinant proteins of MSP1(42 were mixed (MSP1(42-C1. To improve the level of antibody response, MSP1(42-C1 was formulated with Alhydrogel plus the novel adjuvant CPG 7909.A Phase 1 clinical trial was conducted in healthy malaria-naïve adults at the Center for Immunization Research in Washington, D.C., to evaluate the safety and immunogenicity of MSP1(42-C1/Alhydrogel +/- CPG 7909. Sixty volunteers were enrolled in dose escalating cohorts and randomized to receive three vaccinations of either 40 or 160 microg protein adsorbed to Alhydrogel +/- 560 microg CPG 7909 at 0, 1 and 2 months.Vaccinations were well tolerated, with only one related adverse event graded as severe (Grade 3 injection site erythema and all other vaccine related adverse events graded as either mild or moderate. Local adverse events were more frequent and severe in the groups receiving CPG. The addition of CPG enhanced anti-MSP1(42 antibody responses following vaccination by up to 49-fold two weeks after second immunization and 8-fold two weeks after the third immunization when compared to MSP1(42-C1/Alhydrogel alone (p<0.0001. After the third immunization, functionality of the antibody was tested by an in vitro growth inhibition assay. Inhibition was a function of antibody titer, with an average of 3% (range -2 to 10% in the non CPG groups versus 14% (3 to 32% in the CPG groups.The favorable safety profile and high antibody responses induced with MSP1(42-C1/Alhydrogel + CPG 7909 are encouraging. MSP1(42-C1/Alhydrogel is being combined with other blood stage antigens and will be taken forward in a formulation adjuvanted with CPG 7909.ClinicalTrials.gov Identifier: NCT00320658.

  5. Improving educational achievement and anaemia of school children: design of a cluster randomised trial of school-based malaria prevention and enhanced literacy instruction in Kenya

    Directory of Open Access Journals (Sweden)

    Halliday Katherine E

    2010-10-01

    Full Text Available Abstract Background Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence on the benefits of school-based malaria prevention or how health interventions interact with other efforts to improve education quality. This study aims to evaluate the impact of school-based malaria prevention and enhanced literacy instruction on the health and educational achievement of school children in Kenya. Design A factorial, cluster randomised trial is being implemented in 101 government primary schools on the coast of Kenya. The interventions are (i intermittent screening and treatment of malaria in schools by public health workers and (ii training workshops and support for teachers to promote explicit and systematic literacy instruction. Schools are randomised to one of four groups: receiving either (i the malaria intervention alone; (ii the literacy intervention alone; (iii both interventions combined; or (iv control group where neither intervention is implemented. Children from classes 1 and 5 are randomly selected and followed up for 24 months. The primary outcomes are educational achievement and anaemia, the hypothesised mediating variables through which education is affected. Secondary outcomes include malaria parasitaemia, school attendance and school performance. A nested process evaluation, using semi-structured interviews, focus group discussion and a stakeholder analysis will investigate the community acceptability, feasibility and cost-effectiveness of the interventions. Discussion Across Africa, governments are committed to improve health and education of school-aged children, but seek clear policy and technical guidance as to the optimal approach to address malaria and improved literacy. This evaluation will be one of the first to simultaneously evaluate the impact of health and education interventions in the improvement of

  6. Macromolecular systems for vaccine delivery.

    Science.gov (United States)

    MuŽíková, G; Laga, R

    2016-10-20

    Vaccines have helped considerably in eliminating some life-threatening infectious diseases in past two hundred years. Recently, human medicine has focused on vaccination against some of the world's most common infectious diseases (AIDS, malaria, tuberculosis, etc.), and vaccination is also gaining popularity in the treatment of cancer or autoimmune diseases. The major limitation of current vaccines lies in their poor ability to generate a sufficient level of protective antibodies and T cell responses against diseases such as HIV, malaria, tuberculosis and cancers. Among the promising vaccination systems that could improve the potency of weakly immunogenic vaccines belong macromolecular carriers (water soluble polymers, polymer particels, micelles, gels etc.) conjugated with antigens and immunistumulatory molecules. The size, architecture, and the composition of the high molecular-weight carrier can significantly improve the vaccine efficiency. This review includes the most recently developed (bio)polymer-based vaccines reported in the literature.

  7. Hemozoin Inhibition and Control of Clinical Malaria

    Directory of Open Access Journals (Sweden)

    Chibueze Peter Ihekwereme

    2014-01-01

    Full Text Available Malaria has a negative impact on health and social and economic life of residents of endemic countries. The ultimate goals of designing new treatment for malaria are to prevent clinical infection, reduce morbidity, and decrease mortality. There are great advances in the understanding of the parasite-host interaction through studies by various scientists. In some of these studies, attempts were made to evaluate the roles of malaria pigment or toxins in the pathogenesis of malaria. Hemozoin is a key metabolite associated with severe malaria anemia (SMA, immunosuppression, and cytokine dysfunction. Targeting of this pigment may be necessary in the design of new therapeutic products against malaria. In this review, the roles of hemozoin in the morbidity and mortality of malaria are highlighted as an essential target in the quest for effective control of clinical malaria.

  8. Declines in Malaria Burden and All-Cause Child Mortality following Increases in Control Interventions in Senegal, 2005-2010.

    Science.gov (United States)

    Thwing, Julie; Eckert, Erin; Dione, Demba Anta; Tine, Roger; Faye, Adama; Yé, Yazoume; Ndiop, Medoune; Cisse, Moustapha; Ndione, Jacques Andre; Diouf, Mame Birame; Ba, Mady

    2017-09-01

    Malaria is endemic in Senegal. The national malaria control strategy focuses on achieving universal coverage for major interventions, with a goal of reaching preelimination status by 2018. Senegal began distribution of insecticide-treated nets (ITNs) and introduced artemisinin-based combination therapy in 2006, then introduced rapid diagnostic tests in 2007. We evaluated the impact of these efforts using a plausibility design based on malaria's contribution to all-cause under-five mortality (ACCM) and considering other contextual factors which may influence ACCM. Between 2005 and 2010, household ownership of ITNs increased from 20% to 63%, and the proportion of people sleeping under an ITN the night prior to the survey increased from 6% to 29%. Malaria parasite prevalence declined from 6% to 3% from 2008 to 2010 among children under five. Some nonmalaria indicators of child health improved, for example, increase of complete vaccination coverage from 58% to 64%; however, nutritional indicators deteriorated, with an increase in stunting from 16% to 26%. Although economic indicators improved, environmental conditions favored an increase in malaria transmission. ACCM decreased 40% between 2005 and 2010, from 121 (95% confidence interval [CI] 113-129) to 72 (95% CI 66-77) per 1,000, and declines were greater among age groups, epidemiologic zones, and wealth quintiles most at risk for malaria. After considering coverage of malaria interventions, trends in malaria morbidity, effects of contextual factors, and trends in ACCM, it is plausible that malaria control interventions contributed to a reduction in malaria mortality and to the impressive gains in child survival in Senegal.

  9. Malaria and protective behaviours: is there a malaria trap?

    Science.gov (United States)

    Berthélemy, Jean-Claude; Thuilliez, Josselin; Doumbo, Ogobara; Gaudart, Jean

    2013-06-13

    In spite of massive efforts to generalize efficient prevention, such as insecticide-treated mosquito nets (ITN) or long-lasting insecticidal nets (LLINs), malaria remains prevalent in many countries and ITN/LLINs are still only used to a limited extent. This study proposes a new model for malaria economic analysis by combining economic epidemiology tools with the literature on poverty traps. A theoretical model of rational protective behaviour in response to malaria is designed, which includes endogenous externalities and disease characteristics. Survey data available for Uganda provide empirical support to the theory of prevalence-elastic protection behaviours, once endogeneity issues related to epidemiology and poverty are solved. Two important conclusions emerge from the model. First, agents increase their protective behaviour when malaria is more prevalent in a society. This is consistent with the literature on "prevalence-elastic behaviour". Second, a 'malaria trap' defined as the result of malaria reinforcing poverty while poverty reduces the ability to deal with malaria can theoretically exist and the conditions of existence of the malaria trap are identified. These results suggest the possible existence of malaria traps, which provides policy implications. Notably, providing ITN/LLINs at subsidized prices is not sufficient. To be efficient an ITN/LLINs dissemination campaigns should include incentive of the very poor for using ITN/LLINs.

  10. The clinical development process for a novel preventive vaccine: An overview

    Directory of Open Access Journals (Sweden)

    K Singh

    2016-01-01

    Full Text Available Each novel vaccine candidate needs to be evaluated for safety, immunogenicity, and protective efficacy in humans before it is licensed for use. After initial safety evaluation in healthy adults, each vaccine candidate follows a unique development path. This article on clinical development gives an overview on the development path based on the expectations of various guidelines issued by the World Health Organization (WHO, the European Medicines Agency (EMA, and the United States Food and Drug Administration (USFDA. The manuscript describes the objectives, study populations, study designs, study site, and outcome(s of each phase (Phase I-III of a clinical trial. Examples from the clinical development of a malaria vaccine candidate, a rotavirus vaccine, and two vaccines approved for human papillomavirus (HPV have also been discussed. The article also tabulates relevant guidelines, which can be referred to while drafting the development path of a novel vaccine candidate.

  11. Epitope-based peptide vaccine design and target site depiction against Ebola viruses: an immunoinformatics study.

    Science.gov (United States)

    Khan, M A; Hossain, M U; Rakib-Uz-Zaman, S M; Morshed, M N

    2015-07-01

    Ebola viruses (EBOVs) have been identified as an emerging threat in recent year as it causes severe haemorrhagic fever in human. Epitope-based vaccine design for EBOVs remains a top priority because a mere progress has been made in this regard. Another reason is the lack of antiviral drug and licensed vaccine although there is a severe outbreak in Central Africa. In this study, we aimed to design an epitope-based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites using various immunoinformatics and docking simulation tools. The capacity to induce both humoral and cell-mediated immunity by T cell and B cell was checked for the selected protein. The peptide region spanning 9 amino acids from 42 to 50 and the sequence TLASIGTAF were found as the most potential B and T cell epitopes, respectively. This peptide could interact with 12 HLAs and showed high population coverage up to 80.99%. Using molecular docking, the epitope was further appraised for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post-therapeutic strategy, docking study of predicted 3D structure identified suitable therapeutic inhibitor against targeted protein. However, this computational epitope-based peptide vaccine designing and target site prediction against EBOVs open up a new horizon which may be the prospective way in Ebola viruses research; the results require validation by in vitro and in vivo experiments. © 2015 John Wiley & Sons Ltd.

  12. Malaria cerebral Cerebral malaria

    Directory of Open Access Journals (Sweden)

    Carlos Hugo Zapata Zapata

    2003-03-01

    Full Text Available La malaria Cerebral (MC es la complicación más frecuente de la malaria por P. falciparum; aproximadamente el 90% de las personas que la han padecido se recuperan completamente sin secuelas neurológicas. Aún no se conoce con claridad su patogénesis pero se han postulado cuatro hipótesis o mecanismos posibles: 1 citoadherencia y secuestro de glóbulos rojos parasitados en la microvasculatura cerebral; 2 formación de rosetas y aglutinación de glóbulos rojos parasitados; 3 producción de citoquinas y activación de segundos mensajeros y, 4 apertura de la barrera hematoencefálica. Sin embargo, queda un interrogante sin resolver aún: ¿qué proceso se lleva a cabo para que el parásito, desde el espacio microvascular, pueda interferir transitoriamente con la función cerebral? Recientemente se ha utilizado el precursor de la proteína b-Amiloide como un marcador de daño neuronal en MC; este precursor será de gran ayuda en futuras investigaciones realizadas en nuestro medio que aporten información para comprender la patogénesis de la MC. Is the most common complication of P. falciparum malaria; nearly 90% of people who have suffered CM can recover without neurological problems. Currently there are four hypotheses that explain pathogenesis of CM: cytoadherence and sequestering of parasitized red blood cells to cerebral capillaries; rosette formation and parasitized red blood cells agglutination; production of cytokines and activation of second messengers and opening of the blood-brain barrier. However the main question remains to be answered; how the host-parasite interaction in the vascular space interferes transiently with cerebral function? Recently, the beta amyloid precursor peptide has been employed as marker of neural injury in CM. It is expected that the beta amyloid precursor peptide will help to understand the pathogenesis of CM in complicated patients of endemic areas of Colombia.

  13. Basic principles of test-negative design in evaluating influenza vaccine effectiveness.

    Science.gov (United States)

    Fukushima, Wakaba; Hirota, Yoshio

    2017-08-24

    Based on the unique characteristics of influenza, the concept of "monitoring" influenza vaccine effectiveness (VE) across the seasons using the same observational study design has been developed. In recent years, there has been a growing number of influenza VE reports using the test-negative design, which can minimize both misclassification of diseases and confounding by health care-seeking behavior. Although the test-negative designs offer considerable advantages, there are some concerns that widespread use of the test-negative design without knowledge of the basic principles of epidemiology could produce invalid findings. In this article, we briefly review the basic concepts of the test-negative design with respect to classic study design such as cohort studies or case-control studies. We also mention selection bias, which may be of concern in some countries where rapid diagnostic testing is frequently used in routine clinical practices, as in Japan. Copyright © 2017. Published by Elsevier Ltd.

  14. Malaria Matters

    Centers for Disease Control (CDC) Podcasts

    2008-04-18

    This podcast gives an overview of malaria, including prevention and treatment, and what CDC is doing to help control and prevent malaria globally.  Created: 4/18/2008 by National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED).   Date Released: 4/18/2008.

  15. THE APPROACHES TO DESIGNING OF NEW GENERATION VACCINES AGAINST THE SHEEP POX DISEASE

    Directory of Open Access Journals (Sweden)

    E. F. Yilmaz

    2016-12-01

    Full Text Available In this review the authors analyzed the sheep pox disease, which occurs outbreaks all over the world particularly in Asia and Africa causing substantial losses in trade of animal and animal products. They categorized the sheep pox disease is one of the prioritized groups of diseases against which the World Organization for Animal Health is fighting. Data concerning a sheep poxes’ history, epidemiology, epizootiology, mortality and economic impact, clinical and pathological signs, features of capripoxvirus that forms the disease are given. Diagnosis treatment and vaccine have been investigated as well. The main conclusion is done according which the designing of new vaccine generation against the sheep pox disease could be as an alternative approach against sheep pox.

  16. Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: study design and methodology for a cluster randomized controlled trial.

    Science.gov (United States)

    Samuels, Aaron M; Awino, Nobert; Odongo, Wycliffe; Abong'o, Benard; Gimnig, John; Otieno, Kephas; Shi, Ya Ping; Were, Vincent; Allen, Denise Roth; Were, Florence; Sang, Tony; Obor, David; Williamson, John; Hamel, Mary J; Patrick Kachur, S; Slutsker, Laurence; Lindblade, Kim A; Kariuki, Simon; Desai, Meghna

    2017-06-07

    Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti-malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices.

  17. tetanus nearly eliminated after 40 years of vaccination in rural

    African Journals Online (AJOL)

    2014-07-01

    Jul 1, 2014 ... number of admissions and mortality for tetanus and malaria. ... of a neurotoxin, produced by the bacteria when they grow in the ... the tetanus vaccine is often administered as a ... to vaccinate the community against tetanus in.

  18. Malaria in Brazil: an overview.

    Science.gov (United States)

    Oliveira-Ferreira, Joseli; Lacerda, Marcus V G; Brasil, Patrícia; Ladislau, José L B; Tauil, Pedro L; Daniel-Ribeiro, Cláudio Tadeu

    2010-04-30

    Malaria is still a major public health problem in Brazil, with approximately 306,000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in

  19. Malaria in Brazil: an overview

    Directory of Open Access Journals (Sweden)

    Brasil Patrícia

    2010-04-01

    malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates. The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region. As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease.

  20. Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs

    Directory of Open Access Journals (Sweden)

    Touihri Leila

    2012-12-01

    Full Text Available Abstract Background During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV or distemper virus (CDV after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage. Methods We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an “Internal Ribosome Entry Site” (IRES domain. Results The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The

  1. Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs.

    Science.gov (United States)

    Touihri, Leila; Ahmed, Sami Belhaj; Chtourou, Yacine; Daoud, Rahma; Bahloul, Chokri

    2012-12-27

    During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV) or distemper virus (CDV) after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage. We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV) 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an "Internal Ribosome Entry Site" (IRES) domain. The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The FMDV 2A was also efficient in the design of multivalent

  2. Computer-Aided Design of an Epitope-Based Vaccine against Epstein-Barr Virus

    Directory of Open Access Journals (Sweden)

    Julio Alonso-Padilla

    2017-01-01

    Full Text Available Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt’s lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble.

  3. Polymeric micro/nanoparticles: Particle design and potential vaccine delivery applications.

    Science.gov (United States)

    Yue, Hua; Ma, Guanghui

    2015-11-04

    Particle based adjuvant showed promising signs on delivering antigen to immune cells and acting as stimulators to elicit preventive or therapeutic response. Nevertheless, the wide size distribution of available polymeric particles has so far obscured the immunostimulative effects of particle adjuvant, and compromised the progress in pharmacological researches. To conquer this hurdle, our research group has carried out a series of researches regarding the particulate vaccine, by taking advantage of the successful fabrication of polymeric particles with uniform size. In this review, we highlight the insight and practical progress focused on the effects of physiochemical property (e.g. particle size, charge, hydrophobicity, surface chemical group, and particle shape) and antigen loading mode on the resultant biological/immunological outcome. The underlying mechanisms of how the particles-based vaccine functioned in the immune system are also discussed. Based on the knowledge, particles with high antigen payload and optimized attributes could be designed for expected adjuvant purpose, leading to the development of high efficient vaccine candidates. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Placental malaria and neonatal anti-tetanus antibody status: Any ...

    African Journals Online (AJOL)

    Globally, neonatal tetanus accounts for 7% of neonatal mortality,[1] ... There was a statistically significant association between type of placental malaria .... Also excluded were mothers with diabetes ..... Tetanus Vaccine: WHO Position Paper.

  5. Modelling of Malaria Risk Areas in Ghana by using Environmental ...

    African Journals Online (AJOL)

    Michael

    2015-12-02

    Dec 2, 2015 ... control in time and space to be prepared for outbreaks, which ... developing dynamic and area-specific risk maps to ... disease outbreaks including vaccination (Haydon et ... analyse malaria data against certain environmental.

  6. Safety, immunogenicity and duration of protection of a candidate malaria vaccine in Mozambique / Seguridad, inmunogenicidad y duración de protección del candidato a vacuna contra la malaria en Mozambique

    OpenAIRE

    Aide, Pedro Carlos Paulino

    2011-01-01

    La malaria, causada por el parásito Plasmodium falciparum sigue siendo un gran problema de salud pública y una causa importante de mortalidad y morbilidad en el África Sub-Sahariana, especialmente entre los niños y lactantes. El parásito y su vector mosquito Anofeles spp. tienen una tremenda capacidad de adaptación, incluyendo la capacidad de adquirir resistencia a los fármacos antipalúdicos e insecticidas. Es por tanto prioritario desarrollar nuevas herramientas preventivas, entre las cuales...

  7. Behind the scenes of the PRIME intervention: designing a complex intervention to improve malaria care at public health centres in Uganda

    Directory of Open Access Journals (Sweden)

    Deborah D. DiLiberto

    2015-10-01

    Full Text Available Background: In Uganda, health system challenges limit access to good quality healthcare and contribute to slow progress on malaria control. We developed a complex intervention (PRIME, which was designed to improve quality of care for malaria at public health centres. Objective: Responding to calls for increased transparency, we describe the PRIME intervention's design process, rationale, and final content and reflect on the choices and challenges encountered during the design of this complex intervention. Design: To develop the intervention, we followed a multistep approach, including the following: 1 formative research to identify intervention target areas and objectives; 2 prioritization of intervention components; 3 review of relevant evidence; 4 development of intervention components; 5 piloting and refinement of workshop modules; and 6 consolidation of the PRIME intervention theories of change to articulate why and how the intervention was hypothesized to produce desired outcomes. We aimed to develop an intervention that was evidence-based, grounded in theory, and appropriate for the study context; could be evaluated within a randomized controlled trial; and had the potential to be scaled up sustainably. Results: The process of developing the PRIME intervention package was lengthy and dynamic. The final intervention package consisted of four components: 1 training in fever case management and use of rapid diagnostic tests for malaria (mRDTs; 2 workshops in health centre management; 3 workshops in patient-centred services; and 4 provision of mRDTs and antimalarials when stocks ran low. Conclusions: The slow and iterative process of intervention design contrasted with the continually shifting study context. We highlight the considerations and choices made at each design stage, discussing elements we included and why, as well as those that were ultimately excluded. Reflection on and reporting of ‘behind the scenes’ accounts of intervention

  8. Annual Frequency of Malaria Attack in Different Haemoglobin ...

    African Journals Online (AJOL)

    GREG F. FOMBO

    believed to be due to the enzyme deficiency advantage against fatal malaria. However, the mechanism of this .... Fluorescence was produced due to the reduction of NADP+ to. NADPH. ... Presence of fluorescence indicated normal cells while weak fluorescence ..... Molecular Monitoring of Malaria Vaccine Trial. Trends in.

  9. Design of a Two-level Adaptive Multi-Agent System for Malaria Vectors driven by an ontology

    Directory of Open Access Journals (Sweden)

    Etang Josiane

    2007-07-01

    Full Text Available Abstract Background The understanding of heterogeneities in disease transmission dynamics as far as malaria vectors are concerned is a big challenge. Many studies while tackling this problem don't find exact models to explain the malaria vectors propagation. Methods To solve the problem we define an Adaptive Multi-Agent System (AMAS which has the property to be elastic and is a two-level system as well. This AMAS is a dynamic system where the two levels are linked by an Ontology which allows it to function as a reduced system and as an extended system. In a primary level, the AMAS comprises organization agents and in a secondary level, it is constituted of analysis agents. Its entry point, a User Interface Agent, can reproduce itself because it is given a minimum of background knowledge and it learns appropriate "behavior" from the user in the presence of ambiguous queries and from other agents of the AMAS in other situations. Results Some of the outputs of our system present a series of tables, diagrams showing some factors like Entomological parameters of malaria transmission, Percentages of malaria transmission per malaria vectors, Entomological inoculation rate. Many others parameters can be produced by the system depending on the inputted data. Conclusion Our approach is an intelligent one which differs from statistical approaches that are sometimes used in the field. This intelligent approach aligns itself with the distributed artificial intelligence. In terms of fight against malaria disease our system offers opportunities of reducing efforts of human resources who are not obliged to cover the entire territory while conducting surveys. Secondly the AMAS can determine the presence or the absence of malaria vectors even when specific data have not been collected in the geographical area. In the difference of a statistical technique, in our case the projection of the results in the field can sometimes appeared to be more general.

  10. A Design of Experiment approach to predict product and process parameters for a spray dried influenza vaccine.

    Science.gov (United States)

    Kanojia, Gaurav; Willems, Geert-Jan; Frijlink, Henderik W; Kersten, Gideon F A; Soema, Peter C; Amorij, Jean-Pierre

    2016-09-25

    Spray dried vaccine formulations might be an alternative to traditional lyophilized vaccines. Compared to lyophilization, spray drying is a fast and cheap process extensively used for drying biologicals. The current study provides an approach that utilizes Design of Experiments for spray drying process to stabilize whole inactivated influenza virus (WIV) vaccine. The approach included systematically screening and optimizing the spray drying process variables, determining the desired process parameters and predicting product quality parameters. The process parameters inlet air temperature, nozzle gas flow rate and feed flow rate and their effect on WIV vaccine powder characteristics such as particle size, residual moisture content (RMC) and powder yield were investigated. Vaccine powders with a broad range of physical characteristics (RMC 1.2-4.9%, particle size 2.4-8.5μm and powder yield 42-82%) were obtained. WIV showed no significant loss in antigenicity as revealed by hemagglutination test. Furthermore, descriptive models generated by DoE software could be used to determine and select (set) spray drying process parameter. This was used to generate a dried WIV powder with predefined (predicted) characteristics. Moreover, the spray dried vaccine powders retained their antigenic stability even after storage for 3 months at 60°C. The approach used here enabled the generation of a thermostable, antigenic WIV vaccine powder with desired physical characteristics that could be potentially used for pulmonary administration. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Malaria prophylaxis

    African Journals Online (AJOL)

    Malaria D:lay still be contracted despite good cOD:lpliance with ... true that prophylaxis is always better than no prophy- laxis, nor is ... If used during pregnancy, a folic acid supplement ... include folate deficiency, agranulocytosis, illegaloblastic.

  12. Epidemiology of malaria in the forest-savanna transitional zone of Ghana

    Directory of Open Access Journals (Sweden)

    Newton Sam

    2009-09-01

    Full Text Available Abstract Background Information on the epidemiology of malaria is essential for designing and interpreting results of clinical trials of drugs, vaccines and other interventions. As a background to the establishment of a site for anti-malarial drugs and vaccine trials, the epidemiology of malaria in a rural site in central Ghana was investigated. Methods Active surveillance of clinical malaria was carried out in a cohort of children below five years of age (n = 335 and the prevalence of malaria was estimated in a cohort of subjects of all ages (n = 1484 over a 12-month period. Participants were sampled from clusters drawn around sixteen index houses randomly selected from a total of about 22,000 houses within the study area. The child cohort was visited thrice weekly to screen for any illness and a blood slide was taken if a child had a history of fever or a temperature greater than or equal to 37.5 degree Celsius. The all-age cohort was screened for malaria once every eight weeks over a 12-month period. Estimation of Entomological Inoculation Rate (EIR and characterization of Anopheline malaria vectors in the study area were also carried out. Results The average parasite prevalence in the all age cohort was 58% (95% CI: 56.9, 59.4. In children below five years of age, the average prevalence was 64% (95% CI: 61.9, 66.0. Geometric mean parasite densities decreased significantly with increasing age. More than 50% of all children less than 10 years of age were anaemic. Children less than 5 years of age had as many as seven malaria attacks per child per year. The attack rates decreased significantly with increasing cut-offs of parasite density. The average Multiplicity of Infection (MOI was of 6.1. All three pyrimethamine resistance mutant alleles of the Plasmodium falciparum dhfr gene were prevalent in this population and 25% of infections had a fourth mutant of pfdhps-A437G. The main vectors were Anopheles funestus and Anopheles gambiae and the EIR

  13. Vaccines against poverty

    Science.gov (United States)

    MacLennan, Calman A.; Saul, Allan

    2014-01-01

    With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an exciting time for vaccines against poverty, that is, vaccines against diseases that disproportionately affect low- and middle-income countries (LMICs). The Global Burden of Disease Study 2010 has helped better understand which vaccines are most needed. In 2012, US$1.3 billion was spent on research and development for new vaccines for neglected infectious diseases. However, the majority of this went to three diseases: HIV/AIDS, malaria, and tuberculosis, and not neglected diseases. Much of it went to basic research rather than development, with an ongoing decline in funding for product development partnerships. Further investment in vaccines against diarrheal diseases, hepatitis C, and group A Streptococcus could lead to a major health impact in LMICs, along with vaccines to prevent sepsis, particularly among mothers and neonates. The Advanced Market Commitment strategy of the Global Alliance for Vaccines and Immunisation (GAVI) Alliance is helping to implement vaccines against rotavirus and pneumococcus in LMICs, and the roll out of the MenAfriVac meningococcal A vaccine in the African Meningitis Belt represents a paradigm shift in vaccines against poverty: the development of a vaccine primarily targeted at LMICs. Global health vaccine institutes and increasing capacity of vaccine manufacturers in emerging economies are helping drive forward new vaccines for LMICs. Above all, partnership is needed between those developing and manufacturing LMIC vaccines and the scientists, health care professionals, and policy makers in LMICs where such vaccines will be implemented. PMID:25136089

  14. Plasmodium falciparum malaria

    African Journals Online (AJOL)

    Durrheim, Karen Barnes. Objectives. To assess the therapeutic efficacy of sulfadoxine- pyrimethamine (SP) after 5 years of use as first-line treatment of uncomplicated Plasmodium falciparum malaria, and thus guide the selection of artemisinin-based combination therapy in Mpumalanga, South Africa. Design. An open-label ...

  15. Monitoring selective components of primary health care: methodology and community assessment of vaccination, diarrhoea, and malaria practices in Conakry, Guinea. ACSI-CCCD team.

    OpenAIRE

    Dabis, F.; Breman, J. G.; Roisin, A. J.; Haba, F.

    1989-01-01

    The Africa Child Survival Initiative-Combatting Childhood Communicable Diseases (ACSI-CCCD) Project is a primary health care activity that focuses on antenatal care, immunization, diarrhoeal disease control, and malaria control in children under 5 years of age. In order to gauge progress made in the project, a community-based health interview survey to measure simultaneously several prevention and treatment indicators was carried out in 1986 in Conakry, Guinea. A sample of 1415 caretakers and...

  16. Monitoring selective components of primary health care: methodology and community assessment of vaccination, diarrhoea, and malaria practices in Conakry, Guinea. ACSI-CCCD team.

    OpenAIRE

    Dabis , François; Breman , J. G.; Roisin , A. J.; Haba , F.; Team , Acsi-Cccd

    1989-01-01

    International audience; The Africa Child Survival Initiative-Combatting Childhood Communicable Diseases (ACSI-CCCD) Project is a primary health care activity that focuses on antenatal care, immunization, diarrhoeal disease control, and malaria control in children under 5 years of age. In order to gauge progress made in the project, a community-based health interview survey to measure simultaneously several prevention and treatment indicators was carried out in 1986 in Conakry, Guinea. A sampl...

  17. Nanomimics of host cell membranes block invasion and expose invasive malaria parasites.

    Science.gov (United States)

    Najer, Adrian; Wu, Dalin; Bieri, Andrej; Brand, Françoise; Palivan, Cornelia G; Beck, Hans-Peter; Meier, Wolfgang

    2014-12-23

    The fight against most infectious diseases, including malaria, is often hampered by the emergence of drug resistance and lack or limited efficacies of vaccines. Therefore, new drugs, vaccines, or other strategies to control these diseases are needed. Here, we present an innovative nanotechnological strategy in which the nanostructure itself represents the active substance with no necessity to release compounds to attain therapeutic effect and which might act in a drug- and vaccine-like dual function. Invasion of Plasmodium falciparum parasites into red blood cells was selected as a biological model for the initial validation of this approach. Stable nanomimics-polymersomes presenting receptors required for parasite attachment to host cells-were designed to efficiently interrupt the life cycle of the parasite by inhibiting invasion. A simple way to build nanomimics without postformation modifications was established. First, a block copolymer of the receptor with a hydrophobic polymer was synthesized and then mixed with a polymersome-forming block copolymer. The resulting nanomimics bound parasite-derived ligands involved in the initial attachment to host cells and they efficiently blocked reinvasion of malaria parasites after their egress from host cells in vitro. They exhibited efficacies of more than 2 orders of magnitude higher than the soluble form of the receptor, which can be explained by multivalent interactions of several receptors on one nanomimic with multiple ligands on the infective parasite. In the future, our strategy might offer interesting treatment options for severe malaria or a way to modulate the immune response.

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

    Science.gov (United States)

    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.

  19. Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope

    Energy Technology Data Exchange (ETDEWEB)

    Pierce, Brian G.; Boucher, Elisabeth N.; Piepenbrink, Kurt H.; Ejemel, Monir; Rapp, Chelsea A.; Thomas, William D.; Sundberg, Eric J.; Weng, Zhiping; Wang, Yang; Diamond, Michael S.

    2017-08-09

    Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as well as a bivalent immunogen with two copies of the epitope on the E2 surface. We solved the X-ray structure of a cyclic immunogen in complex with the HCV1 antibody and confirmed preservation of the epitope conformation and the HCV1 interface. Mice vaccinated with our designed immunogens produced robust antibody responses to epitope I, and their serum could neutralize HCV. Notably, the cyclic designs induced greater epitope-specific responses and neutralization than the native peptide epitope. Beyond successfully designing several novel HCV immunogens, this study demonstrates the principle that neutralizing anti-HCV antibodies can be induced by epitope-based, engineered vaccines and provides the basis for further efforts in structure-based design of HCV vaccines.

    IMPORTANCEHepatitis C virus is a leading cause of liver disease and liver cancer, with approximately 3% of the world's population infected. To combat this virus, an effective vaccine would have distinct advantages over current therapeutic options, yet experimental vaccines have not been successful to date, due in part to the virus's high sequence variability leading to immune escape. In this study, we rationally designed several vaccine immunogens based on the structure of a conserved epitope that

  20. Defining childhood severe falciparum malaria for intervention studies.

    Directory of Open Access Journals (Sweden)

    Philip Bejon

    2007-08-01

    Full Text Available Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no "gold standard" individual test for severe malaria, malaria-attributable fractions (MAFs can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints.A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor, lower respiratory tract infection (clinician's final diagnosis, meningitis (on cerebrospinal fluid [CSF] examination, and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%-86.1% without excluding these conditions, 89% (95% CI 88.4%-90.2% after exclusions, and 95% (95% CI 94.0%-95.5% when a threshold of 2,500 parasites/mul was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%-83%.The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis, bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition.

  1. Host-parasite interactions and ecology of the malaria parasite-a bioinformatics approach.

    Science.gov (United States)

    Izak, Dariusz; Klim, Joanna; Kaczanowski, Szymon

    2018-04-25

    Malaria remains one of the highest mortality infectious diseases. Malaria is caused by parasites from the genus Plasmodium. Most deaths are caused by infections involving Plasmodium falciparum, which has a complex life cycle. Malaria parasites are extremely well adapted for interactions with their host and their host's immune system and are able to suppress the human immune system, erase immunological memory and rapidly alter exposed antigens. Owing to this rapid evolution, parasites develop drug resistance and express novel forms of antigenic proteins that are not recognized by the host immune system. There is an emerging need for novel interventions, including novel drugs and vaccines. Designing novel therapies requires knowledge about host-parasite interactions, which is still limited. However, significant progress has recently been achieved in this field through the application of bioinformatics analysis of parasite genome sequences. In this review, we describe the main achievements in 'malarial' bioinformatics and provide examples of successful applications of protein sequence analysis. These examples include the prediction of protein functions based on homology and the prediction of protein surface localization via domain and motif analysis. Additionally, we describe PlasmoDB, a database that stores accumulated experimental data. This tool allows data mining of the stored information and will play an important role in the development of malaria science. Finally, we illustrate the application of bioinformatics in the development of population genetics research on malaria parasites, an approach referred to as reverse ecology.

  2. A flow cytometry-based workflow for detection and quantification of anti-plasmodial antibodies in vaccinated and naturally exposed individuals

    DEFF Research Database (Denmark)

    Ajua, Anthony; Engleitner, Thomas; Esen, Meral

    2012-01-01

    information about natural exposure and vaccine immunogenicity. A novel, cytometry-based workflow for the quantitative detection of anti-plasmodial antibodies in human serum is presented. METHODS: Fixed red blood cells (RBCs), infected with late stages of P. falciparum were utilized to detect malaria...... vaccine trials in semiimmune adults and pre-school children residing in a malaria endemic area. RESULTS: Fixation, permeabilization, and staining of infected RBCs were adapted for best operation in flow cytometry. As asexual vaccine candidates are designed to induce antibody patterns similar to semi...... with those obtained by manual gating (r between 0.79 and 0.99) and outperformed other model-driven gating methods. Bland-Altman plots confirmed the agreement of manual gating and OSA derived results. A-1.33 fold increase (p=0.003) in the number of positive cells after vaccination in a subgroup of preschool...

  3. Malaria chemotherapy.

    Science.gov (United States)

    Winstanley, Peter; Ward, Stephen

    2006-01-01

    Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.

  4. Construct design, production, and characterization of Plasmodium falciparum 48/45 R0.6C subunit protein produced in Lactococcus lactis as candidate vaccine

    DEFF Research Database (Denmark)

    Singh, Susheel K; Roeffen, Will; Mistarz, Ulrik H

    2017-01-01

    BACKGROUND: The sexual stages of Plasmodium falciparum are responsible for the spread of the parasite in malaria endemic areas. The cysteine-rich Pfs48/45 protein, exposed on the surface of sexual stages, is one of the most advanced antigens for inclusion into a vaccine that will block transmissi...

  5. Specific β-turns precede PPIIL structures binding to allele-specific HLA-DRβ1* PBRs in fully-protective malaria vaccine components

    Science.gov (United States)

    Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

    2018-04-01

    The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity.

  6. Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanoff, Walter A.; Perez, Edmundo I.; López, Tomás; Arias, Carlos F.; DuBois, Rebecca M. (UNAM-Mexico); (UCSC)

    2017-10-25

    a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.

  7. Pregnancy malaria: cryptic disease, apparent solution

    Directory of Open Access Journals (Sweden)

    Patrick Emmet Duffy

    2011-08-01

    Full Text Available Malaria during pregnancy can be severe in non-immune women, but in areas of stable transmission, where women are semi-immune and often asymptomatic during infection, malaria is an insidious cause of disease and death for mothers and their offspring. Sequelae, such as severe anaemia and hypertension in the mother and low birth weight and infant mortality in the offspring, are often not recognised as consequences of infection. Pregnancy malaria, caused by Plasmodium falciparum, is mediated by infected erythrocytes (IEs that bind to chondroitin sulphate A and are sequestered in the placenta. These parasites have a unique adhesion phenotype and distinct antigenicity, which indicates that novel targets may be required for development of an effective vaccine. Women become resistant to malaria as they acquire antibodies against placental IE, which leads to higher haemoglobin levels and heavier babies. Proteins exported from the placental parasites have been identified, including both variant and conserved antigens, and some of these are in preclinical development for vaccines. A vaccine that prevents P. falciparum malaria in pregnant mothers is feasible and would potentially save hundreds of thousands of lives each year.

  8. Safety and immunogenicity of the malaria vaccine candidate MSP3 long synthetic peptide in 12-24 months-old Burkinabe children.

    NARCIS (Netherlands)

    Sirima, S.B.; Tiono, A.B.; Diarra, A.; Ouedraogo, A.L.; Yaro, J.B.; Ouedraogo, E.; Gansane, A.; Bougouma, E.C.; Konate, A.T.; Kabore, Y.; Traore, A.; Roma, C.; Soulama, I.; Luty, A.J.F.; Cousens, S.; Nebie, I.

    2009-01-01

    BACKGROUND: A Phase Ia trial in European volunteers of the candidate vaccine merozoite surface protein 3 (MSP3), a Plasmodium falciparum blood stage membrane, showed that it induces biologically active antibodies able to achieve parasite killing in vitro, while a phase Ib trial in semi-immune adult

  9. Ab-initio conformational epitope structure prediction using genetic algorithm and SVM for vaccine design.

    Science.gov (United States)

    Moghram, Basem Ameen; Nabil, Emad; Badr, Amr

    2018-01-01

    T-cell epitope structure identification is a significant challenging immunoinformatic problem within epitope-based vaccine design. Epitopes or antigenic peptides are a set of amino acids that bind with the Major Histocompatibility Complex (MHC) molecules. The aim of this process is presented by Antigen Presenting Cells to be inspected by T-cells. MHC-molecule-binding epitopes are responsible for triggering the immune response to antigens. The epitope's three-dimensional (3D) molecular structure (i.e., tertiary structure) reflects its proper function. Therefore, the identification of MHC class-II epitopes structure is a significant step towards epitope-based vaccine design and understanding of the immune system. In this paper, we propose a new technique using a Genetic Algorithm for Predicting the Epitope Structure (GAPES), to predict the structure of MHC class-II epitopes based on their sequence. The proposed Elitist-based genetic algorithm for predicting the epitope's tertiary structure is based on Ab-Initio Empirical Conformational Energy Program for Peptides (ECEPP) Force Field Model. The developed secondary structure prediction technique relies on Ramachandran Plot. We used two alignment algorithms: the ROSS alignment and TM-Score alignment. We applied four different alignment approaches to calculate the similarity scores of the dataset under test. We utilized the support vector machine (SVM) classifier as an evaluation of the prediction performance. The prediction accuracy and the Area Under Receiver Operating Characteristic (ROC) Curve (AUC) were calculated as measures of performance. The calculations are performed on twelve similarity-reduced datasets of the Immune Epitope Data Base (IEDB) and a large dataset of peptide-binding affinities to HLA-DRB1*0101. The results showed that GAPES was reliable and very accurate. We achieved an average prediction accuracy of 93.50% and an average AUC of 0.974 in the IEDB dataset. Also, we achieved an accuracy of 95

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Tools and Strategies for Malaria Control and Elimination: What Do We Need to Achieve a Grand Convergence in Malaria?

    Directory of Open Access Journals (Sweden)

    Janet Hemingway

    2016-03-01

    Full Text Available Progress made in malaria control during the past decade has prompted increasing global dialogue on malaria elimination and eradication. The product development pipeline for malaria has never been stronger, with promising new tools to detect, treat, and prevent malaria, including innovative diagnostics, medicines, vaccines, vector control products, and improved mechanisms for surveillance and response. There are at least 25 projects in the global malaria vaccine pipeline, as well as 47 medicines and 13 vector control products. In addition, there are several next-generation diagnostic tools and reference methods currently in development, with many expected to be introduced in the next decade. The development and adoption of these tools, bolstered by strategies that ensure rapid uptake in target populations, intensified mechanisms for information management, surveillance, and response, and continued financial and political commitment are all essential to achieving global eradication.

  12. Comparative performance of three experimental hut designs for measuring malaria vector responses to insecticides in Tanzania.

    Science.gov (United States)

    Massue, Dennis J; Kisinza, William N; Malongo, Bernard B; Mgaya, Charles S; Bradley, John; Moore, Jason D; Tenu, Filemoni F; Moore, Sarah J

    2016-03-15

    Experimental huts are simplified, standardized representations of human habitations that provide model systems to evaluate insecticides used in indoor residual spray (IRS) and long-lasting insecticidal nets (LLINs) to kill disease vectors. Hut volume, construction materials and size of entry points impact mosquito entry and exposure to insecticides. The performance of three standard experimental hut designs was compared to evaluate insecticide used in LLINs. Field studies were conducted at the World Health Organization Pesticide Evaluation Scheme (WHOPES) testing site in Muheza, Tanzania. Three East African huts, three West African huts, and three Ifakara huts were compared using Olyset(®) and Permanet 2.0(®) versus untreated nets as a control. Outcomes measured were mortality, induced exophily (exit rate), blood feeding inhibition and deterrence (entry rate). Data were analysed using linear mixed effect regression and Bland-Altman comparison of paired differences. A total of 613 mosquitoes were collected in 36 nights, of which 13.5% were Anopheles gambiae sensu lato, 21% Anopheles funestus sensu stricto, 38% Mansonia species and 28% Culex species. Ifakara huts caught three times more mosquitoes than the East African and West African huts, while the West African huts caught significantly fewer mosquitoes than the other hut types. Mosquito densities were low, very little mosquito exit was measured in any of the huts with no measurable exophily caused by the use of either Olyset or Permanet. When the huts were directly compared, the West African huts measured greater exophily than other huts. As unholed nets were used in the experiments and few mosquitoes were captured, it was not possible to measure difference in feeding success either between treatments or hut types. In each of the hut types there was increased mortality when Permanet or Olyset were present inside the huts compared to the control, however this did not vary between the hut types. Both East African

  13. Military Infectious Diseases Update on Vaccine Development

    Science.gov (United States)

    2011-01-24

    Licensed live vaccines (polio, MMR) - Radiation- attenuated sporozoites - Genetically- attenuated sporozoites 2011 MHS Conference Whole Organism...Not sufficiently attenuated Seattle Biomedical , Gates Foundation, WEHI and USMMVP 2011 MHS Conference Subunit approach- RTS,S Vaccine RTS,S is...Ad Boost  DNA plasmids [Prime] – Encoding malaria proteins CSP and AMA1  Adenovirus 5 ( attenuated )[Boost] – Encoding malaria proteins CSP and AMA1

  14. Who pays for cooperation in global health? A comparative analysis of WHO, the World Bank, the Global Fund to Fight HIV/AIDS, Tuberculosis and Malaria, and Gavi, the Vaccine Alliance.

    Science.gov (United States)

    Clinton, Chelsea; Sridhar, Devi

    2017-07-15

    In this report we assess who pays for cooperation in global health through an analysis of the financial flows of WHO, the World Bank, the Global Fund to Fight HIV/AIDS, TB and Malaria, and Gavi, the Vaccine Alliance. The past few decades have seen the consolidation of influence in the disproportionate roles the USA, UK, and the Bill & Melinda Gates Foundation have had in financing three of these four institutions. Current financing flows in all four case study institutions allow donors to finance and deliver assistance in ways that they can more closely control and monitor at every stage. We highlight three major trends in global health governance more broadly that relate to this development: towards more discretionary funding and away from core or longer-term funding; towards defined multi-stakeholder governance and away from traditional government-centred representation and decision-making; and towards narrower mandates or problem-focused vertical initiatives and away from broader systemic goals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Designing CAF-adjuvanted dry powder vaccines: spray drying preserves the adjuvant activity of CAF01.

    Science.gov (United States)

    Ingvarsson, Pall Thor; Schmidt, Signe Tandrup; Christensen, Dennis; Larsen, Niels Bent; Hinrichs, Wouter Leonardus Joseph; Andersen, Peter; Rantanen, Jukka; Nielsen, Hanne Mørck; Yang, Mingshi; Foged, Camilla

    2013-05-10

    Dry powder vaccine formulations are highly attractive due to improved storage stability and the possibility for particle engineering, as compared to liquid formulations. However, a prerequisite for formulating vaccines into dry formulations is that their physicochemical and adjuvant properties remain unchanged upon rehydration. Thus, we have identified and optimized the parameters of importance for the design of a spray dried powder formulation of the cationic liposomal adjuvant formulation 01 (CAF01) composed of dimethyldioctadecylammonium (DDA) bromide and trehalose 6,6'-dibehenate (TDB) via spray drying. The optimal excipient to stabilize CAF01 during spray drying and for the design of nanocomposite microparticles was identified among mannitol, lactose and trehalose. Trehalose and lactose were promising stabilizers with respect to preserving liposome size, as compared to mannitol. Trehalose and lactose were in the glassy state upon co-spray drying with the liposomes, whereas mannitol appeared crystalline, suggesting that the ability of the stabilizer to form a glassy matrix around the liposomes is one of the prerequisites for stabilization. Systematic studies on the effect of process parameters suggested that a fast drying rate is essential to avoid phase separation and lipid accumulation at the surface of the microparticles during spray drying. Finally, immunization studies in mice with CAF01 in combination with the tuberculosis antigen Ag85B-ESAT6-Rv2660c (H56) demonstrated that spray drying of CAF01 with trehalose under optimal processing conditions resulted in the preservation of the adjuvant activity in vivo. These data demonstrate the importance of liposome stabilization via optimization of formulation and processing conditions in the engineering of dry powder liposome formulations. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. A New Decade of Vaccines

    LENUS (Irish Health Repository)

    Murphy, JFA

    2011-09-01

    The call for a new decade of vaccines was made in December 2010. The aims are to secure the further discovery, development and delivery of vaccination. The first challenge is the acquisition of funds for the research and development of 20 new vaccines1. The Gates Foundation has pledged $10 billion for this venture. The other major players are WHO, UNICEF and the US National Institute of Allergy and Infectious Diseases. The top priorities are TB, AIDS and Malaria. It is hoped that a Malaria vaccine will available in 3 years. The ambitious target of saving the lives of over 7 million children has been set. The programme must also address the need for vaccines in insulin dependent diabetes, cancers and degenerative diseases2.

  17. Malaria in pregnancy: pathogenesis and immunity

    DEFF Research Database (Denmark)

    Rogerson, Stephen J; Hviid, Lars; Duffy, Patrick E

    2007-01-01

    Understanding of the biological basis for susceptibility to malaria in pregnancy was recently advanced by the discovery that erythrocytes infected with Plasmodium falciparum accumulate in the placenta through adhesion to molecules such as chondroitin sulphate A. Antibody recognition of placental...... infected erythrocytes is dependent on sex and gravidity, and could protect from malaria complications. Moreover, a conserved parasite gene-var2csa-has been associated with placental malaria, suggesting that its product might be an appropriate vaccine candidate. By contrast, our understanding of placental...... immunopathology and how this contributes to anaemia and low birthweight remains restricted, although inflammatory cytokines produced by T cells, macrophages, and other cells are clearly important. Studies that unravel the role of host response to malaria in pathology and protection in the placenta...

  18. "The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" - Meeting report.

    Science.gov (United States)

    Boggiano, Cesar; Eichelberg, Katrin; Ramachandra, Lakshmi; Shea, Jaqueline; Ramakrishnan, Lalita; Behar, Samuel; Ernst, Joel D; Porcelli, Steven A; Maeurer, Markus; Kornfeld, Hardy

    2017-06-14

    Tuberculosis (TB) is the major cause of death from infectious diseases around the world, particularly in HIV infected individuals. TB vaccine design and development have been focused on improving Bacille Calmette-Guérin (BCG) and evaluating recombinant and viral vector expressed Mycobacterium tuberculosis (Mtb) proteins, for boosting BCG-primed immunity, but these approaches have not yet yielded significant improvements over the modest effects of BCG in protecting against infection or disease. On March 7-8, 2016, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on "The Impact of Mtb Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" with the goal of defining immune mechanisms that could be targeted through novel research approaches, to inform vaccine design and immune therapeutic interventions for prevention of TB. The workshop addressed early infection events, the impact of Mtb evolution on the development and maintenance of an adaptive immune response, and the factors that influence protection against and progression to active disease. Scientific gaps and areas of study to revitalize and accelerate TB vaccine design were discussed and prioritized. These included a comprehensive evaluation of innate and Mtb-specific adaptive immune responses in the lung at different stages of disease; determining the role of B cells and antibodies (Abs) during Mtb infection; development of better assays to measure Mtb burden following exposure, infection, during latency and after treatment, and approaches to improving current animal models to study Mtb immunogenicity, TB disease and transmission. Copyright © 2017.

  19. Kompliceret malaria

    DEFF Research Database (Denmark)

    Rønn, A M; Bygbjerg, Ib Christian; Jacobsen, E

    1989-01-01

    An increasing number of cases of malaria, imported to Denmark, are caused by Plasmodium falciparum and severe and complicated cases are more often seen. In the Department of Infectious Diseases, Rigshospitalet, 23 out of 32 cases, hospitalized from 1.1-30.6.1988, i.e. 72%, were caused by P...

  20. An assessment in rodents of the pathological and immunopathological consequence of multiple vaccinations and challenge with radiation-attenuated malaria parasites (blood forms and sporozoites)

    International Nuclear Information System (INIS)

    Boonpucknavig, S.

    1982-06-01

    Multiple vaccination with irradiated merozoites of Plasmodium berghei resulted in high levels of circulating antibody but a low degree of protection to challenge with normal merozoites. On the other hand, the multiple vaccinations and the challenge resulted in severe immunopathological reactions shortly after the immunization or challenge. These reactions were seen in the liver, kidneys and spleen and included the accumulation of mononuclear cells, severe coagulative necrosis of liver cells and proliferative changes in the splenic white pulp and in the glomeruli. The pathological reactions were more severe than in non-immunized animals but the parasitemia was lower and less malarial antigen was detected in Kupfer Cells of the liver, the sinusoidal cells of the spleen and the reticuloendothelial cells in the interstitial tissue of the kidney. Vaccination with irradiated sporozoites of P. berghei resulted in good protection to challenge with normal sporozoites even before circulating anti-sporozoite antibody could be detected. Only mild pathological changes were associated with up to 4 immunizations followed by challenge and these were largely limited to the liver, and were reversible. Sporozoite antigens were detected in the spleen and immune complexes in the glomeruli for 2-4 weeks following challenge but not later. Immunized mice however often developed some lobular pneumonia of the lung but the severity of this did not increase with challenge

  1. Malaria and World War II: German malaria experiments 1939-45.

    Science.gov (United States)

    Eckart, W U; Vondra, H

    2000-06-01

    The epidemiological and pharmacological fight against malaria and German malaria research during the Nazi dictatorship were completely under the spell of war. The Oberkommando des Heeres (German supreme command of the army) suffered the bitter experience of unexpected high losses caused by malaria especially at the Greek front (Metaxes line) but also in southern Russia and in the Ukraine. Hastily raised anti-malaria units tried to teach soldiers how to use the synthetic malaria drugs (Plasmochine, Atebrine) properly. Overdoses of these drugs were numerous during the first half of the war whereas in the second half it soon became clear that it would not be possible to support the army due to insufficient quantities of plasmochine and atebrine. During both running fights and troop withdrawals at all southern and southeastern fronts there was hardly any malaria prophylaxis or treatment. After war and captivity many soldiers returned home to endure heavy malaria attacks. In German industrial (Bayer, IG-Farben) and military malaria laboratories of the Heeres-Sanitäts-Akademie (Army Medical Academy) the situation was characterised by a hasty search for proper dosages of anti-malaria drugs, adequate mechanical and chemical prophylaxis (Petroleum, DDT, and other insecticides) as well as an anti-malaria vaccine. Most importantly, large scale research for proper atebrine and plasmochine dosages was conducted in German concentration camps and mental homes. In Dachau Professor Claus Schilling tested synthetic malaria drugs and injected helpless prisoners with high and sometimes lethal doses. Since the 1920s he had been furiously looking for an anti-malaria vaccine in Italian mental homes and from 1939 he continued his experiments in Dachau. Similar experiments were also performed in Buchenwald and in a psychiatric clinic in Thuringia, where Professor Gerhard Rose tested malaria drugs with mentally ill Russian prisoners of war. Schilling was put to death for his criminal

  2. A brief review on features of falciparum malaria during pregnancy

    Directory of Open Access Journals (Sweden)

    Alexandre Manirakiza

    2017-12-01

    Full Text Available Malaria in pregnancy is a serious public health problem in tropical areas. Frequently, the placenta is infected by accumulation of Plasmodium falciparum-infected erythrocytes in the intervillous space. Falciparum malaria acts during pregnancy by a range of mechanisms, and chronic or repeated infection and co-infections have insidious effects. The susceptibility of pregnant women to malaria is due to both immunological and humoral changes. Until a malaria vaccine becomes available, the deleterious effects of malaria in pregnancy can be avoided by protection against infection and prompt treatment with safe, effective antimalarial agents; however, concurrent infections such as with HIV and helminths during pregnancy are jeopardizing malaria control in sub-Saharan Africa.

  3. Malaria and Tropical Travel

    Centers for Disease Control (CDC) Podcasts

    Malaria is a serious mosquito-borne disease that can lead to death. This podcast discusses malaria risk when traveling to tropical areas, as well as how to protect yourself and your family from malaria infection.

  4. Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model.

    Directory of Open Access Journals (Sweden)

    Ibrahim Diakite

    2016-08-01

    Full Text Available During the 2014 Ebola virus disease (EVD outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel "ordered stepped-wedge cluster trial" (OSWCT designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor.We constructed a spatially structured mathematical model of the EVD outbreak in Sierra Leone. We used the output of this model to simulate and compare a series of stepped-wedge cluster vaccine studies. Our model reproduced the observed order of first case occurrence within districts of Sierra Leone. Depending on the infection risk within the trial population and the trial start dates, the statistical power to detect a vaccine efficacy of 90% varied from 14% to 32% for standard SWCT, and from 67% to 91% for OSWCTs for an alpha error of 5%. The model's projection of first case occurrence was robust to changes in disease natural history parameters.Ordering clusters in a step-wedge trial based on the cluster's underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints.

  5. 3. barriers to prompt malaria treatment among under five children

    African Journals Online (AJOL)

    Esem

    strategy need to be established. Therefore, this study aimed at determining barriers to prompt malaria treatment among this vulnerable age group in Mpika district. Objective: To determine the barriers to prompt malaria treatment among children under five years of age with malaria in Mpika district. Study design: This was an ...

  6. Prevalence of malaria among pregnant women attending antenatal ...

    African Journals Online (AJOL)

    Malaria is a chronic parasitic disease that affects everybody but with pregnant women and children under the age of 5 years as its main target. The adverse complications of malaria in pregnancy makes it of immense public health importance. This study was designed to evaluate the prevalence of malaria among antenatal ...

  7. Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02.

    Directory of Open Access Journals (Sweden)

    Meta Roestenberg

    Full Text Available Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1 is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies.We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 microg and 50 microg doses with three different adjuvants, Alhydrogel, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8-10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80-100%. Induration occurred in the Montanide 50 microg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1-2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNgamma and IL-5 cytokines.All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.(Clinicaltrials.gov NCT00730782.

  8. Oral vaccination of fish

    OpenAIRE

    Embregts, Carmen W.E.; Forlenza, Maria

    2016-01-01

    The limited number of oral vaccines currently approved for use in humans and veterinary species clearly illustrates that development of efficacious and safe oral vaccines has been a challenge not only for fish immunologists. The insufficient efficacy of oral vaccines is partly due to antigen breakdown in the harsh gastric environment, but also to the high tolerogenic gut environment and to inadequate vaccine design. In this review we discuss current approaches used to develop oral vaccines fo...

  9. [Design and Validation of a Questionnaire on Vaccination in Students of Health Sciences, Spain].

    Science.gov (United States)

    Fernández-Prada, María; Ramos-Martín, Pedro; Madroñal-Menéndez, Jaime; Martínez-Ortega, Carmen; González-Cabrera, Joaquín

    2016-11-07

    Immunization rates among medicine and nursing students -and among health professional in general- during hospital training are low. It is necessary to investigate the causes for these low immunization rates. The objective of this study was to design and validate a questionnaire for exploring the attitudes and behaviours of medicine and nursing students toward immunization of vaccine-preventable diseases. An instrument validation study. The sample included 646 nursing and medicine students at University of Oviedo, Spain. It was a non-ramdom sampling. After the content validation process, a 24-item questionnaire was designed to assess attitudes and behaviours/behavioural intentions. Reliability (ordinal alpha), internal validity (exploratory factor analysis by parellel analysis), ANOVA and mediational model tests were performed. Exploratory factor analysis yielded two factors which accounted for 48.8% of total variance. Ordinal alpha for the total score was 0.92. Differences were observed across academic years in the dimensions of attitudes (F5.447=3.728) and knowledge (F5.448=65.59), but not in behaviours/behavioural intentions (F5.461=1.680). Attitudes demonstrated to be a moderating variable of knowledge and attitudes/behavioural attitudes (Indirect effect B=0.15; SD=0.3; 95% CI:0.09-0.19). We developed a questionnaie based on sufficient evidence of reliability and internal validity. Scores on attitudes and knowledge increase with the academic year. Attitudes act as a moderating variable between knowledge and behaviours/behavioural intentions.

  10. Combining malaria control with rural electrification

    NARCIS (Netherlands)

    Oria, Prisca A.

    2016-01-01

    Chapter 1 presents the background information relevant to the subject matter and methods of this thesis. These include the application of social and behavioural sciences in malaria control, the SolarMal project and malaria in Kenya. It also presents the research objective, question and design

  11. Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: the test-negative design case-control study with different control groups.

    NARCIS (Netherlands)

    Doorn, E. van; Darvishian, M.; Dijkstra, F.; Donker, G.A.; Overduin, P.; Meijer, A.; Hak, E.

    2017-01-01

    Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE

  12. Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014 : The test-negative design case-control study with different control groups

    NARCIS (Netherlands)

    van Doorn, Eva; Darvishian, Maryam; Dijkstra, Frederika; Donker, Gé A; Overduin, Pieter; Meijer, Adam; Hak, Eelko

    2017-01-01

    Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE

  13. Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: The test-negative design case-control study with different control groups.

    NARCIS (Netherlands)

    van Doorn, Eva; Darvishian, Maryam; Dijkstra, Frederika; Donker, Gé A; Overduin, Pieter; Meijer, Adam; Hak, Eelko

    2017-01-01

    Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE

  14. Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

    Science.gov (United States)

    Sampson, Joshua N; Hildesheim, Allan; Herrero, Rolando; Gonzalez, Paula; Kreimer, Aimee R; Gail, Mitchell H

    2018-05-01

    Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. Copyright © 2018. Published by Elsevier Inc.

  15. Co-localization of a CD1d-binding glycolipid with an adenovirus-based malaria vaccine for a potent adjuvant effect.

    Science.gov (United States)

    Li, Xiangming; Huang, Jing; Kawamura, Akira; Funakoshi, Ryota; Porcelli, Steven A; Tsuji, Moriya

    2017-05-31

    A CD1d-binding, invariant (i) natural killer T (NKT)-cell stimulatory glycolipid, α-Galactosylceramide (αGalCer), has been shown to act as an adjuvant. We previously identified a fluorinated phenyl ring-modified αGalCer analog, 7DW8-5, displaying a higher binding affinity for CD1d molecule and more potent adjuvant activity than αGalCer. In the present study, 7DW8-5 co-administered intramuscularly (i.m.) with a recombinant adenovirus expressing a Plasmodium yoelii circumsporozoite protein (PyCSP), AdPyCS, has led to a co-localization of 7DW8-5 and a PyCSP in draining lymph nodes (dLNs), particularly in dendritic cells (DCs). This occurrence initiates a cascade of events, such as the recruitment of DCs to dLNs and their activation and maturation, and the enhancement of the ability of DCs to prime CD8+ T cells induced by AdPyCS and ultimately leading to a potent adjuvant effect and protection against malaria. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design.

    Science.gov (United States)

    Taylor, Adam; Liu, Xiang; Zaid, Ali; Goh, Lucas Y H; Hobson-Peters, Jody; Hall, Roy A; Merits, Andres; Mahalingam, Suresh

    2017-02-21

    Mosquito-transmitted chikungunya virus (CHIKV) is an arthritogenic alphavirus of the Togaviridae family responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP)-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS) in the N-terminal region of capsid protein, previously uncharacterized in CHIKV. Mutation of the NoLS by site-directed mutagenesis reduced efficiency of nuclear import of CHIKV capsid protein. In the virus, mutation of the capsid protein NoLS (CHIKV-NoLS) attenuated replication in mammalian and mosquito cells, producing a small-plaque phenotype. Attenuation of CHIKV-NoLS is likely due to disruption of the viral replication cycle downstream of viral RNA synthesis. In mice, CHIKV-NoLS infection caused no disease signs compared to wild-type CHIKV (CHIKV-WT)-infected mice; lack of disease signs correlated with significantly reduced viremia and decreased expression of proinflammatory factors. Mice immunized with CHIKV-NoLS, challenged with CHIKV-WT at 30 days postimmunization, develop no disease signs and no detectable viremia. Serum from CHIKV-NoLS-immunized mice is able to efficiently neutralize CHIKV infection in vitro Additionally, CHIKV-NoLS-immunized mice challenged with the related alphavirus Ross River virus showed reduced early and peak viremia postchallenge, indicating a cross-protective effect. The high degree of CHIKV-NoLS attenuation may improve CHIKV antiviral and rational vaccine design. IMPORTANCE CHIKV is a mosquito-borne pathogen capable of causing explosive epidemics of incapacitating joint pain

  17. [Current malaria situation in Turkey].

    Science.gov (United States)

    Gockchinar, T; Kalipsi, S

    2001-01-01

    diagnostic services, and to develop mobile diagnostic ones; to make radical treatment and monitoring patients; to conduct regular active case surveillance studies; to conduct regular vector control studies; to monitor the sensitivity of vectors to insecticides and to provide their alternatives; to design malaria control studies for the specialists of districts; to implement educational programmes among the population and attract it in controlling malaria.

  18. The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine.

    Directory of Open Access Journals (Sweden)

    Morten A Nielsen

    Full Text Available The disease caused by Plasmodium falciparum (Pf involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM is one such manifestation in which Pf infected erythrocytes (IE bind to chondroitin sulphate A (CSA through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2 expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens

  19. The HPV Vaccination Crisis

    Science.gov (United States)

    Following the release of a consensus statement from the NCI-Designated Cancer Centers urging HPV vaccination in the United States, Dr. Noel Brewer discusses the country’s low vaccination rates and how clinicians can help to improve them.

  20. Bioorganometallic Chemistry and Malaria

    Science.gov (United States)

    Biot, Christophe; Dive, Daniel

    This chapter summarizes recent developments in the design, synthesis, and structure-activity relationship studies of organometallic antimalarials. It begins with a general introduction to malaria and the biology of the parasite Plasmodium falciparum, with a focus on the heme detoxification system. Then, a number of metal complexes from the literature are reported for their antiplasmodial activity. The second half of the chapter deals with the serendipitous discovery of ferroquine, its mechanism(s) of action, and the failure to induce a resistance. Last, but not least, we suggest that the bioorganometallic approach offers the potential for the design of novel therapeutic agents.

  1. Designing an effective vaccine to prevent Epstein-Barr virus-associated diseases: challenges and opportunities.

    Science.gov (United States)

    Dasari, Vijayendra; Bhatt, Kunal H; Smith, Corey; Khanna, Rajiv

    2017-04-01

    Epstein-Barr virus (EBV) is a ubiquitous herpesvirus associated with a number of clinical manifestations. Primary EBV infection in young adolescents often manifests as acute infectious mononucleosis and latent infection is associated with multiple lymphoid and epithelial cancers and autoimmune disorders, particularly multiple sclerosis. Areas covered: Over the last decade, our understanding of pathogenesis and immune regulation of EBV-associated diseases has provided an important platform for the development of novel vaccine formulations. In this review, we discuss developmental strategies for prophylactic and therapeutic EBV vaccines which have been assessed in preclinical and clinical settings. Expert commentary: Major roadblocks in EBV vaccine development include no precise understanding of the clinical correlates of protection, uncertainty about adjuvant selection and the unavailability of appropriate animal models. Recent development of new EBV vaccine formulations provides exciting opportunities for the formal clinical assessment of novel formulations.

  2. [Development of new vaccines].

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Construct design, production, and characterization of Plasmodium falciparum 48/45 R0.6C subunit protein produced in Lactococcus lactis as candidate vaccine.

    Science.gov (United States)

    Singh, Susheel K; Roeffen, Will; Mistarz, Ulrik H; Chourasia, Bishwanath Kumar; Yang, Fen; Rand, Kasper D; Sauerwein, Robert W; Theisen, Michael

    2017-05-31

    The sexual stages of Plasmodium falciparum are responsible for the spread of the parasite in malaria endemic areas. The cysteine-rich Pfs48/45 protein, exposed on the surface of sexual stages, is one of the most advanced antigens for inclusion into a vaccine that will block transmission. However, clinical Pfs48/45 sub-unit vaccine development has been hampered by the inability to produce high yields of recombinant protein as the native structure is required for the induction of functional transmission-blocking (TB) antibodies. We have investigated a downstream purification process of a sub-unit (R0.6C) fragment representing the C-terminal 6-Cys domain of Pfs48/45 (6C) genetically fused to the R0 region (R0) of asexual stage Glutamate Rich Protein expressed in Lactococcus lactis. A series of R0.6C fusion proteins containing features, which aim to increase expression levels or to facilitate protein purification, were evaluated at small scale. None of these modifications affected the overall yield of recombinant protein. Consequently, R0.6C with a C-terminal his tag was used for upstream and downstream process development. A simple work-flow was developed consisting of batch fermentation followed by two purification steps. As such, the recombinant protein was purified to homogeneity. The composition of the final product was verified by HPLC, mass spectrometry, SDS-PAGE and Western blotting with conformation dependent antibodies against Pfs48/45. The recombinant protein induced high levels of functional TB antibodies in rats. The established production and purification process of the R0.6C fusion protein provide a strong basis for further clinical development of this candidate transmission blocking malaria vaccine.

  5. Controlled Human Malaria Infection: Applications, Advances, and Challenges.

    Science.gov (United States)

    Stanisic, Danielle I; McCarthy, James S; Good, Michael F

    2018-01-01

    Controlled human malaria infection (CHMI) entails deliberate infection with malaria parasites either by mosquito bite or by direct injection of sporozoites or parasitized erythrocytes. When required, the resulting blood-stage infection is curtailed by the administration of antimalarial drugs. Inducing a malaria infection via inoculation with infected blood was first used as a treatment (malariotherapy) for neurosyphilis in Europe and the United States in the early 1900s. More recently, CHMI has been applied to the fields of malaria vaccine and drug development, where it is used to evaluate products in well-controlled early-phase proof-of-concept clinical studies, thus facilitating progression of only the most promising candidates for further evaluation in areas where malaria is endemic. Controlled infections have also been used to immunize against malaria infection. Historically, CHMI studies have been restricted by the need for access to insectaries housing infected mosquitoes or suitable malaria-infected individuals. Evaluation of vaccine and drug candidates has been constrained in these studies by the availability of a limited number of Plasmodium falciparum isolates. Recent advances have included cryopreservation of sporozoites, the manufacture of well-characterized and genetically distinct cultured malaria cell banks for blood-stage infection, and the availability of Plasmodium vivax -specific reagents. These advances will help to accelerate malaria vaccine and drug development by making the reagents for CHMI more widely accessible and also enabling a more rigorous evaluation with multiple parasite strains and species. Here we discuss the different applications of CHMI, recent advances in the use of CHMI, and ongoing challenges for consideration. Copyright © 2017 American Society for Microbiology.

  6. Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design.

    Directory of Open Access Journals (Sweden)

    Pratima Kunwar

    Full Text Available A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i increasing the breadth of vaccine-induced responses or (ii increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+ T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+ T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS by three different methods (prevalence, entropy and conseq on clade-B and group-M sequence alignments. The majority of CD8(+ T cell responses were directed against variable epitopes (p<0.01. Interestingly, increasing breadth of CD8(+ T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009. Moreover, subjects possessing CD8(+ T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021. The association between viral control and the breadth of conserved CD8(+ T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215. The associations with viral control were independent of functional avidity of CD8(+ T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus

  7. External quality assurance of malaria nucleic acid testing for clinical trials and eradication surveillance

    NARCIS (Netherlands)

    Murphy, S.C.; Hermsen, C.C.; Douglas, A.D.; Edwards, N.J.; Petersen, I.; Fahle, G.A.; Adams, M.; Berry, A.A.; Billman, Z.P.; Gilbert, S.C.; Laurens, M.B.; Leroy, O.; Lyke, K.E.; Plowe, C.V.; Seilie, A.M.; Strauss, K.A.; Teelen, K.; Hill, A.V.; Sauerwein, R.W.

    2014-01-01

    Nucleic acid testing (NAT) for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates and is also important in surveillance of malaria control and elimination efforts. A variety of reported NAT assays have been described, yet no formal

  8. 20 YEARS OF PROGRESS IN MALARIA RESEARCH

    Directory of Open Access Journals (Sweden)

    J. Kevin Baird

    2012-09-01

    Full Text Available U.S. Naval Medical Research Unit No. 2 Detachment (NAMRU, in collaboration with National Institute of Health Research and Development (NIHRD and many other Indonesian government agencies and universities, has conducted studies of malaria throughout Java, Sumatra, Sulawesi, Kalimantan, Flores, Timor, and Irian Jaya. Most studies have characterized the disease epidemiologically by defining the parasitologic distribution of the disease in the population, and by defining the entomologic parameters of local transmission. Studies of patterns of resistance to antimalarials have also been done at many field sites. Several studies on the clinical management of malaria occurred in Rumah Sakit Umum Propinsi in Jayapura. In addition to these studies which impact upon local public health planning policy, immunologic studies routinely occurred in support of the global effort to develop a vaccine against malaria. This report summarizes the progress made in these areas of research during the first 20 years of NAMRU in Indonesia.

  9. Sources of Malaria Information among Pregnant Women in Ebonyi State and Implications for Malaria Health Education

    Science.gov (United States)

    Amari-Omaka, Lois Nnenna; Obande-Ogbuinya, Nkiru Edith

    2016-01-01

    The purpose of this study was to determine sources of malaria information among pregnant women in Ebonyi state and implications for malaria education. The cross sectional research design was adopted and stratified sampling technique was used to select a total of five hundred and four (504) pregnant women from 12 hospitals in the state. A self…

  10. Antibiotic Resistance Determinant-Focused Acinetobacter baumannii Vaccine Designed Using Reverse Vaccinology.

    Science.gov (United States)

    Ni, Zhaohui; Chen, Yan; Ong, Edison; He, Yongqun

    2017-02-21

    As one of the most influential and troublesome human pathogens, Acinetobacter baumannii ( A. baumannii ) has emerged with many multidrug-resistant strains. After collecting 33 complete A. baumannii genomes and 84 representative antibiotic resistance determinants, we used the Vaxign reverse vaccinology approach to predict classical type vaccine candidates against A. baumannii infections and new type vaccine candidates against antibiotic resistance. Our genome analysis identified 35 outer membrane or extracellular adhesins that are conserved among all 33 genomes, have no human protein homology, and have less than 2 transmembrane helices. These 35 antigens include 11 TonB dependent receptors, 8 porins, 7 efflux pump proteins, and 2 fimbrial proteins (FilF and CAM87009.1). CAM86003.1 was predicted to be an adhesin outer membrane protein absent from 3 antibiotic-sensitive strains and conserved in 21 antibiotic-resistant strains. Feasible anti-resistance vaccine candidates also include one extracellular protein (QnrA), 3 RND type outer membrane efflux pump proteins, and 3 CTX-M type β-lactamases. Among 39 β-lactamases, A. baumannii CTX-M-2, -5, and -43 enzymes are predicted as adhesins and better vaccine candidates than other β-lactamases to induce preventive immunity and enhance antibiotic treatments. This report represents the first reverse vaccinology study to systematically predict vaccine antigen candidates against antibiotic resistance for a microbial pathogen.

  11. Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011.

    Science.gov (United States)

    Ruffin, Nicolas; Borggren, Marie; Euler, Zelda; Fiorino, Fabio; Grupping, Katrijn; Hallengärd, David; Javed, Aneele; Mendonca, Kevin; Pollard, Charlotte; Reinhart, David; Saba, Elisa; Sheik-Khalil, Enas; Sköld, Annette; Ziglio, Serena; Scarlatti, Gabriella; Gotch, Frances; Wahren, Britta; Shattock, Robin J

    2012-07-11

    Europrise is a Network of Excellence supported by the European Commission within the 6th Framework programme from 2007 to 2012. The Network has involved over 50 institutions from 13 European countries together with 3 industrial partners and 6 African countries. The Network encompasses an integrated program of research, training, dissemination and advocacy within the field of HIV vaccines and microbicides. A central and timely theme of the Network is the development of the unique concept of co-usage of vaccines and microbicides. Training of PhD students has been a major task, and some of these post-graduate students have here summarized novel ideas emanating from presentations at the last annual Europrise meeting in Prague. The latest data and ideas concerning HIV vaccine and microbicide studies are included in this review; these studies are so recent that the majority have yet to be published. Data were presented and discussed concerning novel immunisation strategies; microbicides and PrEP (alone and in combination with vaccines); mucosal transmission of HIV/SIV; mucosal vaccination; novel adjuvants; neutralizing antibodies; innate immune responses; HIV/SIV pathogenesis and disease progression; new methods and reagents. These - necessarily overlapping topics - are comprehensively summarised by the Europrise students in the context of other recent exciting data.

  12. Rational design of HIV vaccines and microbicides: report of the EUROPRISE annual conference 2011

    Directory of Open Access Journals (Sweden)

    Ruffin Nicolas

    2012-07-01

    Full Text Available Abstract Europrise is a Network of Excellence supported by the European Commission within the 6th Framework programme from 2007 to 2012. The Network has involved over 50 institutions from 13 European countries together with 3 industrial partners and 6 African countries. The Network encompasses an integrated program of research, training, dissemination and advocacy within the field of HIV vaccines and microbicides. A central and timely theme of the Network is the development of the unique concept of co-usage of vaccines and microbicides. Training of PhD students has been a major task, and some of these post-graduate students have here summarized novel ideas emanating from presentations at the last annual Europrise meeting in Prague. The latest data and ideas concerning HIV vaccine and microbicide studies are included in this review; these studies are so recent that the majority have yet to be published. Data were presented and discussed concerning novel immunisation strategies; microbicides and PrEP (alone and in combination with vaccines; mucosal transmission of HIV/SIV; mucosal vaccination; novel adjuvants; neutralizing antibodies; innate immune responses; HIV/SIV pathogenesis and disease progression; new methods and reagents. These – necessarily overlapping topics - are comprehensively summarised by the Europrise students in the context of other recent exciting data.

  13. Design and performance prediction of solar adsorption cooling for mobile vaccine refrigerator

    Science.gov (United States)

    Djubaedah, Euis; Taufan, Andi; Ratnasari, Nadhira; Fahrizal, Adjie; Hamidi, Qayyum; Nasruddin

    2017-03-01

    Adsorption cooling is a process that uses a drop-in pressure caused by the adsorption of adsorbate by adsorbent. Adsorption process creates a pressure drop which can bring down the temperature to the intended condition. This approach can be used in vaccine transportation as the vaccines need to be stored at low temperatures (2°C to 8°C for preserving vaccines). The pressure decrease can be obtained by adsorption water in zeolites and can also produce the temperature drop in the main chamber. The adsorption process of water will decrease until reaching saturation condition. Heat is needed to keep the system continuous as it starts a desorption process. From the simulation using MATLAB, it is found that the mobile vaccine refrigerator can reach the temperature of 2°C in 180 seconds with the amount of cooling power generated is up to 1530 W. The insulation can hold the allowable temperature range inside the vaccine cabin for 15.6795 hours.

  14. Challenges and solutions for a rational vaccine design for TB-endemic regions.

    Science.gov (United States)

    Gowthaman, Uthaman; Mushtaq, Khurram; Tan, Amabel C; Rai, Pradeep K; Jackson, David C; Agrewala, Javed N

    2015-01-01

    Vaccines have been successful for global eradication or control of dreaded diseases such as smallpox, diphtheria, tetanus, yellow fever, whooping cough, polio, and measles. Unfortunately, this success has not been achieved for controlling tuberculosis (TB) worldwide. Bacillus Calmette Guérin (BCG) is the only available vaccine against TB. Paradoxically, BCG has deciphered success in the Western world but has failed in TB-endemic areas. In this article, we highlight and discuss the aspects of immunity responsible for controlling Mycobacterium tuberculosis infection and factors responsible for the failure of BCG in TB-endemic countries. In addition, we also suggest strategies that contribute toward the development of successful vaccine in protecting populations where BCG has failed.

  15. Typhoid fever vaccination strategies.

    Science.gov (United States)

    Date, Kashmira A; Bentsi-Enchill, Adwoa; Marks, Florian; Fox, Kimberley

    2015-06-19

    Typhoid vaccination is an important component of typhoid fever prevention and control, and is recommended for public health programmatic use in both endemic and outbreak settings. We reviewed experiences with various vaccination strategies using the currently available typhoid vaccines (injectable Vi polysaccharide vaccine [ViPS], oral Ty21a vaccine, and injectable typhoid conjugate vaccine [TCV]). We assessed the rationale, acceptability, effectiveness, impact and implementation lessons of these strategies to inform effective typhoid vaccination strategies for the future. Vaccination strategies were categorized by vaccine disease control strategy (preemptive use for endemic disease or to prevent an outbreak, and reactive use for outbreak control) and vaccine delivery strategy (community-based routine, community-based campaign and school-based). Almost all public health typhoid vaccination programs used ViPS vaccine and have been in countries of Asia, with one example in the Pacific and one experience using the Ty21a vaccine in South America. All vaccination strategies were found to be acceptable, feasible and effective in the settings evaluated; evidence of impact, where available, was strongest in endemic settings and in the short- to medium-term. Vaccination was cost-effective in high-incidence but not low-incidence settings. Experience in disaster and outbreak settings remains limited. TCVs have recently become available and none are WHO-prequalified yet; no program experience with TCVs was found in published literature. Despite the demonstrated success of several typhoid vaccination strategies, typhoid vaccines remain underused. Implementation lessons should be applied to design optimal vaccination strategies using TCVs which have several anticipated advantages, such as potential for use in infant immunization programs and longer duration of protection, over the ViPS and Ty21a vaccines for typhoid prevention and control. Copyright © 2015. Published by

  16. Immunology, epidemiology and mathematical modelling towards a better understanding of invasive non-typhoidal Salmonella disease and rational vaccination approaches.

    Science.gov (United States)

    Mastroeni, Pietro; Rossi, Omar

    2016-12-01

    Invasive non-typhoidal Salmonella (iNTS) infections cause a high burden of lethal sepsis in young children and HIV patients, often associated with malaria, anaemia, malnutrition and sickle-cell disease. Vaccines against iNTS are urgently needed but none are licensed yet. Areas covered: This review illustrates how immunology, epidemiology and within-host pathogen behaviour affect invasive Salmonella infections and highlights how this knowledge can assist the improvement and choice of vaccines. Expert Commentary: Control of iNTS disease requires approaches that reduce transmission and improve diagnosis and treatment. These are often difficult to implement due to the fragile ecology and economies in endemic countries. Vaccines will be key tools in the fight against iNTS disease. To optimise vaccine design, we need to better define protective antigens and mechanisms of resistance to disease in susceptible populations even in those individuals where innate immunity may be impaired by widespread comorbidities.

  17. Objective sampling design in a highly heterogeneous landscape - characterizing environmental determinants of malaria vector distribution in French Guiana, in the Amazonian region.

    Science.gov (United States)

    Roux, Emmanuel; Gaborit, Pascal; Romaña, Christine A; Girod, Romain; Dessay, Nadine; Dusfour, Isabelle

    2013-12-01

    Sampling design is a key issue when establishing species inventories and characterizing habitats within highly heterogeneous landscapes. Sampling efforts in such environments may be constrained and many field studies only rely on subjective and/or qualitative approaches to design collection strategy. The region of Cacao, in French Guiana, provides an excellent study site to understand the presence and abundance of Anopheles mosquitoes, their species dynamics and the transmission risk of malaria across various environments. We propose an objective methodology to define a stratified sampling design. Following thorough environmental characterization, a factorial analysis of mixed groups allows the data to be reduced and non-collinear principal components to be identified while balancing the influences of the different environmental factors. Such components defined new variables which could then be used in a robust k-means clustering procedure. Then, we identified five clusters that corresponded to our sampling strata and selected sampling sites in each stratum. We validated our method by comparing the species overlap of entomological collections from selected sites and the environmental similarities of the same sites. The Morisita index was significantly correlated (Pearson linear correlation) with environmental similarity based on i) the balanced environmental variable groups considered jointly (p = 0.001) and ii) land cover/use (p-value sampling approach. Land cover/use maps (based on high spatial resolution satellite images) were shown to be particularly useful when studying the presence, density and diversity of Anopheles mosquitoes at local scales and in very heterogeneous landscapes.

  18. The cancer-immunity cycle as rational design for synthetic cancer drugs: Novel DC vaccines and CAR T-cells.

    Science.gov (United States)

    Ramachandran, Mohanraj; Dimberg, Anna; Essand, Magnus

    2017-08-01

    Cell therapy is an advanced form of cancer immunotherapy that has had remarkable clinical progress in the past decade in the search for cure of cancer. Most success has been achieved for chimeric antigen receptor (CAR) T-cells where CAR T-cells targeting CD19 show very high complete response rates for patients with refractory acute B-cell acute lymphoblastic leukemia (ALL) and are close to approval for this indication. CD19 CAR T-cells are also effective against B-cell chronic lymphoblastic leukemia (CLL) and B-cell lymphomas. Although encouraging, CAR T-cells have not yet proven clinically effective for solid tumors. This is mainly due to the lack of specific and homogenously expressed targets to direct the T-cells against and a hostile immunosuppressive tumor microenvironment in solid tumors. Cancer vaccines based on dendritic cells (DC) are also making progress although clinical efficacy is still lacking. The likelihood of success is however increasing now when individual tumors can be sequences and patient-specific neoepitopes identified. Neoepitopes and/or neoantigens can then be included in patient-based DC vaccines. This review discusses recent advancements of DC vaccines and CAR T-cells with emphasis on the cancer-immunity cycle, and current efforts to design novel cell therapies. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  19. Immune activation alters cellular and humoral responses to yellow fever 17D vaccine.

    Science.gov (United States)

    Muyanja, Enoch; Ssemaganda, Aloysius; Ngauv, Pearline; Cubas, Rafael; Perrin, Helene; Srinivasan, Divya; Canderan, Glenda; Lawson, Benton; Kopycinski, Jakub; Graham, Amanda S; Rowe, Dawne K; Smith, Michaela J; Isern, Sharon; Michael, Scott; Silvestri, Guido; Vanderford, Thomas H; Castro, Erika; Pantaleo, Giuseppe; Singer, Joel; Gillmour, Jill; Kiwanuka, Noah; Nanvubya, Annet; Schmidt, Claudia; Birungi, Josephine; Cox, Josephine; Haddad, Elias K; Kaleebu, Pontiano; Fast, Patricia; Sekaly, Rafick-Pierre; Trautmann, Lydie; Gaucher, Denis

    2014-07-01

    Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. We showed that YF-17D-induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D-neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. Registration is not required for observational studies. This study was funded by Canada's Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases

  20. Performance of small cluster surveys and the clustered LQAS design to estimate local-level vaccination coverage in Mali.

    Science.gov (United States)

    Minetti, Andrea; Riera-Montes, Margarita; Nackers, Fabienne; Roederer, Thomas; Koudika, Marie Hortense; Sekkenes, Johanne; Taconet, Aurore; Fermon, Florence; Touré, Albouhary; Grais, Rebecca F; Checchi, Francesco

    2012-10-12

    Estimation of vaccination coverage at the local level is essential to identify communities that may require additional support. Cluster surveys can be used in resource-poor settings, when population figures are inaccurate. To be feasible, cluster samples need to be small, without losing robustness of results. The clustered LQAS (CLQAS) approach has been proposed as an alternative, as smaller sample sizes are required. We explored (i) the efficiency of cluster surveys of decreasing sample size through bootstrapping analysis and (ii) the performance of CLQAS under three alternative sampling plans to classify local VC, using data from a survey carried out in Mali after mass vaccination against meningococcal meningitis group A. VC estimates provided by a 10 × 15 cluster survey design were reasonably robust. We used them to classify health areas in three categories and guide mop-up activities: i) health areas not requiring supplemental activities; ii) health areas requiring additional vaccination; iii) health areas requiring further evaluation. As sample size decreased (from 10 × 15 to 10 × 3), standard error of VC and ICC estimates were increasingly unstable. Results of CLQAS simulations were not accurate for most health areas, with an overall risk of misclassification greater than 0.25 in one health area out of three. It was greater than 0.50 in one health area out of two under two of the three sampling plans. Small sample cluster surveys (10 × 15) are acceptably robust for classification of VC at local level. We do not recommend the CLQAS method as currently formulated for evaluating vaccination programmes.

  1. Performance of small cluster surveys and the clustered LQAS design to estimate local-level vaccination coverage in Mali

    Directory of Open Access Journals (Sweden)

    Minetti Andrea

    2012-10-01

    Full Text Available Abstract Background Estimation of vaccination coverage at the local level is essential to identify communities that may require additional support. Cluster surveys can be used in resource-poor settings, when population figures are inaccurate. To be feasible, cluster samples need to be small, without losing robustness of results. The clustered LQAS (CLQAS approach has been proposed as an alternative, as smaller sample sizes are required. Methods We explored (i the efficiency of cluster surveys of decreasing sample size through bootstrapping analysis and (ii the performance of CLQAS under three alternative sampling plans to classify local VC, using data from a survey carried out in Mali after mass vaccination against meningococcal meningitis group A. Results VC estimates provided by a 10 × 15 cluster survey design were reasonably robust. We used them to classify health areas in three categories and guide mop-up activities: i health areas not requiring supplemental activities; ii health areas requiring additional vaccination; iii health areas requiring further evaluation. As sample size decreased (from 10 × 15 to 10 × 3, standard error of VC and ICC estimates were increasingly unstable. Results of CLQAS simulations were not accurate for most health areas, with an overall risk of misclassification greater than 0.25 in one health area out of three. It was greater than 0.50 in one health area out of two under two of the three sampling plans. Conclusions Small sample cluster surveys (10 × 15 are acceptably robust for classification of VC at local level. We do not recommend the CLQAS method as currently formulated for evaluating vaccination programmes.

  2. Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference

    NARCIS (Netherlands)

    Wahren, Britta; Biswas, Priscilla; Borggren, Marie; Coleman, Adam; Da Costa, Kelly; de Haes, Winni; Dieltjens, Tessa; Dispinseri, Stefania; Grupping, Katrijn; Hallengärd, David; Hornig, Julia; Klein, Katja; Mainetti, Lara; Palma, Paolo; Reudelsterz, Marc; Seifried, Janna; Selhorst, Philippe; Sköld, Annette; Uchtenhagen, Hannes; van Gils, Marit J.; Weber, Caroline; Shattock, Robin; Scarlatti, Gabriella

    2010-01-01

    EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination

  3. Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010

    Directory of Open Access Journals (Sweden)

    Uchtenhagen Hannes

    2011-04-01

    Full Text Available Abstract Novel, exciting intervention strategies to prevent infection with HIV have been tested in the past year, and the field is rapidly evolving. EUROPRISE is a network of excellence sponsored by the European Commission and concerned with a wide range of activities including integrated developmental research on HIV vaccines and microbicides from discovery to early clinical trials. A central and timely theme of the network is the development of the unique concept of co-usage of vaccines and microbicides. This review, prepared by the PhD students of the network captures much of the research ongoing between the partners. The network is in its 5th year and involves over 50 institutions from 13 European countries together with 3 industrial partners; GSK, Novartis and Sanofi-Pasteur. EUROPRISE is involved in 31 separate world-wide trials of Vaccines and Microbicides including 6 in African countries (Tanzania, Mozambique, South Africa, Kenya, Malawi, Rwanda, and is directly supporting clinical trials including MABGEL, a gp140-hsp70 conjugate trial and HIVIS, vaccine trials in Europe and Africa.

  4. Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference.

    Science.gov (United States)

    Wahren, Britta; Biswas, Priscilla; Borggren, Marie; Coleman, Adam; Da Costa, Kelly; De Haes, Winni; Dieltjens, Tessa; Dispinseri, Stefania; Grupping, Katrijn; Hallengärd, David; Hornig, Julia; Klein, Katja; Mainetti, Lara; Palma, Paolo; Reudelsterz, Marc; Seifried, Janna; Selhorst, Philippe; Sköld, Annette; Uchtenhagen, Hannes; van Gils, Marit J; Weber, Caroline; Shattock, Robin; Scarlatti, Gabriella

    2010-07-26

    EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.

  5. Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010.

    Science.gov (United States)

    Brinckmann, Sarah; da Costa, Kelly; van Gils, Marit J; Hallengärd, David; Klein, Katja; Madeira, Luisa; Mainetti, Lara; Palma, Paolo; Raue, Katharina; Reinhart, David; Reudelsterz, Marc; Ruffin, Nicolas; Seifried, Janna; Schäfer, Katrein; Sheik-Khalil, Enas; Sköld, Annette; Uchtenhagen, Hannes; Vabret, Nicolas; Ziglio, Serena; Scarlatti, Gabriella; Shattock, Robin; Wahren, Britta; Gotch, Frances

    2011-04-12

    Novel, exciting intervention strategies to prevent infection with HIV have been tested in the past year, and the field is rapidly evolving. EUROPRISE is a network of excellence sponsored by the European Commission and concerned with a wide range of activities including integrated developmental research on HIV vaccines and microbicides from discovery to early clinical trials. A central and timely theme of the network is the development of the unique concept of co-usage of vaccines and microbicides. This review, prepared by the PhD students of the network captures much of the research ongoing between the partners. The network is in its 5th year and involves over 50 institutions from 13 European countries together with 3 industrial partners; GSK, Novartis and Sanofi-Pasteur. EUROPRISE is involved in 31 separate world-wide trials of Vaccines and Microbicides including 6 in African countries (Tanzania, Mozambique, South Africa, Kenya, Malawi, Rwanda), and is directly supporting clinical trials including MABGEL, a gp140-hsp70 conjugate trial and HIVIS, vaccine trials in Europe and Africa.

  6. Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference

    Directory of Open Access Journals (Sweden)

    Mainetti Lara

    2010-07-01

    Full Text Available Abstract EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.

  7. Malaria rapid diagnostic kits: quality of packaging, design and labelling of boxes and components and readability and accuracy of information inserts

    Directory of Open Access Journals (Sweden)

    Bruggeman Cathrien

    2011-02-01

    Full Text Available Abstract Background The present study assessed malaria RDT kits for adequate and correct packaging, design and labelling of boxes and components. Information inserts were studied for readability and accuracy of information. Methods Criteria for packaging, design, labelling and information were compiled from Directive 98/79 of the European Community (EC, relevant World Health Organization (WHO documents and studies on end-users' performance of RDTs. Typography and readability level (Flesch-Kincaid grade level were assessed. Results Forty-two RDT kits from 22 manufacturers were assessed, 35 of which had evidence of good manufacturing practice according to available information (i.e. CE-label affixed or inclusion in the WHO list of ISO13485:2003 certified manufacturers. Shortcomings in devices were (i insufficient place for writing sample identification (n = 40 and (ii ambiguous labelling of the reading window (n = 6. Buffer vial labels were lacking essential information (n = 24 or were of poor quality (n = 16. Information inserts had elevated readability levels (median Flesch Kincaid grade 8.9, range 7.1 - 12.9 and user-unfriendly typography (median font size 8, range 5 - 10. Inadequacies included (i no referral to biosafety (n = 18, (ii critical differences between depicted and real devices (n = 8, (iii figures with unrealistic colours (n = 4, (iv incomplete information about RDT line interpretations (n = 31 and no data on test characteristics (n = 8. Other problems included (i kit names that referred to Plasmodium vivax although targeting a pan-species Plasmodium antigen (n = 4, (ii not stating the identity of the pan-species antigen (n = 2 and (iii slight but numerous differences in names displayed on boxes, device packages and information inserts. Three CE labelled RDT kits produced outside the EC had no authorized representative affixed and the shape and relative dimensions of the CE symbol affixed did not comply with the Directive 98/79/EC

  8. Malaria rapid diagnostic kits: quality of packaging, design and labelling of boxes and components and readability and accuracy of information inserts.

    Science.gov (United States)

    Gillet, Philippe; Maltha, Jessica; Hermans, Veerle; Ravinetto, Raffaella; Bruggeman, Cathrien; Jacobs, Jan

    2011-02-13

    The present study assessed malaria RDT kits for adequate and correct packaging, design and labelling of boxes and components. Information inserts were studied for readability and accuracy of information. Criteria for packaging, design, labelling and information were compiled from Directive 98/79 of the European Community (EC), relevant World Health Organization (WHO) documents and studies on end-users' performance of RDTs. Typography and readability level (Flesch-Kincaid grade level) were assessed. Forty-two RDT kits from 22 manufacturers were assessed, 35 of which had evidence of good manufacturing practice according to available information (i.e. CE-label affixed or inclusion in the WHO list of ISO13485:2003 certified manufacturers). Shortcomings in devices were (i) insufficient place for writing sample identification (n=40) and (ii) ambiguous labelling of the reading window (n=6). Buffer vial labels were lacking essential information (n=24) or were of poor quality (n=16). Information inserts had elevated readability levels (median Flesch Kincaid grade 8.9, range 7.1-12.9) and user-unfriendly typography (median font size 8, range 5-10). Inadequacies included (i) no referral to biosafety (n=18), (ii) critical differences between depicted and real devices (n=8), (iii) figures with unrealistic colours (n=4), (iv) incomplete information about RDT line interpretations (n=31) and no data on test characteristics (n=8). Other problems included (i) kit names that referred to Plasmodium vivax although targeting a pan-species Plasmodium antigen (n=4), (ii) not stating the identity of the pan-species antigen (n=2) and (iii) slight but numerous differences in names displayed on boxes, device packages and information inserts. Three CE labelled RDT kits produced outside the EC had no authorized representative affixed and the shape and relative dimensions of the CE symbol affixed did not comply with the Directive 98/79/EC. Overall, RDTs with evidence of GMP scored better

  9. Reduced antibody responses against Plasmodium falciparum vaccine candidate antigens in the presence of Trichuris trichiura

    DEFF Research Database (Denmark)

    Esen, Meral; Mordmüller, Benjamin; de Salazar, Pablo Martinez

    2012-01-01

    BACKGROUND: Helminth infections are highly prevalent in the tropics and may have an effect on immune responses to vaccines due to their immunomodulatory effect. The prevalence of helminth infections in young children, the target group for malaria and most other vaccines, is high. Therefore we...... assessed the influence of helminth infection on vaccine-induced immune responses in a phase I clinical trial of the malaria vaccine candidate GMZ2. METHODS: Twenty Gabonese preschool-age children were vaccinated with GMZ2, a blood stage malaria vaccine candidate. Humoral immune response against the vaccine...... antigens and parasitological status were assessed. Vaccine-specific antibody concentrations and memory B-cell numbers were compared in worm infected and non-infected participants. RESULTS: Antibody response to GMZ2 was 3.4-fold (95% confidence interval: 1.6, 7.4) higher in Trichuris trichiura negative...

  10. Malaria Treatment (United States)

    Science.gov (United States)

    ... Providers, Emergency Consultations, and General Public. Contact Us Malaria Treatment (United States) Recommend on Facebook Tweet Share Compartir Treatment of Malaria: Guidelines For Clinicians (United States) Download PDF version ...

  11. Malaria and Travelers

    Science.gov (United States)

    ... Providers, Emergency Consultations, and General Public. Contact Us Malaria and Travelers for U.S. Residents Recommend on Facebook ... may be at risk for infection. Determine if malaria transmission occurs at the destinations Obtain a detailed ...

  12. Malaria: prevention in travellers.

    Science.gov (United States)

    Croft, Ashley M

    2010-07-12

    Malaria transmission occurs most frequently in environments with humidity greater than 60% and ambient temperature of 25 °C to 30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10 to 14 days but can be up to 18 months depending on the strain of parasite. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in non-pregnant adult travellers? What are the effects of drug prophylaxis in non-pregnant adult travellers? What are the effects of antimalaria vaccines in adult and child travellers? What are the effects of antimalaria interventions in child travellers, pregnant travellers, and in airline pilots? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), dietary supplementation, doxycycline, electronic mosquito repellents, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vapourising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines.

  13. STATUS HEMATOLOGI PENDERITA MALARIA SEREBRAL

    Directory of Open Access Journals (Sweden)

    Nurhayati Nurhayati

    2009-05-01

    Full Text Available AbstrakMalaria masih merupakan masalah kesehatan masyarakat dunia. Berdasarkan klasifikasi klinis, malaria dibedakan atas malaria berat dan malaria tanpa komplikasi. Malaria serebral merupakan komplikasi terberat dari malaria falsiparum.Telah dilakukan penelitian seksi silang terhadap penderita malaria falciparum yang dirawat inap di Bangsal Penyakit Dalam RS. Perjan. Dr. M. Djamil Padang dari bulan Juni 2002 sampai Juni 2006. Pada penelitian ini didapatkan jumlah sampel sebanyak 60 orang, terdiri dari 16 orang penderita malaria serebral dan 44 orang penderita malaria tanpa komplikasi.Data penelitian menunjukan terdapat perbedaan bermakna nilai hematokrit (p<0,05 dan jumlah leukosit (p<0,05 antara penderita malaria serebral dengan penderita malaria tanpa komplikasi. Dan terdapat korelasi positif antara nilai hemoglobin dengan hematokrit (r=0,864; p<0,05 pada penderita malaria falsiparum.Kata kunci: malaria serebral, malaria tanpa komplikasi, malaria falsiparumAbstract Malaria is still a problem of health of world society. Based on the clinical classification, are distinguished on severe malaria and uncomplicated malaria. Cerebral malaria is the worst complication of falciparum malaria. Cross section of the research done at the Hospital Dr. M. Djamil Padang againts medical record of malaria patients who are hospitalized in the Internal Medicine from June 2002 until June 2004. In this study, a total sample of 60 people, consisting of 16 cerebral malaria and 44 uncomplicated malaria. Data showed there were significant differences for hematocrit values (p <0.05 and total leukocytes values (p <0.05 between cerebral malaria and uncomplicated malaria patients. There is a positive correlation between hemoglobin with hematocrit values (r = 0.864; p <0.05 of falciparum malaria patients. Keywords: cerebral malaria, uncomplicated malaria, falciparum malaria

  14. Carrier protein influences immunodominance of a known epitope: implication in peptide vaccine design.

    Science.gov (United States)

    Ghosh, Moumita; Solanki, Ashish K; Roy, Koushik; Dhoke, Reema R; Ashish; Roy, Syamal

    2013-09-23

    We investigated how the processing of a given antigen by antigen presenting cells (APC) is dictated by the conformation of the antigen and how this governs the immunodominance hierarchy. To address the question, a known immunodominant sequence of bacteriophage lambda repressor N-terminal sequence 12-26 [λR(12-26)] was engineered at the N and C termini of a heterologous leishmanial protein, Kinetoplastid membrane protein-11 (KMP-11); the resulting proteins were defined as N-KMP-11 and C-KMP-11 respectively. The presence of λR(12-26) in N-KMP-11 and C-KMP-11 was established by western blot analysis with antibody to λR(12-26) peptide. N-KMP-11 but not C-KMP-11 could stimulate the anti λR(12-26) T-cell clonal population very efficiently in the presence of APCs. Priming of BALB/c mice with N-KMP-11 or C-KMP-11 generated similar levels of anti-KMP-11 IgG, but anti-λR(12-26) specific IgG was observed only upon priming with N-KMP-11. Interestingly, uptake of both N-KMP-11 and C-KMP-11 by APCs was similar but catabolism of N-KMP-11 but not C-KMP-11 was biphasic and fast at the initial time point. Kratky plots of small angle X-ray scattering showed that while N-KMP-11 adopts flexible Gaussian type of topology, C-KMP-11 prefers Globular nature. To show that KMP-11 is not unique as a carrier protein, an epitope (SPITBTNLBTMBK) of Plasmodium yoelii (PY) apical membrane protein 1[AMA-1 (136-148)], is placed at the C and N terminals of a dominant T-cell epitope of ovalbumin protein OVA(323-339) and the resulting peptides are defined as PY-OVA and OVA-PY respectively. Interestingly, only OVA-PY could stimulate anti-OVA T-cells and produce IgG response upon priming of BALB/c mice with it. Thus for rational design of peptide vaccine it is important to place the dominant epitope appropriately in the context of the carrier protein. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Vector incrimination and effects of antimalarial drugs on malaria transmission and control in the Amazon Basin of Brazil

    Directory of Open Access Journals (Sweden)

    T. A. Klein

    1992-01-01

    Full Text Available World ecosystems differ significantly and a multidisciplinary malaria control approach must be adjusted to meet these requirements. These include a comprehensive understanding of the malaria vectors, their behavior, seasonal distribution and abundance, susceptibility to insecticides (physiological and behavioral, methods to reduce the numbers of human gametocyte carriers through effective health care systems and antimalarial drug treatment, urban malaria transmission versus rural or forest malaria transmission, and the impact of vaccine development. Many malaria vectors are members of species complexes and individual relationship to malaria transmission, seasonal distribution, bitting behavior, etc. is poorly understood. Additionaly, malaria patients are not examined for circulating gametocytes and both falciparum and vivax malaria patients may be highly infective to mosquitoes after treatment with currently used antimalarial drugs. Studies on the physiological and behavioral effects of DDT and other insecticides are inconclusive and need to be evalusted.

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

    Science.gov (United States)

    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

  17. A practical approach for exploration and modeling of the design space of a bacterial vaccine cultivation process.

    Science.gov (United States)

    Streefland, M; Van Herpen, P F G; Van de Waterbeemd, B; Van der Pol, L A; Beuvery, E C; Tramper, J; Martens, D E; Toft, M

    2009-10-15

    A licensed pharmaceutical process is required to be executed within the validated ranges throughout the lifetime of product manufacturing. Changes to the process, especially for processes involving biological products, usually require the manufacturer to demonstrate that the safety and efficacy of the product remains unchanged by new or additional clinical testing. Recent changes in the regulations for pharmaceutical processing allow broader ranges of process settings to be submitted for regulatory approval, the so-called process design space, which means that a manufacturer can optimize his process within the submitted ranges after the product has entered the market, which allows flexible processes. In this article, the applicability of this concept of the process design space is investigated for the cultivation process step for a vaccine against whooping cough disease. An experimental design (DoE) is applied to investigate the ranges of critical process parameters that still result in a product that meets specifications. The on-line process data, including near infrared spectroscopy, are used to build a descriptive model of the processes used in the experimental design. Finally, the data of all processes are integrated in a multivariate batch monitoring model that represents the investigated process design space. This article demonstrates how the general principles of PAT and process design space can be applied for an undefined biological product such as a whole cell vaccine. The approach chosen for model development described here, allows on line monitoring and control of cultivation batches in order to assure in real time that a process is running within the process design space.

  18. Comparison of clinical and parasitological data from controlled human malaria infection trials.

    Directory of Open Access Journals (Sweden)

    Meta Roestenberg

    Full Text Available Exposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility.We reviewed safety and parasitological data from 128 malaria-naïve subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program.We show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates.Procedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development.

  19. Fc gamma receptor IIIB (Fc gamma RIIIB) polymorphisms are associated with clinical malaria in Ghanaian children

    DEFF Research Database (Denmark)

    Adu, Bright; Dodoo, Daniel; Adukpo, Selorme

    2012-01-01

    Plasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from...... by allele specific restriction enzyme digestion. FCGR3B-exon 3 was sequenced in 585 children, aged 1 to 12 years living in a malaria endemic region of Ghana. Multivariate logistic regression analysis found no association between Fc¿RIIA-166H/R polymorphism and clinical malaria. The A-allele of FCGR3B-c.233C...... malaria vaccines....

  20. Perceived Threat of Malaria and the Use of Insecticide Treated Bed ...

    African Journals Online (AJOL)

    2013-12-17

    Dec 17, 2013 ... Keywords: malaria; children; insecticide treated nets; health belief model; .... including malaria, were usually handled by the only designated nurse. .... The familiar saying that “prevention is better and cheaper than cure” may ...

  1. Designing and overproducing a tandem epitope of gp350/220 that shows a potential to become an EBV vaccine

    Directory of Open Access Journals (Sweden)

    Widodo

    2018-03-01

    Full Text Available Background: Epstein-Barr virus (EBV can cause cancer in people from around the world. There is no EBV vaccine available for use on a global scale. However, emerging evidence suggests that the epitope on the gp350/220 capsid protein may be developed into an EBV vaccine. Nevertheless, the production of small, single epitope is challenging of stability issues and possible alteration of peptide structure. In this study, a tandem epitope was developed consisting of three single epitopes, aimed to improve stability, antigenicity and preserve epitope structure. Materials and methods: A tandem epitope was designed using bioinformatics based on the epitope structure of the gp350/220 protein. The tandem epitope structure was analyzed using a protein folding method with Abalone software, which was further refined via YASARA force field and molecular repairing using a FoldX method. Immunogenicity was examined with Epitopia software, whereas allergen properties were tested using AlgPred. The pattern of the tandem epitope binding with anti-gp350/220 antibodies was performed using Z-dock and snugDock. The tandem epitope was then overproduced in E. coli strain BL21 as a host cell. Result: Our model demonstrated a successfully designed and overproduced tandem epitope. The tandem epitope demonstrated a similar structure compared with the epitope of whole protein gp350/220. Our epitope also demonstrated non-allergen and antigenicity properties, and possessed antibody binding patterns consistent with whole protein gp350/220. Conclusion and recommendation: These data suggest a novel tandem epitope composed of three similar epitopes demonstrates antigenicity, structure, and binding properties consistent with whole protein gp350/220. We also demonstrate successful production of the tandem epitope using E. coli strain BL21 as a host. Future in vivo experimental animal research is necessary to test the ability of this tandem epitope to stimulate antibody production

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

    Science.gov (United States)

    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.

  3. Malaria in Children.

    Science.gov (United States)

    Cohee, Lauren M; Laufer, Miriam K

    2017-08-01

    Malaria is a leading cause of morbidity and mortality in endemic areas, leading to an estimated 438,000 deaths in 2015. Malaria is also an important health threat to travelers to endemic countries and should be considered in evaluation of any traveler returning from a malaria-endemic area who develops fever. Considering the diagnosis of malaria in patients with potential exposure is critical. Prompt provision of effective treatment limits the complications of malaria and can be life-saving. Understanding Plasmodium species variation, epidemiology, and drug-resistance patterns in the geographic area where infection was acquired is important for determining treatment choices. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Combining malaria control with rural electrification

    OpenAIRE

    Oria, Prisca A.

    2016-01-01

    Chapter 1 presents the background information relevant to the subject matter and methods of this thesis. These include the application of social and behavioural sciences in malaria control, the SolarMal project and malaria in Kenya. It also presents the research objective, question and design that informed this thesis. Chapter 2 systematically documented and analysed how the mosquito trapping technology and related social contexts mutually shaped each other and how this mutual shaping impacte...

  5. Malaria og graviditet

    DEFF Research Database (Denmark)

    Hoffmann, A L; Rønn, A M; Langhoff-Roos, J

    1992-01-01

    In regions where malaria is endemism, the disease is a recognised cause of complications of pregnancy such as spontaneous abortion, premature delivery, intrauterine growth retardation and foetal death. Malaria is seldom seen in pregnant women in Denmark but, during the past two years, the authors...... the patients but also their practitioners were unaware that malaria can occur several years after exposure. Three out of the four patients had employed malaria prophylaxis. As resistance to malarial prophylactics in current use is increasing steadily, chemoprophylaxis should be supplemented by mechanical...... protection against malaria and insect repellents. As a rule, malaria is treated with chloroquine. In cases of Falciparum malaria in whom chloroquine resistance is suspected, treatment with mefloquine may be employed although this should only be employed in cases of dire necessity in pregnant patients during...

  6. PATTERNS OF SEVEN AND COMPLICATED MALARIA IN CHILDREN

    African Journals Online (AJOL)

    GB

    2017-01-01

    Jan 1, 2017 ... Vaccines Directorate, Ethiopia. 4Department of ... and III were given 400 and 800 mg/kg body weight/day plant .... Experimental animals preparation: A total of thirty adult ..... Tesgaye K. In-vivo anti-malaria activity of plants ...

  7. Defining malaria burden from morbidity and mortality records, self ...

    African Journals Online (AJOL)

    Abstract: Malaria morbidity and mortality data from clinical records provide essential information .... Babati District is one of the eight sentinel sites in Tanzania for monitoring anti- ... treatment given before leaving the health facility was documented. ..... Targett, G. (1999) Vaccine efficacy, and immunity affecting transmission.

  8. Estimation of effectiveness of interventions for malaria control in pregnancy using the screening method

    NARCIS (Netherlands)

    Msyamboza, K.; Senga, E.; Tetteh-Ashong, E.; Kazembe, P.; Brabin, B. J.

    2007-01-01

    BACKGROUND: The evaluation of the effectiveness of antimalarial drugs and bed net use in pregnant women is an important aspect of monitoring and surveillance of malaria control in pregnancy. In principle the screening method for assessing vaccine efficacy can be applied in non-vaccine settings for

  9. [Development of current smallpox vaccines].

    Science.gov (United States)

    Maksiutov, R A; Gavrilova, E V; Shchelkunov, S N

    2011-01-01

    The review gives data on the history of smallpox vaccination and shows the high topicality of designing the current safe vaccines against orthopoxviruses. Four generations of live smallpox, protein subunit, and DNA vaccines are considered. Analysis of the data published leads to the conclusion that it is promising to use the up-to-date generations of safe smallpox subunit or DNA vaccines for mass primary immunization with possible further revaccination with classical live vaccine.

  10. Newer Vaccines against Mosquito-borne Diseases.

    Science.gov (United States)

    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.

  11. Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naïve volunteers: effect of injection volume and dose on infectivity rates

    NARCIS (Netherlands)

    Gómez-Pérez, Gloria P.; Legarda, Almudena; Muñoz, Jose; Sim, B. Kim Lee; Ballester, María Rosa; Dobaño, Carlota; Moncunill, Gemma; Campo, Joseph J.; Cisteró, Pau; Jimenez, Alfons; Barrios, Diana; Mordmüller, Benjamin; Pardos, Josefina; Navarro, Mireia; Zita, Cecilia Justino; Nhamuave, Carlos Arlindo; García-Basteiro, Alberto L.; Sanz, Ariadna; Aldea, Marta; Manoj, Anita; Gunasekera, Anusha; Billingsley, Peter F.; Aponte, John J.; James, Eric R.; Guinovart, Caterina; Antonijoan, Rosa M.; Kremsner, Peter G.; Hoffman, Stephen L.; Alonso, Pedro L.

    2015-01-01

    Controlled human malaria infection (CHMI) by mosquito bite is a powerful tool for evaluation of vaccines and drugs against Plasmodium falciparum malaria. However, only a small number of research centres have the facilities required to perform such studies. CHMI by needle and syringe could help to

  12. Home-based malaria management in children by women: Evidence from a malaria endemic community in sub-Saharan Africa

    Directory of Open Access Journals (Sweden)

    Doreen Nkiru Eugene-Ezebilo

    2015-07-01

    Full Text Available Objective: To examine the medicines and dosage that mothers who engage in home-based malaria management administer to children aged ≤ 5 years having signs and symptoms associated with malaria and to discuss the possibilities of designing an effective home-based malaria management strategy. Methods: The data were obtained from face-to-face semi-structured interviews conducted with mothers in the Ugbowo Community of Benin City, Nigeria who were selected using multistage systematic random sampling technique. The data were analyzed by qualitative content analysis, arithmetic mean, simple percentages and bar chart. Results: Approximately 90% of the interviewees engaged in home-based malaria management and 10% patronized the hospital. Most of the interviewees who engaged in home-based malaria management administered medicines that stimulates the production of red blood cells and supplies vitamins to children having signs and symptoms of malaria, followed by painkillers and anti-malaria and cough medicine was the least. Of the anti-malaria medicines administered to children, almost 80% of the interviewees administered chloroquine to children, 15% quinine and 3% halfan. Approximately 60% of the interviewees had the correct knowledge of the dosage regime for chloroquine, 38% for quinine and 9% for halfan. Conclusions: Although home-based malaria management is important, it cannot serve as a substitute to the hospital. Some diseases have signs and symptoms that are similar to that of malaria which implies that administering anti-malaria medicines to a child without confirmatory tests might lead to irredeemable complications in that child. If the strategy is to make home-based malaria management effective and sustainable mothers, community health officials should be involved in designing the strategy. Simple rapid diagnostic test kits for malaria should be made available to community health officials and pharmacists so that confirmatory tests could be

  13. Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant

    OpenAIRE

    Li, Xiangming; Fujio, Masakazu; Imamura, Masakazu; Wu, Douglass; Vasan, Sandhya; Wong, Chi-Huey; Ho, David D.; Tsuji, Moriya

    2010-01-01

    The glycolipid α-galactosylceramide (α-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, α-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNK...

  14. Peptide Vaccines for Leishmaniasis

    Directory of Open Access Journals (Sweden)

    Rory C. F. De Brito

    2018-05-01

    Full Text Available Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

  15. Peptide Vaccines for Leishmaniasis.

    Science.gov (United States)

    De Brito, Rory C F; Cardoso, Jamille M De O; Reis, Levi E S; Vieira, Joao F; Mathias, Fernando A S; Roatt, Bruno M; Aguiar-Soares, Rodrigo Dian D O; Ruiz, Jeronimo C; Resende, Daniela de M; Reis, Alexandre B

    2018-01-01

    Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

  16. The "Performance of Rotavirus and Oral Polio Vaccines in Developing Countries" (PROVIDE) study: description of methods of an interventional study designed to explore complex biologic problems.

    Science.gov (United States)

    Kirkpatrick, Beth D; Colgate, E Ross; Mychaleckyj, Josyf C; Haque, Rashidul; Dickson, Dorothy M; Carmolli, Marya P; Nayak, Uma; Taniuchi, Mami; Naylor, Caitlin; Qadri, Firdausi; Ma, Jennie Z; Alam, Masud; Walsh, Mary Claire; Diehl, Sean A; Petri, William A

    2015-04-01

    Oral vaccines appear less effective in children in the developing world. Proposed biologic reasons include concurrent enteric infections, malnutrition, breast milk interference, and environmental enteropathy (EE). Rigorous study design and careful data management are essential to begin to understand this complex problem while assuring research subject safety. Herein, we describe the methodology and lessons learned in the PROVIDE study (Dhaka, Bangladesh). A randomized clinical trial platform evaluated the efficacy of delayed-dose oral rotavirus vaccine as well as the benefit of an injectable polio vaccine replacing one dose of oral polio vaccine. This rigorous infrastructure supported the additional examination of hypotheses of vaccine underperformance. Primary and secondary efficacy and immunogenicity measures for rotavirus and polio vaccines were measured, as well as the impact of EE and additional exploratory variables. Methods for the enrollment and 2-year follow-up of a 700 child birth cohort are described, including core laboratory, safety, regulatory, and data management practices. Intense efforts to standardize clinical, laboratory, and data management procedures in a developing world setting provide clinical trials rigor to all outcomes. Although this study infrastructure requires extensive time and effort, it allows optimized safety and confidence in the validity of data gathered in complex, developing country settings. © The American Society of Tropical Medicine and Hygiene.

  17. Malaria immunity in man and mosquito: insights into unsolved mysteries of a deadly infectious disease

    Science.gov (United States)

    Crompton, Peter D.; Moebius, Jacqueline; Portugal, Silvia; Waisberg, Michael; Hart, Geoffrey; Garver, Lindsey S.; Miller, Louis H.; Barillas, Carolina; Pierce, Susan K.

    2014-01-01

    Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa family, the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world’s most vulnerable populations, claiming the lives of nearly a million children and pregnant women each year in Africa alone. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite’s complex life cycle with a view towards developing the tools that will contribute to the prevention of disease and death and ultimately the goal of malaria eradication. In so doing we hope to inspire immunologists to participate in defeating this devastating disease. PMID:24655294

  18. Parasite threshold associated with clinical malaria in areas of different transmission intensities in north eastern Tanzania

    DEFF Research Database (Denmark)

    Mmbando, Bruno P; Lusingu, John P; Vestergaard, Lasse S

    2009-01-01

    BACKGROUND: In Sub-Sahara Africa, malaria due to Plasmodium falciparum is the main cause of ill health. Evaluation of malaria interventions, such as drugs and vaccines depends on clinical definition of the disease, which is still a challenge due to lack of distinct malaria specific clinical...... features. Parasite threshold is used in definition of clinical malaria in evaluation of interventions. This however, is likely to be influenced by other factors such as transmission intensity as well as individual level of immunity against malaria. METHODS: This paper describes step function and dose...... response model with threshold parameter as a tool for estimation of parasite threshold for onset of malaria fever in highlands (low transmission) and lowlands (high transmission intensity) strata. These models were fitted using logistic regression stratified by strata and age groups (0-1, 2-3, 4-5, 6...

  19. Reduction in malaria prevalence and increase in malaria awareness in endemic districts of Bangladesh.

    Science.gov (United States)

    Alam, Mohammad Shafiul; Kabir, Mohammad Moktadir; Hossain, Mohammad Sharif; Naher, Shamsun; Ferdous, Nur E Naznin; Khan, Wasif Ali; Mondal, Dinesh; Karim, Jahirul; Shamsuzzaman, A K M; Ahmed, Be-Nazir; Islam, Akramul; Haque, Rashidul

    2016-11-11

    Malaria is endemic in 13 districts of Bangladesh. A baseline malaria prevalence survey across the endemic districts of Bangladesh was conducted in 2007, when the prevalence was reported around 39.7 per 1000 population. After two rounds of Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-funded intervention by the National Malaria Control Programme (NMCP) and a BRAC-led NGO consortium, a follow-up survey was conducted across the malaria-endemic districts of Bangladesh to measure the change in prevalence rate and in people's knowledge of malaria. The survey was carried out from August to November 2013 in 70 upazilas (sub-districts) of 13 malaria-endemic districts of Bangladesh, following the same multi-stage cluster sampling design and the same number of households enrolled during the baseline prevalence survey in 2007, to collect 9750 randomly selected blood samples. For on-the-spot diagnosis of malaria, a rapid diagnostic test was used. The household head or eldest person available was interviewed using a pre-coded structured questionnaire to collect data on the knowledge and awareness of malaria in the household. Based on a weighted calculation, the overall malaria prevalence was found to be 1.41 per 1000 population. The proportion of Plasmodium falciparum mono-infection was 77.78% while both Plasmodium vivax mono-infection and mixed infection of the two species were found to be 11.11%. Bandarban had the highest prevalence (6.67 per 1000 population). Knowledge of malaria signs, symptoms and mode of transmission were higher in the follow-up survey (97.26%) than the baseline survey. Use of bed nets for prevention of malaria was found to be high (90.15%) at respondent level. People's knowledge of selected parameters increased significantly during the follow-up survey compared to the baseline survey conducted in 2007. A reduced prevalence rate of malaria and increased level of knowledge were observed in the present malaria prevalence survey in Bangladesh.

  20. Genetic Diversity Underlying the Envelope Glycoproteins of Hepatitis C Virus: Structural and Functional Consequences and the Implications for Vaccine Design

    Directory of Open Access Journals (Sweden)

    Alexander W. Tarr

    2015-07-01

    Full Text Available In the 26 years since the discovery of Hepatitis C virus (HCV a major global research effort has illuminated many aspects of the viral life cycle, facilitating the development of targeted antivirals. Recently, effective direct-acting antiviral (DAA regimens with >90% cure rates have become available for treatment of chronic HCV infection in developed nations, representing a significant advance towards global eradication. However, the high cost of these treatments results in highly restricted access in developing nations, where the disease burden is greatest. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in at risk groups and resource constrained settings due to limited surveillance. Consequently a prophylactic vaccine is much needed. The HCV envelope glycoproteins E1 and E2 are located on the surface of viral lipid envelope, facilitate viral entry and are the targets for host immunity, in addition to other functions. Unfortunately, the extreme global genetic and antigenic diversity exhibited by the HCV glycoproteins represents a significant obstacle to vaccine development. Here we review current knowledge of HCV envelope protein structure, integrating knowledge of genetic, antigenic and functional diversity to inform rational immunogen design.

  1. Vaccinomics Approach for Designing Potential Peptide Vaccine by Targeting Shigella spp. Serine Protease Autotransporter Subfamily Protein SigA

    Directory of Open Access Journals (Sweden)

    Arafat Rahman Oany

    2017-01-01

    Full Text Available Shigellosis, a bacillary dysentery, is closely associated with diarrhoea in human and causes infection of 165 million people worldwide per year. Casein-degrading serine protease autotransporter of enterobacteriaceae (SPATE subfamily protein SigA, an outer membrane protein, exerts both cytopathic and enterotoxic effects especially cytopathic to human epithelial cell type-2 (HEp-2 and is shown to be highly immunogenic. In the present study, we have tried to impose the vaccinomics approach for designing a common peptide vaccine candidate against the immunogenic SigA of Shigella spp. At first, 44 SigA proteins from different variants of S. flexneri, S. dysenteriae, S. boydii, and S. sonnei were assessed to find the most antigenic protein. We retrieved 12 peptides based on the highest score for human leukocyte antigen (HLA supertypes analysed by NetCTL. Initially, these peptides were assessed for the affinity with MHC class I and class II alleles, and four potential core epitopes VTARAGLGY, FHTVTVNTL, HTTWTLTGY, and IELAGTLTL were selected. From these, FHTVTVNTL and IELAGTLTL peptides were shown to have 100% conservancy. Finally, IELAGTLTL was shown to have the highest population coverage (83.86% among the whole world population. In vivo study of the proposed epitope might contribute to the development of functional and unique widespread vaccine, which might be an operative alleyway to thwart dysentery from the world.

  2. Vaccination Perceptions of College Students: With and without Vaccination Waiver.

    Science.gov (United States)

    Jadhav, Emmanuel D; Winkler, Danielle L; Anderson, Billie S

    2018-01-01

    The resurgence of vaccine preventable diseases occurs more often among intentionally unvaccinated individuals, placing at direct risk young adults not caught up on vaccinations. The objectives of this study were to characterize the sociodemographic characteristics of young adults with and without vaccination waivers and identify their perceived benefits, barriers, and influencers of vaccination. Young adults ( n  = 964) from a Midwestern rural university responded to a survey (fall 2015-spring 2016) designed to identify their perception toward vaccination. Instrument consistency was measured using the Cronbach α-scores. The Chi-square test was used to test any sociodemographic differences and Mann-Whitney U -tests results for differences between exempt and non-exempt students. Analysis occurred in spring 2017. A little over one-third of young adults with a vaccination waiver were not up to date on their vaccinations, and think that vaccinations can cause autism. The biggest identifiable benefit was effective control against disease. The surveyed young adults ranked the out of pocket cost associated with vaccination as the most important barrier and safe and easy to use vaccines as the most important influencer of vaccination. Young adults who have had a vaccination waiver appear to not be up to date on their vaccinations. Vaccine administration programs, such as university campus clinics, would benefit from addressing perceptions unique to young adults with and without a vaccine waiver. This would subsequently better provide young adults a second shot for getting appropriately caught up on vaccinations.

  3. Influence Of Demographic Factors And History Of Malaria With The Incidence Malaria In MORU PHC

    Directory of Open Access Journals (Sweden)

    Sudirman Manumpa

    2017-01-01

    Full Text Available Malaria morbidity in Moru health center, with parameter Annual Parasite Incident (API, amounted to 16.9% in 2014. This figure was still high when compared to the target of eliminating malaria in Indonesia about <1% in 2030. Incidence of malaria is more common in children aged 5 months - <12 years. This high rates of malaria leads to poverty, low level of learning achievement of children and in pregnant women causing low birth weight in babies and death. The purpose of this study was to analyze the factors that influence the incidence of tertian and Tropikana malaria or combined Tropikana and tertian (mix in Moru PHC in sub-district Alor Southwestern, Alor Regency.This study used a cross-sectional design, the population of study were all patients undergoing peripheral blood examination in Moru PHC’s laboratory from June to October 2015. The number of samples in this study was 173 respondents. The sampling technique was Simple Random Sampling. Instruments of data collection were a questionnaire and observation sheet.Results of the study by Chi-Square test showed that the factors influencing the incidence of malaria were socioeconomic status (sig 0,000, education level (sig 0.001. By using multivariate analysis with logistic regression test, results were obtained the age of 5 months - <12 value (sig 0.025 and socioeconomic status (sig 0,000 influencing the incidence of malaria.Variables that affect the incidence of malaria were demographic factors such as age, education level, socioeconomic status. It is advisable to harness swamp thus improving the economic status of society and build permanent house. Keywords: incidence malaria, demographic factors, history of malaria

  4. Heterologous prime-boost vaccinations for poverty-related diseases: advantages and future prospects

    NARCIS (Netherlands)

    Radosević, Katarina; Rodriguez, Ariane; Lemckert, Angelique; Goudsmit, Jaap

    2009-01-01

    Classical vaccination approaches, based on a single vaccine administered in a homologous prime-boost schedule and optimized to induce primarily neutralizing antibodies, are unlikely to be sufficiently efficacious to prevent TB, malaria or HIV infections. Novel vaccines, capable of inducing a more

  5. Congenital malaria in China.

    Directory of Open Access Journals (Sweden)

    Zhi-Yong Tao

    2014-03-01

    Full Text Available BACKGROUND: Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria-endemic regions. It is recognized as a serious problem in Plasmodium falciparum-endemic sub-Saharan Africa, where recent data suggests that it is more common than previously believed. In such regions where malaria transmission is high, neonates may be protected from disease caused by congenital malaria through the transfer of maternal antibodies against the parasite. However, in low P. vivax-endemic regions, immunity to vivax malaria is low; thus, there is the likelihood that congenital vivax malaria poses a more significant threat to newborn health. Malaria had previously been a major parasitic disease in China, and congenital malaria case reports in Chinese offer valuable information for understanding the risks posed by congenital malaria to neonatal health. As most of the literature documenting congenital malaria cases in China are written in Chinese and therefore are not easily accessible to the global malaria research community, we have undertaken an extensive review of the Chinese literature on this subject. METHODS/PRINCIPAL FINDINGS: Here, we reviewed congenital malaria cases from three major searchable Chinese journal databases, concentrating on data from 1915 through 2011. Following extensive screening, a total of 104 cases of congenital malaria were identified. These cases were distributed mainly in the eastern, central, and southern regions of China, as well as in the low-lying region of southwest China. The dominant species was P. vivax (92.50%, reflecting the malaria parasite species distribution in China. The leading clinical presentation was fever, and other clinical presentations were anaemia, jaundice, paleness, diarrhoea, vomiting, and general weakness. With the exception of two cases, all patients

  6. Vaccines (immunizations) - overview

    Science.gov (United States)

    Vaccinations; Immunizations; Immunize; Vaccine shots; Prevention - vaccine ... of the vaccine. VACCINE SCHEDULE The recommended vaccination (immunization) schedule is updated every 12 months by the ...

  7. Malaria and the Millennium Development Goals.

    Science.gov (United States)

    Owens, Stephen

    2015-02-01

    Malaria, as a key disease of poverty, was singled out for special attention in the Millennium Project of 2000. Recent data suggest that malaria incidence and mortality are now declining all over the world. While these figures are cause for celebration, they must be interpreted carefully and with caution, particularly in relation to Africa. There are daunting challenges ahead for those working to achieve malaria eradication, not least of which is the poor quality of the data on which the work is based. In the absence of an affordable and fully effective vaccine, international funding for malaria control needs to be escalated still further. The money is essential to pay for universal access to a set of simple and proven interventions which would save the lives of millions of children over the next 15 years. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Incidence of Severe Malaria Syndromes and Status of Immune Responses among Khat Chewer Malaria Patients in Ethiopia.

    Directory of Open Access Journals (Sweden)

    Tsige Ketema

    Full Text Available Although more emphasis has been given to the genetic and environmental factors that determine host vulnerability to malaria, other factors that might have a crucial role in burdening the disease have not been evaluated yet. Therefore, this study was designed to assess the effect of khat chewing on the incidence of severe malaria syndromes and immune responses during malaria infection in an area where the two problems co-exist. Clinical, physical, demographic, hematological, biochemical and immunological data were collected from Plasmodium falciparum mono-infected malaria patients (age ≥ 10 years seeking medication in Halaba Kulito and Jimma Health Centers. In addition, incidences of severe malaria symptoms were assessed. The data were analyzed using SPSS (version 20 software. Prevalence of current khat chewer malaria patients was 57.38% (95%CI =53-61.56%. Malaria symptoms such as hyperpyrexia, prostration and hyperparasitemia were significantly lower (P0.05, IgG3 antibody was significantly higher (P<0.001 among khat chewer malaria patients. Moreover, IgM, IgG, IgG1and IgG3 antibodies had significant negative association (P<0.001 with parasite burden and clinical manifestations of severe malaria symptoms, but not with severe anemia and hypoglycemia. Additionally, a significant increment (P<0.05 in CD4+ T-lymphocyte population was observed among khat users. Khat might be an important risk factor for incidence of some severe malaria complications. Nevertheless, it can enhance induction of humoral immune response and CD4+ T-lymphocyte population during malaria infection. This calls for further investigation on the effect of khat on parasite or antigen-specifc protective malaria immunity and analysis of cytokines released upon malaria infection among khat chewers.

  9. Design, implementation and evaluation of a training programme for school teachers in the use of malaria rapid diagnostic tests as part of a basic first aid kit in southern Malawi.

    Science.gov (United States)

    Witek-McManus, Stefan; Mathanga, Don P; Verney, Allison; Mtali, Austin; Ali, Doreen; Sande, John; Mwenda, Reuben; Ndau, Saidi; Mazinga, Charles; Phondiwa, Emmanuel; Chimuna, Tiyese; Melody, David; Roschnik, Natalie; Brooker, Simon J; Halliday, Katherine E

    2015-09-17

    With increasing levels of enrolment, primary schools present a pragmatic opportunity to improve the access of school children to timely diagnosis and treatment of malaria, increasingly recognised as a major health problem within this age group. The expanded use of malaria rapid diagnostic tests (RDTs) and artemisinin combination therapy (ACT) by community health workers (CHWs) has raised the prospect of whether teachers can provide similar services for school children. We describe and evaluate the training of primary school teachers to use a first aid kit containing malaria RDTs and ACT for the diagnosis and treament of uncomplicated malaria in school children in southern Malawi. We outline the development of the intervention as: (1) conception and design, (2) pilot training, (3) final training, and (4) 7-month follow up. The training materials were piloted at a four-day workshop in July 2013 following their design at national stakeholders meetings. The evaluation of the pilot training and materials were assessed in relation to increased knowledge and skill sets using checklist evaluations and questionnaires, the results of which informed the design of a final seven-day training programme held in December 2013. A follow up of trained teachers was carried out in July 2014 following 7 months of routine implementation. A total of 15 teachers were evaluated at four stages: pilot training, two weeks following pilot, final training and seven months following final training. A total of 15 and 92 teachers were trained at the pilot and final training respectively. An average of 93 % of the total steps required to use RDTs were completed correctly at the final training, declining to 87 % after 7 months. All teachers were observed correctly undertaking safe blood collection and handling, accurate RDT interpretation, and correct dispensing of ACT. The most commonly observed errors were a failure to wait 20 minutes before reading the test result, and adding an incorrect volume

  10. Malaria and Tropical Travel

    Centers for Disease Control (CDC) Podcasts

    2008-05-15

    Malaria is a serious mosquito-borne disease that can lead to death. This podcast discusses malaria risk when traveling to tropical areas, as well as how to protect yourself and your family from malaria infection.  Created: 5/15/2008 by National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED).   Date Released: 5/29/2008.

  11. Differing patterns of selection and geospatial genetic diversity within two leading Plasmodium vivax candidate vaccine antigens.

    Directory of Open Access Journals (Sweden)

    Christian M Parobek

    2014-04-01

    Full Text Available Although Plasmodium vivax is a leading cause of malaria around the world, only a handful of vivax antigens are being studied for vaccine development. Here, we investigated genetic signatures of selection and geospatial genetic diversity of two leading vivax vaccine antigens--Plasmodium vivax merozoite surface protein 1 (pvmsp-1 and Plasmodium vivax circumsporozoite protein (pvcsp. Using scalable next-generation sequencing, we deep-sequenced amplicons of the 42 kDa region of pvmsp-1 (n = 44 and the complete gene of pvcsp (n = 47 from Cambodian isolates. These sequences were then compared with global parasite populations obtained from GenBank. Using a combination of statistical and phylogenetic methods to assess for selection and population structure, we found strong evidence of balancing selection in the 42 kDa region of pvmsp-1, which varied significantly over the length of the gene, consistent with immune-mediated selection. In pvcsp, the highly variable central repeat region also showed patterns consistent with immune selection, which were lacking outside the repeat. The patterns of selection seen in both genes differed from their P. falciparum orthologs. In addition, we found that, similar to merozoite antigens from P. falciparum malaria, genetic diversity of pvmsp-1 sequences showed no geographic clustering, while the non-merozoite antigen, pvcsp, showed strong geographic clustering. These findings suggest that while immune selection may act on both vivax vaccine candidate antigens, the geographic distribution of genetic variability differs greatly between these two genes. The selective forces driving this diversification could lead to antigen escape and vaccine failure. Better understanding the geographic distribution of genetic variability in vaccine candidate antigens will be key to designing and implementing efficacious vaccines.

  12. Sustainable vaccine development: a vaccine manufacturer's perspective.

    Science.gov (United States)

    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.

  13. Design and Performance Analysis of a Biodiesel Engine Driven Refrigeration System for Vaccine Storage

    Directory of Open Access Journals (Sweden)

    K Kamsuk

    2013-06-01

    Full Text Available A compact, stand-alone, refrigeration module powered by a small biodiesel engine for vaccine storage in rural use was proposed. The engine was of single cylinder, four-stroke, directinjection with displacement of 0.296 cm3 and compression ratio of 20:1. The refrigeration system was modified from an automotive vapor compression system. The system performance was analytically investigated. From the simulation, it was found to have acceptable operation over a range of speeds and loads. Performance of the system in terms of fuel consumption and torque tended to decrease with an increase in engine speed. The modular system was able to operate at cooling loads above 4.6 kW, with proper speed ratio between the engine and the compressor. Overall, primary energy ratio of the refrigeration was found to be maximum at 0.54.

  14. Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite

    NARCIS (Netherlands)

    Mistarz, U.H.; Singh, S.K; Nguyen, T.; Roeffen, W.; Lissau, C.; Madsen, S.M.; Vrang, A.; Tiendrebeogo, R.W.; Kana, I.H.; Sauerwein, R.W.; Theisen, M.; Rand, K.D.

    2017-01-01

    PURPOSE: Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a

  15. The Long-Term Economic Impact of In Utero and Postnatal Exposure to Malaria

    OpenAIRE

    Alan Barreca

    2009-01-01

    I use an instrumental-variables identification strategy and historical data from the United States to estimate the long-term economic impact of in utero and postnatal exposure to malaria. My research design matches adults in the 1960 Decennial Census to the malaria death rate in their respective state and year of birth. To address potential omitted variables bias and measurement-error bias, I use variation in "malaria-ideal" temperatures to instrument for malaria exposure. My estimates indica...

  16. Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice.

    Directory of Open Access Journals (Sweden)

    David C Pryde

    Full Text Available Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer and the quality (affinity of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist and aluminum hydroxide (Al(OH3 as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences.

  17. Variation in the immune responses against Plasmodium falciparum merozoite surface protein-1 and apical membrane antigen-1 in children residing in the different epidemiological strata of malaria in Cameroon.

    Science.gov (United States)

    Kwenti, Tebit Emmanuel; Moye, Adzemye Linus; Wiylanyuy, Adzemye Basil; Njunda, Longdoh Anna; Nkuo-Akenji, Theresa

    2017-11-09

    Studies to assess the immune responses against malaria in Cameroonian children are limited. The purpose of this study was to assess the immune responses against Plasmodium falciparum merozoite surface protein-1 (MSP-1 19 ) and apical membrane antigen-1 (AMA-1) in children residing in the different epidemiological strata of malaria in Cameroon. In a cross-sectional survey performed between April and July 2015, 602 children between 2 and 15 years (mean ± SD = 5.7 ± 3.7), comprising 319 (53%) males were enrolled from five epidemiological strata of malaria in Cameroon including: the sudano-sahelian (SS) strata, the high inland plateau (HIP) strata, the south Cameroonian equatorial forest (SCEF) strata, the high western plateau (HWP) strata, and the coastal (C) strata. The children were screened for clinical malaria (defined by malaria parasitaemia ≥ 5000 parasites/µl plus axillary temperature ≥ 37.5 °C). Their antibody responses were measured against P. falciparum MSP-1 19 and AMA-1 vaccine candidate antigens using standard ELISA technique. A majority of the participants were IgG responders 72.1% (95% CI 68.3-75.6). The proportion of responders was higher in females (p = 0.002) and in children aged 10 years and above (p = 0.005). The proportion of responders was highest in Limbe (C strata) and lowest in Ngaoundere (HIP strata) (p malaria (p malaria parasites. The immune responses varied considerably across the different strata: the highest levels observed in the C strata and the lowest in the HIP strata. Furthermore, malaria transmission in Cameroon could be categorized into two major groups based on the serological reaction of the children: the southern (comprising C and SCEF strata) and northern (comprising HWP, HIP and SS strata) groups. These findings may have significant implications in the design of future trials for evaluating malaria vaccine candidates in Cameroon.

  18. High prevalence of Plasmodium falciparum malaria among Human ...

    African Journals Online (AJOL)

    Malaria and Human Immunodeficiency Virus (HIV) infections are major public health problems in Sub-Saharan Africa. Their overlapping geographical distribution and co-existence often result into high morbidity and mortality. This study was designed to establish the prevalence of Plasmodium falciparum malaria among HIV ...

  19. Association between serum transferrin receptor levels and malaria ...

    African Journals Online (AJOL)

    Background: The relationship between body iron levels and malaria presents a complex interaction that provide variable and contradicting results. We designed a study to investigate associations between concentrations of biomarkers of body iron and malaria recurrence among children. Methods: We conducted a ...

  20. Thrombocyte counts in malaria patients at East Kalimantan

    Science.gov (United States)

    Siagian, L. R. D.; Asfirizal, V.; Toruan, V. D. L.; Hasanah, N.

    2018-04-01

    Malaria still becoming a serious health problem in Indonesia. Beside disorders of erythrocytes, there are some data that Plasmodium caused the other blood cells like leukocyte and thrombocyte. In malaria, changes of thrombocyte is thrombocytopenia that would be a complication from malaria vivax or malaria falciparum. The aim of this study is to know the thrombocyte count of malaria patients in East Kalimantan. Design of this study is descriptic retrospective from medical record’s data from 2011-2016 in 7 hospitals (AW Syahranie at Samarinda, Kanudjoso at Balikpapan, Penajam Paser Utara at Panajam, AM Parikesit at Tenggarong, Taman Husada at Bontang, Kudungga at Sangata and Abdul Rivai at Tanjung Redeb. We collected the data from June-August 2017. There are 1041 malaria patients with male and female respectively 88.2% and 11.2%. The etiology of malaria were Plasmodium falciparum, Plasmodium vivax and mixed infection (P.f and P.v) respectively 62.6%, 38% and 6.1%. We found thrombocyte count was normal, decrease and increase respectively 11%, 85% and 1.7%. The degree of thrombocytopenia in malaria patients were mild (100.000-150.000/µl) 31.8%, moderate (50.000-100.000/µL) 45.6% and severe (malaria patients at East Kalimantan was thrombocytopenia with moderate degree of thrombocytopenia.

  1. Epitope design of L1 protein for vaccine production against Human Papilloma Virus types 16 and 18.

    Science.gov (United States)

    Baidya, Sunanda; Das, Rasel; Kabir, Md Golam; Arifuzzaman, Md

    2017-01-01

    Cervical cancer accounts for about two-thirds of all cancer cases linked etiologically to Human Papilloma Virus (HPV). 15 oncogenic HPV types can cause cervical cancer, of which HPV16 and HPV18 combinedly account for about 70% of it. So, effective epitope design for the clinically relevant HPV types 16 and 18 would be of major medical benefit. Here, a comprehensive analysis is carried out to predict the epitopes against HPV types 16 and 18 through "reverse vaccinology" approach. We attempted to identify the evolutionarily conserved regions of major capsid protein (L1) as well as minor capsid protein (L2) of HPV and designed epitopes within these regions. In this study, we analyzed about 49 and 27 sequences of HPV L2 and L1 proteins respectively. Since we found that the intertype variability of L2 is higher than for L1 proteins, our analysis was emphasized on epitopes of L1 of HPV types 16 and 18. We had selected HLA-A*0201, DRB1*1501, DQB1*0602, DRB1*0401 and DQB1*0301 alleles for the prediction of T cell epitopes of L1 of HPV 16 and 18. Finally, we reported that predicted epitope sequences EEYDLQFIFQLCKITLTA, and RHGEEYDLQFIFQLCKITLTA of L1 protein of HPV 16, and LPDPNKF, PETQRLVWAC, PVPGQYDA, YNPETQRLVWAC, DTGYGAMD, PVPGQYDATK, KQDIPKVSAYQYRVFRV, RDNVSVDYKQTQLCI and YSRHVEEYDLQFIF of L1 protein of HPV 18 could be therapeutic tools for vaccine design against HPV.

  2. Design of a Type-1 Diabetes Vaccine Candidate Using Edible Plants Expressing a Major Autoantigen

    Directory of Open Access Journals (Sweden)

    Edoardo Bertini

    2018-05-01

    Full Text Available Type-1 diabetes (T1D is a metabolic disease involving the autoimmune destruction of insulin-producing pancreatic beta cells. It is often diagnosed by the detection of autoantibodies, typically those recognizing insulin itself or the 65-kDa isoform of glutamic acid decarboxylase (GAD65. Oral insulin can be used to induce systemic immunological tolerance and thus prevent or delay the onset of T1D, suggesting that combination treatments with other autoantigens such as GAD65 could be even more successful. GAD65 has induced oral tolerance and prevented T1D in preclinical studies but it is difficult to produce in sufficient quantities for clinical testing. Here we combined edible plant systems, namely spinach (Spinacia oleracea cv Industra and red beet (Beta vulgaris cv Moulin Rouge, with the magnICON® expression system to develop a safe, cost-effective and environmentally sustainable platform for the large-scale production of GAD65. The superior red beet platform was extensively characterized in terms of recombinant protein yields and bioequivalence to wild-type plants, and the product was tested for its ability to resist simulated gastric digestion. Our results indicate that red beet plants are suitable for the production of a candidate oral vaccine based on GAD65 for the future preclinical and clinical testing of T1D immunotherapy approaches.

  3. Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design

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    Emma Rey-Jurado

    2017-03-01

    Full Text Available The human respiratory syncytial virus (hRSV is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently to respiratory failure. Upon infection, different pattern recognition receptors recognize the virus and trigger the innate immune response against the hRSV. Further, T cell immunity plays an important role for virus clearance. Based on animal studies, it is thought that the host immune response to hRSV is based on a biased T helper (Th-2 and Th17 T cell responses with the recruitment of T cells, neutrophils and eosinophils to the lung, causing inflammation and tissue damage. In contrast, human immunity against RSV has been shown to be more complex with no definitive T cell polarization profile. Nowadays, only a humanized monoclonal antibody, known as palivizumab, is available to protect against hRSV infection in high-risk infants. However, such treatment involves several injections at a significantly high cost. For these reasons, intense research has been focused on finding novel vaccines or therapies to prevent hRSV infection in the population. Here, we comprehensively review the recent literature relative to the immunological features during hRSV infection, as well as the new insights into preventing the disease caused by this virus.

  4. Malaria, malnutrition, and birthweight

    DEFF Research Database (Denmark)

    Cates, Jordan E.; Unger, Holger W.; Briand, Valerie

    2017-01-01

    were identified by the Maternal Malaria and Malnutrition (M3) initiative using a convenience sampling approach and were eligible for pooling given adequate ethical approval and availability of essential variables. Study-specific adjusted effect estimates were calculated using inverse probability...... be multiplicative interaction between malaria infection at enrollment and low MUAC within studies conducted in Africa; however, this finding was not consistent on the additive scale, when accounting for multiple comparisons, or when using other definitions of malaria and malnutrition. The major limitations...... of the study included availability of only 2 cross-sectional measurements of malaria and the limited availability of ultrasound-based pregnancy dating to assess impacts on preterm birth and fetal growth in all studies.  Conclusions : Pregnant women with malnutrition and malaria infection are at increased risk...

  5. Severe malaria in Europe

    DEFF Research Database (Denmark)

    Kurth, Florian; Develoux, Michel; Mechain, Matthieu

    2017-01-01

    BACKGROUND: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria. METHODS: The European Network for Tropical Medicine and Travel Health (Trop......Net) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre...... for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria. RESULTS: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections...

  6. The London School of Hygiene and Tropical Medicine: a new century of malaria research

    Directory of Open Access Journals (Sweden)

    Riley Eleanor M

    2000-01-01

    Full Text Available The global malaria situation has scarcely improved in the last 100 years, despite major advances in our knowledge of the basic biology, epidemiology and clinical basis of the disease. Effective malaria control, leading to a significant decrease in the morbidity and mortality attributable to malaria, will require a multidisciplinary approach. New tools - drugs, vaccine and insecticides - are needed but there is also much to be gained by better use of existing tools: using drugs in combination in order to slow the development of drug resistance; targeting resources to areas of greatest need; using geographic information systems to map the populations at risk and more sophisticated marketing techniques to distribute bed nets and insecticides. Sustainable malaria control may require the deployment of a highly effective vaccine, but there is much that can be done in the meantime to reduce the burden of disease.

  7. Green revolution vaccines, edible vaccines

    African Journals Online (AJOL)

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    of development. Food vaccines may also help to suppress autoimmunity disorders such as Type-1. Diabetes. Key words: Edible vaccines, oral vaccines, antigen expression, food vaccines. INTRODUCTION. Vaccination involves the stimulation of the immune system to prepare it for the event of an invasion from a particular ...

  8. Vaccine Safety

    Science.gov (United States)

    ... During Pregnancy Frequently Asked Questions about Vaccine Recalls Historical Vaccine Safety Concerns FAQs about GBS and Menactra ... CISA Resources for Healthcare Professionals Evaluation Current Studies Historical Background 2001-12 Publications Technical Reports Vaccine Safety ...

  9. Development of a human live attenuated West Nile infectious DNA vaccine: Suitability of attenuating mutations found in SA14-14-2 for WN vaccine design

    Energy Technology Data Exchange (ETDEWEB)

    Yamshchikov, Vladimir, E-mail: yaximik@gmail.com; Manuvakhova, Marina; Rodriguez, Efrain

    2016-01-15

    Direct attenuation of West Nile (WN) virus strain NY99 for the purpose of vaccine development is not feasible due to its high virulence and pathogenicity. Instead, we created highly attenuated chimeric virus W1806 with the serological identity of NY99. To further attenuate W1806, we investigated effects of mutations found in Japanese encephalitis virus vaccine SA14-14-2. WN viruses carrying all attenuating mutations lost infectivity in mammalian, but not in mosquito cells. No single reversion restored infectivity in mammalian cells, although increased infectivity in mosquito cells was observed. To identify a subset of mutations suitable for further attenuation of W1806, we analyzed effects of E{sub 138}K and K{sub 279}M changes on virulence, growth properties, and immunogenicity of derivatized W956, from which chimeric W1806 inherited its biological properties and attenuation profile. Despite strong dominant attenuating effect, introduction of only two mutations was not sufficient for attenuating W1806 to the safety level acceptable for human use. - Highlights: • Further attenuation of a WN vaccine precursor is outlined. • Effect of SA14-14-2 attenuating mutations is tested. • Mechanism of attenuation is proposed and illustrated. • The need for additional attenuating mutations is justified.

  10. Quality-by-Design approach to monitor the operation of a batch bioreactor in an industrial avian vaccine manufacturing process.

    Science.gov (United States)

    Largoni, Martina; Facco, Pierantonio; Bernini, Donatella; Bezzo, Fabrizio; Barolo, Massimiliano

    2015-10-10

    Monitoring batch bioreactors is a complex task, due to the fact that several sources of variability can affect a running batch and impact on the final product quality. Additionally, the product quality itself may not be measurable on line, but requires sampling and lab analysis taking several days to be completed. In this study we show that, by using appropriate process analytical technology tools, the operation of an industrial batch bioreactor used in avian vaccine manufacturing can be effectively monitored as the batch progresses. Multivariate statistical models are built from historical databases of batches already completed, and they are used to enable the real time identification of the variability sources, to reliably predict the final product quality, and to improve process understanding, paving the way to a reduction of final product rejections, as well as to a reduction of the product cycle time. It is also shown that the product quality "builds up" mainly during the first half of a batch, suggesting on the one side that reducing the variability during this period is crucial, and on the other side that the batch length can possibly be shortened. Overall, the study demonstrates that, by using a Quality-by-Design approach centered on the appropriate use of mathematical modeling, quality can indeed be built "by design" into the final product, whereas the role of end-point product testing can progressively reduce its importance in product manufacturing. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Rationale and design of the CAPAMIS study: Effectiveness of pneumococcal vaccination against community-acquired pneumonia, acute myocardial infarction and stroke

    Directory of Open Access Journals (Sweden)

    Salsench Elisabet

    2010-01-01

    Full Text Available Abstract Background The 23-valent polysaccharide pneumococcal vaccine (PPV-23 is recommended for elderly and high-risk people, although its effectiveness is controversial. Some studies have reported an increasing risk of acute vascular events among patients with pneumonia, and a recent case-control study has reported a reduction in the risk of myocardial infarction among patients vaccinated with PPV-23. Given that animal experiments have shown that pneumococcal vaccination reduces the extent of atherosclerotic lesions, it has been hypothesized that PPV-23 could protect against acute vascular events by an indirect effect preventing pneumonia or by a direct effect on oxidized low-density lipoproteins. The main objective of this study is to evaluate the clinical effectiveness of PPV-23 in reducing the risk of pneumonia and acute vascular events (related or nonrelated with prior pneumonia in the general population over 60 years. Methods/Design Cohort study including 27,000 individuals 60 years or older assigned to nine Primary Care Centers in the region of Tarragona, Spain. According to the reception of PPV-23 before the start of the study, the study population will be divided into vaccinated and nonvaccinated groups, which will be followed during a consecutive 30-month period. Primary Care and Hospitals discharge databases will initially be used to identify study events (community-acquired pneumonia, hospitalisation for acute myocardial infarction and stroke, but all cases will be further validated by checking clinical records. Multivariable Cox regression analyses estimating hazard ratios (adjusted for age, sex and comorbidities will be used to estimate vaccine effectiveness. Discussion The results of the study will contribute to clarify the controversial effect of the PPV-23 in preventing community-acquired pneumonia and they will be critical in determining the posible role of pneumococcal vaccination in cardiovascular prevention.

  12. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area1

    Science.gov (United States)

    Weiss, Greta E; Crompton, Peter D.; Li, Shanping; Walsh, Laura A.; Moir, Susan; Traore, Boubacar; Kayentao, Kassoum; Ongoiba, Aissata; Doumbo, Ogobara K.; Pierce, Susan K.

    2009-01-01

    Epidemiological observations in malaria endemic areas have long suggested a deficiency in the generation and maintenance of B cell memory to Plasmodium falciparum (Pf) in individuals chronically reinfected with the parasite. Recently, a functionally and phenotypically distinct population of FCRL4+ hypo-responsive memory B cells (MBCs) was reported to be expanded in HIV-infected individuals with high viral loads. Here we provide evidence that a phenotypically similar atypical MBC population is significantly expanded in Pf-exposed Malian adults and children as young as two years of age as compared to healthy U.S. adult controls. The number of these atypical MBCs was higher in children with chronic asymptomatic Pf infections compared to uninfected children suggesting that the chronic presence of the parasite may drive expansion of these distinct MBCs. This is the first description of an atypical MBC phenotype associated with malaria. Understanding the origin and function of these MBCs could be important in informing the design of malaria vaccines. PMID:19592645

  13. Disruption of IL-21 signaling affects T cell-B cell interactions and abrogates protective humoral immunity to malaria.

    Directory of Open Access Journals (Sweden)

    Damián Pérez-Mazliah

    2015-03-01

    Full Text Available Interleukin-21 signaling is important for germinal center B-cell responses, isotype switching and generation of memory B cells. However, a role for IL-21 in antibody-mediated protection against pathogens has not been demonstrated. Here we show that IL-21 is produced by T follicular helper cells and co-expressed with IFN-γ during an erythrocytic-stage malaria infection of Plasmodium chabaudi in mice. Mice deficient either in IL-21 or the IL-21 receptor fail to resolve the chronic phase of P. chabaudi infection and P. yoelii infection resulting in sustained high parasitemias, and are not immune to re-infection. This is associated with abrogated P. chabaudi-specific IgG responses, including memory B cells. Mixed bone marrow chimeric mice, with T cells carrying a targeted disruption of the Il21 gene, or B cells with a targeted disruption of the Il21r gene, demonstrate that IL-21 from T cells signaling through the IL-21 receptor on B cells is necessary to control chronic P. chabaudi infection. Our data uncover a mechanism by which CD4+ T cells and B cells control parasitemia during chronic erythrocytic-stage malaria through a single gene, Il21, and demonstrate the importance of this cytokine in the control of pathogens by humoral immune responses. These data are highly pertinent for designing malaria vaccines requiring long-lasting protective B-cell responses.

  14. Culminating anti-malaria efforts at long lasting insecticidal net?

    Directory of Open Access Journals (Sweden)

    Sunil Dhiman

    2014-11-01

    . Focused research on developing effective anti-malarial drugs, vaccines and new insecticides to reduce resistance is imperative to tackle malaria in the future. Keywords: LLIN, Insecticide resistance, Malaria, Immunity, Vector

  15. External quality assurance of malaria nucleic acid testing for clinical trials and eradication surveillance.

    Science.gov (United States)

    Murphy, Sean C; Hermsen, Cornelus C; Douglas, Alexander D; Edwards, Nick J; Petersen, Ines; Fahle, Gary A; Adams, Matthew; Berry, Andrea A; Billman, Zachary P; Gilbert, Sarah C; Laurens, Matthew B; Leroy, Odile; Lyke, Kristen E; Plowe, Christopher V; Seilie, Annette M; Strauss, Kathleen A; Teelen, Karina; Hill, Adrian V S; Sauerwein, Robert W

    2014-01-01

    Nucleic acid testing (NAT) for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates and is also important in surveillance of malaria control and elimination efforts. A variety of reported NAT assays have been described, yet no formal external quality assurance (EQA) program provides validation for the assays in use. Here, we report results of an EQA exercise for malaria NAT assays. Among five centers conducting controlled human malaria infection trials, all centers achieved 100% specificity and demonstrated limits of detection consistent with each laboratory's pre-stated expectations. Quantitative bias of reported results compared to expected results was generally Quality Assessment program that fulfills the need for EQA of malaria NAT assays worldwide.

  16. Challenges and prospects for dengue and malaria control in Thailand, Southeast Asia.

    Science.gov (United States)

    Corbel, Vincent; Nosten, Francois; Thanispong, Kanutcharee; Luxemburger, Christine; Kongmee, Monthathip; Chareonviriyaphap, Theeraphap

    2013-12-01

    Despite significant advances in the search for potential dengue vaccines and new therapeutic schemes for malaria, the control of these diseases remains difficult. In Thailand, malaria incidence is falling whereas that of dengue is rising, with an increase in the proportion of reported severe cases. In the absence of antiviral therapeutic options for acute dengue, appropriate case management reduces mortality. However, the interruption of transmission still relies on vector control measures that are currently insufficient to curtail the cycle of epidemics. Drug resistance in malaria parasites is increasing, compromising malaria control and elimination. Deficiencies in our knowledge of vector biology and vectorial capacity also hinder public health efforts for vector control. Challenges to dengue and malaria control are discussed, and research priorities identified. Copyright © 2013. Published by Elsevier Ltd.

  17. Frequently Asked Questions (FAQs) about Malaria

    Science.gov (United States)

    ... Facebook Tweet Share Compartir The Disease What is Malaria? Malaria is a serious and sometimes fatal disease ... cycle of disease and poverty. How People Get Malaria (Transmission) How is malaria transmitted? Usually, people get ...

  18. Vaccines.gov

    Science.gov (United States)

    ... Vaccine