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Sample records for antigen-based malaria vaccine

  1. Malaria vaccine.

    PubMed

    1994-05-01

    Some have argued that the vaccine against malaria developed by Manuel Pattaroyo, a Colombian scientist, is being tested prematurely in humans and that it is unlikely to be successful. While the Pattaroyo vaccine has been shown to confer protection against the relatively mild malaria found in Colombia, doubts exist over whether it will be effective in Africa. Encouraging first results, however, are emerging from field tests in Tanzania. The vaccine triggered a strong new immune response, even in individuals previously exposed to malaria. Additional steps must be taken to establish its impact upon mortality and morbidity. Five major trials are underway around the world. The creator estimates that the first ever effective malaria vaccine could be available for widespread use within five years and he has no intention of securing a patent for the discovery. In another development, malaria specialists from 35 African countries convened at an international workshop in Zimbabwe to compare notes. Participants disparaged financial outlays for the fight against malaria equivalent to 2% of total AIDS funding as insufficient; noted intercountry differences in prevention, diagnosis, and treatment; and found information exchange between anglophone and francophone doctors to be generally poor. PMID:12287671

  2. Malaria vaccine.

    PubMed

    Khurana, S K; Talib, V H

    1996-12-01

    Recently it has become evident that he same candidate antigen can be shared by several of the parasite stages, and thus the concept of a multistage vaccine is becoming more and more attractive. A TDR Task Force evaluated the promise and stage of development of some 20 existing asexual blood stage candidate antigens and prepared a strategy for their development leading to clinical testing and field trials, Amongst these are merozoite surface protein 1 (MSP-1), Serine Rich Antigen (SERA), Apical Membrane Antigen (AMA-1), and Erythrocyte Binding Antigen (EBA). A field study conducted in Tanzanian children showed that the SPf66 Colombian vaccine was safe, induced antibodies, and reduced the risk of developing clinical malaria by around 30%. This study, confirmed the potential of the vaccine to confer partial protection in areas of high as well as low intensity of transmission. Pfs25 is a leading candidate antigen for a transmission blocking vaccine. It is found in the ookinete stage of the parasite in the mosquito midgut. Gramme amounts of GMP-grade material have been produced and a vaccine based on the Pfs25 antigen formulated with alum should have gone into phase I and II clinical trials in the USA and Africa during 1995. Because the first malaria prototype vaccine to be tried out in people on a large scale has been the polymerized synthetic peptide developed by patarroye on the basis of the SPf66 antigen of P. faliciparum, the results are with much interest. It is still premature to predict the effectiveness of this vaccine globally, but its development will encourage further progress in a fields that has repeatedly been characterized by raised and then dashed drops. These various vaccines are based on the classical approach to vaccination, which is to raise host immunity against the parasite so as to reduce parasite densities or to sterilize an infection. A newer approach is development of antidisease vaccines which aim to alleviate morbidity by suppressing

  3. Vaccines against malaria.

    PubMed

    Hill, Adrian V S

    2011-10-12

    There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates. PMID:21893544

  4. Research toward Malaria Vaccines

    NASA Astrophysics Data System (ADS)

    Miller, Louis H.; Howard, Russell J.; Carter, Richard; Good, Michael F.; Nussenzweig, Victor; Nussenzweig, Ruth S.

    1986-12-01

    Malaria exacts a toll of disease to people in the Tropics that seems incomprehensible to those only familiar with medicine and human health in the developed world. The methods of molecular biology, immunology, and cell biology are now being used to develop an antimalarial vaccine. The Plasmodium parasites that cause malaria have many stages in their life cycle. Each stage is antigenically distinct and potentially could be interrupted by different vaccines. However, achieving complete protection by vaccination may require a better understanding of the complexities of B- and T-cell priming in natural infections and the development of an appropriate adjuvant for use in humans.

  5. Progress with new malaria vaccines.

    PubMed Central

    Webster, Daniel; Hill, Adrian V. S.

    2003-01-01

    Malaria is a parasitic disease of major global health significance that causes an estimated 2.7 million deaths each year. In this review we describe the burden of malaria and discuss the complicated life cycle of Plasmodium falciparum, the parasite responsible for most of the deaths from the disease, before reviewing the evidence that suggests that a malaria vaccine is an attainable goal. Significant advances have recently been made in vaccine science, and we review new vaccine technologies and the evaluation of candidate malaria vaccines in human and animal studies worldwide. Finally, we discuss the prospects for a malaria vaccine and the need for iterative vaccine development as well as potential hurdles to be overcome. PMID:14997243

  6. The March Toward Malaria Vaccines.

    PubMed

    Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L; Duffy, Patrick E

    2015-12-01

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  7. The march toward malaria vaccines.

    PubMed

    Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L; Duffy, Patrick E

    2015-11-27

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  8. The March Toward Malaria Vaccines

    PubMed Central

    Hoffman, Stephen L.; Vekemans, Johan; Richie, Thomas L.; Duffy, Patrick E.

    2016-01-01

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  9. Profiling the host response to malaria vaccination and malaria challenge

    PubMed Central

    Dunachie, Susanna; Hill, Adrian V.S.; Fletcher, Helen A.

    2015-01-01

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research. PMID:26256528

  10. Profiling the host response to malaria vaccination and malaria challenge.

    PubMed

    Dunachie, Susanna; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research.

  11. Designing malaria vaccines to circumvent antigen variability.

    PubMed

    Ouattara, Amed; Barry, Alyssa E; Dutta, Sheetij; Remarque, Edmond J; Beeson, James G; Plowe, Christopher V

    2015-12-22

    Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines.

  12. Reducing empiricism in malaria vaccine design.

    PubMed

    Moorthy, Vasee S; Kieny, Marie Paule

    2010-03-01

    Gains in the control of malaria and the promising progress of a malaria vaccine that is partly efficacious do not reduce the need for a high-efficacy vaccine in the longer term. Evidence supports the feasibility of developing a highly efficacious malaria vaccine. However, design of candidate malaria vaccines remains empirical and is necessarily based on many unproven assumptions because much of the knowledge needed to design vaccines and to predict efficacy is not available. Data to inform key questions of vaccine science might allow the design of vaccines to progress to a less empirical stage, for example through availability of assay results associated with vaccine efficacy. We discuss six strategic gaps in knowledge that contribute to empiricism in the design of vaccines. Comparative evaluation, assay and model standardisation, greater sharing of information, collaboration and coordination between groups, and rigorous evaluation of existing datasets are steps that can be taken to enable reductions in empiricism over time.

  13. A Research Agenda for Malaria Eradication: Vaccines

    PubMed Central

    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 malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of “vaccines that interrupt malaria transmission” (VIMT), which includes not only “classical” transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented. PMID:21311586

  14. Advances and challenges in malaria vaccine development

    PubMed Central

    Wang, Ruobing; Smith, Joseph D.; Kappe, Stefan H.I.

    2010-01-01

    Malaria remains one of the most devastating infectious diseases that threaten humankind. Human malaria is caused by five different species of Plasmodium parasites, each transmitted by the bite of female Anopheles mosquitoes. Plasmodia are eukaryotic protozoans with more than 5000 genes and a complex life cycle that takes place in the mosquito vector and the human host. The life cycle can be divided into pre-erythrocytic stages, erythrocytic stages and mosquito stages. Malaria vaccine research and development faces formidable obstacles because many vaccine candidates will probably only be effective in a specific species at a specific stage. In addition, Plasmodium actively subverts and escapes immune responses, possibly foiling vaccine-induced immunity. Although early successful vaccinations with irradiated, live-attenuated malaria parasites suggested that a vaccine is possible, until recently, most efforts have focused on subunit vaccine approaches. Blood-stage vaccines remain a primary research focus, but real progress is evident in the development of a partially efficacious recombinant pre-erythrocytic subunit vaccine and a live-attenuated sporozoite vaccine. It is unlikely that partially effective vaccines will eliminate malaria; however, they might prove useful in combination with existing control strategies. Elimination of malaria will probably ultimately depend on the development of highly effective vaccines. PMID:20003658

  15. Whole organism blood stage vaccines against malaria.

    PubMed

    Stanisic, Danielle I; Good, Michael F

    2015-12-22

    Despite a century of research focused on the development and implementation of effective control strategies, infection with the malaria parasite continues to result in significant morbidity and mortality worldwide. An effective malaria vaccine is considered by many to be the definitive solution. Yet, after decades of research, we are still without a vaccine that is capable of inducing robust, long lasting protection in naturally exposed individuals. Extensive sub-unit vaccine development focused on the blood stage of the malaria parasite has thus far yielded disappointing results. There is now a renewed focus on whole parasite vaccine strategies, particularly as they may overcome some of the inherent weaknesses deemed to be associated with the sub-unit approach. This review discusses the whole parasite vaccine strategy focusing on the blood stage of the malaria parasite, with an emphasis on recent advances and challenges in the development of killed and live attenuated vaccines.

  16. Malaria vaccines: looking back and lessons learnt

    PubMed Central

    Lorenz, Veronique; Karanis, Panagiotis

    2011-01-01

    The current status of malaria vaccine approaches has the background of a long and arduous path of malaria disease control and vaccine development. Here, we critically review with regard to unilateral interventional approaches and highlight the impact of socioeconomic elements of malaria endemicity. The necessity of re-energizing basic research of malaria life-cycle and Plasmodium developmental biology to provide the basis for promising and cost-effective vaccine approaches and to reach eradication goals is more urgent than previously believed. We closely analyse the flaws of various vaccine approaches, outline future directions and challenges that still face us and conclude that the focus of the field must be shifted to the basic research efforts including findings on the skin stage of infection. We also reflect on economic factors of vaccine development and the impact of public perception when it comes to vaccine uptake. PMID:23569729

  17. Malaria Vaccine Protection Short-Lived in Young Children

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159656.html Malaria Vaccine Protection Short-Lived in Young Children Kids ... 30, 2016 (HealthDay News) -- The world's most promising malaria vaccine appears to offer short-lived protection, fading ...

  18. Malaria: Immunity and Prospects for Vaccination

    PubMed Central

    Hommel, Marcel

    1981-01-01

    Malaria infections elicit a complex chain of cellular events which can, in some instances, lead to a state of immunity. Although there is strong evidence that a collaboration between specific antibodies and activated macrophages plays the central effector role in malaria immunity, alternative interpretations are possible. It is, for example, not known which malarial antigens are essential for triggering the critical effector functions and how these antigens are presented to the immune system. Under these circumstances, it is not surprising that the search for a vaccine against malaria has used rather empirical methods. Three invasive stages of the parasite (merozoites, sporozoites and gametes) have so far shown a potential efficiency in inducing protection in experimental models, but there is much to be done before vaccination can be an effective tool in malaria control. PMID:7043898

  19. Development of vaccines for Plasmodium vivax malaria.

    PubMed

    Mueller, Ivo; Shakri, Ahmad Rushdi; Chitnis, Chetan E

    2015-12-22

    Plasmodium vivax continues to cause significant morbidity outside Africa with more than 50% of malaria cases in many parts of South and South-east Asia, Pacific islands, Central and South America being attributed to P. vivax infections. The unique biology of P. vivax, including its ability to form latent hypnozoites that emerge months to years later to cause blood stage infections, early appearance of gametocytes before clinical symptoms are apparent and a shorter development cycle in the vector makes elimination of P. vivax using standard control tools difficult. The availability of an effective vaccine that provides protection and prevents transmission would be a valuable tool in efforts to eliminate P. vivax. Here, we review the latest developments related to P. vivax malaria vaccines and discuss the challenges as well as directions toward the goal of developing highly efficacious vaccines against P. vivax malaria.

  20. Perceptions of malaria and vaccines in Kenya.

    PubMed

    Ojakaa, David; Yamo, Emmanuel; Collymore, Yvette; Ba-Nguz, Antoinette; Bingham, Allison

    2011-10-01

    Malaria is a leading cause of morbidity and mortality in Kenya. To confront malaria, the Government of Kenya has been implementing and coordinating three approaches - vector control by distributing insecticide-treated bed nets and indoor residual spraying, case management, and the management of malaria during pregnancy. Immunization is recognized as one of the most cost-effective public health interventions. Efforts are underway to develop a malaria vaccine. The most advanced (RTS,S), is currently going through phase 3 trials. Although recent studies show the overwhelming support in the community for the introduction of a malaria vaccine, two issues - culture and the delivery of child immunization services - need to be considered. Alongside the modern methods of malaria control described above, traditional methods coexist and act as barriers to attainment of universal immunization. The gender dimension of the immunization programme (where women are the main child caretakers) will also need to be addressed. There is an age dimension to child immunization programmes. Two age cohorts of parents, caregivers, or family members deserve particular attention. These are the youth who are about to initiate childbearing, and the elderly (particularly mother-in-laws who often play a role in child-rearing). Mothers who are less privileged and socially disadvantaged need particular attention when it comes to child immunization. Access to immunization services is often characterized in some Kenyan rural communities in terms of living near the main road, or in the remote inaccessible areas. Should a malaria vaccine become available in the future, a strategy to integrate it into the immunization programme in Kenya should take into account at least two issues. First, it must address the fact that alongside the formal approach in malaria control, there exist the informal traditional practices among communities. Secondly, it must address particular issues in the delivery of

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

    PubMed

    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.

  2. Vaccine candidates for malaria: what's new?

    PubMed

    Takashima, Eizo; Morita, Masayuki; Tsuboi, Takafumi

    2016-01-01

    Although it is more than a decade since the parasite genome information was obtained, standardized novel genome-wide selection/prioritization strategies for candidacy of malaria vaccine antigens are still sought. In the quest to systematically identify candidates, it is impossible to overemphasize the usefulness of wheat germ cell-free technology in expressing quality proteins for the post-genome vaccine candidate discovery.

  3. Malaria vaccine offers hope. International / Africa.

    PubMed

    1995-04-01

    The World Health Organization (WHO) may soon sign an agreement with the Colombian government to build a plant in Colombia for the mass production of the malaria vaccine SPf66. SPf66 consists of a combination of synthetic peptides. It will eventually be available in Africa, where 90% of all recorded malaria cases occur each year. 1 million of the 1.5-3 million malaria-related deaths each year also occur in Africa. Many of these deaths take place in children. The indirect costs of malaria in Africa is expected to increase from $800 million to $1.8 billion between 1987 and the end of 1995. Based on findings from the various clinical trials in Colombia, Thailand, The Gambia, and Tanzania, WHO's director of Training in Tropical Diseases (TDR) claims that, if SPf66 can reduce the malaria incidence rate by 50% and thereby also the malaria-related death rate, the lives of 500,000 children in Africa would be spared. TDR will meet in mid-1996 to sort through all the SPf66 findings and then develop a policy for further development or production and use of SPf66. The price of each SPf66 vaccination should be around $5, comparable with the higher range of costs of other vaccines provided by WHO's Expanded Program of Immunization and UNICEF. At the 1992 WHO summit in Amsterdam, the president of the Congo called for the international community to join forces to eliminate malaria. When it was first tested on humans, in Colombia, the protection rate of SPf66 ranged from 22% to 77%, with the best results among the young and the very old. It has not caused any harmful side effects.

  4. Malaria vaccine based on self-assembling protein nanoparticles.

    PubMed

    Burkhard, Peter; Lanar, David E

    2015-01-01

    Despite recent progress with GSK's RTS,S malaria vaccine, there remains a desperate need for an efficient malaria vaccine. We have used a repetitive antigen display technology to display malaria specific B cell and T cell epitopes in an effort to design a vaccine against Plasmodium falciparum malaria. Our protein sequence when assembled into a nanoparticle induces strong, long-lived and protective immune responses against infection with the parasite. We are confident that the clinical trials with our most developed vaccine candidate will show good protection in a controlled human malaria infection trial.

  5. Particle-based platforms for malaria vaccines.

    PubMed

    Wu, Yimin; Narum, David L; Fleury, Sylvain; Jennings, Gary; Yadava, Anjali

    2015-12-22

    Recombinant subunit vaccines in general are poor immunogens likely due to the small size of peptides and proteins, combined with the lack or reduced presentation of repetitive motifs and missing complementary signal(s) for optimal triggering of the immune response. Therefore, recombinant subunit vaccines require enhancement by vaccine delivery vehicles in order to attain adequate protective immunity. Particle-based delivery platforms, including particulate antigens and particulate adjuvants, are promising delivery vehicles for modifying the way in which immunogens are presented to both the innate and adaptive immune systems. These particle delivery platforms can also co-deliver non-specific immunostimodulators as additional adjuvants. This paper reviews efforts and advances of the Particle-based delivery platforms in development of vaccines against malaria, a disease that claims over 600,000 lives per year, most of them are children under 5 years of age in sub-Sahara Africa.

  6. Malaria vaccines: identifying Plasmodium falciparum liver-stage targets.

    PubMed

    Longley, Rhea J; Hill, Adrian V S; Spencer, Alexandra J

    2015-01-01

    The development of a highly efficacious and durable vaccine for malaria remains a top priority for global health researchers. Despite the huge rise in recognition of malaria as a global health problem and the concurrent rise in funding over the past 10-15 years, malaria continues to remain a widespread burden. The evidence of increasing resistance to anti-malarial drugs and insecticides is a growing concern. Hence, an efficacious and durable preventative vaccine for malaria is urgently needed. Vaccines are one of the most cost-effective tools and have successfully been used in the prevention and control of many diseases, however, the development of a vaccine for the Plasmodium parasite has proved difficult. Given the early success of whole sporozoite mosquito-bite delivered vaccination strategies, we know that a vaccine for malaria is an achievable goal, with sub-unit vaccines holding great promise as they are simple and cheap to both manufacture and deploy. However a major difficulty in development of sub-unit vaccines lies within choosing the appropriate antigenic target from the 5000 or so genes expressed by the parasite. Given the liver-stage of malaria represents a bottle-neck in the parasite's life cycle, there is widespread agreement that a multi-component sub-unit malaria vaccine should preferably contain a liver-stage target. In this article we review progress in identifying and screening Plasmodium falciparum liver-stage targets for use in a malaria vaccine. PMID:26441899

  7. Cross-stage immunity for malaria vaccine development.

    PubMed

    Nahrendorf, Wiebke; Scholzen, Anja; Sauerwein, Robert W; Langhorne, Jean

    2015-12-22

    A vaccine against malaria is urgently needed for control and eventual eradication. Different approaches are pursued to induce either sterile immunity directed against pre-erythrocytic parasites or to mimic naturally acquired immunity by controlling blood-stage parasite densities and disease severity. Pre-erythrocytic and blood-stage malaria vaccines are often seen as opposing tactics, but it is likely that they have to be combined into a multi-stage malaria vaccine to be optimally safe and effective. Since many antigenic targets are shared between liver- and blood-stage parasites, malaria vaccines have the potential to elicit cross-stage protection with immune mechanisms against both stages complementing and enhancing each other. Here we discuss evidence from pre-erythrocytic and blood-stage subunit and whole parasite vaccination approaches that show that protection against malaria is not necessarily stage-specific. Parasites arresting at late liver-stages especially, can induce powerful blood-stage immunity, and similarly exposure to blood-stage parasites can afford pre-erythrocytic immunity. The incorporation of a blood-stage component into a multi-stage malaria vaccine would hence not only combat breakthrough infections in the blood should the pre-erythrocytic component fail to induce sterile protection, but would also actively enhance the pre-erythrocytic potency of this vaccine. We therefore advocate that future studies should concentrate on the identification of cross-stage protective malaria antigens, which can empower multi-stage malaria vaccine development.

  8. Overview of Plant-Made Vaccine Antigens against Malaria

    PubMed Central

    Clemente, Marina; Corigliano, Mariana G.

    2012-01-01

    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. PMID:22911156

  9. Malaria vaccine clinical trials: what’s on the horizon

    PubMed Central

    Moreno, Alberto; Joyner, Chester

    2015-01-01

    Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been made in the past few years with the completion of numerous clinical trials. Each trial has utilized a unique combination of antigens, delivery platforms, and adjuvants, and the data that has been obtained provides critical information that has poises the research community for the development of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P. vivax vaccine research requires more momentum and additional investigations to identify novel vaccine candidates. In this review, recently completed and ongoing malaria vaccine clinical trials as well as vaccine candidates that are in the development pipeline are reviewed. Perspectives for future research using post-genomic mining, nonhuman primate models, and systems biology are also discussed. PMID:26172291

  10. Large screen approaches to identify novel malaria vaccine candidates.

    PubMed

    Davies, D Huw; Duffy, Patrick; Bodmer, Jean-Luc; Felgner, Philip L; Doolan, Denise L

    2015-12-22

    Until recently, malaria vaccine development efforts have focused almost exclusively on a handful of well characterized Plasmodium falciparum antigens. Despite dedicated work by many researchers on different continents spanning more than half a century, a successful malaria vaccine remains elusive. Sequencing of the P. falciparum genome has revealed more than five thousand genes, providing the foundation for systematic approaches to discover candidate vaccine antigens. We are taking advantage of this wealth of information to discover new antigens that may be more effective vaccine targets. Herein, we describe different approaches to large-scale screening of the P. falciparum genome to identify targets of either antibody responses or T cell responses using human specimens collected in Controlled Human Malaria Infections (CHMI) or under conditions of natural exposure in the field. These genome, proteome and transcriptome based approaches offer enormous potential for the development of an efficacious malaria vaccine. PMID:26428458

  11. Strain Selection for Generation of O-Antigen-Based Glycoconjugate Vaccines against Invasive Nontyphoidal Salmonella Disease

    PubMed Central

    Saul, Allan; MacLennan, Calman A.; Micoli, Francesca; Rondini, Simona

    2015-01-01

    Nontyphoidal Salmonellae, principally S. Typhimurium and S. Enteritidis, are a major cause of invasive bloodstream infections in sub-Saharan Africa with no vaccine currently available. Conjugation of lipopolysaccharide O-antigen to a carrier protein constitutes a promising vaccination strategy. Here we describe a rational process to select the most appropriate isolates of Salmonella as source of O-antigen for developing a bivalent glycoconjugate vaccine. We screened a library of 30 S. Typhimurium and 21 S. Enteritidis in order to identify the most suitable strains for large scale O-antigen production and generation of conjugate vaccines. Initial screening was based on growth characteristics, safety profile of the isolates, O-antigen production, and O-antigen characteristics in terms of molecular size, O-acetylation and glucosylation level and position, as determined by phenol sulfuric assay, NMR, HPLC-SEC and HPAEC-PAD. Three animal isolates for each serovar were identified and used to synthesize candidate glycoconjugate vaccines, using CRM197 as carrier protein. The immunogenicity of these conjugates and the functional activity of the induced antibodies was investigated by ELISA, serum bactericidal assay and flow cytometry. S. Typhimurium O-antigen showed high structural diversity, including O-acetylation of rhamnose in a Malawian invasive strain generating a specific immunodominant epitope. S. Typhimurium conjugates provoked an anti-O-antigen response primarily against the O:5 determinant. O-antigen from S. Enteritidis was structurally more homogeneous than from S. Typhimurium, and no idiosyncratic antibody responses were detected for the S. Enteritidis conjugates. Of the three initially selected isolates, two S. Typhimurium (1418 and 2189) and two S. Enteritidis (502 and 618) strains generated glycoconjugates able to induce high specific antibody levels with high breadth of serovar-specific strain coverage, and were selected for use in vaccine production. The

  12. Strain Selection for Generation of O-Antigen-Based Glycoconjugate Vaccines against Invasive Nontyphoidal Salmonella Disease.

    PubMed

    Lanzilao, Luisa; Stefanetti, Giuseppe; Saul, Allan; MacLennan, Calman A; Micoli, Francesca; Rondini, Simona

    2015-01-01

    Nontyphoidal Salmonellae, principally S. Typhimurium and S. Enteritidis, are a major cause of invasive bloodstream infections in sub-Saharan Africa with no vaccine currently available. Conjugation of lipopolysaccharide O-antigen to a carrier protein constitutes a promising vaccination strategy. Here we describe a rational process to select the most appropriate isolates of Salmonella as source of O-antigen for developing a bivalent glycoconjugate vaccine. We screened a library of 30 S. Typhimurium and 21 S. Enteritidis in order to identify the most suitable strains for large scale O-antigen production and generation of conjugate vaccines. Initial screening was based on growth characteristics, safety profile of the isolates, O-antigen production, and O-antigen characteristics in terms of molecular size, O-acetylation and glucosylation level and position, as determined by phenol sulfuric assay, NMR, HPLC-SEC and HPAEC-PAD. Three animal isolates for each serovar were identified and used to synthesize candidate glycoconjugate vaccines, using CRM197 as carrier protein. The immunogenicity of these conjugates and the functional activity of the induced antibodies was investigated by ELISA, serum bactericidal assay and flow cytometry. S. Typhimurium O-antigen showed high structural diversity, including O-acetylation of rhamnose in a Malawian invasive strain generating a specific immunodominant epitope. S. Typhimurium conjugates provoked an anti-O-antigen response primarily against the O:5 determinant. O-antigen from S. Enteritidis was structurally more homogeneous than from S. Typhimurium, and no idiosyncratic antibody responses were detected for the S. Enteritidis conjugates. Of the three initially selected isolates, two S. Typhimurium (1418 and 2189) and two S. Enteritidis (502 and 618) strains generated glycoconjugates able to induce high specific antibody levels with high breadth of serovar-specific strain coverage, and were selected for use in vaccine production. The

  13. Workshop report: Malaria vaccine development in Europe--preparing for the future.

    PubMed

    Viebig, Nicola K; D'Alessio, Flavia; Draper, Simon J; Sim, B Kim Lee; Mordmüller, Benjamin; Bowyer, Paul W; Luty, Adrian J F; Jungbluth, Stefan; Chitnis, Chetan E; Hill, Adrian V S; Kremsner, Peter; Craig, Alister G; Kocken, Clemens H M; Leroy, Odile

    2015-11-17

    The deployment of a safe and effective malaria vaccine will be an important tool for the control of malaria and the reduction in malaria deaths. With the launch of the 2030 Malaria Vaccine Technology Roadmap, the malaria community has updated the goals and priorities for the development of such a vaccine and is now paving the way for a second phase of malaria vaccine development. During a workshop in Brussels in November 2014, hosted by the European Vaccine Initiative, key players from the European, North American and African malaria vaccine community discussed European strategies for future malaria vaccine development in the global context. The recommendations of the European malaria community should guide researchers, policy makers and funders of global health research and development in fulfilling the ambitious goals set in the updated Malaria Vaccine Technology Roadmap.

  14. The Use of Synthetic Carriers in Malaria Vaccine Design.

    PubMed

    Powles, Liam; Xiang, Sue D; Selomulya, Cordelia; Plebanski, Magdalena

    2015-01-01

    Malaria vaccine research has been ongoing since the 1980s with limited success. However, recent improvements in our understanding of the immune responses required to combat each stage of infection will allow for intelligent design of both antigens and their associated delivery vaccine vehicles/vectors. Synthetic carriers (also known as vectors) are usually particulate and have multiple properties, which can be varied to control how an associated vaccine interacts with the host, and consequently how the immune response develops. This review comprehensively analyzes both historical and recent studies in which synthetic carriers are used to deliver malaria vaccines. Furthermore, the requirements for a synthetic carrier, such as size, charge, and surface chemistry are reviewed in order to understand the design of effective particle-based vaccines against malaria, as well as providing general insights. Synthetic carriers have the ability to alter and direct the immune response, and a better control of particle properties will facilitate improved vaccine design in the near future.

  15. A vaccine against human malaria--an utopia?

    PubMed

    Peltola, H

    1982-12-01

    At the beginning of the 1980s, the future of the malaria vaccines looks bright; in recent years a number of basic problems have been solved. Among the major landmarks have been the discovery of a suitable animal model for human malaria infections; the technique of culturing Plasmodium falciparum; the findings that sporozoites, merozoites and gametocytes, or possibly antigens characterized with the hybridoma technique, can be used as vaccine antigens at least in animals; and that excellent protection from fatal disease is obtainable in owl monkeys by using the merozoite vaccine with a suitable adjuvant. Many questions remain still unanswered. The foremost, of course, is whether the vaccine(s) is efficient in humans. Other major problems still existing are identification, characterization and purification of the protective antigen(s) of human malarias, assessment of the clinical effects of the vaccines produced, new methods for the mass production of the antigens, and studies on duration of the clinical protection.

  16. Stability Characterization of a Vaccine Antigen Based on the Respiratory Syncytial Virus Fusion Glycoprotein

    PubMed Central

    Flynn, Jessica A.; Durr, Eberhard; Swoyer, Ryan; Cejas, Pedro J.; Horton, Melanie S.; Galli, Jennifer D.; Cosmi, Scott A.; Espeseth, Amy S.; Bett, Andrew J.; Zhang, Lan

    2016-01-01

    Infection with Respiratory Syncytial Virus (RSV) causes both upper and lower respiratory tract disease in humans, leading to significant morbidity and mortality in both young children and older adults. Currently, there is no licensed vaccine available, and therapeutic options are limited. During the infection process, the type I viral fusion (F) glycoprotein on the surface of the RSV particle rearranges from a metastable prefusion conformation to a highly stable postfusion form. In people naturally infected with RSV, most potent neutralizing antibodies are directed to the prefusion form of the F protein. Therefore, an engineered RSV F protein stabilized in the prefusion conformation (DS-Cav1) is an attractive vaccine candidate. Long-term stability at 4°C or higher is a desirable attribute for a commercial subunit vaccine antigen. To assess the stability of DS-Cav1, we developed assays using D25, an antibody which recognizes the prefusion F-specific antigenic site Ø, and a novel antibody 4D7, which was found to bind antigenic site I on the postfusion form of RSV F. Biophysical analysis indicated that, upon long-term storage at 4°C, DS-Cav1 undergoes a conformational change, adopting alternate structures that concomitantly lose the site Ø epitope and gain the ability to bind 4D7. PMID:27764150

  17. Malaria Vaccine: A Future Hope to Curtail the Global Malaria Burden

    PubMed Central

    Karunamoorthi, Kaliyaperumal

    2014-01-01

    It has been estimated that nearly half of the world's population is at the risk of contracting malaria with sub Saharan Africa being the most risky area. The existing frontline malaria control interventions are not only expensive but also become ineffective owing to the emergence of insecticide and drug resistance. It calls for an innovative approach in terms of potential and reliable vaccine as an additional tool. Over centuries, the public health experts have been actively engaged to formulate a safe, affordable and potential malaria vaccine and accordingly a notable achievement has also been attained. However, many challenges are required to be flagged immediately and effectively to devise an ideal prophylactic malaria vaccine. Therefore, the global community has to remain waiting quite a few more years to build a wannabe malaria-free world in the near future. PMID:24932383

  18. Progress and prospects for blood-stage malaria vaccines

    PubMed Central

    Miura, Kazutoyo

    2016-01-01

    ABSTRACT There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part. PMID:26760062

  19. Recent advances in recombinant protein-based malaria vaccines.

    PubMed

    Draper, Simon J; Angov, Evelina; Horii, Toshihiro; Miller, Louis H; Srinivasan, Prakash; Theisen, Michael; Biswas, Sumi

    2015-12-22

    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 to target antigen discovery, protein expression platforms, adjuvant testing, and development of soluble and virus-like particle (VLP) delivery platforms. The breadth of approaches to protein-based vaccines is continuing to expand as innovative new concepts in next-generation subunit design are explored, 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-, merozoite- and sexual-stages of the parasite's lifecycle-including PfCelTOS, PfMSP1, PfAMA1, PfRH5, PfSERA5, PfGLURP, PfMSP3, Pfs48/45 and Pfs25. Future prospects and challenges for the development, production, human delivery and assessment of protein-based malaria vaccines are discussed.

  20. Recent advances in recombinant protein-based malaria vaccines

    PubMed Central

    Draper, Simon J.; Angov, Evelina; Horii, Toshihiro; Miller, Louis H.; Srinivasan, Prakash; Theisen, Michael; Biswas, Sumi

    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 to target antigen discovery, protein expression platforms, adjuvant testing, and development of soluble and virus-like particle (VLP) delivery platforms. The breadth of approaches to protein-based vaccines is continuing to expand as innovative new concepts in next-generation subunit design are explored, 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-, merozoite- and sexual-stages of the parasite's lifecycle–including PfCelTOS, PfMSP1, PfAMA1, PfRH5, PfSERA5, PfGLURP, PfMSP3, Pfs48/45 and Pfs25. Future prospects and challenges for the development, production, human delivery and assessment of protein-based malaria vaccines are discussed. PMID:26458807

  1. Extreme Polymorphism in a Vaccine Antigen and Risk of Clinical Malaria: Implications for Vaccine Development

    PubMed Central

    Takala, Shannon L.; Coulibaly, Drissa; Thera, Mahamadou A.; Batchelor, Adrian H.; Cummings, Michael P.; Escalante, Ananias A.; Ouattara, Amed; Traoré, Karim; Niangaly, Amadou; Djimdé, Abdoulaye A.; Doumbo, Ogobara K.; Plowe, Christopher V.

    2010-01-01

    Vaccines directed against the blood stages of Plasmodium falciparum malaria are intended to prevent the parasite from invading and replicating within host cells. No blood-stage malaria vaccine has shown clinical efficacy in humans. Most malaria vaccine antigens are parasite surface proteins that have evolved extensive genetic diversity, and this diversity could allow malaria parasites to escape vaccine-induced immunity. We examined the extent and within-host dynamics of genetic diversity in the blood-stage malaria vaccine antigen apical membrane antigen–1 in a longitudinal study in Mali. Two hundred and fourteen unique apical membrane antigen–1 haplotypes were identified among 506 human infections, and amino acid changes near a putative invasion machinery binding site were strongly associated with the development of clinical symptoms, suggesting that these residues may be important to consider in designing polyvalent apical membrane antigen–1 vaccines and in assessing vaccine efficacy in field trials. This extreme diversity may pose a serious obstacle to an effective polyvalent recombinant subunit apical membrane antigen–1 vaccine. PMID:20165550

  2. Malaria invasion ligand RH5 and its prime candidacy in blood-stage malaria vaccine design

    PubMed Central

    Ord, Rosalynn L; Rodriguez, Marilis; Lobo, Cheryl A

    2015-01-01

    With drug resistance to available therapeutics continuing to develop against Plasmodium falciparum malaria, the development of an effective vaccine candidate remains a major research goal. Successful interruption of invasion of parasites into erythrocytes during the blood stage of infection will prevent the severe clinical symptoms and complications associated with malaria. Previously studied blood stage antigens have highlighted the hurdles that are inherent to this life-cycle stage, namely that highly immunogenic antigens are also globally diverse, resulting in protection only against the vaccine strain, or that naturally acquired immunity to blood stage antigens do not always correlate with actual protection. The blood stage antigen reticulocyte binding homolog RH5 is essential for parasite viability, has globally limited diversity, and is associated with protection from disease. Here we summarize available information on this invasion ligand and recent findings that highlight its candidacy for inclusion in a blood-stage malaria vaccine. PMID:25844685

  3. Clinical development of malaria vaccines: should earlier trials be done in malaria endemic countries?

    PubMed

    Chilengi, Roma

    2009-09-01

    Clinical development of malaria vaccines has had remarkable achievements in the past decade, but an efficacious vaccine is yet to be licensed. There are many scientific and technical challenges that hamper progress ranging from parasite to host to technical and to mere traditional convention factors. This paper outlines some of the key issues along the pathway and proposes the need for much earlier phase clinical research within Africa suggesting rationale and ethical justification for doing so. Challenge model studies could particularly be employed within malaria endemic country settings which may have critical advantages to complement the currently available sites in developed countries. PMID:19617708

  4. Transmission blocking malaria vaccines: Assays and candidates in clinical development.

    PubMed

    Sauerwein, R W; Bousema, T

    2015-12-22

    Stimulated by recent advances in malaria control and increased funding, the elimination of malaria is now considered to be an attainable goal for an increasing number of malaria-endemic regions. This has boosted the interest in transmission-reducing interventions including vaccines that target sexual, sporogenic, and/or mosquito-stage antigens to interrupt malaria transmission (SSM-VIMT). SSM-VIMT aim to prevent human malaria infection in vaccinated communities by inhibiting parasite development within the mosquito after a blood meal taken from a gametocyte carrier. Only a handful of target antigens are in clinical development and progress has been slow over the years. Major stumbling blocks include (i) the expression of appropriately folded target proteins and their downstream purification, (ii) insufficient induction of sustained functional blocking antibody titers by candidate vaccines in humans, and (iii) validation of a number of (bio)-assays as correlate for blocking activity in the field. Here we discuss clinical manufacturing and testing of current SSM-VIMT candidates and the latest bio-assay development for clinical evaluation. New testing strategies are discussed that may accelerate the evaluation and application of SSM-VIMT.

  5. The Use of Synthetic Carriers in Malaria Vaccine Design

    PubMed Central

    Powles, Liam; Xiang, Sue D.; Selomulya, Cordelia; Plebanski, Magdalena

    2015-01-01

    Malaria vaccine research has been ongoing since the 1980s with limited success. However, recent improvements in our understanding of the immune responses required to combat each stage of infection will allow for intelligent design of both antigens and their associated delivery vaccine vehicles/vectors. Synthetic carriers (also known as vectors) are usually particulate and have multiple properties, which can be varied to control how an associated vaccine interacts with the host, and consequently how the immune response develops. This review comprehensively analyzes both historical and recent studies in which synthetic carriers are used to deliver malaria vaccines. Furthermore, the requirements for a synthetic carrier, such as size, charge, and surface chemistry are reviewed in order to understand the design of effective particle-based vaccines against malaria, as well as providing general insights. Synthetic carriers have the ability to alter and direct the immune response, and a better control of particle properties will facilitate improved vaccine design in the near future. PMID:26529028

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

    PubMed Central

    2010-01-01

    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 distribution issues

  7. Paths to a malaria vaccine illuminated by parasite genomics

    PubMed Central

    Conway, David J.

    2015-01-01

    More human death and disease is caused by malaria parasites than by all other eukaryotic pathogens combined. As early as the sequencing of the first human genome, malaria parasite genomics was prioritized to fuel the discovery of vaccine candidate antigens. This stimulated increased research on malaria, generating new understanding of the cellular and molecular mechanisms of infection and immunity. This review of recent developments illustrates how new approaches in parasite genomics, and increasingly large amounts of data from population studies, are helping to identify antigens that are promising lead targets. Although these results have been encouraging, effective discovery and characterization need to be coupled with more innovation and funding to translate findings into newly designed vaccine products for clinical trials. PMID:25620796

  8. Development of vaccines to prevent malaria in pregnant women: WHO MALVAC meeting report.

    PubMed

    Menéndez, Clara; Moorthy, Vasee S; Reed, Zarifah; Bardají, Azucena; Alonso, Pedro; Brown, Graham V

    2011-09-01

    The major public health consequences of malaria in pregnancy have long been acknowledged. However, further information is still required for development and implementation of a malaria vaccine specifically directed to prevent malaria in pregnant women and improve maternal, fetal and infant outcomes. The WHO Malaria Vaccine Advisory Committee (MALVAC) provides guidance to the WHO on strategic priorities and research needs for development of vaccines to prevent malaria. Here we summarize the discussions and conclusions of a MALVAC scientific forum meeting on considerations in the development of vaccines to prevent malaria in pregnant women. This report includes brief summaries of what is known, and major knowledge gaps in disease burden estimation, pathogenesis and immunity, and the challenges with current preventive strategies for malaria in pregnancy. We conclude with the formulation of a conceptual framework for research and development for vaccines to prevent malaria in pregnant women.

  9. Malaria.

    PubMed

    Garcia, Lynne S

    2010-03-01

    Malaria has had a greater impact on world history than any other infectious disease. More than 300 to 500 million individuals worldwide are infected with Plasmodium spp, and 1.5 to 2.7 million people a year, most of whom are children, die from the infection. Malaria is endemic in over 90 countries in which 2400 million people live; this represents 40% of the world's population. Approximately 90% of malaria deaths occur in Africa. Despite continuing efforts in vaccine development, malaria prevention is difficult, and no drug is universally effective. This article examines malaria caused by the 4 most common Plasmodium spp that infect humans, P vivax, P ovale, P malariae, and P falciparum, as well as mixed infections and the simian parasite P knowlesi. A comprehensive review of the microbiology, clinical presentation, pathogenesis, diagnosis, and treatment of these forms of malaria is given.

  10. A Novel Malaria Vaccine Candidate Antigen Expressed in Tetrahymena thermophila

    PubMed Central

    Eleni-Muus, Janna; Aldag, Ingo; Samuel, Kay; Creasey, Alison M.; Hartmann, Marcus W. W.; Cavanagh, David R.

    2014-01-01

    Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens. PMID:24489871

  11. Steps toward a globally available malaria vaccine: harnessing the potential of algae for future low cost vaccines.

    PubMed

    Jones, Carla S; Mayfield, Stephen P

    2013-01-01

    Malaria is an infectious disease that threatens half of the world's population. This debilitating disease is caused by infection from parasites of the genus Plasmodium. Insecticides, bed nets and drug therapies have lowered the prevalence and death rate associated with malaria but this disease continues to plague many populations around the world. In recent years, many organizations have suggested developing methods for a complete eradication of malaria. The most straightforward and effective method for this potential eradication will be through the development of a low-cost vaccine. To achieve eradication, it will be necessary to develop new vaccine candidates and novel systems for both the production and delivery of these vaccines. Recently, the green algae Chlamydomonas reinhardtii has been used for the recombinant expression of malaria vaccine candidates including the transmission blocking vaccine candidate Pfs48/45. Here, we discuss the potential of this research on the future development of a low-cost malaria vaccine candidate.

  12. Steps toward a globally available malaria vaccine: harnessing the potential of algae for future low cost vaccines.

    PubMed

    Jones, Carla S; Mayfield, Stephen P

    2013-01-01

    Malaria is an infectious disease that threatens half of the world's population. This debilitating disease is caused by infection from parasites of the genus Plasmodium. Insecticides, bed nets and drug therapies have lowered the prevalence and death rate associated with malaria but this disease continues to plague many populations around the world. In recent years, many organizations have suggested developing methods for a complete eradication of malaria. The most straightforward and effective method for this potential eradication will be through the development of a low-cost vaccine. To achieve eradication, it will be necessary to develop new vaccine candidates and novel systems for both the production and delivery of these vaccines. Recently, the green algae Chlamydomonas reinhardtii has been used for the recombinant expression of malaria vaccine candidates including the transmission blocking vaccine candidate Pfs48/45. Here, we discuss the potential of this research on the future development of a low-cost malaria vaccine candidate. PMID:23090388

  13. Malaria Vaccine Development and How External Forces Shape It: An Overview

    PubMed Central

    Lorenz, Veronique; Karanis, Gabriele; Karanis, Panagiotis

    2014-01-01

    The aim of this paper is to analyse the current status and scientific value of malaria vaccine approaches and to provide a realistic prognosis for future developments. We systematically review previous approaches to malaria vaccination, address how vaccine efforts have developed, how this issue may be fixed, and how external forces shape vaccine development. Our analysis provides significant information on the various aspects and on the external factors that shape malaria vaccine development and reveal the importance of vaccine development in our society. PMID:24983392

  14. Novel approaches to whole sporozoite vaccination against malaria.

    PubMed

    Bijker, Else M; Borrmann, Steffen; Kappe, Stefan H; Mordmüller, Benjamin; Sack, Brandon K; Khan, Shahid M

    2015-12-22

    The parasitic disease malaria threatens more than 3 billion people worldwide, resulting in more than 200 million clinical cases and almost 600,000 deaths annually. Vaccines remain crucial for prevention and ultimately eradication of infectious diseases and, for malaria, whole sporozoite based immunization has been shown to be the most effective in experimental settings. In addition to immunization with radiation-attenuated sporozoites, chemoprophylaxis and sporozoites (CPS) is a highly efficient strategy to induce sterile protection in humans. Genetically attenuated parasites (GAP) have demonstrated significant protection in rodent studies, and are now being advanced into clinical testing. This review describes the existing pre-clinical and clinical data on CPS and GAP, discusses recent developments and examines how to transform these immunization approaches into vaccine candidates for clinical development.

  15. Experimental models in vaccine research: malaria and leishmaniasis.

    PubMed

    Teixeira, C; Gomes, R

    2013-02-01

    Animal models have a long history of being useful tools, not only to test and select vaccines, but also to help understand the elaborate details of the immune response that follows infection. Different models have been extensively used to investigate putative immunological correlates of protection against parasitic diseases that are important to reach a successful vaccine. The greatest challenge has been the improvement and adaptation of these models to reflect the reality of human disease and the screening of vaccine candidates capable of overcoming the challenge of natural transmission. This review will discuss the advantages and challenges of using experimental animal models for vaccine development and how the knowledge achieved can be extrapolated to human disease by looking into two important parasitic diseases: malaria and leishmaniasis.

  16. A malaria vaccine for travelers and military personnel: Requirements and top candidates.

    PubMed

    Teneza-Mora, Nimfa; Lumsden, Joanne; Villasante, Eileen

    2015-12-22

    Malaria remains an important health threat to non-immune travelers with the explosive growth of global travel. Populations at high risk of acquiring malaria infections include once semi-immune travelers who visit friends and relatives, military forces, business travelers and international tourists with destinations to sub-Saharan Africa, where malaria transmission intensity is high. Most malaria cases have been associated with poor compliance with existing preventive measures, including chemoprophylaxis. High risk groups would benefit immensely from an efficacious vaccine to protect them against malaria infection and together make up a sizable market for such a vaccine. The attributes of an ideal malaria vaccine for non-immune travelers and military personnel include a protective efficacy of 80% or greater, durability for at least 6 months, an acceptable safety profile and compatibility with existing preventive measures. It is very likely that a malaria vaccine designed to effectively prevent infection and clinical disease in the non-immune traveler and military personnel will also protect semi-immune residents of malaria-endemic areas and contribute to malaria elimination by reducing or blocking malaria transmission. The RTS,S vaccine (GlaxoSmithKline) and the PfSPZ Vaccine (Sanaria Inc) are the leading products that would make excellent vaccine candidates for these vulnerable populations.

  17. Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model

    PubMed Central

    Dunachie, Susanna; Berthoud, Tamara; Hill, Adrian V.S.; Fletcher, Helen A.

    2015-01-01

    Introduction The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. Methods We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. Results Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. Conclusions These results represent novel insights into the immune repertoires involved in malaria vaccination. PMID:26256523

  18. Malaria transmission blocking immunity and sexual stage vaccines for interrupting malaria transmission in Latin America.

    PubMed

    Arévalo-Herrera, Myriam; Solarte, Yezid; Marin, Catherin; Santos, Mariana; Castellanos, Jenniffer; Beier, John C; Valencia, Sócrates Herrera

    2011-08-01

    Malaria is a vector-borne disease that is considered to be one of the most serious public health problems due to its high global mortality and morbidity rates. Although multiple strategies for controlling malaria have been used, many have had limited impact due to the appearance and rapid dissemination of mosquito resistance to insecticides, parasite resistance to multiple antimalarial drug, and the lack of sustainability. Individuals in endemic areas that have been permanently exposed to the parasite develop specific immune responses capable of diminishing parasite burden and the clinical manifestations of the disease, including blocking of parasite transmission to the mosquito vector. This is referred to as transmission blocking (TB) immunity (TBI) and is mediated by specific antibodies and other factors ingested during the blood meal that inhibit parasite development in the mosquito. These antibodies recognize proteins expressed on either gametocytes or parasite stages that develop in the mosquito midgut and are considered to be potential malaria vaccine candidates. Although these candidates, collectively called TB vaccines (TBV), would not directly stop malaria from infecting individuals, but would stop transmission from infected person to non-infected person. Here, we review the progress that has been achieved in TBI studies and the development of TBV and we highlight their potential usefulness in areas of low endemicity such as Latin America. PMID:21881775

  19. Malaria transmission blocking immunity and sexual stage vaccines for interrupting malaria transmission in Latin America

    PubMed Central

    Arévalo-Herrera, Myriam; Solarte, Yezid; Marin, Catherin; Santos, Mariana; Castellanos, Jenniffer; Beier, John C; Valencia, Sócrates Herrera

    2016-01-01

    Malaria is a vector-borne disease that is considered to be one of the most serious public health problems due to its high global mortality and morbidity rates. Although multiple strategies for controlling malaria have been used, many have had limited impact due to the appearance and rapid dissemination of mosquito resistance to insecticides, parasite resistance to multiple antimalarial drug, and the lack of sustainability. Individuals in endemic areas that have been permanently exposed to the parasite develop specific immune responses capable of diminishing parasite burden and the clinical manifestations of the disease, including blocking of parasite transmission to the mosquito vector. This is referred to as transmission blocking (TB) immunity (TBI) and is mediated by specific antibodies and other factors ingested during the blood meal that inhibit parasite development in the mosquito. These antibodies recognize proteins expressed on either gametocytes or parasite stages that develop in the mosquito midgut and are considered to be potential malaria vaccine candidates. Although these candidates, collectively called TB vaccines (TBV), would not directly stop malaria from infecting individuals, but would stop transmission from infected person to non-infected person. Here, we review the progress that has been achieved in TBI studies and the development of TBV and we highlight their potential usefulness in areas of low endemicity such as Latin America. PMID:21881775

  20. Vaccination with SPf66, a chemically synthesised vaccine, against Plasmodium falciparum malaria in Colombia.

    PubMed

    Valero, M V; Amador, L R; Galindo, C; Figueroa, J; Bello, M S; Murillo, L A; Mora, A L; Patarroyo, G; Rocha, C L; Rojas, M

    1993-03-20

    Preclinical and clinical studies have established the safety and immunogenicity of the chemically synthesised SPf66 malaria vaccine. The present study is a phase III randomised, double-blind, placebo-controlled, efficacy trial completed in La Tola, Colombia. 1548 volunteers over one year of age received three doses of either the vaccine (n = 738) or placebo (n = 810). Active and passive case detection methods were used to document clinical episodes of malaria among the study population. The follow-up period began one month after the third dose and lasted for one year. 168 and 297 episodes of Plasmodium falciparum malaria were documented in the SPf66 group and the placebo group, respectively; this corresponds to a crude protective efficacy of 38.8%. Incidence rates for first or only P falciparum malarial episodes were 22.3% per annum among the vaccinee group and 33.5% among the placebo group (RR = 1.5; 95% Cl 1.23, 1.84). Therefore, the protective efficacy of SPf66 against first or only episodes was 33.6% (95% Cl 18.8, 45.7), being highest in children aged 1-4 years (77%) and adults older than 45 years (67%). The estimated protective efficacy against second episodes was 50.5% (95% Cl 12.9-71.9). Our study shows that the chemically synthesised SPf66 malaria vaccine is safe, immunogenic, and protective against P falciparum malaria in semi-immune populations subject to natural challenge.

  1. Community perceptions of a malaria vaccine in the Kintampo districts of Ghana

    PubMed Central

    2013-01-01

    Background Malaria remains the leading cause of morbidity and mortality in sub-Saharan Africa despite tools currently available for its control. Making malaria vaccine available for routine use will be a major hallmark, but its acceptance by community members and health professionals within the health system could pose considerable challenge as has been found with the introduction of polio vaccinations in parts of West Africa. Some of these challenges may not be expected since decisions people make are many a time driven by a complex myriad of perceptions. This paper reports knowledge and perceptions of community members in the Kintampo area of Ghana where malaria vaccine trials have been ongoing as part of the drive for the first-ever licensed malaria vaccine in the near future. Methods Both qualitative and quantitative methods were used in the data collection processes. Women and men whose children were or were not involved in the malaria vaccine trial were invited to participate in focus group discussions (FGDs). Respondents, made up of heads of religious groupings in the study area, health care providers, traditional healers and traditional birth attendants, were also invited to participate in in-depth interviews (IDIs). A cross-sectional survey was conducted in communities where the malaria vaccine trial (Mal 047RTS,S) was carried out. In total, 12 FGDs, 15 IDIs and 466 household head interviews were conducted. Results Knowledge about vaccines was widespread among participants. Respondents would like their children to be vaccinated against all childhood illnesses including malaria. Knowledge of the long existing routine vaccines was relatively high among respondents compared to hepatitis B and Haemophilus influenza type B vaccines that were introduced more recently in 2002. There was no clear religious belief or sociocultural practice that will serve as a possible barrier to the acceptance of a malaria vaccine. Conclusion With the assumption that a malaria

  2. High-Density Peptide Arrays for Malaria Vaccine Development.

    PubMed

    Loeffler, Felix F; Pfeil, Johannes; Heiss, Kirsten

    2016-01-01

    The development of an efficacious and practicable vaccine conferring sterile immunity towards a Plasmodium infection represents a not yet achieved goal. A crucial factor for the impact of a given anti-plasmodial subunit vaccine is the identification of the most potent parasitic components required to induce protection from both infection and disease. Here, we present a method based on a novel high-density peptide array technology that allows for a flexible readout of malaria antibodies. Peptide arrays applied as a screening method can be used to identify novel immunogenic antibody epitopes under a large number of potential antigens/peptides. Ultimately, discovered antigen candidates and/or epitope sequences can be translated into vaccine prototype design. The technology can be further utilized to unravel antibody-mediated immune responses (e.g., involved in the establishment of semi-immunity) and moreover to confirm vaccine potency during the process of clinical development by verifying the induced antibody responses following vaccination. PMID:27076154

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

    MedlinePlus

    ... Malaria > Research Malaria Understanding Research NIAID Role Basic Biology Prevention and Control Strategies Strategic Partnerships and Research ... the malaria parasite. Related Links Global Research​ Vector Biology International Centers of Excellence for Malaria Research (ICEMR) ...

  4. Unexpected fold in the circumsporozoite protein target of malaria vaccines

    SciTech Connect

    Doud, Michael B.; Koksal, Adem C.; Mi, Li-Zhi; Song, Gaojie; Lu, Chafen; Springer, Timothy A.

    2012-10-09

    Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an '{alpha}TSR' domain. The {alpha}TSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but {alpha}TSR does not. Interestingly, polymorphic T-cell epitopes map to specialized {alpha}TSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket.

  5. Clinical development of placental malaria vaccines and immunoassays harmonization: a workshop report.

    PubMed

    Chêne, Arnaud; Houard, Sophie; Nielsen, Morten A; Hundt, Sophia; D'Alessio, Flavia; Sirima, Sodiomon B; Luty, Adrian J F; Duffy, Patrick; Leroy, Odile; Gamain, Benoit; Viebig, Nicola K

    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 with a goal to define standards that will allow comparative assessment of different placental malaria vaccine candidates. The recommendations of these workshops should guide researchers and clinicians in the further development of placental malaria vaccines. PMID:27639691

  6. Synergistic and antagonistic interactions between bednets and vaccines in the control of malaria

    PubMed Central

    Artzy-Randrup, Yael; Dobson, Andrew P.; Pascual, Mercedes

    2015-01-01

    It is extremely likely that the malaria vaccines currently in development will be used in conjunction with treated bednets and other forms of malaria control. The interaction of different intervention methods is at present poorly understood in a disease such as malaria where immunity is more complex than for other pathogens that have been successfully controlled by vaccination. Here we develop a general mathematical model of malaria transmission to examine the interaction between vaccination and bednets. Counterintuitively, we find that the frailty of malaria immunity will potentially cause both synergistic and antagonistic interactions between vaccination and the use of bednets. We explore the conditions that create these tensions, and outline strategies that minimize their detrimental impact. Our analysis specifically considers the three leading vaccine classes currently in development: preerythrocytic (PEV), blood stage (BSV), and transmission blocking (TBV). We find that the combination of BSV with treated bednets can lead to increased morbidity with no added value in terms of elimination; the interaction is clearly antagonistic. In contrast, there is strong synergy between PEV and treated bednets that may facilitate elimination, although transient stages are likely to increase morbidity. The combination of TBV with treated bednets is synergistic, lowering both morbidity and elimination thresholds. Our results suggest that vaccines will not provide a straightforward solution to malaria control, and that future programs need to consider the synergistic and antagonistic interactions between vaccines and treated bednets. PMID:25605894

  7. Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research

    PubMed Central

    Mata, Elena; Salvador, Aiala; Igartua, Manoli; Hernández, Rosa María; Pedraz, José Luis

    2013-01-01

    There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages. PMID:23710439

  8. Malaria vaccines: using models of immunity and functional genomics tools to accelerate the development of vaccines against Plasmodium falciparum.

    PubMed

    Duffy, Patrick E; Krzych, Urszula; Francis, Susan; Fried, Michal

    2005-03-18

    Naturally acquired immunity and immunity acquired after immunization with attenuated parasites indicate that a vaccine against malaria is feasible. Several obstacles have stymied malaria vaccine development, among them our poor understanding of protective immunity and technical difficulties for studying gene and protein expression in the Plasmodium falciparum parasite. Pregnancy malaria offers a model approach for vaccine development: recent findings have elucidated the basis for disease pathogenesis and protective immunity in this syndrome, and this understanding has focused the effort to identify the optimal antigens for a pregnancy malaria vaccine. In parallel, functional genomics tools are overcoming several of the obstacles for studying protein expression in the malaria parasite, vastly accelerating the pace for antigen discovery. Together, these conceptual and technological advances allow a rational approach to vaccine antigen selection, in which a finite number of antigens are selected from the entire genome by merit of the expression patterns and specific features. These candidate antigens are then subjected to detailed studies according to criteria established by the understanding of pathogenesis and protective immunity, to identify the optimal antigens for inclusion in subunit vaccines.

  9. Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data

    PubMed Central

    Bejon, Philip; White, Michael T; Olotu, Ally; Bojang, Kalifa; Lusingu, John PA; Salim, Nahya; Otsyula, Nekoye N; Agnandji, Selidji T; Asante, Kwaku Poku; Owusu-Agyei, Seth; Abdulla, Salim; Ghani, Azra C

    2013-01-01

    Summary Background The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data. Methods We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2–10 years (PrP2–10), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02. Findings Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP2–10 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP2–10 20%) it was 41% (21 to 57), and at high transmission (PrP2–10 70%) the efficacy was 4% (−10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)—eg, at low transmission (PrP2–10 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (−38 to 38) after 3 years. Interpretation Vaccine efficacy against clinical disease was of

  10. Superparamagnetic nanoparticles for effective delivery of malaria DNA vaccine.

    PubMed

    Al-Deen, Fatin Nawwab; Ho, Jenny; Selomulya, Cordelia; Ma, Charles; Coppel, Ross

    2011-04-01

    Low efficiency is often observed in the delivery of DNA vaccines. The use of superparamagnetic nanoparticles (SPIONs) to deliver genes via magnetofection could improve transfection efficiency and target the vector to its desired locality. Here, magnetofection was used to enhance the delivery of a malaria DNA vaccine encoding Plasmodium yoelii merozoite surface protein MSP1(19) (VR1020-PyMSP1(19)) that plays a critical role in Plasmodium immunity. The plasmid DNA (pDNA) containing membrane associated 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 (PyMSP1(19)) was conjugated with superparamagnetic nanoparticles coated with polyethyleneimine (PEI) polymer, with different molar ratio of PEI nitrogen to DNA phosphate. We reported the effects of SPIONs-PEI complexation pH values on the properties of the resulting particles, including their ability to condense DNA and the gene expression in vitro. By initially lowering the pH value of SPIONs-PEI complexes to 2.0, the size of the complexes decreased since PEI contained a large number of amino groups that became increasingly protonated under acidic condition, with the electrostatic repulsion inducing less aggregation. Further reaggregation was prevented when the pHs of the complexes were increased to 4.0 and 7.0, respectively, before DNA addition. SPIONs/PEI complexes at pH 4.0 showed better binding capability with PyMSP1(19) gene-containing pDNA than those at neutral pH, despite the negligible differences in the size and surface charge of the complexes. This study indicated that the ability to protect DNA molecules due to the structure of the polymer at acidic pH could help improve the transfection efficiency. The transfection efficiency of magnetic nanoparticle as carrier for malaria DNA vaccine in vitro into eukaryotic cells, as indicated via PyMSP1(19) expression, was significantly enhanced under the application of external magnetic field, while the cytotoxicity was comparable to the benchmark nonviral

  11. How might infant and paediatric immune responses influence malaria vaccine efficacy?

    PubMed Central

    MOORMANN, A M

    2009-01-01

    Naturally acquired immunity to malaria requires repeat infections yet does not engender sterile immunity or long-lasting protective immunologic memory. This renders infants and young children the most susceptible to malaria-induced morbidity and mortality, and the ultimate target for a malaria vaccine. The prevailing paradigm is that infants initially garner protection due to transplacentally transferred anti-malarial antibodies and other intrinsic factors such as foetal haemoglobin. As these wane infants have an insufficient immune repertoire to prevent genetically diverse Plasmodium infections and an inability to control malaria-induced immunopathology. This Review discusses humoral, cell-mediated and innate immune responses to malaria and how each contributes to protection – focusing on how deficiencies in infant and paediatric immune responses might influence malaria vaccine efficacy in this population. In addition, burgeoning evidence suggests a role for inhibitory receptors that limit immunopathology and guide the development of long-lived immunity. Precisely how age or malaria infections influence the function of these regulators is unknown. Therefore the possibility that infants may not have the immune-dexterity to balance effective parasite clearance with timely immune-regulation leading to protective immunologic memory is considered. And thus, malaria vaccines tested in adults and older children may not be predictive for trials conducted in infants. PMID:19691558

  12. Malaria vaccines: high-throughput tools for antigens discovery with potential for their development.

    PubMed

    Céspedes, Nora; Vallejo, Andrés; Arévalo-Herrera, Myriam; Herrera, Sócrates

    2013-04-01

    Malaria is a disease induced by parasites of the Plasmodium genus, which are transmitted by Anopheles mosquitoes and represents a great socio-economic burden Worldwide. Plasmodium vivax is the second species of malaria Worldwide, but it is the most prevalent in Latin America and other regions of the planet. It is currently considered that vaccines represent a cost-effective strategy for controlling transmissible diseases and could complement other malaria control measures; however, the chemical and immunological complexity of the parasite has hindered development of effective vaccines. Recent availability of several genomes of Plasmodium species, as well as bioinformatic tools are allowing the selection of large numbers of proteins and analysis of their immune potential. Herein, we review recently developed strategies for discovery of novel antigens with potential for malaria vaccine development.

  13. RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap.

    PubMed

    Kaslow, David C; Biernaux, Sophie

    2015-12-22

    The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first-generation malaria vaccine that has protective efficacy against severe disease and death, lasting longer than one year. This review focuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinant subunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vaccine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicity study. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria were averted over a 3-4 years period, particularly in settings of significant disease burden. European regulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of active immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectiveness of RTS,S are now anticipated through policy and financing reviews at the global and national levels.

  14. Malaria Vaccine Development: Are Bacterial Flagellin Fusion Proteins the Bridge between Mouse and Humans?

    PubMed Central

    Bargieri, Daniel Y.; Soares, Irene S.; Costa, Fabio T. M.; Braga, Catarina J.; Ferreira, Luis C. S.; Rodrigues, Mauricio M.

    2011-01-01

    In the past 25 years, the development of an effective malaria vaccine has become one of the biggest riddles in the biomedical sciences. Experimental data using animal infection models demonstrated that it is possible to induce protective immunity against different stages of malaria parasites. Nonetheless, the vast body of knowledge has generated disappointments when submitted to clinical conditions and presently a single antigen formulation has progressed to the point where it may be translated into a human vaccine. In parallel, new means to increase the protective effects of antigens in general have been pursued and depicted, such as the use of bacterial flagellins as carriers/adjuvants. Flagellins activate pathways in the innate immune system of both mice and humans. The recent report of the first Phase I clinical trial of a vaccine containing a Salmonella flagellin as carrier/adjuvant may fuel the use of these proteins in vaccine formulations. Herein, we review the studies on the use of recombinant flagellins as vaccine adjuvants with malarial antigens in the light of the current state of the art of malaria vaccine development. The available information indicates that bacterial flagellins should be seriously considered for malaria vaccine formulations to the development of effective human vaccines. PMID:21603205

  15. Comparative efficacy of pre-erythrocytic whole organism vaccine strategies against the malaria parasite.

    PubMed

    Friesen, Johannes; Matuschewski, Kai

    2011-09-16

    Despite major efforts over the past 50 years to develop a malaria vaccine, no product has been licensed yet. Irradiated sporozoites are the benchmark for an experimental live-attenuated malaria vaccine that induces potent protection against re-infection in humans and animal models. Lasting protection can also be elicited by parasite attenuation via tailored genetic modification or drug cover leading to renewed interest in whole-organism vaccination strategies. In this study, we systematically compared the protective efficacy of different whole-organism vaccination approaches in the Plasmodium berghei/C57bl/6 rodent malaria model. We applied blood stage parasitemia and quantitative RT-PCR of liver parasite loads as two complementary primary endpoints of a malaria challenge infection. We were able to demonstrate similar potency of genetic attenuation, i.e., uis3(-) and p36p(-) parasites, and prophylactic drug cover, i.e., azithromycin, pyrimethamine, primaquine and chloroquine, during sporozoite exposure in comparison to irradiated sporozoites. Importantly, when animals were covered with the antibiotic azithromycin during sporozoite exposure we observed superior protection. On the other end, immunizations with heat-killed and over-irradiated sporozoites failed to confer any detectable protection. Together, we show that systematic pre-clinical evaluation and quantification of vaccine efficacy is vital for identification of the most potent whole organism anti-malaria vaccine strategy.

  16. Role of non-human primates in malaria vaccine development: Memorandum from a WHO Meeting*

    PubMed Central

    1988-01-01

    This Memorandum discusses the coordination and standardization of malaria vaccine research in non-human primates to encourage optimum use of the available animals in experiments that are fully justified both scientifically and ethically. The requirements for experimentation in non-human primates, the availability of suitable animals for malaria vaccine studies, and the criteria for testing candidate vaccines are considered. The policy and legislation relevant to the use of non-human primates in biomedical research are also briefly discussed. The Memorandum concludes with eight recommendations. PMID:3266112

  17. A Plant-Based Transient Expression System for the Rapid Production of Malaria Vaccine Candidates.

    PubMed

    Boes, Alexander; Reimann, Andreas; Twyman, Richard M; Fischer, Rainer; Schillberg, Stefan; Spiegel, Holger

    2016-01-01

    There are currently no vaccines that provide sterile immunity against malaria. Various proteins from different stages of the Plasmodium falciparum life cycle have been evaluated as vaccine candidates, but none of them have fulfilled expectations. Therefore, combinations of key antigens from different stages of the parasites life cycle may be essential for the development of efficacious malaria vaccines. Following the identification of promising antigens using bioinformatics, proteomics, and/or immunological approaches, it is necessary to express, purify, and characterize these proteins and explore the potential of fusion constructs combining different antigens or antigen domains before committing to expensive and time-consuming clinical development. Here, using malaria vaccine candidates as an example, we describe how Agrobacterium tumefaciens-based transient expression in plants can be combined with a modular and flexible cloning strategy as a robust and versatile tool for the rapid production of candidate antigens during research and development. PMID:27076325

  18. Experience and challenges from clinical trials with malaria vaccines in Africa

    PubMed Central

    2013-01-01

    Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available. African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need. However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained. PMID:23496910

  19. The first field trials of the chemically synthesized malaria vaccine SPf66: safety, immunogenicity and protectivity.

    PubMed

    Amador, R; Moreno, A; Valero, V; Murillo, L; Mora, A L; Rojas, M; Rocha, C; Salcedo, M; Guzman, F; Espejo, F

    1992-01-01

    This paper reports the results of the first field study performed to assess the safety, immunogenicity and protectivity of the synthetic malaria vaccine SPf66 directed against the asexual blood stages of Plasmodium falciparum. Clinical and laboratory tests were performed on all volunteers prior to and after each immunization, demonstrating that no detectable alteration was induced by the immunization process. The vaccines were grouped as high, intermediate or low responders according to their antibody titres directed against the SPf66 molecule. Two of the 185 (1.08%) SPf66-vaccinated and nine of the 214 (4.20%) placebo-vaccinated volunteers developed P. falciparum malaria. The efficacy of the vaccine was calculated as 82.3% against P. falciparum and 60.6% against Plasmodium vivax.

  20. Induction of strain-transcending immunity against Plasmodium chabaudi adami malaria with a multiepitope DNA vaccine.

    PubMed

    Scorza, T; Grubb, K; Smooker, P; Rainczuk, A; Proll, D; Spithill, T W

    2005-05-01

    A major goal of current malaria vaccine programs is to develop multivalent vaccines that will protect humans against the many heterologous malaria strains that circulate in endemic areas. We describe a multiepitope DNA vaccine, derived from a genomic Plasmodium chabaudi adami DS DNA expression library of 30,000 plasmids, which induces strain-transcending immunity in mice against challenge with P. c. adami DK. Segregation of this library and DNA sequence analysis identified vaccine subpools encoding open reading frames (ORFs)/peptides of >9 amino acids [aa] (the V9+ pool, 303 plasmids) and >50 aa (V50+ pool, 56 plasmids), respectively. The V9+ and V50+ plasmid vaccine subpools significantly cross-protected mice against heterologous P. c. adami DK challenge, and protection correlated with the induction of both specific gamma interferon production by splenic cells and opsonizing antibodies. Bioinformatic analysis showed that 22 of the V50+ ORFs were polypeptides conserved among three or more Plasmodium spp., 13 of which are predicted hypothetical proteins. Twenty-nine of these ORFs are orthologues of predicted Plasmodium falciparum sequences known to be expressed in the blood stage, suggesting that this vaccine pool encodes multiple blood-stage antigens. The results have implications for malaria vaccine design by providing proof-of-principle that significant strain-transcending immunity can be induced using multiepitope blood-stage DNA vaccines and suggest that both cellular responses and opsonizing antibodies are necessary for optimal protection against P. c. adami.

  1. Genome-based vaccine design: the promise for malaria and other infectious diseases.

    PubMed

    Doolan, Denise L; Apte, Simon H; Proietti, Carla

    2014-10-15

    Vaccines are one of the most effective interventions to improve public health, however, the generation of highly effective vaccines for many diseases has remained difficult. Three chronic diseases that characterise these difficulties include malaria, tuberculosis and HIV, and they alone account for half of the global infectious disease burden. The whole organism vaccine approach pioneered by Jenner in 1796 and refined by Pasteur in 1857 with the "isolate, inactivate and inject" paradigm has proved highly successful for many viral and bacterial pathogens causing acute disease but has failed with respect to malaria, tuberculosis and HIV as well as many other diseases. A significant advance of the past decade has been the elucidation of the genomes, proteomes and transcriptomes of many pathogens. This information provides the foundation for new 21st Century approaches to identify target antigens for the development of vaccines, drugs and diagnostic tests. Innovative genome-based vaccine strategies have shown potential for a number of challenging pathogens, including malaria. We advocate that genome-based rational vaccine design will overcome the problem of poorly immunogenic, poorly protective vaccines that has plagued vaccine developers for many years.

  2. Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria

    PubMed Central

    Beeson, James G.; Drew, Damien R.; Boyle, Michelle J.; Feng, Gaoqian; Fowkes, Freya J.I.; Richards, Jack S.

    2016-01-01

    Malaria accounts for an enormous burden of disease globally, with Plasmodium falciparum accounting for the majority of malaria, and P. vivax being a second important cause, especially in Asia, the Americas and the Pacific. During infection with Plasmodium spp., the merozoite form of the parasite invades red blood cells and replicates inside them. It is during the blood-stage of infection that malaria disease occurs and, therefore, understanding merozoite invasion, host immune responses to merozoite surface antigens, and targeting merozoite surface proteins and invasion ligands by novel vaccines and therapeutics have been important areas of research. Merozoite invasion involves multiple interactions and events, and substantial processing of merozoite surface proteins occurs before, during and after invasion. The merozoite surface is highly complex, presenting a multitude of antigens to the immune system. This complexity has proved challenging to our efforts to understand merozoite invasion and malaria immunity, and to developing merozoite antigens as malaria vaccines. In recent years, there has been major progress in this field, and several merozoite surface proteins show strong potential as malaria vaccines. Our current knowledge on this topic is reviewed, highlighting recent advances and research priorities. PMID:26833236

  3. Vaccination Strategies against Malaria: novel carrier(s) more than a tour de force.

    PubMed

    Tyagi, Rajeev K; Garg, Neeraj K; Sahu, Tejram

    2012-08-20

    The introduction of vaccine technology has facilitated an unprecedented multi-antigen approach to develop an effective vaccine against complex systemic inflammatory pathogens such as Plasmodium spp. that cause severe malaria. The capacity of multi subunit DNA vaccine encoding different stage Plasmodium antigens to induce CD8(+) cytotoxic T lymphocytes and interferon-γ responses in mice, monkeys and humans has been observed. Moreover, genetic vaccination may be capable of eliciting both cell mediated and humoral immune responses. The cytotoxic T cell responses are categorically needed against intracellular hepatic stage and humoral response with antibodies targeted against antigens from all stages of malaria parasite life cycle. Therefore, the key to success for any DNA based vaccine is to design a vector able to serve as a safe and efficient delivery system. This has encouraged the development of non-viral DNA-mediated gene transfer techniques such as liposome, virosomes, microsphere and nanoparticles. Efficient and relatively safe DNA transfection using lipoplexes makes them an appealing alternative to be explored for gene delivery. Also, liposome-entrapped DNA has been shown to enhance the potency of DNA vaccines, possibly by facilitating uptake of the plasmid by antigen-presenting cells (APC). Another recent technology using cationic lipids has been deployed and has generated substantial interest in this approach to gene transfer. In this review we discussed various aspects that could be decisive in the formulation of efficient and stable carrier system(s) for the development of malaria vaccine.

  4. Safety and immunogenicity of the synthetic malaria vaccine SPf66 in a large field trial.

    PubMed

    Amador, R; Moreno, A; Murillo, L A; Sierra, O; Saavedra, D; Rojas, M; Mora, A L; Rocha, C L; Alvarado, F; Falla, J C

    1992-07-01

    In the first field trial with synthetic malaria vaccine SPf66 in a large population naturally exposed to malaria, 9957 persons greater than 1 year old and residing on the Colombian Pacific coast received three doses of the vaccine. To evaluate vaccine safety, clinical observations were made 30 min and 48 h after each immunization. There were no adverse reactions in 95.7% of cases. In the 4.3% of cases with adverse reactions, local induration and erythema were the most frequent. In a randomly selected group of vaccinees, anti-SPf66 antibody titers were measured after the third dose: 93% of the vaccinees raised antibodies to SPf66. Among these, 55% had titers greater than 1:1600. These results demonstrate the safety and immunogenicity of the SPf66 vaccine in a large field trial.

  5. Two decades of commitment to malaria vaccine development: GlaxoSmithKline Biologicals.

    PubMed

    Ballou, W Ripley; Cahill, Conor P

    2007-12-01

    GlaxoSmithKline Biologicals (GSK) is committed to the development of a safe and effective malaria vaccine. Its research program in this field was initiated in 1984 and has been continuously active to this day, making it unparalleled within the vaccine industry. Although it works in partnerships with several leading organizations from the public sector, this effort has required GSK to invest major financial and human resource commitments, and its partners rely heavily on the company's global infrastructure and expertise in research, advanced clinical development, regulatory, large-scale manufacturing, and commercialization. Through GSK's pioneering business model and working in partnership with global vaccine funding agencies, the company is committed to seeing that, once approved, a safe and effective malaria vaccine will be available to everyone that needs it.

  6. Recombinant gamma interferon is a potent adjuvant for a malaria vaccine in mice.

    PubMed Central

    Playfair, J H; De Souza, J B

    1987-01-01

    Mice were protected against lethal Plasmodium yoelii malaria by vaccination with a Triton X-100 lysate of whole parasitized erythrocytes. For full effectiveness this vaccine required an adjuvant, and we have found that recombinant gamma-interferon has strong adjuvanticity in this model when given either intraperitoneally or subcutaneously. Specific immune responses that were enhanced included antibody, T cell help, and delayed hypersensitivity. PMID:3113784

  7. The rodent malaria lactate dehydrogenase assay provides a high throughput solution for in vivo vaccine studies.

    PubMed

    Otsuki, Hitoshi; Yokouchi, Yuki; Iyoku, Natsumi; Tachibana, Mayumi; Tsuboi, Takafumi; Torii, Motomi

    2015-08-01

    Rodent malaria is a useful model for evaluating the efficacy of malaria vaccine candidates; however, labor-intensive microscopic parasite counting hampers the use of an in vivo parasite challenge in high-throughput screening. The measurement of malaria parasite lactate dehydrogenase (pLDH) activity, which is commonly used in the in vitro growth inhibition assay of Plasmodium falciparum, may be the cheapest and simplest alternative to microscopic parasite counting. However, the pLDH assay has not been applied in the in vivo rodent malaria model. Here, we showed that the pLDH assay is reliable and accurately determines parasitemia in the rodent malaria model. pLDH activity measured using a chromogenic substrate reflects the parasite number in the blood; it allows fast and easy assessment using a conventional microplate reader. To validate this approach, we synthesized recombinant PyMSP1-19 protein (rPyMSP1-19) using a wheat germ cell-free protein synthesis system and immunized mice with rPyMSP1-19. The antisera showed specific reactivity on the surface of the Plasmodium yoelii merozoite and immunized mice were protected against a lethal P. yoelii 17 XL challenge. The pLDH assay quickly and easily demonstrated a significant reduction of the parasite numbers in the immunized mice. Accordingly, the pLDH assay proved to be an efficient alternative to rodent malaria parasite counting, and may therefore accelerate in vivo vaccine candidate screening.

  8. Modeling the public health impact of malaria vaccines for developers and policymakers

    PubMed Central

    2013-01-01

    Background Efforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model’s functionality is demonstrated through a hypothetical vaccine. Methods The MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were $0.40 per dose. Results The model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is

  9. Mixed allele malaria vaccines: Host protection and within-host selection

    PubMed Central

    Barclay, Victoria C.; Chan, Brian H.K.; Anders, Robin F.; Read, Andrew F.

    2008-01-01

    Malaria parasites are frequently polymorphic at the antigenic targets of many candidate vaccines, presumably as a consequence of selection pressure from protective immune responses. Conventional wisdom is therefore that vaccines directed against a single variant could select for non-target variants, rendering the vaccine useless. Many people have argued that a solution is to develop vaccines containing the products of more than one variant of the target. However, we are unaware of any evidence that multi-allele vaccines better protect hosts against parasites or morbidity. Moreover, selection of antigen-variants is not the only evolution that could occur in response to vaccination. Increased virulence could also be favored if more aggressive strains are less well controlled by vaccine-induced immunity. Virulence and antigenic identity have been confounded in all studies so far, and so we do not know formally from any animal or human studies whether vaccine failure has been due to evasion of protective responses by variants at target epitopes, or whether vaccines are just less good at protecting against more aggressive strains. Using the rodent malaria model Plasmodium chabaudi and recombinant apical membrane antigen-1 (AMA-1), we tested whether a bi-allelic vaccine afforded greater protection from parasite infection and morbidity than did vaccination with the component alleles alone. We also tested the effect of mono- and bi-allelic vaccination on within-host selection of mixed P. chabaudi infections, and whether parasite virulence mediates pathogen titres in immunized hosts. We found that vaccination with the bi-allelic AMA-1 formulation did not afford the host greater protection from parasite infection or morbidity than did mono-allelic AMA-1 immunization. Mono-allelic immunization increased the frequency of heterologous clones in mixed clone infections. There was no evidence that any type of immunization regime favored virulence. A single AMA-1 variant is a

  10. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine.

    PubMed

    Seder, Robert A; Chang, Lee-Jah; Enama, Mary E; Zephir, Kathryn L; Sarwar, Uzma N; Gordon, Ingelise J; Holman, LaSonji A; James, Eric R; Billingsley, Peter F; Gunasekera, Anusha; Richman, Adam; Chakravarty, Sumana; Manoj, Anita; Velmurugan, Soundarapandian; Li, MingLin; Ruben, Adam J; Li, Tao; Eappen, Abraham G; Stafford, Richard E; Plummer, Sarah H; Hendel, Cynthia S; Novik, Laura; Costner, Pamela J M; Mendoza, Floreliz H; Saunders, Jamie G; Nason, Martha C; Richardson, Jason H; Murphy, Jittawadee; Davidson, Silas A; Richie, Thomas L; Sedegah, Martha; Sutamihardja, Awalludin; Fahle, Gary A; Lyke, Kirsten E; Laurens, Matthew B; Roederer, Mario; Tewari, Kavita; Epstein, Judith E; Sim, B Kim Lee; Ledgerwood, Julie E; Graham, Barney S; Hoffman, Stephen L

    2013-09-20

    Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards. PMID:23929949

  11. Development and application of next generation SE36 malaria vaccine formulated with a novel adjuvant: approach to travelers' vaccine.

    PubMed

    Tougan, Takahiro; Ishii, Ken J; Horii, Toshihiro

    2013-01-01

    The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Previous clinical trials indicated the protective efficacy of BK-SE36 malaria vaccine that is constituted of SE36 recombinant protein and aluminum hydroxide gel. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized SE36/AHG with K3 ODN effectively suppressed parasitemia and symptoms of malaria following challenge infection. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG is safety, potent immunogenicity and efficacy in nonhuman primates. We are conducting the first in human clinical trials with this formulation. PMID:24189556

  12. Community perceptions of malaria and vaccines in the South Coast and Busia regions of Kenya

    PubMed Central

    2011-01-01

    Background Malaria is a leading cause of morbidity and mortality in children younger than 5 years in Kenya. Within the context of planning for a vaccine to be used alongside existing malaria control methods, this study explores sociocultural and health communications issues among individuals who are responsible for or influence decisions on childhood vaccination at the community level. Methods This qualitative study was conducted in two malaria-endemic regions of Kenya--South Coast and Busia. Participant selection was purposive and criterion based. A total of 20 focus group discussions, 22 in-depth interviews, and 18 exit interviews were conducted. Results Participants understand that malaria is a serious problem that no single tool can defeat. Communities would welcome a malaria vaccine, although they would have questions and concerns about the intervention. While support for local child immunization programs exists, limited understanding about vaccines and what they do is evident among younger and older people, particularly men. Even as health care providers are frustrated when parents do not have their children vaccinated, some parents have concerns about access to and the quality of vaccination services. Some women, including older mothers and those less economically privileged, see themselves as the focus of health workers' negative comments associated with either their parenting choices or their children's appearance. In general, parents and caregivers weigh several factors--such as personal opportunity costs, resource constraints, and perceived benefits--when deciding whether or not to have their children vaccinated, and the decision often is influenced by a network of people, including community leaders and health workers. Conclusions The study raises issues that should inform a communications strategy and guide policy decisions within Kenya on eventual malaria vaccine introduction. Unlike the current practice, where health education on child welfare and

  13. Plasmodium falciparum serine repeat antigen 5 (SE36) as a malaria vaccine candidate.

    PubMed

    Palacpac, Nirianne Marie Q; Arisue, Nobuko; Tougan, Takahiro; Ishii, Ken J; Horii, Toshihiro

    2011-08-11

    A devastating disease spread by mosquitoes with high-efficiency, malaria imposes an enormous burden for which no licensed vaccine currently exists. Although the genome complexity of the parasite has made vaccine development tenuous, an effective malaria vaccine would be a valuable tool for control, elimination and eventual eradication. The Plasmodium serine repeat antigen 5 (SERA5) is an abundant asexual blood stage antigen that does not show any antigenic variation and exhibits limited polymorphism, making it a suitable vaccine candidate. Identified by comparing the IgG status of people in endemic areas with protective immunity and those with malaria symptoms, the vaccine potential of the N-terminal domain of Plasmodium falciparum SERA5 is also strongly supported by experimental data and immune responses both measured in vitro and in animal challenge models. The current understanding of SERA5 will be presented, particularly in relation to its path towards clinical development. The review highlights lessons learned and sorts out issues upon which further research efforts are needed. PMID:21718740

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

    PubMed

    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.

  15. The case for a rational genome-based vaccine against malaria

    PubMed Central

    Proietti, Carla; Doolan, Denise L.

    2015-01-01

    Historically, vaccines have been designed to mimic the immunity induced by natural exposure to the target pathogen, but this approach has not been effective for any parasitic pathogen of humans or complex pathogens that cause chronic disease in humans, such as Plasmodium. Despite intense efforts by many laboratories around the world on different aspects of Plasmodium spp. molecular and cell biology, epidemiology and immunology, progress towards the goal of an effective malaria vaccine has been disappointing. The premise of rational vaccine design is to induce the desired immune response against the key pathogen antigens or epitopes targeted by protective immune responses. We advocate that development of an optimally efficacious malaria vaccine will need to improve on nature, and that this can be accomplished by rational vaccine design facilitated by mining genomic, proteomic and transcriptomic datasets in the context of relevant biological function. In our opinion, modern genome-based rational vaccine design offers enormous potential above and beyond that of whole-organism vaccines approaches established over 200 years ago where immunity is likely suboptimal due to the many genetic and immunological host-parasite adaptations evolved to allow the Plasmodium parasite to coexist in the human host, and which are associated with logistic and regulatory hurdles for production and delivery. PMID:25657640

  16. Malaria

    MedlinePlus

    MENU Return to Web version Malaria Overview What is malaria? Malaria is an infection of a part of the blood called the red blood cells. It is ... by mosquitoes that carry a parasite that causes malaria. If a mosquito carrying this parasite bites you, ...

  17. Factors Likely to Affect Community Acceptance of a Malaria Vaccine in Two Districts of Ghana: A Qualitative Study

    PubMed Central

    Meñaca, Arantza; Tagbor, Harry; Adjei, Rose; Bart-Plange, Constance; Collymore, Yvette; Ba-Nguz, Antoinette; Mertes, Kelsey; Bingham, Allison

    2014-01-01

    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 be important to

  18. Application of a Scalable Plant Transient Gene Expression Platform for Malaria Vaccine Development.

    PubMed

    Spiegel, Holger; Boes, Alexander; Voepel, Nadja; Beiss, Veronique; Edgue, Gueven; Rademacher, Thomas; Sack, Markus; Schillberg, Stefan; Reimann, Andreas; Fischer, Rainer

    2015-01-01

    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 toward 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 proteins. Our

  19. Application of a Scalable Plant Transient Gene Expression Platform for Malaria Vaccine Development

    PubMed Central

    Spiegel, Holger; Boes, Alexander; Voepel, Nadja; Beiss, Veronique; Edgue, Gueven; Rademacher, Thomas; Sack, Markus; Schillberg, Stefan; Reimann, Andreas; Fischer, Rainer

    2015-01-01

    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 toward 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 proteins. Our

  20. Using infective mosquitoes to challenge monkeys with Plasmodium knowlesi in malaria vaccine studies

    PubMed Central

    2014-01-01

    Background When rhesus monkeys (Macaca mulatta) are used to test malaria vaccines, animals are often challenged by the intravenous injection of sporozoites. However, natural exposure to malaria comes via mosquito bite, and antibodies can neutralize sporozoites as they traverse the skin. Thus, intravenous injection may not fairly assess humoral immunity from anti-sporozoite malaria vaccines. To better assess malaria vaccines in rhesus, a method to challenge large numbers of monkeys by mosquito bite was developed. Methods Several species and strains of mosquitoes were tested for their ability to produce Plasmodium knowlesi sporozoites. Donor monkey parasitaemia effects on oocyst and sporozoite numbers and mosquito mortality were documented. Methylparaben added to mosquito feed was tested to improve mosquito survival. To determine the number of bites needed to infect a monkey, animals were exposed to various numbers of P. knowlesi-infected mosquitoes. Finally, P. knowlesi-infected mosquitoes were used to challenge 17 monkeys in a malaria vaccine trial, and the effect of number of infectious bites on monkey parasitaemia was documented. Results Anopheles dirus, Anopheles crascens, and Anopheles dirus X (a cross between the two species) produced large numbers of P. knowlesi sporozoites. Mosquito survival to day 14, when sporozoites fill the salivary glands, averaged only 32% when donor monkeys had a parasitaemia above 2%. However, when donor monkey parasitaemia was below 2%, mosquitoes survived twice as well and contained ample sporozoites in their salivary glands. Adding methylparaben to sugar solutions did not improve survival of infected mosquitoes. Plasmodium knowlesi was very infectious, with all monkeys developing blood stage infections if one or more infected mosquitoes successfully fed. There was also a dose-response, with monkeys that received higher numbers of infected mosquito bites developing malaria sooner. Conclusions Anopheles dirus, An. crascens and a

  1. Determination of the immunization schedule for field trials with the synthetic malaria vaccine SPf 66.

    PubMed

    Rocha, C L; Murillo, L A; Mora, A L; Rojas, M; Franco, L; Cote, J; Valero, M V; Moreno, A; Amador, R; Nuñez, F

    1992-01-01

    The synthetic malaria vaccine SPf 66 has been shown to be safe, immunogenic and effective in trials performed with controlled groups naturally and experimentally exposed to the disease. In order to continue the trials in open populations, it was necessary to standardize the vaccination characteristics. We have performed four field trials with soldier volunteers with the aim, among others, of defining the number of doses required, the intervals between applications, the protein concentration, and the adjuvant to be used. In these trials, the vaccinated individuals' immune responses were evaluated by assaying anti-SPf 66 antibody titres, in vitro growth inhibition of the P. falciparum parasite, and the vaccinees' capacity to recognize P. falciparum native proteins. From these results we conclude that the best vaccination schedule, for adults, is three doses administered subcutaneously on days 0, 30 and 180, each containing 2 mg of the synthetic polymerized petide SPf 66 adsorbed to alum hydroxide.

  2. Mosquitocidal vaccines: a neglected addition to malaria and dengue control strategies.

    PubMed

    Billingsley, Peter F; Foy, Brian; Rasgon, Jason L

    2008-09-01

    The transmission of vector-borne diseases is dependent upon the ability of the vector to survive for longer than the period of development of the pathogen within the vector. One means of reducing mosquito lifespan, and thereby reducing their capacity to transmit diseases, is to target mosquitoes with vaccines. Here, the principle behind mosquitocidal vaccines is described, their potential impact in malaria and dengue control is modeled and the current research that could make these vaccines a reality is reviewed. Mosquito genome data, combined with modern molecular techniques, can be exploited to overcome the limited advances in this field. Given the large potential benefit to vector-borne disease control, research into the development of mosquitocidal vaccines deserves a high profile. PMID:18678529

  3. Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein

    PubMed Central

    Sahu, Tejram; Malkov, Vlad; Morrison, Robert; Pei, Ying; Juompan, Laure; Milman, Neta; Zarling, Stasya; Anderson, Charles; Wong-Madden, Sharon; Wendler, Jason; Ishizuka, Andrew; MacMillen, Zachary W.; Garcia, Valentino; Kappe, Stefan H. I.; Krzych, Urszula; Duffy, Patrick E.

    2016-01-01

    Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP. PMID:27434123

  4. Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein.

    PubMed

    Speake, Cate; Pichugin, Alexander; Sahu, Tejram; Malkov, Vlad; Morrison, Robert; Pei, Ying; Juompan, Laure; Milman, Neta; Zarling, Stasya; Anderson, Charles; Wong-Madden, Sharon; Wendler, Jason; Ishizuka, Andrew; MacMillen, Zachary W; Garcia, Valentino; Kappe, Stefan H I; Krzych, Urszula; Duffy, Patrick E

    2016-01-01

    Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP. PMID:27434123

  5. Design of a Phase III cluster randomized trial to assess the efficacy and safety of a malaria transmission blocking vaccine.

    PubMed

    Delrieu, Isabelle; Leboulleux, Didier; Ivinson, Karen; Gessner, Bradford D

    2015-03-24

    Vaccines interrupting Plasmodium falciparum malaria transmission targeting sexual, sporogonic, or mosquito-stage antigens (SSM-VIMT) are currently under development to reduce malaria transmission. An international group of malaria experts was established to evaluate the feasibility and optimal design of a Phase III cluster randomized trial (CRT) that could support regulatory review and approval of an SSM-VIMT. The consensus design is a CRT with a sentinel population randomly selected from defined inner and buffer zones in each cluster, a cluster size sufficient to assess true vaccine efficacy in the inner zone, and inclusion of ongoing assessment of vaccine impact stratified by distance of residence from the cluster edge. Trials should be conducted first in areas of moderate transmission, where SSM-VIMT impact should be greatest. Sample size estimates suggest that such a trial is feasible, and within the range of previously supported trials of malaria interventions, although substantial issues to implementation exist. PMID:25681064

  6. Vaccination and Malaria Prevention among International Travelers Departing from Athens International Airport to African Destinations.

    PubMed

    Pavli, Androula; Spilioti, Athina; Smeti, Paraskevi; Patrinos, Stavros; Maltezou, Helena C

    2014-01-01

    Background. International travel to Africa has grown dramatically over the last decade along with an increasing need to understand the health issues for travelers. The current survey aimed to assess vaccination and malaria prevention of travelers visiting Africa. Methods. A questionnaire-based survey was conducted from of November 1, 2011 to of April 30, 2013 at Athens International Airport. Results. A total of 360 travelers were studied; 68% were men. Their mean age was 39.9 years. Previous travel to tropical countries was reported by 71.9% of them. Most frequent destination was sub-Saharan Africa (60%). Most of them traveled for ≥1 month (62%). The main reason for travel was work (39.7%). Only 47% sought pretravel consultation. Hepatitis A, typhoid, and meningococcal vaccines were administered to 49.8%, 28%, and 26.6%, respectively, and malaria chemoprophylaxis to 66.8% of those who visited sub-Saharan Africa. A history of previous travel to a tropical country, elementary level of education, and traveling for visiting friends and relatives, and for short duration were significant determinants for not pursuing pretravel consultation. Conclusions. The current survey revealed important inadequacies in vaccine and malaria prophylaxis of travelers departing to Africa. Educational tools should be developed in order to improve awareness of travelers to risk destinations.

  7. Vaccination and Malaria Prevention among International Travelers Departing from Athens International Airport to African Destinations

    PubMed Central

    Pavli, Androula; Spilioti, Athina; Smeti, Paraskevi; Patrinos, Stavros; Maltezou, Helena C.

    2014-01-01

    Background. International travel to Africa has grown dramatically over the last decade along with an increasing need to understand the health issues for travelers. The current survey aimed to assess vaccination and malaria prevention of travelers visiting Africa. Methods. A questionnaire-based survey was conducted from of November 1, 2011 to of April 30, 2013 at Athens International Airport. Results. A total of 360 travelers were studied; 68% were men. Their mean age was 39.9 years. Previous travel to tropical countries was reported by 71.9% of them. Most frequent destination was sub-Saharan Africa (60%). Most of them traveled for ≥1 month (62%). The main reason for travel was work (39.7%). Only 47% sought pretravel consultation. Hepatitis A, typhoid, and meningococcal vaccines were administered to 49.8%, 28%, and 26.6%, respectively, and malaria chemoprophylaxis to 66.8% of those who visited sub-Saharan Africa. A history of previous travel to a tropical country, elementary level of education, and traveling for visiting friends and relatives, and for short duration were significant determinants for not pursuing pretravel consultation. Conclusions. The current survey revealed important inadequacies in vaccine and malaria prophylaxis of travelers departing to Africa. Educational tools should be developed in order to improve awareness of travelers to risk destinations. PMID:24719621

  8. Malaria.

    ERIC Educational Resources Information Center

    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…

  9. Baculovirus-Vectored Multistage Plasmodium vivax Vaccine Induces Both Protective and Transmission-Blocking Immunities against Transgenic Rodent Malaria Parasites

    PubMed Central

    Mizutani, Masanori; Iyori, Mitsuhiro; Blagborough, Andrew M.; Fukumoto, Shinya; Funatsu, Tomohiro; Sinden, Robert E.

    2014-01-01

    A multistage malaria vaccine targeting the pre-erythrocytic and sexual stages of Plasmodium could effectively protect individuals against infection from mosquito bites and provide transmission-blocking (TB) activity against the sexual stages of the parasite, respectively. This strategy could help prevent malaria infections in individuals and, on a larger scale, prevent malaria transmission in communities of endemicity. Here, we describe the development of a multistage Plasmodium vivax vaccine which simultaneously expresses P. vivax circumsporozoite protein (PvCSP) and P25 (Pvs25) protein of this species as a fusion protein, thereby acting as a pre-erythrocytic vaccine and a TB vaccine, respectively. A new-concept vaccine platform based on the baculovirus dual-expression system (BDES) was evaluated. The BDES-Pvs25-PvCSP vaccine displayed correct folding of the Pvs25-PvCSP fusion protein on the viral envelope and was highly expressed upon transduction of mammalian cells in vitro. This vaccine induced high levels of antibodies to Pvs25 and PvCSP and elicited protective (43%) and TB (82%) efficacies against transgenic P. berghei parasites expressing the corresponding P. vivax antigens in mice. Our data indicate that our BDES, which functions as both a subunit and DNA vaccine, can offer a promising multistage vaccine capable of delivering a potent antimalarial pre-erythrocytic and TB response via a single immunization regimen. PMID:25092912

  10. Expression, purification and re folding of a self-assembling protein nanoparticle (SAPN) malaria vaccine

    PubMed Central

    Guo, Qin; Dasgupta, Debleena; Doll, Tais A.P.F.; Burkhard, Peter; Lanar, David E.

    2013-01-01

    There are many ways to present antigens to the immune system. We have used a repetitive antigen display technology that relies on the self-assembly of 60 protein chains into a spherical self-assembling protein nanoparticle (SAPN) to develop a vaccine against Plasmodium falciparum malaria. The protein sequence contains selected B- and T-cell epitopes of the circumsporozoite protein of P. falciparum (PfCSP) and, when assembled into a nanoparticle induces strong, long-lived and protective immune responses against the PfCSP. Here we describe the conditions needed for promoting self-assembly of a P. falciparum vaccine nanoparticle, PfCSP-KMY-SAPN, and note pitfalls that may occur when determining conditions for other SAPN vaccines. Attention was paid to selecting processes that were amenable to scale up and cGMP manufacturing. PMID:23548672

  11. Expression, purification and refolding of a self-assembling protein nanoparticle (SAPN) malaria vaccine.

    PubMed

    Guo, Qin; Dasgupta, Debleena; Doll, Tais A P F; Burkhard, Peter; Lanar, David E

    2013-05-01

    There are many ways to present antigens to the immune system. We have used a repetitive antigen display technology that relies on the self-assembly of 60 protein chains into a spherical self-assembling protein nanoparticle (SAPN) to develop a vaccine against Plasmodium falciparum malaria. The protein sequence contains selected B- and T-cell epitopes of the circumsporozoite protein of P. falciparum (PfCSP) and, when assembled into a nanoparticle induces strong, long-lived and protective immune responses against the PfCSP. Here we describe the conditions needed for promoting self-assembly of a P. falciparum vaccine nanoparticle, PfCSP-KMY-SAPN, and note pitfalls that may occur when determining conditions for other SAPN vaccines. Attention was paid to selecting processes that were amenable to scale up and cGMP manufacturing.

  12. Development of a Pfs25-EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle.

    PubMed

    Shimp, Richard L; Rowe, Christopher; Reiter, Karine; Chen, Beth; Nguyen, Vu; Aebig, Joan; Rausch, Kelly M; Kumar, Krishan; Wu, Yimin; Jin, Albert J; Jones, David S; Narum, David L

    2013-06-19

    Successful efforts to control infectious diseases have often required the use of effective vaccines. The current global strategy for control of malaria, including elimination and eradication will also benefit from the development of an effective vaccine that interrupts malaria transmission. To this end, a vaccine that disrupts malaria transmission within the mosquito host has been investigated for several decades targeting a 25 kDa ookinete specific surface protein, identified as Pfs25. Phase 1 human trial results using a recombinant Pfs25H/Montanide ISA51 formulation demonstrated that human Pfs25 specific antibodies block parasite infectivity to mosquitoes; however, the extent of blocking was likely insufficient for an effective transmission blocking vaccine. To overcome the poor immunogenicity, processes to produce and characterize recombinant Pfs25H conjugated to a detoxified form of Pseudomonas aeruginosa exoprotein A (EPA) have been developed and used to manufacture a cGMP pilot lot for use in human clinical trials. The Pfs25-EPA conjugate appears as a nanoparticle with an average molar mass in solution of approximately 600 kDa by static light scattering with an average diameter 20 nm (range 10-40 nm) by dynamic light scattering. The molar ratio of Pfs25H to EPA is about 3 to 1 by amino acid analysis, respectively. Outbred mice immunized with the Pfs25-EPA conjugated nanoparticle formulated on Alhydrogel(®) had a 75-110 fold increase in Pfs25H specific antibodies when compared to an unconjugated Pfs25H/Alhydrogel(®) formulation. A phase 1 human trial using the Pfs25-EPA/Alhydrogel(®) formulation is ongoing in the United States.

  13. Optimal vaccination and bednet maintenance for the control of malaria in a region with naturally acquired immunity.

    PubMed

    Prosper, Olivia; Ruktanonchai, Nick; Martcheva, Maia

    2014-07-21

    Following over two decades of research, the malaria vaccine candidate RTS,S has reached the final stages of vaccine trials, demonstrating an efficacy of roughly 50% in young children. Regions with high malaria prevalence tend to have high levels of naturally acquired immunity (NAI) to severe malaria; NAI is caused by repeated exposure to infectious bites and results in large asymptomatic populations. To address concerns about how these vaccines will perform in regions with existing NAI, we developed a simple malaria model incorporating vaccination and NAI. Typically, if the basic reproduction number (R0) for malaria is greater than unity, the disease will persist; otherwise, the disease will become extinct. However, analysis of this model revealed that NAI, compounded by a subpopulation with only partial protection to malaria, may render vaccination efforts ineffective and potentially detrimental to malaria control, by increasing R0 and increasing the likelihood of malaria persistence even when R0<1. The likelihood of this scenario increases when non-immune infected individuals are treated disproportionately compared with partially immune individuals - a plausible scenario since partially immune individuals are more likely to be asymptomatically infected. Consequently, we argue that active case-detection of asymptomatic infections is a critical component of an effective malaria control program. We then investigated optimal vaccination and bednet control programs under two endemic settings with varying levels of naturally acquired immunity: a typical setting under which prevalence decays when R0<1, and a setting in which subthreshold endemic equilibria exist. A qualitative comparison of the optimal control results under the first setting revealed that the optimal policy differs depending on whether the goal is to reduce total morbidity, or to reduce clinical infections. Furthermore, this comparison dictates that control programs should place less effort in

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

    PubMed

    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.

  15. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.

    PubMed

    Richie, Thomas L; Billingsley, Peter F; Sim, B Kim Lee; James, Eric R; Chakravarty, Sumana; Epstein, Judith E; Lyke, Kirsten E; Mordmüller, Benjamin; Alonso, Pedro; Duffy, Patrick E; Doumbo, Ogobara K; Sauerwein, Robert W; Tanner, Marcel; Abdulla, Salim; Kremsner, Peter G; Seder, Robert A; Hoffman, Stephen L

    2015-12-22

    Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015-2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regional malaria elimination and eventual global eradication.

  16. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines

    PubMed Central

    Richie, Thomas L.; Billingsley, Peter F.; Sim, B. Kim Lee; James, Eric R.; Chakravarty, Sumana; Epstein, Judith E.; Lyke, Kirsten E.; Mordmüller, Benjamin; Alonso, Pedro; Duffy, Patrick E.; Doumbo, Ogobara K.; Sauerwein, Robert W.; Tanner, Marcel; Abdulla, Salim; Kremsner, Peter G.; Seder, Robert A.; Hoffman, Stephen L.

    2016-01-01

    Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015–2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regional malaria elimination and eventual global eradication. PMID:26469720

  17. Implementation workshop of WHO guidelines on evaluation of malaria vaccines: Current regulatory concepts and issues related to vaccine quality, Pretoria, South Africa 07 Nov 2014.

    PubMed

    Ho, Mei Mei; Baca-Estrada, Maria; Conrad, Christoph; Karikari-Boateng, Eric; Kang, Hye-Na

    2015-08-26

    The current World Health Organization (WHO) guidelines on the quality, safety and efficacy of recombinant malaria vaccines targeting the pre-erythrocytic and blood stages of Plasmodium falciparum were adopted by the WHO Expert Committee on Biological Standardization in 2012 to provide guidance on the quality, nonclinical and clinical aspects of recombinant malaria vaccines. A WHO workshop was organised to facilitate implementation into African (national/regional) regulatory practices, of the regulatory evaluation principles outlined in the guidelines regarding quality aspects. The workshop was used also to share knowledge and experience on regulatory topics of chemistry, manufacturing and control with a focus on vaccines through presentations and an interactive discussion using a case study approach. The basic principles and concepts of vaccine quality including consistency of production, quality control and manufacturing process were presented and discussed in the meeting. By reviewing and practicing a case study, better understanding on the relationship between consistency of production and batch release tests of an adjuvanted pre-erythrocytic recombinant malaria vaccine was reached. The case study exercise was considered very useful to understand regulatory evaluation principles of vaccines and a suggestion was made to WHO to provide such practices also through its Global Learning Opportunities for Vaccine Quality programme.

  18. [Malaria].

    PubMed

    Burchard, G D

    2014-02-01

    Malaria is the most important infectious disease imported by travelers and migrants from tropical and subtropical areas. It is imported quite frequently. It is a life-threatening disease. Symptoms are nonspecific and cannot easily be distinguished from a wide range of other febrile conditions. Therefore, travel history must be taken in all patients with fever of unknown origin and malaria diagnostics must be performed immediately on suspicion of malaria. Uncomplicated falciparum malaria should be treated in the hospital with either atovaquone-proguanil or with an artemisinin-based combination preparation. If there is evidence of severe malaria, the patient must be moved to an intensive care unit. The antiparasitic agent of choice is then artesunate.

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

    PubMed Central

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

    2016-01-01

    Background 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. Methods 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 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL 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. Results 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. Significance 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

  20. Decrease in circulating CD25(hi)Foxp3(+) regulatory T cells following vaccination with the candidate malaria vaccine RTS,S.

    PubMed

    Parsons, Emily; Epstein, Judith; Sedegah, Martha; Villasante, Eileen; Stewart, Ann

    2016-08-31

    Regulatory T (Treg) cells have been shown in some cases to limit vaccine-specific immune responses and impact efficacy. Very little is known about the regulatory responses to the leading malaria vaccine candidate, RTS,S. The goal of this study was to begin to characterize the regulatory responses to the RTS,S vaccine. Using multi-parameter flow cytometry, we examined responses in 13 malaria naïve adult volunteers who received 2 doses of RTS,S given eight weeks apart. Five of these volunteers had previously received 3 doses of a candidate DNA-CSP vaccine, with the final dose given approximately one year prior to the first dose of the RTS,S vaccine. We found that the frequency of CD25(hi)Foxp3(+) Treg cells decreased following administration of RTS,S (p=0.0195), with no differences based on vaccine regimen. There was a concomitant decrease in CTLA-4 expression on CD25(hi)Foxp3(+) Treg cells (p=0.0093) and PD-1 levels on CD8(+) T cells (p=0.0002). Additionally, the frequency of anergic CTLA-4(+)CCR7(+) T cells decreased following vaccination. An inverse correlation was observed between the frequency of Plasmodium falciparum circumsporozoite protein (PfCSP)-specific IFN-γ and PfCSP-specific IL-10, as well as an inverse correlation between IL-10 induced by Hepatitis B surface antigen, the carrier of RTS,S, and PfCSP-specific IFN-γ, suggesting that immunity against the vaccine backbone could impact vaccine immunogenicity. These results have implications for future malaria vaccine design.

  1. Decrease in circulating CD25(hi)Foxp3(+) regulatory T cells following vaccination with the candidate malaria vaccine RTS,S.

    PubMed

    Parsons, Emily; Epstein, Judith; Sedegah, Martha; Villasante, Eileen; Stewart, Ann

    2016-08-31

    Regulatory T (Treg) cells have been shown in some cases to limit vaccine-specific immune responses and impact efficacy. Very little is known about the regulatory responses to the leading malaria vaccine candidate, RTS,S. The goal of this study was to begin to characterize the regulatory responses to the RTS,S vaccine. Using multi-parameter flow cytometry, we examined responses in 13 malaria naïve adult volunteers who received 2 doses of RTS,S given eight weeks apart. Five of these volunteers had previously received 3 doses of a candidate DNA-CSP vaccine, with the final dose given approximately one year prior to the first dose of the RTS,S vaccine. We found that the frequency of CD25(hi)Foxp3(+) Treg cells decreased following administration of RTS,S (p=0.0195), with no differences based on vaccine regimen. There was a concomitant decrease in CTLA-4 expression on CD25(hi)Foxp3(+) Treg cells (p=0.0093) and PD-1 levels on CD8(+) T cells (p=0.0002). Additionally, the frequency of anergic CTLA-4(+)CCR7(+) T cells decreased following vaccination. An inverse correlation was observed between the frequency of Plasmodium falciparum circumsporozoite protein (PfCSP)-specific IFN-γ and PfCSP-specific IL-10, as well as an inverse correlation between IL-10 induced by Hepatitis B surface antigen, the carrier of RTS,S, and PfCSP-specific IFN-γ, suggesting that immunity against the vaccine backbone could impact vaccine immunogenicity. These results have implications for future malaria vaccine design. PMID:27443592

  2. Malaria

    MedlinePlus

    ... Malaria can be carried by mosquitoes in temperate climates, but the parasite disappears over the winter. The ... a major disease hazard for travelers to warm climates. In some areas of the world, mosquitoes that ...

  3. Malaria

    MedlinePlus

    ... a parasite. You get it when an infected mosquito bites you. Malaria is a major cause of ... insect repellent with DEET Cover up Sleep under mosquito netting Centers for Disease Control and Prevention

  4. Recent developments in the assessment of the immune response to malaria, especially as related to vaccination: Malaria vaccination with irradiated sporozoites: serological evaluation of the antigen and antibody responses*

    PubMed Central

    Bawden, M. P.; Palmer, T. T.; Leef, M. F.; Beaudoin, R. L.

    1979-01-01

    Vaccination against Plasmodium falciparum with attenuated sporozoites is the goal of the US Navy's Malaria Vaccine Program. One requirement in the development of this vaccine is an immunological test to study the sporozoite antigen and immune responses it induces. Using an indirect fluorescent antibody test (IFAT) and P. berghei in the mouse or rat as a model, we have made significant progress toward this goal. Four antigens were detected in vaccine preparations: sporozoite-specific antigens, mosquito antigens, antigens on the sporozoite that are common to erythrocytic stages, and bovine serum albumm, an antigenic element of the isolation medium no longer employed. The IFAT was a reliable monitor of vaccination in a mouse and rat model in conjunction with protection to challenge. The test was a sensitive monitor of vaccine quality. Anamnestic responses to bites of infected mosquitos were detected in mice previously immunized with irradiated sporozoites. PMID:120769

  5. Laser mimicking mosquito bites for skin delivery of malaria sporozoite vaccines.

    PubMed

    Zhou, Chang; Chen, Xinyuan; Zhang, Qi; Wang, Ji; Wu, Mei X

    2015-04-28

    Immunization with radiation-attenuated sporozoites (RAS) via mosquito bites has been shown to induce sterile immunity against malaria in humans, but this route of vaccination is neither practical nor ethical. The importance of delivering RAS to the liver through circulation in eliciting immunity against this parasite has been recently verified by human studies showing that high-level protection was achieved only by intravenous (IV) administration of RAS, not by intradermal (ID) or subcutaneous (SC) vaccination. Here, we report in a murine model that ID inoculation of RAS into laser-illuminated skin confers immune protection against malarial infection almost as effectively as IV immunization. Brief illumination of the inoculation site with a low power 532 nm Nd:YAG laser enhanced the permeability of the capillary beneath the skin, owing to hemoglobin-specific absorbance of the light. The increased blood vessel permeability appeared to facilitate an association of RAS with blood vessel walls by an as-yet-unknown mechanism, ultimately promoting a 7-fold increase in RAS entering circulation and reaching the liver over ID administration. Accordingly, ID immunization of RAS at a laser-treated site stimulated much stronger sporozoite-specific antibody and CD8(+)IFN-γ(+) T cell responses than ID vaccination and provided nearly full protection against malarial infection, whereas ID immunization alone was ineffective. This novel, safe, and convenient strategy to augment efficacy of ID sporozoite-based vaccines warrants further investigation in large animals and in humans.

  6. Laser mimicking mosquito bites for skin delivery of malaria sporozoite vaccines.

    PubMed

    Zhou, Chang; Chen, Xinyuan; Zhang, Qi; Wang, Ji; Wu, Mei X

    2015-04-28

    Immunization with radiation-attenuated sporozoites (RAS) via mosquito bites has been shown to induce sterile immunity against malaria in humans, but this route of vaccination is neither practical nor ethical. The importance of delivering RAS to the liver through circulation in eliciting immunity against this parasite has been recently verified by human studies showing that high-level protection was achieved only by intravenous (IV) administration of RAS, not by intradermal (ID) or subcutaneous (SC) vaccination. Here, we report in a murine model that ID inoculation of RAS into laser-illuminated skin confers immune protection against malarial infection almost as effectively as IV immunization. Brief illumination of the inoculation site with a low power 532 nm Nd:YAG laser enhanced the permeability of the capillary beneath the skin, owing to hemoglobin-specific absorbance of the light. The increased blood vessel permeability appeared to facilitate an association of RAS with blood vessel walls by an as-yet-unknown mechanism, ultimately promoting a 7-fold increase in RAS entering circulation and reaching the liver over ID administration. Accordingly, ID immunization of RAS at a laser-treated site stimulated much stronger sporozoite-specific antibody and CD8(+)IFN-γ(+) T cell responses than ID vaccination and provided nearly full protection against malarial infection, whereas ID immunization alone was ineffective. This novel, safe, and convenient strategy to augment efficacy of ID sporozoite-based vaccines warrants further investigation in large animals and in humans. PMID:25725360

  7. Creation of first malaria vaccine raises troubling questions about "intellectual racism". Interview by Kirsteen MacLeod.

    PubMed

    Patarroyo, M

    1995-11-01

    Some of the problems caused by malaria, which places a huge roadblock in front of economic progress in the Third World, may be solved by a new vaccine created by Dr. Manuel Patarroyo, a Columbian physician and researcher. "Imagine how things would be if Canadians had malaria," he says. "Episodes last 10 days, then there are 10 days of recovering. This leaves only 10 days each month in which to do some productive work. Then imagine killing the population of Toronto each year, and you can see the huge toll in terms of the number of yearly deaths globally from malaria." His discovery also raises the issue of "intellectual racism" because of criticism of Patarroyo's methods by Western scientists. Patarroyo, meanwhile, turned down a $60-million offer for his vaccine, and instead donated the patent to the World Health Organization.

  8. Induction of CD4(+) T cell-dependent CD8(+) type 1 responses in humans by a malaria DNA vaccine.

    PubMed

    Wang, R; Epstein, J; Baraceros, F M; Gorak, E J; Charoenvit, Y; Carucci, D J; Hedstrom, R C; Rahardjo, N; Gay, T; Hobart, P; Stout, R; Jones, T R; Richie, T L; Parker, S E; Doolan, D L; Norman, J; Hoffman, S L

    2001-09-11

    We assessed immunogenicity of a malaria DNA vaccine administered by needle i.m. or needleless jet injection [i.m. or i.m./intradermally (i.d.)] in 14 volunteers. Antigen-specific IFN-gamma responses were detected by enzyme-linked immunospot (ELISPOT) assays in all subjects to multiple 9- to 23-aa peptides containing class I and/or class II restricted epitopes, and were dependent on both CD8(+) and CD4(+) T cells. Overall, frequency of response was significantly greater after i.m. jet injection. CD8(+)-dependent cytotoxic T lymphocytes (CTL) were detected in 8/14 volunteers. Demonstration in humans of elicitation of the class I restricted IFN-gamma responses we believe necessary for protection against the liver stage of malaria parasites brings us closer to an effective malaria vaccine.

  9. Creation of first malaria vaccine raises troubling questions about "intellectual racism". Interview by Kirsteen MacLeod.

    PubMed

    Patarroyo, M

    1995-11-01

    Some of the problems caused by malaria, which places a huge roadblock in front of economic progress in the Third World, may be solved by a new vaccine created by Dr. Manuel Patarroyo, a Columbian physician and researcher. "Imagine how things would be if Canadians had malaria," he says. "Episodes last 10 days, then there are 10 days of recovering. This leaves only 10 days each month in which to do some productive work. Then imagine killing the population of Toronto each year, and you can see the huge toll in terms of the number of yearly deaths globally from malaria." His discovery also raises the issue of "intellectual racism" because of criticism of Patarroyo's methods by Western scientists. Patarroyo, meanwhile, turned down a $60-million offer for his vaccine, and instead donated the patent to the World Health Organization. PMID:7497394

  10. Creation of first malaria vaccine raises troubling questions about "intellectual racism". Interview by Kirsteen MacLeod.

    PubMed Central

    Patarroyo, M

    1995-01-01

    Some of the problems caused by malaria, which places a huge roadblock in front of economic progress in the Third World, may be solved by a new vaccine created by Dr. Manuel Patarroyo, a Columbian physician and researcher. "Imagine how things would be if Canadians had malaria," he says. "Episodes last 10 days, then there are 10 days of recovering. This leaves only 10 days each month in which to do some productive work. Then imagine killing the population of Toronto each year, and you can see the huge toll in terms of the number of yearly deaths globally from malaria." His discovery also raises the issue of "intellectual racism" because of criticism of Patarroyo's methods by Western scientists. Patarroyo, meanwhile, turned down a $60-million offer for his vaccine, and instead donated the patent to the World Health Organization. Images p1320-a PMID:7497394

  11. Malaria: deploying a candidate vaccine (RTS,S/AS02A) for an old scourge of humankind.

    PubMed

    Alonso, Pedro L

    2006-06-01

    Malaria is an infectious disease caused by the protist Plasmodium spp. and it currently kills more than one million people annually. The burden of malaria is concentrated in sub-Saharan Africa, India, and Southeast Asia. The parasite's resistance to commonly used anti-malarial drugs has worsened the situation in the poorest countries. The World Health Organization (WHO) estimates that more than 100 countries suffer from endemic malaria episodes. In addition to numerous control measures and treatments, several vaccines are at different research stages and trials. We have assayed RTS,S/AS02A, a pre-erythrocytic candidate vaccine that has shown promising protection levels in phase IIb trials in Mozambique. The vaccine is directed against the sporozoite form of the parasite, which is injected by the mosquito Anopheles spp. The vaccine induces a strong antibody response and stimulates Th1 cells-a subset of helper T cells that participates in cell-mediated immunity. Recent interest by international funding agencies has provided new inputs into initiatives and programs to fight malaria, which, under normal welfare and adequate social development conditions, is a curable disease.

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

    PubMed

    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. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships.

    PubMed

    Walker, Karen M; Okitsu, Shinji; Porter, David W; Duncan, Christopher; Amacker, Mario; Pluschke, Gerd; Cavanagh, David R; Hill, Adrian V S; Todryk, Stephen M

    2015-05-01

    This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119 , correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. PMID:25471322

  14. TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models

    PubMed Central

    Tougan, Takahiro; Aoshi, Taiki; Coban, Cevayir; Katakai, Yuko; Kai, Chieko; Yasutomi, Yasuhiro; Ishii, Ken J.; Horii, Toshihiro

    2013-01-01

    The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparum parasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine. PMID:23291928

  15. TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models.

    PubMed

    Tougan, Takahiro; Aoshi, Taiki; Coban, Cevayir; Katakai, Yuko; Kai, Chieko; Yasutomi, Yasuhiro; Ishii, Ken J; Horii, Toshihiro

    2013-02-01

    The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparum parasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine. PMID:23291928

  16. Impact of malaria and helminth infections on immunogenicity of the human papillomavirus-16/18 AS04-adjuvanted vaccine in Tanzania☆☆☆

    PubMed Central

    Brown, Joelle; Baisley, Kathy; Kavishe, Bazil; Changalucha, John; Andreasen, Aura; Mayaud, Philippe; Gumodoka, Balthazar; Kapiga, Saidi; Hayes, Richard; Watson-Jones, Deborah

    2014-01-01

    Background 

 Endemic malaria and helminth infections in sub-Saharan Africa can act as immunological modulators and impact responses to standard immunizations. We conducted a cohort study to measure the influence of malaria and helminth infections on the immunogenicity of the bivalent HPV-16/18 vaccine. Methods 

 We evaluated the association between malaria and helminth infections, and HPV-16/18 antibody responses among 298 Tanzanian females aged 10–25 years enrolled in a randomized controlled trial of the HPV-16/18 vaccine. Malaria parasitaemia was diagnosed by examination of blood smears, and helminth infections were diagnosed by examination of urine and stool samples, respectively. Geometric mean antibody titres (GMT) against HPV-16/18 antibodies were measured by enzyme-linked immunosorbent assay. Results 

 Parasitic infections were common; one-third (30.4%) of participants had a helminth infection and 10.2% had malaria parasitaemia. Overall, the vaccine induced high HPV-16/18 GMTs, and there was no evidence of a reduction in HPV-16 or HPV-18 GMT at Month 7 or Month 12 follow-up visits among participants with helminths or malaria. There was some evidence that participants with malaria had increased GMTs compared to those without malaria. Conclusions 

 The data show high HPV immunogenicity regardless of the presence of malaria and helminth infections. The mechanism and significance for the increase in GMT in those with malaria is unknown. PMID:24291193

  17. Antibody levels to multiple malaria vaccine candidate antigens in relation to clinical malaria episodes in children in the Kasena-Nankana district of Northern Ghana

    PubMed Central

    2011-01-01

    Background Considering the natural history of malaria of continued susceptibility to infection and episodes of illness that decline in frequency and severity over time, studies which attempt to relate immune response to protection must be longitudinal and have clearly specified definitions of immune status. Putative vaccines are expected to protect against infection, mild or severe disease or reduce transmission, but so far it has not been easy to clearly establish what constitutes protective immunity or how this develops naturally, especially among the affected target groups. The present study was done in under six year old children to identify malaria antigens which induce antibodies that correlate with protection from Plasmodium falciparum malaria. Methods In this longitudinal study, the multiplex assay was used to measure IgG antibody levels to 10 malaria antigens (GLURP R0, GLURP R2, MSP3 FVO, AMA1 FVO, AMA1 LR32, AMA1 3D7, MSP1 3D7, MSP1 FVO, LSA-1and EBA175RII) in 325 children aged 1 to 6 years in the Kassena Nankana district of northern Ghana. The antigen specific antibody levels were then related to the risk of clinical malaria over the ensuing year using a negative binomial regression model. Results IgG levels generally increased with age. The risk of clinical malaria decreased with increasing antibody levels. Except for FMPOII-LSA, (p = 0.05), higher IgG levels were associated with reduced risk of clinical malaria (defined as axillary temperature ≥37.5°C and parasitaemia of ≥5000 parasites/ul blood) in a univariate analysis, upon correcting for the confounding effect of age. However, in a combined multiple regression analysis, only IgG levels to MSP1-3D7 (Incidence rate ratio = 0.84, [95% C.I.= 0.73, 0.97, P = 0.02]) and AMA1 3D7 (IRR = 0.84 [95% C.I.= 0.74, 0.96, P = 0.01]) were associated with a reduced risk of clinical malaria over one year of morbidity surveillance. Conclusion The data from this study support the view that a multivalent vaccine

  18. Geographic differentiation of polymorphism in the Plasmodium falciparum malaria vaccine candidate gene SERA5.

    PubMed

    Tanabe, Kazuyuki; Arisue, Nobuko; Palacpac, Nirianne M Q; Yagi, Masanori; Tougan, Takahiro; Honma, Hajime; Ferreira, Marcelo U; Färnert, Anna; Björkman, Anders; Kaneko, Akira; Nakamura, Masatoshi; Hirayama, Kenji; Mita, Toshihiro; Horii, Toshihiro

    2012-02-21

    SERA5 is regarded as a promising malaria vaccine candidate of the most virulent human malaria parasite Plasmodium falciparum. SERA5 is a 120 kDa abundantly expressed blood-stage protein containing a papain-like protease. Since substantial polymorphism in blood-stage vaccine candidates may potentially limit their efficacy, it is imperative to fully investigate polymorphism of the SERA5 gene (sera5). In this study, we performed evolutionary and population genetic analysis of sera5. The level of inter-species divergence (kS=0.076) between P. falciparum and Plasmodium reichenowi, a closely related chimpanzee malaria parasite is comparable to that of housekeeping protein genes. A signature of purifying selection was detected in the proenzyme and enzyme domains. Analysis of 445 near full-length P. falciparum sera5 sequences from nine countries in Africa, Southeast Asia, Oceania and South America revealed extensive variations in the number of octamer repeat (OR) and serine repeat (SR) regions as well as substantial level of single nucleotide polymorphism (SNP) in non-repeat regions (2562 bp). Remarkably, a 14 amino acid sequence of SERA5 (amino acids 59-72) that is known to be the in vitro target of parasite growth inhibitory antibodies was found to be perfectly conserved in all 445 worldwide isolates of P. falciparum evaluated. Unlike other major vaccine target antigen genes such as merozoite surface protein-1, apical membrane antigen-1 or circumsporozoite protein, no strong evidence for positive selection was detected for SNPs in the non-repeat regions of sera5. A biased geographical distribution was observed in SNPs as well as in the haplotypes of the sera5 OR and SR regions. In Africa, OR- and SR-haplotypes with low frequency (<5%) and SNPs with minor allele frequency (<5%) were abundant and were mostly continent-specific. Consistently, significant genetic differentiation, assessed by the Wright's fixation index (Fst) of inter-population variance in allele frequencies

  19. Protective epitopes of the Plasmodium falciparum SERA5 malaria vaccine reside in intrinsically unstructured N-terminal repetitive sequences.

    PubMed

    Yagi, Masanori; Bang, Gilles; Tougan, Takahiro; Palacpac, Nirianne M Q; Arisue, Nobuko; Aoshi, Taiki; Matsumoto, Yoshitsugu; Ishii, Ken J; Egwang, Thomas G; Druilhe, Pierre; Horii, Toshihiro

    2014-01-01

    The malaria vaccine candidate antigen, SE36, is based on the N-terminal 47 kDa domain of Plasmodium falciparum serine repeat antigen 5 (SERA5). In epidemiological studies, we have previously shown the inhibitory effects of SE36 specific antibodies on in vitro parasite growth and the negative correlation between antibody level and malaria symptoms. A phase 1 b trial of the BK-SE36 vaccine in Uganda elicited 72% protective efficacy against symptomatic malaria in children aged 6-20 years during the follow-up period 130-365 days post-second vaccination. Here, we performed epitope mapping with synthetic peptides covering the whole sequence of SE36 to identify and map dominant epitopes in Ugandan adult serum presumed to have clinical immunity to P. falciparum malaria. High titer sera from the Ugandan adults predominantly reacted with peptides corresponding to two successive N-terminal regions of SERA5 containing octamer repeats and serine rich sequences, regions of SERA5 that were previously reported to have limited polymorphism. Affinity purified antibodies specifically recognizing the octamer repeats and serine rich sequences exhibited a high antibody-dependent cellular inhibition (ADCI) activity that inhibited parasite growth. Furthermore, protein structure predictions and structural analysis of SE36 using spectroscopic methods indicated that N-terminal regions possessing inhibitory epitopes are intrinsically unstructured. Collectively, these results suggest that strict tertiary structure of SE36 epitopes is not required to elicit protective antibodies in naturally immune Ugandan adults. PMID:24886718

  20. Protective Epitopes of the Plasmodium falciparum SERA5 Malaria Vaccine Reside in Intrinsically Unstructured N-Terminal Repetitive Sequences

    PubMed Central

    Tougan, Takahiro; Palacpac, Nirianne M. Q.; Arisue, Nobuko; Aoshi, Taiki; Matsumoto, Yoshitsugu; Ishii, Ken J.; Egwang, Thomas G.; Druilhe, Pierre; Horii, Toshihiro

    2014-01-01

    The malaria vaccine candidate antigen, SE36, is based on the N-terminal 47 kDa domain of Plasmodium falciparum serine repeat antigen 5 (SERA5). In epidemiological studies, we have previously shown the inhibitory effects of SE36 specific antibodies on in vitro parasite growth and the negative correlation between antibody level and malaria symptoms. A phase 1 b trial of the BK-SE36 vaccine in Uganda elicited 72% protective efficacy against symptomatic malaria in children aged 6–20 years during the follow-up period 130–365 days post–second vaccination. Here, we performed epitope mapping with synthetic peptides covering the whole sequence of SE36 to identify and map dominant epitopes in Ugandan adult serum presumed to have clinical immunity to P. falciparum malaria. High titer sera from the Ugandan adults predominantly reacted with peptides corresponding to two successive N-terminal regions of SERA5 containing octamer repeats and serine rich sequences, regions of SERA5 that were previously reported to have limited polymorphism. Affinity purified antibodies specifically recognizing the octamer repeats and serine rich sequences exhibited a high antibody-dependent cellular inhibition (ADCI) activity that inhibited parasite growth. Furthermore, protein structure predictions and structural analysis of SE36 using spectroscopic methods indicated that N-terminal regions possessing inhibitory epitopes are intrinsically unstructured. Collectively, these results suggest that strict tertiary structure of SE36 epitopes is not required to elicit protective antibodies in naturally immune Ugandan adults. PMID:24886718

  1. Study of the safety and immunogenicity of the synthetic malaria SPf66 vaccine in children aged 1-14 years.

    PubMed

    Patarroyo, G; Franco, L; Amador, R; Murillo, L A; Rocha, C L; Rojas, M; Patarroyo, M E

    1992-01-01

    Safety and immunogenicity tests of the SPf66 malaria vaccine have been carried out on a population of children, aged 1 to 14 years, in the town of Tumaco, Colombia. Adverse reactions measured after each vaccination were local and minimal, and observed in only a small percentage of the vaccinated children. One year later, no delayed reaction was evident. The majority of the child population developed high antibody titres against SPf66 and the degree of response did not vary with age. These induced antibodies recognize the native parasite proteins, in particular the molecules from which the amino acid sequence of this vaccine was deduced. These studies demonstrate that the SPf66 vaccine is safe and highly immunogenic for use in children greater than 1 year old.

  2. Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites

    PubMed Central

    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<0.01 across all sites). VE during the 20 mo 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 was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol). VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from −1 to 49, respectively; corresponding ranges among infants were −10 to 1,402 and −13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively. Conclusions RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at

  3. Vaccination with a purified blood-stage malaria antigen in mice: correlation of protection with T cell mediated immunity.

    PubMed Central

    Playfair, J H; De Souza, J B; Freeman, R R; Holder, A A

    1985-01-01

    A purified 230,000 mol wt protein antigen from the lethal mouse malaria parasite Plasmodium yoelii YM which had previously been shown to be highly effective as a vaccine, was tested for its ability to stimulate specific helper T cells and T cells responsible for delayed hypersensitivity. Strong stimulation was found in both assays, but larger doses were required for delayed hypersensitivity, correlating well with the requirements for protection. It is suggested that T stimulation may be a requirement for effective protection by purified antigens in malaria. PMID:2933196

  4. A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

    PubMed Central

    2014-01-01

    Background The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria. Methods Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios. Results Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals. Conclusions Vaccine-induced anti-CSP antibody titres and transmission intensity can

  5. A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119

    PubMed Central

    Fonseca, Jairo Andres; Cabrera-Mora, Monica; Singh, Balwan; Oliveira-Ferreira, Joseli; da Costa Lima-Junior, Josué; Calvo-Calle, J. Mauricio; Lozano, Jose Manuel; Moreno, Alberto

    2016-01-01

    The most widespread Plasmodium species, Plasmodium vivax, poses a significant public health threat. An effective vaccine is needed to reduce global malaria burden. Of the erythrocytic stage vaccine candidates, the 19 kDa fragment of the P. vivax Merozoite Surface Protein 1 (PvMSP119) is one of the most promising. Our group has previously defined several promiscuous T helper epitopes within the PvMSP1 protein, with features that allow them to bind multiple MHC class II alleles. We describe here a P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) that includes defined T cell epitopes genetically fused to PvMSP119. This vaccine candidate preserved structural elements of the native PvMSP119 and elicited cytophilic antibody responses, and CD4+ and CD8+ T cells capable of recognizing PvMSP119. Although CD8+ T cells that recognize blood stage antigens have been reported to control blood infection, CD8+ T cell responses induced by P. falciparum or P. vivax vaccine candidates based on MSP119 have not been reported. To our knowledge, this is the first time a protein based subunit vaccine has been able to induce CD8+ T cell against PvMSP119. The PvRMC-MSP1 protein was also recognized by naturally acquired antibodies from individuals living in malaria endemic areas with an antibody profile associated with protection from infection. These features make PvRMC-MSP1 a promising vaccine candidate. PMID:27708348

  6. Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults

    PubMed Central

    2011-01-01

    Background To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays. Methods In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinant Plasmodium falciparum CSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured by ex vivo IFN-γ ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of individual samples using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing samples collected two weeks apart. Results In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of ex vivo ELISpot activities were similar in both communities. DR-restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants. Conclusions All participants were positive for

  7. Early Phase Clinical Trials with Human Immunodeficiency Virus-1 and Malaria Vectored Vaccines in The Gambia: Frontline Challenges in Study Design and Implementation

    PubMed Central

    Afolabi, Muhammed O.; Adetifa, Jane U.; Imoukhuede, Egeruan B.; Viebig, Nicola K.; Kampmann, Beate; Bojang, Kalifa

    2014-01-01

    Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria are among the most important infectious diseases in developing countries. Existing control strategies are unlikely to curtail these diseases in the absence of efficacious vaccines. Testing of HIV and malaria vaccines candidates start with early phase trials that are increasingly being conducted in developing countries where the burden of the diseases is high. Unique challenges, which affect planning and implementation of vaccine trials according to internationally accepted standards have thus been identified. In this review, we highlight specific challenges encountered during two early phase trials of novel HIV-1 and malaria vectored vaccine candidates conducted in The Gambia and how some of these issues were pragmatically addressed. We hope our experience will be useful for key study personnel involved in day-to-day running of similar clinical trials. It may also guide future design and implementation of vaccine trials in resource-constrained settings. PMID:24615122

  8. Imaging murine NALT following intranasal immunization with flagellin-modified circumsporozoite protein malaria vaccines

    PubMed Central

    Nacer, Adéla; Carapau, Daniel; Mitchell, Robert; Meltzer, Abby; Shaw, Alan; Frevert, Ute; Nardin, Elizabeth H

    2013-01-01

    Intranasal (IN) immunization with a Plasmodium circumsporozoite (CS) protein conjugated to flagellin, a TLR5 agonist, was found to elicit antibody mediated protective immunity in our previous murine studies. To better understand IN elicited immune responses, we examined the nasopharynx-associated lymphoid tissue (NALT) in immunized mice and the interaction of flagellin-modified CS with murine dendritic cells (DC) in vitro. NALT of immunized mice contained a predominance of germinal center (GC) B cells and increased numbers of CD11c+ DC localized beneath the epithelium and within the GC T cell area. We detected microfold (M) cells distributed throughout the NALT epithelial cell layer and DC dendrites extending into the nasal cavity which could potentially function in luminal CS antigen uptake. Flagellin-modified CS taken up by DC in vitro was initially localized within intracellular vesicles followed by a cytosolic distribution. Vaccine modifications to enhance delivery to the NALT and specifically target NALT APC populations will advance development of an efficacious needle-free vaccine for the 40% of the world's population at risk of malaria. PMID:23820750

  9. Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein.

    PubMed

    Parra, Marcela; Liu, Xia; Derrick, Steven C; Yang, Amy; Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Zheng, Hong; Thao Pham, Phuong; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D; Waldmann, Thomas A; Kumar, Sanjai; Morris, Sheldon L; Perera, Liyanage P

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies.

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

    PubMed Central

    Thrane, Susan; Janitzek, Christoph M.; Agerbæk, Mette Ø.; Ditlev, Sisse B.; Resende, Mafalda; Nielsen, Morten A.; Theander, Thor G.; Salanti, Ali; Sander, Adam F.

    2015-01-01

    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 parasites to CSA

  11. The application of anti-Toso antibody enhances CD8(+) T cell responses in experimental malaria vaccination and disease.

    PubMed

    Lapke, Nina; Tartz, Susanne; Lee, Kyeong-Hee; Jacobs, Thomas

    2015-11-27

    Toso is a molecule highly expressed on B cells. It influences their survival and was identified as an IgM binding molecule. B cells and natural antibodies play a role in vaccination-induced CD8(+) T cell responses. We investigated the impact of an anti-Toso antibody on vaccination efficiency in a malaria vaccination model. In this model, CD8(+) T cells exert antiparasitic functions on infected hepatocytes in the liver stage of the disease. In vaccinated anti-Toso treated mice, more antigen-specific CD8(+) T cells were induced than in control mice and after infection with Plasmodium berghei ANKA (PbA) sporozoites, the liver parasite burden was lower. In B cell deficient mice, the anti-Toso antibody did not stimulate the CD8(+) T cell response, indicating that B cells were mediating this effect. Furthermore, we analyzed the influence of anti-Toso treatment on non-vaccinated mice in the PbA infection model, in which CD8(+) T cells cause brain pathology. Anti-Toso treatment increased cerebral pathology and the accumulation of CD8(+) T cells in the brain. Thus, anti-Toso treatment enhanced the CD8(+) T cell response against PbA in a vaccination and in an infection model. Our findings indicate that Toso may be a novel target to boost vaccine-induced CD8(+) T cell responses.

  12. Feedback of research findings for vaccine trials: experiences from two malaria vaccine trials involving healthy children on the Kenyan Coast.

    PubMed

    Gikonyo, Caroline; Kamuya, Dorcas; Mbete, Bibi; Njuguna, Patricia; Olotu, Ally; Bejon, Philip; Marsh, Vicki; Molyneux, Sassy

    2013-04-01

    Internationally, calls for feedback of findings to be made an 'ethical imperative' or mandatory have been met with both strong support and opposition. Challenges include differences in issues by type of study and context, disentangling between aggregate and individual study results, and inadequate empirical evidence on which to draw. In this paper we present data from observations and interviews with key stakeholders involved in feeding back aggregate study findings for two Phase II malaria vaccine trials among children under the age of 5 years old on the Kenyan Coast. In our setting, feeding back of aggregate findings was an appreciated set of activities. The inclusion of individual results was important from the point of view of both participants and researchers, to reassure participants of trial safety, and to ensure that positive results were not over-interpreted and that individual level issues around blinding and control were clarified. Feedback sessions also offered an opportunity to re-evaluate and re-negotiate trial relationships and benefits, with potentially important implications for perceptions of and involvement in follow-up work for the trials and in future research. We found that feedback of findings is a complex but key step in a continuing set of social interactions between community members and research staff (particularly field staff who work at the interface with communities), and among community members themselves; a step which needs careful planning from the outset. We agree with others that individual and aggregate results need to be considered separately, and that for individual results, both the nature and value of the information, and the context, including social relationships, need to be taken into account.

  13. Vaccinations and malaria prophylaxis for long-term travellers travelling from Greece: a prospective, questionnaire-based analysis.

    PubMed

    Pavli, Androula; Smeti, Paraskevi; Spilioti, Athina; Silvestros, Chrysovalantis; Katerelos, Panagiotis; Maltezou, Helena C

    2014-01-01

    The purpose of this prospective, questionnaire-based study is to assess pre-travel vaccinations and malaria prophylaxis for long-term travellers who receive pre-travel advice in Greece. A total of 4721 travellers were studied from January 1, 2009 through December 31, 2012. Travellers sought pre-travel advice at a mean of 19.7 days (range: 0-349 days) before departure. Long-term travellers (≥ 1 month) accounted for 2205 (46.7%) of all travellers. Long-term travellers had a mean age of 34.5 years. The majority of them were men (79.8%). In terms of destinations, 84% were visiting malaria-endemic countries and sub-Saharan Africa was the most common destination (17.7%). Most long-term travellers pursued trips for work purposes (70%), visited urban areas (79.6%) and stayed in hotels (29.2%). Yellow fever, typhoid fever, hepatitis A and tetanus/diphtheria vaccines were administered to 1647 (74.7%), 741 (33.6%), 652 (29.5%), and 589 (26.7%) travellers, respectively. Yellow fever vaccine was administered to 339 (87%) and 132 (71%) of long-term travellers to sub-Saharan Africa and South America respectively, whereas typhoid vaccine to 119 (90.8%) and 330 (84.6%) of those travelling to the Indian subcontinent and sub-Saharan Africa respectively. Rabies vaccine was administered to 14 (0.6%) of them. Malaria prophylaxis was recommended to 446 (20%) of long-term travellers. Mefloquine was the most commonly (49%) prescribed agent, and was prescribed to 26.7% of long-term travellers to sub-Sahara Africa. In conclusion, this study revealed that recommendations for vaccine and malaria prophylaxis for long-term travellers to developing countries should be more selective, based on the assessment of all travellers' and travel characteristics, in order to provide adequate pre-travel preparation for this high risk group of travellers. More focused studies are suggested in order to understand the particular needs of long-term travellers. Increasing awareness of travellers and travel

  14. Country planning for health interventions under development: lessons from the malaria vaccine decision-making framework and implications for other new interventions

    PubMed Central

    Brooks, Alan; Ba-Nguz, Antoinette

    2012-01-01

    Traditionally it has taken years or decades for new public health interventions targeting diseases found in developing countries to be accessible to those most in need. One reason for the delay has been insufficient anticipation of the eventual processes and evidence required for decision making by countries. This paper describes research into the anticipated processes and data needed to inform decision making on malaria vaccines, the most advanced of which is still in phase 3 trials. From 2006 to 2008, a series of country consultations in Africa led to the development of a guide to assist countries in preparing their malaria vaccine decision-making frameworks. The guide builds upon the World Health Organization’s Vaccine Introduction Guidelines. It identifies the processes and data for decisions, when they would be needed relative to the development timelines of the intervention, and where they will come from. Policy development will be supported by data (e.g. malaria disease burden; roles of other malaria interventions; malaria vaccine impact; economic and financial issues; malaria vaccine efficacy, quality and safety) as will implementation decisions (e.g. programmatic issues and socio-cultural environment). This generic guide can now be applied to any future malaria vaccine. The paper discusses the opportunities and challenges to early planning for country decision-making—from the potential for timely, evidence-informed decisions to the risks of over-promising around an intervention still under development. Careful and well-structured planning by countries is an important way to ensure that new interventions do not remain unused for years or decades after they become available. PMID:22513733

  15. Country planning for health interventions under development: lessons from the malaria vaccine decision-making framework and implications for other new interventions.

    PubMed

    Brooks, Alan; Ba-Nguz, Antoinette

    2012-05-01

    Traditionally it has taken years or decades for new public health interventions targeting diseases found in developing countries to be accessible to those most in need. One reason for the delay has been insufficient anticipation of the eventual processes and evidence required for decision making by countries. This paper describes research into the anticipated processes and data needed to inform decision making on malaria vaccines, the most advanced of which is still in phase 3 trials. From 2006 to 2008, a series of country consultations in Africa led to the development of a guide to assist countries in preparing their malaria vaccine decision-making frameworks. The guide builds upon the World Health Organization's Vaccine Introduction Guidelines. It identifies the processes and data for decisions, when they would be needed relative to the development timelines of the intervention, and where they will come from. Policy development will be supported by data (e.g. malaria disease burden; roles of other malaria interventions; malaria vaccine impact; economic and financial issues; malaria vaccine efficacy, quality and safety) as will implementation decisions (e.g. programmatic issues and socio-cultural environment). This generic guide can now be applied to any future malaria vaccine. The paper discusses the opportunities and challenges to early planning for country decision-making-from the potential for timely, evidence-informed decisions to the risks of over-promising around an intervention still under development. Careful and well-structured planning by countries is an important way to ensure that new interventions do not remain unused for years or decades after they become available.

  16. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

    PubMed Central

    White, Michael T; Verity, Robert; Griffin, Jamie T; Asante, Kwaku Poku; Owusu-Agyei, Seth; Greenwood, Brian; Drakeley, Chris; Gesase, Samwel; Lusingu, John; Ansong, Daniel; Adjei, Samuel; Agbenyega, Tsiri; Ogutu, Bernhards; Otieno, Lucas; Otieno, Walter; Agnandji, Selidji T; Lell, Bertrand; Kremsner, Peter; Hoffman, Irving; Martinson, Francis; Kamthunzu, Portia; Tinto, Halidou; Valea, Innocent; Sorgho, Hermann; Oneko, Martina; Otieno, Kephas; Hamel, Mary J; Salim, Nahya; Mtoro, Ali; Abdulla, Salim; Aide, Pedro; Sacarlal, Jahit; Aponte, John J; Njuguna, Patricia; Marsh, Kevin; Bejon, Philip; Riley, Eleanor M; Ghani, Azra C

    2015-01-01

    Summary Background The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. Methods Using data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. Findings RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher

  17. The Anopheles-midgut APN1 structure reveals a new malaria transmission-blocking vaccine epitope.

    PubMed

    Atkinson, Sarah C; Armistead, Jennifer S; Mathias, Derrick K; Sandeu, Maurice M; Tao, Dingyin; Borhani-Dizaji, Nahid; Tarimo, Brian B; Morlais, Isabelle; Dinglasan, Rhoel R; Borg, Natalie A

    2015-07-01

    Mosquito-based malaria transmission-blocking vaccines (mTBVs) target midgut-surface antigens of the Plasmodium parasite's obligate vector, the Anopheles mosquito. The alanyl aminopeptidase N (AnAPN1) is the leading mTBV immunogen; however, AnAPN1's role in Plasmodium infection of the mosquito and how anti-AnAPN1 antibodies functionally block parasite transmission have remained elusive. Here we present the 2.65-Å crystal structure of AnAPN1 and the immunoreactivity and transmission-blocking profiles of three monoclonal antibodies (mAbs) to AnAPN1, including mAb 4H5B7, which effectively blocks transmission of natural strains of Plasmodium falciparum. Using the AnAPN1 structure, we map the conformation-dependent 4H5B7 neoepitope to a previously uncharacterized region on domain 1 and further demonstrate that nonhuman-primate neoepitope-specific IgG also blocks parasite transmission. We discuss the prospect of a new biological function of AnAPN1 as a receptor for Plasmodium in the mosquito midgut and the implications for redesigning the AnAPN1 mTBV. PMID:26075520

  18. Malaria vaccine candidate antigen targeting the pre-erythrocytic stage of Plasmodium falciparum produced at high level in plants.

    PubMed

    Voepel, Nadja; Boes, Alexander; Edgue, Güven; Beiss, Veronique; Kapelski, Stephanie; Reimann, Andreas; Schillberg, Stefan; Pradel, Gabriele; Fendel, Rolf; Scheuermayer, Matthias; Spiegel, Holger; Fischer, Rainer

    2014-11-01

    Plants have emerged as low-cost production platforms suitable for vaccines targeting poverty-related diseases. Besides functional efficacy, the stability, yield, and purification process determine the production costs of a vaccine and thereby the feasibility of plant-based production. We describe high-level plant production and functional characterization of a malaria vaccine candidate targeting the pre-erythrocytic stage of Plasmodium falciparum. CCT, a fusion protein composed of three sporozoite antigens (P. falciparum cell traversal protein for ookinetes and sporozoites [PfCelTOS], P. falciparum circumsporozoite protein [PfCSP], and P. falciparum thrombospondin-related adhesive protein [PfTRAP]), was transiently expressed by agroinfiltration in Nicotiana benthamiana leaves, accumulated to levels up to 2 mg/g fresh leaf weight (FLW), was thermostable up to 80°C and could be purified to >95% using a simple two-step procedure. Reactivity of sera from malaria semi-immune donors indicated the immunogenic conformation of the purified fusion protein consisting of PfCelTOS, PfCSP_TSR, PfTRAP_TSR domains (CCT) protein. Total IgG from the CCT-specific mouse immune sera specifically recognized P. falciparum sporozoites in immunofluorescence assays and induced up to 35% inhibition in hepatocyte invasion assays. Featuring domains from three promising sporozoite antigens with different roles (attachment and cell traversal) in the hepatocyte invasion process, CCT has the potential to elicit broader immune responses against the pre-erythrocytic stage of P. falciparum and represents an interesting new candidate, also as a component of multi-stage, multi-subunit malaria vaccine cocktails. PMID:25200253

  19. Skin scarification with Plasmodium falciparum peptide vaccine using synthetic TLR agonists as adjuvants elicits malaria sporozoite neutralizing immunity

    PubMed Central

    Mitchell, Robert A.; Altszuler, Rita; Frevert, Ute; Nardin, Elizabeth H.

    2016-01-01

    Malaria eradication will require a combination of vector control, chemotherapy and an easily administered vaccine. Sterile immunity can be elicited in humans by immunization with sporozoites, the infective stage injected by bite of the mosquito vector, however, whole parasite vaccines present formidable logistical challenges for production, storage and administration. The “gold standard” for infectious disease eradiation, the Smallpox Eradication Programme, utilized mass immunization using the skin scarification (SS) route. SS may more closely mimic the natural route of malaria infection initiated by sporozoites injected by mosquito bite which elicits both neutralizing antibodies and protective cell mediated immunity. We investigated the potential of SS immunization using a malaria repeat peptide containing a protective B cell epitope of Plasmodium falciparum, the most lethal human species, and delivery vehicles containing TLR agonists as adjuvants. In a murine model, SS immunization with peptide in combination with TLR-7/8 and -9 agonists elicited high levels of systemic sporozoite neutralizing antibody, Th1- type CD4+ T cells and resistance to challenge by bites of infected mosquitoes. SS provides the potential to elicit humoral immunity to target Plasmodium at multiple stages of its complex life cycle. PMID:27624667

  20. Skin scarification with Plasmodium falciparum peptide vaccine using synthetic TLR agonists as adjuvants elicits malaria sporozoite neutralizing immunity.

    PubMed

    Mitchell, Robert A; Altszuler, Rita; Frevert, Ute; Nardin, Elizabeth H

    2016-01-01

    Malaria eradication will require a combination of vector control, chemotherapy and an easily administered vaccine. Sterile immunity can be elicited in humans by immunization with sporozoites, the infective stage injected by bite of the mosquito vector, however, whole parasite vaccines present formidable logistical challenges for production, storage and administration. The "gold standard" for infectious disease eradiation, the Smallpox Eradication Programme, utilized mass immunization using the skin scarification (SS) route. SS may more closely mimic the natural route of malaria infection initiated by sporozoites injected by mosquito bite which elicits both neutralizing antibodies and protective cell mediated immunity. We investigated the potential of SS immunization using a malaria repeat peptide containing a protective B cell epitope of Plasmodium falciparum, the most lethal human species, and delivery vehicles containing TLR agonists as adjuvants. In a murine model, SS immunization with peptide in combination with TLR-7/8 and -9 agonists elicited high levels of systemic sporozoite neutralizing antibody, Th1- type CD4+ T cells and resistance to challenge by bites of infected mosquitoes. SS provides the potential to elicit humoral immunity to target Plasmodium at multiple stages of its complex life cycle. PMID:27624667

  1. The TatD-like DNase of Plasmodium is a virulence factor and a potential malaria vaccine candidate

    PubMed Central

    Chang, Zhiguang; Jiang, Ning; Zhang, Yuanyuan; Lu, Huijun; Yin, Jigang; Wahlgren, Mats; Cheng, Xunjia; Cao, Yaming; Chen, Qijun

    2016-01-01

    Neutrophil extracellular traps (NETs), composed primarily of DNA and proteases, are released from activated neutrophils and contribute to the innate immune response by capturing pathogens. Plasmodium falciparum, the causative agent of severe malaria, thrives in its host by counteracting immune elimination. Here, we report the discovery of a novel virulence factor of P. falciparum, a TatD-like DNase (PfTatD) that is expressed primarily in the asexual blood stage and is likely utilized by the parasite to counteract NETs. PfTatD exhibits typical deoxyribonuclease activity, and its expression is higher in virulent parasites than in avirulent parasites. A P. berghei TatD-knockout parasite displays reduced pathogenicity in mice. Mice immunized with recombinant TatD exhibit increased immunity against lethal challenge. Our results suggest that the TatD-like DNase is an essential factor for the survival of malarial parasites in the host and is a potential malaria vaccine candidate. PMID:27151551

  2. Complex realities: community engagement for a paediatric randomized controlled malaria vaccine trial in Kilifi, Kenya

    PubMed Central

    2014-01-01

    Background Community engagement (CE) is increasingly promoted for biomedical research conducted in resource poor settings for both intrinsic and instrumental purposes. Given the potential importance of CE, but also complexities and possibility of unexpected negative outcomes, there is need for more documentation of CE processes in practice. We share experiences of formal CE for a paediatric randomized controlled malaria vaccine trial conducted in three sites within Kilifi County, Kenya. Methods Social scientists independent of the trial held in-depth individual interviews with trial researchers (n = 5), community leaders (n = 8) and parents (15 with enrolled children and 4 without); and group discussions with fieldworkers (n = 6) and facility staff (n = 2). We conducted a survey of participating households (n = 200) and observed over 150 CE activities. Results The overall CE plan was similar across the three study sites, although less community-based information in site C. Majority perceived CE activities to clear pre-existing concerns and misconceptions; increase visibility, awareness of and trust in trial staff. Challenges included: some community leaders attempting to exert pressure on people to enrol; local wording in information sheets and consent forms feeding into serious anxieties about the trial; and concerns about reduced CE over time. Negative effects of these challenges were mitigated through changes to on-going CE activities, and final information sharing and consent being conducted individually by trained clinical staff. One year after enrolment, 31% (n = 62) of participants’ parents reported malaria prevention as the main aim of the activities their children were involved in, and 93% wanted their children to remain involved. Conclusion The trial teams’ goals for CE were relatively clear from the outset. Other actors’ hopes and expectations (like higher allowances and future employment) were not openly discussed, but emerged

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

    PubMed Central

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

    2009-01-01

    Summary 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-γ 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. PMID:20051036

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

    PubMed Central

    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

  5. Immunogenicity and protection from malaria infection in BK-SE36 vaccinated volunteers in Uganda is not influenced by HLA-DRB1 alleles.

    PubMed

    Tougan, Takahiro; Ito, Kazuya; Palacpac, Nirianne Marie Q; Egwang, Thomas G; Horii, Toshihiro

    2016-10-01

    SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Designated as BK-SE36, the SE36 antigen was formulated with aluminum hydroxyl gel (AHG) and produced under Good Manufacturing Practice (GMP) constraints. In a Phase Ib clinical trial and follow-up study in Uganda, the risk for malaria symptoms was reduced by 72% compared with the control group. Although promising, the number of responders to the vaccine in 6-20years-olds was approximately 30% with the majority in the younger cohort. This is in contrast to the phase Ia clinical trial where response to the vaccine was 100% in Japanese malaria naive adults. A consideration that can be of importance is the involvement of host genetic factors that may influence the ability to mount an effective immune response to vaccination as well as susceptibility to malaria infection. We, therefore, analyzed allelic polymorphism of human leukocyte antigen (HLA)-DRB1 alleles using sequence-based typing (SBT). In this study, DRB1 alleles did not influence antibody response to BK-SE36 and the vaccinees susceptibility to clinical malaria. PMID:27343834

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

    PubMed Central

    Mushi, Adiel K; Schellenberg, Joanna; Mrisho, Mwifadhi; Manzi, Fatuma; Mbuya, Conrad; Mponda, Haji; Mshinda, Hassan; Tanner, Marcel; Alonso, Pedro; Pool, Robert; Schellenberg, David

    2008-01-01

    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, which explained the

  7. Preliminary results of an anticircumsporozoite DNA vaccine trial for protection against avian malaria in captive African black-footed penguins (Spheniscus demersus).

    PubMed

    Grim, K Christiana; McCutchan, Thomas; Li, Jun; Sullivan, Margery; Graczyk, Thaddeus K; McConkey, Glenn; Cranfield, Michael

    2004-06-01

    Captive juvenile African black-footed penguins (Spheniscus demersus) housed in an outdoor enclosure at the Baltimore Zoo have an average 50% mortality from avian malarial (Plasmodium sp.) infection each year without intense monitoring for disease and chemotherapeutic intervention. During the 1996 malaria transmission season, the safety and efficacy of an anti-circumsporozoite (CSP) DNA vaccine encoding the Plasmodium gallinaceum CSP protein against P. relictum were studied. The goal was to reduce clinical disease and death without initiating sterile immunity after release into an area with stable, endemic avian malaria. The birds were monitored for adverse clinical signs associated with vaccination, the stimulation of an anti-CSP antibody response, and protection afforded by the vaccine. The presence of P. relictum in trapped culicine mosquitoes within the penguin enclosure was monitored to assess parasite pressure. Among the vaccinated penguins, the parasitemia rate dropped from approximately 50% to approximately 17% despite intense parasite pressure, as determined by mosquito infection rate. During the year of the vaccine trial, no mortalities due to malaria occurred and no undesirable vaccination side effects occurred. This is the first trial of an antimalarial vaccine in a captive penguin colony.

  8. Antibody titres and boosting after natural malaria infection in BK-SE36 vaccine responders during a follow-up study in Uganda

    PubMed Central

    Yagi, Masanori; Palacpac, Nirianne M. Q.; Ito, Kazuya; Oishi, Yuko; Itagaki, Sawako; Balikagala, Betty; Ntege, Edward H.; Yeka, Adoke; Kanoi, Bernard N.; Katuro, Osbert; Shirai, Hiroki; Fukushima, Wakaba; Hirota, Yoshio; Egwang, Thomas G.; Horii, Toshihiro

    2016-01-01

    The malaria vaccine BK-SE36 is a recombinant protein (SE36) based on the Honduras 1 serine repeat antigen-5 of Plasmodium falciparum, adsorbed to aluminium hydroxide gel. The phase Ib trial in Uganda demonstrated the safety and immunogenicity of BK-SE36. Ancillary analysis in the follow-up study of 6–20 year-old volunteers suggest significant differences in time to first episodes of clinical malaria in vaccinees compared to placebo/control group. Here, we aimed to get further insights into the association of anti-SE36 antibody titres and natural P. falciparum infection. Children who received BK-SE36 and whose antibody titres against SE36 increased by ≥1.92-fold after vaccination were categorised as responders. Most responders did not have or only had a single episode of natural P. falciparum infection. Notably, responders who did not experience infection had relatively high anti-SE36 antibody titres post-second vaccination compared to those who were infected. The anti-SE36 antibody titres of the responders who experienced malaria were boosted after infection and they had lower risk of reinfection. These findings show that anti-SE36 antibody titres induced by BK-SE36 vaccination offered protection against malaria. The vaccine is now being evaluated in a phase Ib trial in children less than 5 years old. PMID:27703240

  9. Comparative cost models of a liquid nitrogen vapor phase (LNVP) cold chain-distributed cryopreserved malaria vaccine vs. a conventional vaccine

    PubMed Central

    Garcia, Cristina Reyes; Manzi, Fatuma; Tediosi, Fabrizio; Hoffman, Stephen L.; James, Eric R.

    2013-01-01

    Typically, vaccines distributed through the Expanded Program on Immunization (EPI) use a 2–8 °C cold chain with 4–5 stops. The PfSPZ Vaccine comprises whole live-attenuated cryopreserved sporozoites stored in liquid nitrogen (LN2) vapor phase (LNVP) below −140 °C and would be distributed through a LNVP cold chain. The purpose of this study was to model LNVP cold chain distribution for the cryopreserved PfSPZ Vaccine in Tanzania, estimate the costs and compare these costs to those that would be incurred in distributing a ‘conventional’ malaria vaccine through the EPI. Capital and recurrent costs for storage, transportation, labor, energy usage and facilities were determined for the birth cohort in Tanzania over five years. Costs were calculated using WHO/UNESCO calculators. These were applied to a 2–8 °C distribution model with national, regional, district, and health facility levels, and for the cryopreserved vaccine using a ‘modified hub-and-spoke’ (MH-S) LNVP distribution system comprising a central national store, peripheral health facilities and an intermediate district-level transhipment stop. Estimated costs per fully immunized child (FIC) were $ 6.11 for the LNVP-distributed cryopreserved vaccine where the LN2 is generated, and $ 6.04 with purchased LN2 (assuming US $ 1.00/L). The FIC costs for distributing a conventional vaccine using the four level 2–8 °C cold chain were $ 6.10, and with a tariff distribution system as occurs in Tanzania the FIC cost was $ 5.53. The models, therefore, predicted little difference in 5-year distribution costs between the PfSPZ Vaccine distributed through a MH-S LNVP cold chain and a conventional vaccine distributed through the more traditional EPI system. A LNVP cold chain provides additional benefits through the use of durable dry shippers because no refrigerators, freezers or refrigerated trucks are required. Thus strain at the cold chain periphery, vaccine wastage from cold chain failures and the

  10. Heat-precipitation allows the efficient purification of a functional plant-derived malaria transmission-blocking vaccine candidate fusion protein.

    PubMed

    Beiss, Veronique; Spiegel, Holger; Boes, Alexander; Kapelski, Stephanie; Scheuermayer, Matthias; Edgue, Gueven; Sack, Markus; Fendel, Rolf; Reimann, Andreas; Schillberg, Stefan; Pradel, Gabriele; Fischer, Rainer

    2015-07-01

    Malaria is a vector-borne disease affecting more than two million people and accounting for more than 600,000 deaths each year, especially in developing countries. The most serious form of malaria is caused by Plasmodium falciparum. The complex life cycle of this parasite, involving pre-erythrocytic, asexual and sexual stages, makes vaccine development cumbersome but also offers a broad spectrum of vaccine candidates targeting exactly those stages. Vaccines targeting the sexual stage of P. falciparum are called transmission-blocking vaccines (TBVs). They do not confer protection for the vaccinated individual but aim to reduce or prevent the transmission of the parasite within a population and are therefore regarded as an essential tool in the fight against the disease. Malaria predominantly affects large populations in developing countries, so TBVs need to be produced in large quantities at low cost. Combining the advantages of eukaryotic expression with a virtually unlimited upscaling potential and a good product safety profile, plant-based expression systems represent a suitable alternative for the production of TBVs. We report here the high level (300 μg/g fresh leaf weight (FLW)) transient expression in Nicotiana benthamiana leaves of an effective TBV candidate based on a fusion protein F0 comprising Pfs25 and the C0-domain of Pfs230, and the implementation of a simple and cost-effective heat treatment step for purification that yields intact recombinant protein at >90% purity with a recovery rate of >70%. The immunization of mice clearly showed that antibodies raised against plant-derived F0 completely blocked the formation of oocysts in a malaria transmission-blocking assay (TBA) making F0 an interesting TBV candidate or a component of a multi-stage malaria vaccine cocktail.

  11. A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites.

    PubMed

    van Schaijk, Ben C L; Ploemen, Ivo H J; Annoura, Takeshi; Vos, Martijn W; Foquet, Lander; van Gemert, Geert-Jan; Chevalley-Maurel, Severine; van de Vegte-Bolmer, Marga; Sajid, Mohammed; Franetich, Jean-Francois; Lorthiois, Audrey; Leroux-Roels, Geert; Meuleman, Philip; Hermsen, Cornelius C; Mazier, Dominique; Hoffman, Stephen L; Janse, Chris J; Khan, Shahid M; Sauerwein, Robert W

    2014-01-01

    A highly efficacious pre-erythrocytic stage vaccine would be an important tool for the control and elimination of malaria but is currently unavailable. High-level protection in humans can be achieved by experimental immunization with Plasmodium falciparum sporozoites attenuated by radiation or under anti-malarial drug coverage. Immunization with genetically attenuated parasites (GAP) would be an attractive alternative approach. In this study, we present data on safety and protective efficacy using sporozoites with deletions of two genes, that is the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, PbΔb9ΔslarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high-level protection. The human PfΔb9ΔslarpGAP generated without drug resistance markers were infective to human hepatocytes in vitro and to humanized mice engrafted with human hepatocytes in vivo but completely aborted development after infection. These findings support the clinical development of a PfΔb9ΔslarpSPZ vaccine. PMID:25407681

  12. A genetically attenuated malaria vaccine candidate based on P. falciparum b9/slarp gene-deficient sporozoites

    PubMed Central

    van Schaijk, Ben C L; Ploemen, Ivo H J; Annoura, Takeshi; Vos, Martijn W; Foquet, Lander; van Gemert, Geert-Jan; Chevalley-Maurel, Severine; van de Vegte-Bolmer, Marga; Sajid, Mohammed; Franetich, Jean-Francois; Lorthiois, Audrey; Leroux-Roels, Geert; Meuleman, Philip; Hermsen, Cornelius C; Mazier, Dominique; Hoffman, Stephen L; Janse, Chris J; Khan, Shahid M; Sauerwein, Robert W

    2014-01-01

    A highly efficacious pre-erythrocytic stage vaccine would be an important tool for the control and elimination of malaria but is currently unavailable. High-level protection in humans can be achieved by experimental immunization with Plasmodium falciparum sporozoites attenuated by radiation or under anti-malarial drug coverage. Immunization with genetically attenuated parasites (GAP) would be an attractive alternative approach. In this study, we present data on safety and protective efficacy using sporozoites with deletions of two genes, that is the newly identified b9 and slarp, which govern independent and critical processes for successful liver-stage development. In the rodent malaria model, PbΔb9ΔslarpGAP was completely attenuated showing no breakthrough infections while efficiently inducing high-level protection. The human PfΔb9ΔslarpGAP generated without drug resistance markers were infective to human hepatocytes in vitro and to humanized mice engrafted with human hepatocytes in vivo but completely aborted development after infection. These findings support the clinical development of a PfΔb9ΔslarpSPZ vaccine. DOI: http://dx.doi.org/10.7554/eLife.03582.001 PMID:25407681

  13. Iron oxide nanoparticles as a clinically acceptable delivery platform for a recombinant blood-stage human malaria vaccine.

    PubMed

    Pusic, Kae; Aguilar, Zoraida; McLoughlin, Jaclyn; Kobuch, Sophie; Xu, Hong; Tsang, Mazie; Wang, Andrew; Hui, George

    2013-03-01

    This study explored the novel use of iron oxide (IO) nanoparticles (<20 nm) as a vaccine delivery platform without additional adjuvants. A recombinant malaria vaccine antigen, the merozoite surface protein 1 (rMSP1), was conjugated to IO nanoparticles (rMSP1-IO). Immunizations in outbred mice with rMSP1-IO achieved 100% responsiveness with antibody titers comparable to those obtained with rMSP1 formulated with a clinically acceptable adjuvant, Montanide ISA51 (2.7×10 vs. 1.6×10; respectively). Only rMSP1-1O could induce significant levels (80%) of parasite inhibitory antibodies. The rMSP1-IO was highly stable at 4°C and was amenable to lyophilization, maintaining its antigenicity, immunogenicity, and ability to induce inhibitory antibodies. Further testing in nonhuman primates, Aotus monkeys, also elicited 100% immune responsiveness and high levels of parasite inhibitory antibodies (55-100% inhibition). No apparent local or systemic toxicity was associated with IO immunizations. Murine macrophages and dendritic cells efficiently (>90%) internalized IO nanoparticles, but only the latter were significantly activated, with elevated expression/secretion of CD86, cytokines (IL-6, TNF-α, IL1-b, IFN-γ, and IL-12), and chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, and CXCL10). Thus, the IO nanoparticles is a novel, safe, and effective vaccine platform, with built-in adjuvancy, that is highly stable and field deployable for cost-effective vaccine delivery.

  14. Genetic variation in the Plasmodium falciparum circumsporozoite protein in India and its relevance to RTS,S malaria vaccine.

    PubMed

    Zeeshan, Mohammad; Alam, Mohammad Tauqeer; Vinayak, Sumiti; Bora, Hema; Tyagi, Rupesh Kumar; Alam, Mohd Shoeb; Choudhary, Vandana; Mittra, Pooja; Lumb, Vanshika; Bharti, Praveen Kumar; Udhayakumar, Venkatachalam; Singh, Neeru; Jain, Vidhan; Singh, Pushpendra Pal; Sharma, Yagya Dutta

    2012-01-01

    RTS,S is the most advanced malaria vaccine candidate, currently under phase-III clinical trials in Africa. This Plasmodium falciparum vaccine contains part of the central repeat region and the complete C-terminal T cell epitope region (Th2R and Th3R) of the circumsporozoite protein (CSP). Since naturally occurring polymorphisms at the vaccine candidate loci are critical determinants of the protective efficacy of the vaccines, it is imperative to investigate these polymorphisms in field isolates. In this study we have investigated the genetic diversity at the central repeat, C-terminal T cell epitope (Th2R and Th3R) and N-terminal T cell epitope regions of the CSP, in P. falciparum isolates from Madhya Pradesh state of India. These isolates were collected through a 5-year prospective study aimed to develop a well-characterized field-site for the future evaluation of malaria vaccine in India. Our results revealed that the central repeat (63 haplotypes, n = 161) and C-terminal Th2R/Th3R epitope (24 haplotypes, n = 179) regions were highly polymorphic, whereas N-terminal non-repeat region was less polymorphic (5 haplotypes, n = 161) in this population. We did not find any evidence of the role of positive natural selection in maintaining the genetic diversity at the Th2R/Th3R regions of CSP. Comparative analysis of the Th2R/Th3R sequences from this study to the global isolates (n = 1160) retrieved from the GenBank database revealed two important points. First, the majority of the sequences (~61%, n = 179) from this study were identical to the Dd2/Indochina type, which is also the predominant Th2R/Th3R haplotype in Asia (~59%, n = 974). Second, the Th2R/Th3R sequences in Asia, South America and Africa are geographically distinct with little allele sharing between continents. In conclusion, this study provides an insight on the existing polymorphisms in the CSP in a parasite population from India that could potentially influence the efficacy of RTS,S vaccine in this

  15. Protective Vaccination against Blood-Stage Malaria of Plasmodium chabaudi: Differential Gene Expression in the Liver of Balb/c Mice toward the End of Crisis Phase.

    PubMed

    Al-Quraishy, Saleh A; Dkhil, Mohamed A; Abdel-Baki, Abdel-Azeem A; Delic, Denis; Wunderlich, Frank

    2016-01-01

    Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination-protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0.01) differences in hepatic gene and lincRNA expression in vaccination-protected vs. non-vaccinated mice toward the end of crisis phase. In vaccination-protected mice, infections induce up-regulations of 276 genes and 40 lincRNAs and down-regulations of 200 genes and 43 lincRNAs, respectively, by >3-fold as compared to the corresponding constitutive expressions. Massive up-regulations, partly by >100-fold, are found for genes as RhD, Add2, Ank1, Ermap, and Slc4a, which encode proteins of erythrocytic surface membranes, and as Gata1 and Gfi1b, which encode transcription factors involved in erythrocytic development. Also, Cldn13 previously predicted to be expressed on erythroblast surfaces is up-regulated by >200-fold, though claudins are known as main constituents of tight junctions acting as paracellular barriers between epithelial cells. Other genes are up-regulated by <100- and >10-fold, which can be subgrouped in genes encoding proteins known to be involved in mitosis, in cell cycle regulation, and in DNA repair. Our data suggest that protective vaccination enables the liver to respond to P. chabaudi infections with accelerated regeneration and extramedullary erythropoiesis during crisis, which contributes to survival of otherwise lethal blood-stage malaria. PMID:27471498

  16. Protective Vaccination against Blood-Stage Malaria of Plasmodium chabaudi: Differential Gene Expression in the Liver of Balb/c Mice toward the End of Crisis Phase.

    PubMed

    Al-Quraishy, Saleh A; Dkhil, Mohamed A; Abdel-Baki, Abdel-Azeem A; Delic, Denis; Wunderlich, Frank

    2016-01-01

    Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination-protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0.01) differences in hepatic gene and lincRNA expression in vaccination-protected vs. non-vaccinated mice toward the end of crisis phase. In vaccination-protected mice, infections induce up-regulations of 276 genes and 40 lincRNAs and down-regulations of 200 genes and 43 lincRNAs, respectively, by >3-fold as compared to the corresponding constitutive expressions. Massive up-regulations, partly by >100-fold, are found for genes as RhD, Add2, Ank1, Ermap, and Slc4a, which encode proteins of erythrocytic surface membranes, and as Gata1 and Gfi1b, which encode transcription factors involved in erythrocytic development. Also, Cldn13 previously predicted to be expressed on erythroblast surfaces is up-regulated by >200-fold, though claudins are known as main constituents of tight junctions acting as paracellular barriers between epithelial cells. Other genes are up-regulated by <100- and >10-fold, which can be subgrouped in genes encoding proteins known to be involved in mitosis, in cell cycle regulation, and in DNA repair. Our data suggest that protective vaccination enables the liver to respond to P. chabaudi infections with accelerated regeneration and extramedullary erythropoiesis during crisis, which contributes to survival of otherwise lethal blood-stage malaria.

  17. Protective Vaccination against Blood-Stage Malaria of Plasmodium chabaudi: Differential Gene Expression in the Liver of Balb/c Mice toward the End of Crisis Phase

    PubMed Central

    Al-Quraishy, Saleh A.; Dkhil, Mohamed A.; Abdel-Baki, Abdel-Azeem A.; Delic, Denis; Wunderlich, Frank

    2016-01-01

    Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination-protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0.01) differences in hepatic gene and lincRNA expression in vaccination-protected vs. non-vaccinated mice toward the end of crisis phase. In vaccination-protected mice, infections induce up-regulations of 276 genes and 40 lincRNAs and down-regulations of 200 genes and 43 lincRNAs, respectively, by >3-fold as compared to the corresponding constitutive expressions. Massive up-regulations, partly by >100-fold, are found for genes as RhD, Add2, Ank1, Ermap, and Slc4a, which encode proteins of erythrocytic surface membranes, and as Gata1 and Gfi1b, which encode transcription factors involved in erythrocytic development. Also, Cldn13 previously predicted to be expressed on erythroblast surfaces is up-regulated by >200-fold, though claudins are known as main constituents of tight junctions acting as paracellular barriers between epithelial cells. Other genes are up-regulated by <100- and >10-fold, which can be subgrouped in genes encoding proteins known to be involved in mitosis, in cell cycle regulation, and in DNA repair. Our data suggest that protective vaccination enables the liver to respond to P. chabaudi infections with accelerated regeneration and extramedullary erythropoiesis during crisis, which contributes to survival of otherwise lethal blood-stage malaria. PMID:27471498

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

    PubMed Central

    Voepel, Nadja; Edgue, Gueven; Beiss, Veronique; Kapelski, Stephanie; Fendel, Rolf; Scheuermayer, Matthias; Pradel, Gabriele; Bolscher, Judith M.; Behet, Marije C.; Dechering, Koen J.; Hermsen, Cornelus C.; Sauerwein, Robert W.; Schillberg, Stefan; Reimann, Andreas; Fischer, Rainer

    2015-01-01

    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. PMID:26147206

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

    PubMed Central

    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

  20. A Malaria Vaccine Based on the Polymorphic Block 2 Region of MSP-1 that Elicits a Broad Serotype-Spanning Immune Response

    PubMed Central

    Cowan, Graeme J. M.; Creasey, Alison M.; Dhanasarnsombut, Kelwalin; Thomas, Alan W.; Remarque, Edmond J.; Cavanagh, David R.

    2011-01-01

    Polymorphic parasite antigens are known targets of protective immunity to malaria, but this antigenic variation poses challenges to vaccine development. A synthetic MSP-1 Block 2 construct, based on all polymorphic variants found in natural Plasmodium falciparum isolates has been designed, combined with the relatively conserved Block 1 sequence of MSP-1 and expressed in E.coli. The MSP-1 Hybrid antigen has been produced with high yield by fed-batch fermentation and purified without the aid of affinity tags resulting in a pure and extremely thermostable antigen preparation. MSP-1 hybrid is immunogenic in experimental animals using adjuvants suitable for human use, eliciting antibodies against epitopes from all three Block 2 serotypes. Human serum antibodies from Africans naturally exposed to malaria reacted to the MSP-1 hybrid as strongly as, or better than the same serum reactivities to individual MSP-1 Block 2 antigens, and these antibody responses showed clear associations with reduced incidence of malaria episodes. The MSP-1 hybrid is designed to induce a protective antibody response to the highly polymorphic Block 2 region of MSP-1, enhancing the repertoire of MSP-1 Block 2 antibody responses found among immune and semi-immune individuals in malaria endemic areas. The target population for such a vaccine is young children and vulnerable adults, to accelerate the acquisition of a full range of malaria protective antibodies against this polymorphic parasite antigen. PMID:22073118

  1. Dynamics of the Major Histocompatibility Complex Class I Processing and Presentation Pathway in the Course of Malaria Parasite Development in Human Hepatocytes: Implications for Vaccine Development

    PubMed Central

    Ma, Jinxia; Trop, Stefanie; Baer, Samantha; Rakhmanaliev, Elian; Arany, Zita; Dumoulin, Peter; Zhang, Hao; Romano, Julia; Coppens, Isabelle; Levitsky, Victor; Levitskaya, Jelena

    2013-01-01

    Control of parasite replication exerted by MHC class I restricted CD8+ T-cells in the liver is critical for vaccination-induced protection against malaria. While many intracellular pathogens subvert the MHC class I presentation machinery, its functionality in the course of malaria replication in hepatocytes has not been characterized. Using experimental systems based on specific identification, isolation and analysis of human hepatocytes infected with P. berghei ANKA GFP or P. falciparum 3D7 GFP sporozoites we demonstrated that molecular components of the MHC class I pathway exhibit largely unaltered expression in malaria-infected hepatocytes until very late stages of parasite development. Furthermore, infected cells showed no obvious defects in their capacity to upregulate expression of different molecular components of the MHC class I machinery in response to pro-inflammatory lymphokines or trigger direct activation of allo-specific or peptide-specific human CD8+ T-cells. We further demonstrate that ectopic expression of circumsporozoite protein does not alter expression of critical genes of the MHC class I pathway and its response to pro-inflammatory cytokines. In addition, we identified supra-cellular structures, which arose at late stages of parasite replication, possessed the characteristic morphology of merosomes and exhibited nearly complete loss of surface MHC class I expression. These data have multiple implications for our understanding of natural T-cell immunity against malaria and may promote development of novel, efficient anti-malaria vaccines overcoming immune escape of the parasite in the liver. PMID:24086507

  2. Pooled analysis of safety data from pediatric Phase II RTS,S/AS malaria candidate vaccine trials.

    PubMed

    Vekemans, Johan; Guerra, Yolanda; Lievens, Marc; Benns, Sarah; Lapierre, Didier; Leach, Amanda; Verstraeten, Thomas

    2011-12-01

    Prior to progression to Clinical Development Phase III, GlaxoSmithKline Biologicals performed a pooled analysis of phase two safety data following administration of 8860 doses of RTS,S/AS to 2981 children under 5 years old. RTS,S/AS was associated with increased rates of non-serious URTI, rash and diaper dermatitis graded mild or moderate. There was no significant increased rate of overall or single SAEs. Two episodes of simple febrile seizure were estimated to be related to vaccination. Significant decreased relative risks of death, any SAE, any SAE excluding malaria and pneumonia were observed. The results suggest a favourable risk-benefit balance which is to be confirmed in the ongoing Phase III trials. PMID:22108035

  3. Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models

    PubMed Central

    Penny, Melissa A; Verity, Robert; Bever, Caitlin A; Sauboin, Christophe; Galactionova, Katya; Flasche, Stefan; White, Michael T; Wenger, Edward A; Van de Velde, Nicolas; Pemberton-Ross, Peter; Griffin, Jamie T; Smith, Thomas A; Eckhoff, Philip A; Muhib, Farzana; Jit, Mark; Ghani, Azra C

    2016-01-01

    Summary Background The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. Methods We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5–17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2–10 year olds (PfPR2–10; range 3–65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2–10 per dose. Findings In regions with a PfPR2–10 of 10–65%, RTS,S/AS01 is predicted to avert a median of 93 940 (range 20 490–126 540) clinical cases and 394 (127–708) deaths for the three-dose schedule, or 116 480 (31 450–160 410) clinical cases and 484 (189–859) deaths for the four-dose schedule, per 100 000 fully vaccinated children. A positive impact is also predicted at a PfPR2–10 of 5–10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2–10 of 10–65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18–211) per clinical case averted and $80 (44

  4. Minimal role for the circumsporozoite protein in the induction of sterile immunity by vaccination with live rodent malaria sporozoites.

    PubMed

    Mauduit, Marjorie; Tewari, Rita; Depinay, Nadya; Kayibanda, Michèle; Lallemand, Eliette; Chavatte, Jean-Marc; Snounou, Georges; Rénia, Laurent; Grüner, Anne Charlotte

    2010-05-01

    Immunization with live Plasmodium sporozoites under chloroquine prophylaxis (Spz plus CQ) induces sterile immunity against sporozoite challenge in rodents and, more importantly, in humans. Full protection is obtained with substantially fewer parasites than with the classic immunization with radiation-attenuated sporozoites. The sterile protection observed comprised a massive reduction in the hepatic parasite load and an additional effect at the blood stage level. Differences in the immune responses induced by the two protocols occur but are as yet little characterized. We have previously demonstrated that in mice immunized with irradiated sporozoites, immune responses against the circumsporozoite protein (CSP), the major component of the sporozoite's surface and the leading malaria vaccine candidate, were not essential for sterile protection. Here, we have employed transgenic Plasmodium berghei parasites in which the endogenous CSP was replaced by that of Plasmodium yoelii, another rodent malaria species, to assess the role of CSP in the sterile protection induced by the Spz-plus-CQ protocol. The data demonstrated that this role was minor because sterile immunity was obtained irrespective of the origin of CSP expressed by the parasites in this model of protection. The immunity was obtained through a single transient exposure of the host to the immunizing parasites (preerythrocytic and erythrocytic), a dose much smaller than that required for immunization with radiation-attenuated sporozoites.

  5. Insights into Long-Lasting Protection Induced by RTS,S/AS02A Malaria Vaccine: Further Results from a Phase IIb Trial in Mozambican Children

    PubMed Central

    Guinovart, Caterina; Aponte, John J.; Sacarlal, Jahit; Aide, Pedro; Leach, Amanda; Bassat, Quique; Macete, Eusébio; Dobaño, Carlota; Lievens, Marc; Loucq, Christian; Ballou, W. Ripley; Cohen, Joe; Alonso, Pedro L.

    2009-01-01

    Background 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. Methodology/Principal Findings 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. Conclusions/Significance 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

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

    PubMed Central

    Fonseca, Jairo Andres; Cabrera-Mora, Monica; Kashentseva, Elena A.; Dmitriev, Igor P.; Curiel, David T.; Moreno, Alberto

    2016-01-01

    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 and protective

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

    PubMed

    Fonseca, Jairo Andres; Cabrera-Mora, Monica; Kashentseva, Elena A; Villegas, John Paul; Fernandez, Alejandra; Van Pelt, Amelia; Dmitriev, Igor P; Curiel, David T; Moreno, Alberto

    2016-01-01

    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 and protective

  8. Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

    PubMed Central

    Richards, Jack S.; Arumugam, Thangavelu U.; Reiling, Linda; Healer, Julie; Hodder, Anthony N.; Fowkes, Freya J. I.; Cross, Nadia; Langer, Christine; Takeo, Satoru; Uboldi, Alex D.; Thompson, Jennifer K.; Gilson, Paul R.; Coppel, Ross L.; Siba, Peter M.; King, Christopher L.; Torii, Motomi; Chitnis, Chetan E.; Narum, David L.; Mueller, Ivo; Crabb, Brendan S.; Cowman, Alan F.; Tsuboi, Takafumi

    2013-01-01

    The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control. PMID:23776179

  9. Vaccination with Lipid Core Peptides Fails to Induce Epitope-Specific T Cell Responses but Confers Non-Specific Protective Immunity in a Malaria Model

    PubMed Central

    Apte, Simon H.; Groves, Penny L.; Skwarczynski, Mariusz; Fujita, Yoshio; Chang, Chenghung; Toth, Istvan; Doolan, Denise L.

    2012-01-01

    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. PMID:22936972

  10. Strain-transcending immune response generated by chimeras of the malaria vaccine candidate merozoite surface protein 2

    PubMed Central

    Krishnarjuna, Bankala; Andrew, Dean; MacRaild, Christopher A.; Morales, Rodrigo A. V.; Beeson, James G.; Anders, Robin F.; Richards, Jack S.; Norton, Raymond S.

    2016-01-01

    MSP2 is an intrinsically disordered protein that is abundant on the merozoite surface and essential to the parasite Plasmodium falciparum. Naturally-acquired antibody responses to MSP2 are biased towards dimorphic sequences within the central variable region of MSP2 and have been linked to naturally-acquired protection from malaria. In a phase IIb study, an MSP2-containing vaccine induced an immune response that reduced parasitemias in a strain-specific manner. A subsequent phase I study of a vaccine that contained both dimorphic forms of MSP2 induced antibodies that exhibited functional activity in vitro. We have assessed the contribution of the conserved and variable regions of MSP2 to the generation of a strain-transcending antibody response by generating MSP2 chimeras that included conserved and variable regions of the 3D7 and FC27 alleles. Robust anti-MSP2 antibody responses targeting both conserved and variable regions were generated in mice, although the fine specificity and the balance of responses to these regions differed amongst the constructs tested. We observed significant differences in antibody subclass distribution in the responses to these chimeras. Our results suggest that chimeric MSP2 antigens can elicit a broad immune response suitable for protection against different strains of P. falciparum. PMID:26865062

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

    PubMed Central

    Talaat, Kawsar R.; Ellis, Ruth D.; Hurd, Janet; Hentrich, Autumn; Gabriel, Erin; Hynes, Noreen A.; Rausch, Kelly M.; Zhu, Daming; Muratova, Olga; Herrera, Raul; Anderson, Charles; Jones, David; Aebig, Joan; Brockley, Sarah; MacDonald, Nicholas J.; Wang, Xiaowei; Fay, Michael P.; Healy, Sara A.; Durbin, Anna P.; Narum, David L.; Wu, Yimin; Duffy, Patrick E.

    2016-01-01

    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. PMID:27749907

  12. Plasmodium falciparum circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya.

    PubMed

    Sherwood, J A; Copeland, R S; Taylor, K A; Abok, K; Oloo, A J; Were, J B; Strickland, G T; Gordon, D M; Ballou, W R; Bales, J D; Wirtz, R A; Wittes, J; Gross, M; Que, J U; Cryz, S J; Oster, C N; Roberts, C R; Sadoff, J C

    1996-06-01

    It has been hypothesized that antibody induced by Plasmodium falciparum circumsporozoite protein vaccine would be effective against endemic human malaria. In a malaria endemic region of Kenya, 76 volunteers, in 38 pairs sleeping adjacently, were immunized with subunit circumsporozoite protein Asn-Ala-Asn-Pro tetrapeptide repeat-pseudomonas toxin A, or hepatitis B vaccine. After quinine and doxcycycline, volunteers were followed for illness daily, parasitemia weekly, antibody, T-lymphocyte responses, and treated if indicated. Anopheles mosquitoes resting in houses were collected, and tested for P. falciparum antigen, or dissected for sporozoites and tested for blood meal ABO type and P. falciparum antigen. Vaccine was safe, with side-effects similar in both groups, and immunogenic, engendering IgG antibody as high as 600 micrograms ml-1, but did not increase the proportion of volunteers with T-lymphocyte responses. Estimation of P. falciparum challenge averaged 0.194 potentially infective Anopheles bites/volunteer/ day. Mosquito blood meals showed no difference in biting intensity between vaccine and control groups. Both groups had similar malaria-free survival curves, cumulative positive blood slides, cumulative parasites mm-3, and numbers of parasites mm-3 on first positive blood slide, during three post-vaccination observation periods. Every volunteer had P. falciparum parastemia at least once. Vaccinees had 82% and controls 89% incidences of symptomatic parasitemia (P = 0.514, efficacy 9%, statistical power 95% probability of efficacy < 50%). Vaccine-induced anti-sporozoite antibody was not protective in this study. Within designed statistical precisions the present study is in agreement with efficacy studies in Colombia, Venezuela and Tanzania.

  13. Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175

    PubMed Central

    Chitnis, Chetan E.; Mukherjee, Paushali; Mehta, Shantanu; Yazdani, Syed Shams; Dhawan, Shikha; Shakri, Ahmad Rushdi; Bharadwaj, Rukmini; Gupta, Puneet Kumar; Hans, Dhiraj; Mazumdar, Suman; Singh, Bijender; Kumar, Sanjeev; Pandey, Gaurav; Parulekar, Varsha; Imbault, Nathalie; Shivyogi, Preethi; Godbole, Girish; Mohan, Krishna; Leroy, Odile; Singh, Kavita; Chauhan, Virander S.

    2015-01-01

    Background A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-119, the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. Method Healthy malaria naïve Indian male subjects aged 18–45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10μg, 25μg and 50μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. Results JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-119. Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. Conclusion Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-119 construct needs to be optimised to improve its immunogenicity. Trial Registration Clinical Trial Registry, India CTRI/2010/091/000301 PMID:25927360

  14. Immunogenicity and in vitro Protective Efficacy of a Recombinant Multistage Plasmodium falciparum Candidate Vaccine

    NASA Astrophysics Data System (ADS)

    Shi, Ya Ping; Hasnain, Seyed E.; Sacci, John B.; Holloway, Brian P.; Fujioka, Hisashi; Kumar, Nirbhay; Wohlhueter, Robert; Hoffman, Stephen L.; Collins, William E.; Lal, Altaf A.

    1999-02-01

    Compared with a single-stage antigen-based vaccine, a multistage and multivalent Plasmodium falciparum vaccine would be more efficacious by inducing "multiple layers" of immunity. We have constructed a synthetic gene that encodes for 12 B cell, 6 T cell proliferative, and 3 cytotoxic T lymphocyte epitopes derived from 9 stage-specific P. falciparum antigens corresponding to the sporozoite, liver, erythrocytic asexual, and sexual stages. The gene was expressed in the baculovirus system, and a 41-kDa antigen, termed CDC/NIIMALVAC-1, was purified. Immunization in rabbits with the purified protein in the presence of different adjuvants generated antibody responses that recognized vaccine antigen, linear peptides contained in the vaccine, and all stages of P. falciparum. In vitro assays of protection revealed that the vaccine-elicited antibodies strongly inhibited sporozoite invasion of hepatoma cells and growth of blood-stage parasites in the presence of monocytes. These observations demonstrate that a multicomponent, multistage malaria vaccine can induce immune responses that inhibit parasite development at multiple stages. The rationale and approach used in the development of a multicomponent P. falciparum vaccine will be useful in the development of a multispecies human malaria vaccine and vaccines against other infectious diseases.

  15. Using Malaria Medication for Leg Cramps Is Risky

    MedlinePlus

    ... Products Vaccines, Blood & Biologics Articulos en Espanol Using Malaria Medication for Leg Cramps is Risky Printer-friendly ... approved only to treat a certain type of malaria (uncomplicated malaria) caused by the parasite Plasmodium falciparum. ...

  16. Structural analysis of Anopheles midgut aminopeptidase N reveals a novel malaria transmission-blocking vaccine B-cell epitope

    PubMed Central

    Atkinson, Sarah C.; Armistead, Jennifer S.; Mathias, Derrick K.; Sandeu, Maurice M.; Tao, Dingyin; Borhani-Dizaji, Nahid; Tarimo, Brian B.; Morlais, Isabelle; Dinglasan, Rhoel R.; Borg, Natalie A.

    2015-01-01

    Mosquito-based malaria transmission-blocking vaccines (mTBVs) target midgut-surface antigens of the Plasmodium parasite's obligate vector, the Anopheles mosquito. The alanyl aminopeptidase N (AnAPN1) is the leading mTBV immunogen; however AnAPN1's role in Plasmodium infection of the mosquito and how anti-AnAPN1 antibodies functionally block parasite transmission remains elusive. Here we present the 2.65 Å crystal structure of AnAPN1 and the immunoreactivity and transmission-blocking profile of three AnAPN1 monoclonal antibodies (mAb), including mAb 4H5B7, which effectively block transmission of natural strains of Plasmodium falciparum. Utilizing the AnAPN1 structure we map the conformation-dependent 4H5B7 neo-epitope to a previously uncharacterized region on domain 1, and further demonstrate that non-human primate neo-epitope-specific IgG also block parasite transmission. We discuss the prospect of a novel biological function of AnAPN1 as a receptor for Plasmodium in the mosquito midgut and the implications for redesigning the AnAPN1 mTBV. PMID:26075520

  17. Gene-therapy for malaria prevention.

    PubMed

    Rodrigues, Mauricio M; Soares, Irene S

    2014-11-01

    The limited number of tools for malaria prevention and the inability to eradicate the disease have required large investments in vaccine development, as vaccines have been the only foreseeable type of immunoprophylaxis against malaria. An alternative strategy named vectored immunoprophylaxis (VIP) now would allow genetically transduced host cells to assemble and secrete antibodies that neutralize the infectivity of the malaria parasite and prevent disease.

  18. Genetic diversity of VAR2CSA ID1-DBL2Xb in worldwide Plasmodium falciparum populations: impact on vaccine design for placental malaria.

    PubMed

    Bordbar, Bita; Tuikue Ndam, Nicaise; Renard, Emmanuelle; Jafari-Guemouri, Sayeh; Tavul, Livingstone; Jennison, Charlie; Gnidehou, Sédami; Tahar, Rachida; Gamboa, Dionicia; Bendezu, Jorge; Menard, Didier; Barry, Alyssa E; Deloron, Philippe; Sabbagh, Audrey

    2014-07-01

    In placental malaria (PM), sequestration of infected erythrocytes in the placenta is mediated by an interaction between VAR2CSA, a Plasmodium falciparum protein expressed on erythrocytes, and chondroitin sulfate A (CSA) on syncytiotrophoblasts. Recent works have identified ID1-DBL2Xb as the minimal CSA-binding region within VAR2CSA able to induce strong protective immunity, making it the leading candidate for the development of a vaccine against PM. Assessing the existence of population differences in the distribution of ID1-DBL2Xb polymorphisms is of paramount importance to determine whether geographic diversity must be considered when designing a candidate vaccine based on this fragment. In this study, we examined patterns of sequence variation of ID1-DBL2Xb in a large collection of P. falciparum field isolates (n=247) from different malaria-endemic areas, including Africa (Benin, Senegal, Cameroon and Madagascar), Asia (Cambodia), Oceania (Papua New Guinea), and Latin America (Peru). Detection of variants and estimation of their allele frequencies were performed using next-generation sequencing of DNA pools. A considerable amount of variation was detected along the whole gene segment, suggesting that several allelic variants may need to be included in a candidate vaccine to achieve broad population coverage. However, most sequence variants were common and extensively shared among worldwide parasite populations, demonstrating long term persistence of those polymorphisms, probably maintained through balancing selection. Therefore, a vaccine mixture including such stable antigen variants will be putatively applicable and efficacious in all world regions where malaria occurs. Despite similarity in ID1-DBL2Xb allele repertoire across geographic areas, several peaks of strong population differentiation were observed at specific polymorphic loci, pointing out putative targets of humoral immunity subject to positive immune selection.

  19. Development of malaria vaccines: Memorandum from a USAID/WHO meeting

    PubMed Central

    1983-01-01

    The fifth meeting of the Scientific Working Group on the Immunology of Malaria evaluated studies of the production and analysis of defined malarial antigens. Rapid progress has been made in the study of protective antigens on the surface of sporozoites and it is likely that a family of analogous polypeptides occurs in several species of Plasmodium. New assays have been developed for the detection of these antigens and for the detection of infected mosquitos. Exoerythrocytic stages of several parasite species can be cultivated in vitro, providing an assay system for antibody and allowing the characterization of exoerythrocytic stage antigens. Progress has also been made in the identification of species- and stage-specific antigens of the asexual blood stages of rodent, simian, and human malaria parasites. In some instances, protective immunity has been shown to be directed against polypeptides (with a high relative molecular mass) synthesized at a late stage of schizont development. Messenger RNA (mRNA) species from P. knowlesi and P. yoelii have been successfully translated in vitro to give polypeptides with a high relative molecular mass (Mr). Monoclonal antibodies have been used to identify and to purify important parasite antigens and purified P. yoelii antigens induced protective immunity. Monoclonal antibodies reactive with merozoite surface antigens have been used, as well as S-antigens, to distinguish between different isolates of P. falciparum. Recombinant DNA technology is being applied to Plasmodium: differences were found between repetitive DNA sequences from the genome of two isolates of P. falciparum; the genes for ribosomal RNA of P. falciparum and P. yoelii, and sequences homologous to the actin gene were identified in fragments of Plasmodium DNA cloned in prokaryotic vectors; by means of hybrid selection, complementary DNA (cDNA) probes were used to purify mRNAs encoding proteins of P. knowlesi of up to 100 000 Mr. PMID:6340848

  20. Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial.

    PubMed

    Hodgson, Susanne H; Choudhary, Prateek; Elias, Sean C; Milne, Kathryn H; Rampling, Thomas W; Biswas, Sumi; Poulton, Ian D; Miura, Kazutoyo; Douglas, Alexander D; Alanine, Daniel Gw; Illingworth, Joseph J; de Cassan, Simone C; Zhu, Daming; Nicosia, Alfredo; Long, Carole A; Moyle, Sarah; Berrie, Eleanor; Lawrie, Alison M; Wu, Yimin; Ellis, Ruth D; Hill, Adrian V S; Draper, Simon J

    2014-12-01

    The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines--chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible. PMID:25156127

  1. Macrophage cytotoxicity in lethal and non-lethal murine malaria and the effect of vaccination.

    PubMed Central

    Taverne, J; Treagust, J D; Playfair, J H

    1986-01-01

    We investigated the development of cell-mediated immunity in lethal and non-lethal malarial infections by assaying the cytotoxic activity of spleen cells for L929 tumour cells at different times after infection of mice with the lethal P. berghei, a lethal variant of Plasmodium yoelii and the non-lethal P. yoelii and P. chabaudi. In all cases the cytotoxicity increased to a peak during the first week and then diminished but the time of the peak varied with the infection; its activity was lowest with P. berghei. A second peak occurred in the non-lethal infections at the time of recovery. A protective vaccine accelerated and enhanced the early peak of cytotoxicity. The activity was mediated by adherent phagocytic cells, probably through the release of tumour necrosis factor (TNF) by macrophages since it was inhibited by antiserum against recombinant mouse TNF and did not destroy TNF-resistant L929 cells. Its induction was not dependent on T cells since it occurred in T cell-deficient mice infected with non-lethal P. yoelii. However, the accelerated increase associated with vaccination could be adoptively transferred by spleen lymphocytes from vaccinated mice. PMID:3542317

  2. Phase 1b Randomized Trial and Follow-Up Study in Uganda of the Blood-Stage Malaria Vaccine Candidate BK-SE36

    PubMed Central

    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

    Background 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. Methods 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. Results 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

  3. Changes in oxidative burst capacity during murine malaria and the effect of vaccination.

    PubMed Central

    Dockrell, H M; Alavi, A; Playfair, J H

    1986-01-01

    Adherent spleen and liver cells from mice infected with Plasmodium yoelii 17X or P. chabaudi AS were tested for production of reactive oxygen intermediates to measure their state of activation. Phorbol myristate acetate (PMA) was used to trigger the respiratory burst and production of superoxide anions was measured by the reduction of nitroblue tetrazolium. Spleen cells from mice infected with P. chabaudi showed an early increase in oxidative activity on day 3, and when the oxidative capacity of the whole spleen was calculated, it was maximal on day 9, just as the mice began to recover. In mice infected with P. yoelii, spleen cells showed an early peak in activity on day 5, and then returned to normal, although the mice did not recover for a further 2-3 weeks. However the total oxidative capacity of the spleen remained high throughout the infection. Mice vaccinated against P. yoelii with a killed blood-stage vaccine showed increased activity on day 3 (spleen) and day 5 (liver), compared with infected control mice. Thus macrophages in these organs could, if given an appropriate trigger, release high levels of these potentially toxic molecules during infection. PMID:3026701

  4. Studies on the humoral immune response to a synthetic vaccine against Plasmodium falciparum malaria.

    PubMed Central

    Salcedo, M; Barreto, L; Rojas, M; Moya, R; Cote, J; Patarroyo, M E

    1991-01-01

    A synthetic vaccine against the asexual blood stages of P. falciparum, the SPf 66 synthetic hybrid polymer, composed of peptides derived from three merozoite membrane proteins as well as one peptide from the sporozoite CS protein, has been developed by our group and tested in different protection assays in Aotus monkeys as well as in human volunteers. This study evaluates the humoral immune response induced by the SPf 66 protein vaccination in adult human volunteers from the Colombian Pacific coast as follows: determination of specific IgG antibody levels against SPf 66 by FAST-ELISA after each immunization; analysis of antibody reactivity with P. falciparum schizont lysates by immunoblots; and determination of the in vitro parasite growth inhibition. A clear boosting effect, dependent on time and dose, was observed in the antibody production kinetics. These antibodies also specifically recognize three proteins of the P. falciparum schizont lysate corresponding to the molecular weights of the proteins from which the amino acid sequence was derived. These sera were also capable of markedly inhibiting in vitro parasite growth. PMID:2015702

  5. Optimized Blanching Reduces the Host Cell Protein Content and Substantially Enhances the Recovery and Stability of Two Plant-Derived Malaria Vaccine Candidates

    PubMed Central

    Menzel, Stephan; Holland, Tanja; Boes, Alexander; Spiegel, Holger; Bolzenius, Johanna; Fischer, Rainer; Buyel, Johannes F.

    2016-01-01

    Plants provide an advantageous expression platform for biopharmaceutical proteins because of their low pathogen burden and potential for inexpensive, large-scale production. However, the purification of target proteins can be challenging due to issues with extraction, the removal of host cell proteins (HCPs), and low expression levels. The heat treatment of crude extracts can reduce the quantity of HCPs by precipitation thus increasing the purity of the target protein and streamlining downstream purification. In the overall context of downstream process (DSP) development for plant-derived malaria vaccine candidates, we applied a design-of-experiments approach to enhance HCP precipitation from Nicotiana benthamiana extracts generated after transient expression, using temperatures in the 20–80°C range, pH values of 3.0–8.0 and incubation times of 0–60 min. We also investigated the recovery of two protein-based malaria vaccine candidates under these conditions and determined their stability in the heat-treated extract while it was maintained at room temperature for 24 h. The heat precipitation of HCPs was also carried out by blanching intact plants in water or buffer prior to extraction in a blender. Our data show that all the heat precipitation methods reduced the amount of HCP in the crude plant extracts by more than 80%, simplifying the subsequent DSP steps. Furthermore, when the heat treatment was performed at 80°C rather than 65°C, both malaria vaccine candidates were more stable after extraction and the recovery of both proteins increased by more than 30%. PMID:26925077

  6. Optimized Blanching Reduces the Host Cell Protein Content and Substantially Enhances the Recovery and Stability of Two Plant-Derived Malaria Vaccine Candidates.

    PubMed

    Menzel, Stephan; Holland, Tanja; Boes, Alexander; Spiegel, Holger; Bolzenius, Johanna; Fischer, Rainer; Buyel, Johannes F

    2016-01-01

    Plants provide an advantageous expression platform for biopharmaceutical proteins because of their low pathogen burden and potential for inexpensive, large-scale production. However, the purification of target proteins can be challenging due to issues with extraction, the removal of host cell proteins (HCPs), and low expression levels. The heat treatment of crude extracts can reduce the quantity of HCPs by precipitation thus increasing the purity of the target protein and streamlining downstream purification. In the overall context of downstream process (DSP) development for plant-derived malaria vaccine candidates, we applied a design-of-experiments approach to enhance HCP precipitation from Nicotiana benthamiana extracts generated after transient expression, using temperatures in the 20-80°C range, pH values of 3.0-8.0 and incubation times of 0-60 min. We also investigated the recovery of two protein-based malaria vaccine candidates under these conditions and determined their stability in the heat-treated extract while it was maintained at room temperature for 24 h. The heat precipitation of HCPs was also carried out by blanching intact plants in water or buffer prior to extraction in a blender. Our data show that all the heat precipitation methods reduced the amount of HCP in the crude plant extracts by more than 80%, simplifying the subsequent DSP steps. Furthermore, when the heat treatment was performed at 80°C rather than 65°C, both malaria vaccine candidates were more stable after extraction and the recovery of both proteins increased by more than 30%.

  7. Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant.

    PubMed

    Hoffman, S L; Edelman, R; Bryan, J P; Schneider, I; Davis, J; Sedegah, M; Gordon, D; Church, P; Gross, M; Silverman, C

    1994-11-01

    A Plasmodium falciparum circumsporozoite protein (PfCSP) recombinant fusion protein, R32NS1(81), formulated with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane (Detox) was administered to 12 volunteers. One volunteer had malaise and self-limited painful induration at the injection site after the second dose and declined further immunization. The other 11 volunteers tolerated the three doses of 1,230 micrograms of vaccine, but most complained of sore arms; in five cases the pain or malaise was severe enough to interfere with work or sleep. Two weeks after the third dose of vaccine, four of the 11 immunized volunteers had > or = 14 micrograms/ml of antibodies to the repeat region of the PfCSP in their serum. Two of these four volunteers did not develop P. falciparum parasitemia when challenged by the bite of five mosquitoes carrying P. falciparum sporozoites. The seven volunteers with lower levels of antibodies and 11 of 11 controls developed parasitemia. These data are consistent with other studies, and indicate that vaccine-induced antibodies against the repeat region of PfCSP can prevent effective sporozoite infection of hepatocytes in humans. The challenge is to improve the immunogenicity of PfCSP-based vaccines, and to develop methods for including PfCSP peptides as components of multitarget malaria vaccines.

  8. Nanoparticle formulation enhanced protective immunity provoked by PYGPI8p-transamidase related protein (PyTAM) DNA vaccine in Plasmodium yoelii malaria model.

    PubMed

    Cherif, Mahamoud Sama; Shuaibu, Mohammed Nasir; Kodama, Yukinobu; Kurosaki, Tomoaki; Helegbe, Gideon Kofi; Kikuchi, Mihoko; Ichinose, Akitoyo; Yanagi, Tetsuo; Sasaki, Hitoshi; Yui, Katsuyuki; Tien, Nguyen Huy; Karbwang, Juntra; Hirayama, Kenji

    2014-04-01

    We have previously reported the new formulation of polyethylimine (PEI) with gamma polyglutamic acid (γ-PGA) nanoparticle (NP) to have provided Plasmodium yoelii merozoite surface protein-1 (PyMSP-1) plasmid DNA vaccine with enhanced protective cellular and humoral immunity in the lethal mouse malaria model. PyGPI8p-transamidase-related protein (PyTAM) was selected as a possible candidate vaccine antigen by using DNA vaccination screening from 29 GPI anchor and signal sequence motif positive genes picked up using web-based bioinformatics tools; though the observed protection was not complete. Here, we observed augmented protective effect of PyTAM DNA vaccine by using PEI and γ-PGA complex as delivery system. NP-coated PyTAM plasmid DNA immunized mice showed a significant survival rate from lethal P. yoelii challenge infection compared with naked PyTAM plasmid or with NP-coated empty plasmid DNA group. Antigen-specific IgG1 and IgG2b subclass antibody levels, proportion of CD4 and CD8T cells producing IFN-γ in the splenocytes and IL-4, IFN-γ, IL-12 and TNF-α levels in the sera and in the supernatants from ex vivo splenocytes culture were all enhanced by the NP-coated PyTAM DNA vaccine. These data indicates that NP augments PyTAM protective immune response, and this enhancement was associated with increased DC activation and concomitant IL-12 production.

  9. Combining Viral Vectored and Protein-in-adjuvant Vaccines Against the Blood-stage Malaria Antigen AMA1: Report on a Phase 1a Clinical Trial

    PubMed Central

    Hodgson, Susanne H; Choudhary, Prateek; Elias, Sean C; Milne, Kathryn H; Rampling, Thomas W; Biswas, Sumi; Poulton, Ian D; Miura, Kazutoyo; Douglas, Alexander D; Alanine, Daniel GW; Illingworth, Joseph J; de Cassan, Simone C; Zhu, Daming; Nicosia, Alfredo; Long, Carole A; Moyle, Sarah; Berrie, Eleanor; Lawrie, Alison M; Wu, Yimin; Ellis, Ruth D; Hill, Adrian V S; Draper, Simon J

    2014-01-01

    The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines—chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising “mixed-modality” regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible. PMID:25156127

  10. 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

    PubMed Central

    Koram, Kwadwo A.; 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. Trial registration ClinicalTrials.gov. Identifier: NCT01026246 PMID:27644034

  11. Vaccinations

    MedlinePlus

    ... vaccinated? For many years, a set of annual vaccinations was considered normal and necessary for dogs and ... to protect for a full year. Consequently, one vaccination schedule will not work well for all pets. ...

  12. A Model to Study the Impact of Polymorphism Driven Liver-Stage Immune Evasion by Malaria Parasites, to Help Design Effective Cross-Reactive Vaccines

    PubMed Central

    Wilson, Kirsty L.; Xiang, Sue D.; Plebanski, Magdalena

    2016-01-01

    Malaria parasites engage a multitude of strategies to evade the immune system of the host, including the generation of polymorphic T cell epitope sequences, termed altered peptide ligands (APLs). Herein we use an animal model to study how single amino acid changes in the sequence of the circumsporozoite protein (CSP), a major target antigen of pre-erythrocytic malaria vaccines, can lead to a reduction of cross reactivity by T cells. For the first time in any APL model, we further compare different inflammatory adjuvants (Montanide, Poly I:C), non-inflammatory adjuvants (nanoparticles), and peptide pulsed dendritic cells (DCs) for their potential capacity to induce broadly cross reactive immune responses. Results show that the capacity to induce a cross reactive response is primarily controlled by the T cell epitope sequence and cannot be modified by the use of different adjuvants. Moreover, we identify how specific amino acid changes lead to a one-way cross reactivity: where variant-x induced responses are re-elicited by variant-x and not variant-y, but variant-y induced responses can be re-elicited by variant-y and variant-x. We discuss the consequences of the existence of this one-way cross reactivity phenomenon for parasite immune evasion in the field, as well as the use of variant epitopes as a potential tool for optimized vaccine design. PMID:27014226

  13. A Model to Study the Impact of Polymorphism Driven Liver-Stage Immune Evasion by Malaria Parasites, to Help Design Effective Cross-Reactive Vaccines.

    PubMed

    Wilson, Kirsty L; Xiang, Sue D; Plebanski, Magdalena

    2016-01-01

    Malaria parasites engage a multitude of strategies to evade the immune system of the host, including the generation of polymorphic T cell epitope sequences, termed altered peptide ligands (APLs). Herein we use an animal model to study how single amino acid changes in the sequence of the circumsporozoite protein (CSP), a major target antigen of pre-erythrocytic malaria vaccines, can lead to a reduction of cross reactivity by T cells. For the first time in any APL model, we further compare different inflammatory adjuvants (Montanide, Poly I:C), non-inflammatory adjuvants (nanoparticles), and peptide pulsed dendritic cells (DCs) for their potential capacity to induce broadly cross reactive immune responses. Results show that the capacity to induce a cross reactive response is primarily controlled by the T cell epitope sequence and cannot be modified by the use of different adjuvants. Moreover, we identify how specific amino acid changes lead to a one-way cross reactivity: where variant-x induced responses are re-elicited by variant-x and not variant-y, but variant-y induced responses can be re-elicited by variant-y and variant-x. We discuss the consequences of the existence of this one-way cross reactivity phenomenon for parasite immune evasion in the field, as well as the use of variant epitopes as a potential tool for optimized vaccine design. PMID:27014226

  14. 3D Analysis of the TCR/pMHCII Complex Formation in Monkeys Vaccinated with the First Peptide Inducing Sterilizing Immunity against Human Malaria

    PubMed Central

    López, Carolina; Yepes, Gloria; Patarroyo, Manuel E.

    2010-01-01

    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-DRβ1*0403 molecules with high capacity. Spectratyping analysis showed a preferential usage of Vβ12 and Vβ6 TCR gene families in 67% of HLA-DRβ1*0403-like genotyped monkeys. Docking of peptide 24112 into the HLA-DRβ1*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. PMID:20333301

  15. Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

    PubMed Central

    Carapau, Daniel; Mitchell, Robert; Nacer, Adéla; Shaw, Alan; Othoro, Caroline; Frevert, Ute

    2013-01-01

    Immunization with Plasmodium sporozoites can elicit high levels of sterile immunity, and neutralizing antibodies from protected hosts are known to target the repeat region of the circumsporozoite (CS) protein on the parasite surface. CS-based subunit vaccines have been hampered by suboptimal immunogenicity and the requirement for strong adjuvants to elicit effective humoral immunity. Pathogen-associated molecular patterns (PAMPs) that signal through Toll-like receptors (TLRs) can function as potent adjuvants for innate and adaptive immunity. We examined the immunogenicity of recombinant proteins containing a TLR5 agonist, flagellin, and either full-length or selected epitopes of the Plasmodium falciparum CS protein. Mice immunized with either of the flagellin-modified CS constructs, administered intranasally (i.n.) or subcutaneously (s.c.), developed similar levels of malaria-specific IgG1 antibody and interleukin-5 (IL-5)-producing T cells. Importantly, immunization via the i.n. but not the s.c. route elicited sporozoite neutralizing antibodies capable of inhibiting >90% of sporozoite invasion in vitro and in vivo, as measured using a transgenic rodent parasite expressing P. falciparum CS repeats. These findings demonstrate that functional sporozoite neutralizing antibody can be elicited by i.n. immunization with a flagellin-modified P. falciparum CS protein and raise the potential of a scalable, safe, needle-free vaccine for the 40% of the world's population at risk of malaria. PMID:24042110

  16. The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody.

    PubMed

    Douglas, Alexander D; Williams, Andrew R; Illingworth, Joseph J; Kamuyu, Gathoni; Biswas, Sumi; Goodman, Anna L; Wyllie, David H; Crosnier, Cécile; Miura, Kazutoyo; Wright, Gavin J; Long, Carole A; Osier, Faith H; Marsh, Kevin; Turner, Alison V; Hill, Adrian V S; Draper, Simon J

    2011-12-20

    Current vaccine strategies against the asexual blood stage of Plasmodium falciparum are mostly focused on well-studied merozoite antigens that induce immune responses after natural exposure, but have yet to induce robust protection in any clinical trial. Here we compare human-compatible viral-vectored vaccines targeting ten different blood-stage antigens. We show that the full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) is highly susceptible to cross-strain neutralizing vaccine-induced antibodies, out-performing all other antigens delivered by the same vaccine platform. We find that, despite being susceptible to antibody, PfRH5 is unlikely to be under substantial immune selection pressure; there is minimal acquisition of anti-PfRH5 IgG antibodies in malaria-exposed Kenyans. These data challenge the widespread beliefs that any merozoite antigen that is highly susceptible to immune attack would be subject to significant levels of antigenic polymorphism, and that erythrocyte invasion by P. falciparum is a degenerate process involving a series of parallel redundant pathways.

  17. Adjuvant-like Effect of Vaccinia Virus 14K Protein: A Case Study with Malaria Vaccine Based on the Circumsporozoite Protein

    PubMed Central

    Vijayan, Aneesh; Gómez, Carmen E.; Espinosa, Diego A.; Goodman, Alan G.; Sanchez-Sampedro, Lucas; Sorzano, Carlos Oscar S.; Zavala, Fidel; Esteban, Mariano

    2014-01-01

    Development of subunit vaccines for malaria that elicit a strong, long-term memory response is an intensive area of research, with the focus on improving the immunogenicity of a circumsporozoite (CS) protein-based vaccine. In this study, we found that a chimeric protein, formed by fusing vaccinia virus protein 14K (A27) to the CS of Plasmodium yoelii, induces strong effector memory CD8+ T cell responses in addition to high-affinity Abs when used as a priming agent in the absence of any adjuvant, followed by an attenuated vaccinia virus boost expressing CS in murine models. Moreover, priming with the chimeric protein improved the magnitude and polyfunctionality of cytokine-secreting CD8+ T cells. This fusion protein formed oligomers/aggregates that led to activation of STAT-1 and IFN regulatory factor-3 in human macrophages, indicating a type I IFN response, resulting in NO, IL-12, and IL-6 induction. Furthermore, this vaccination regimen inhibited the liver stage development of the parasite, resulting in sterile protection. In summary, we propose a novel approach in designing CS based pre-erythrocytic vaccines against Plasmodium using the adjuvant-like effect of the immunogenic vaccinia virus protein 14K. PMID:22615208

  18. A Phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel with CPG 7909, using two different formulations and dosing intervals.

    PubMed

    Ellis, Ruth D; Mullen, Gregory E D; Pierce, Mark; Martin, Laura B; Miura, Kazutoyo; Fay, Michael P; Long, Carole A; Shaffer, Donna; Saul, Allan; Miller, Louis H; Durbin, Anna P

    2009-06-24

    A Phase 1 study was conducted in 24 malaria naïve adults to assess the safety and immunogenicity of the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with CPG 7909 in two different formulations (phosphate buffer and saline), and given at two different dosing schedules, 0 and 1 month or 0 and 2 months. Both formulations were well tolerated and frequency of local reactions and solicited adverse events was similar among the groups. Peak antibody levels in the groups receiving CPG 7909 in saline were not significantly different than those receiving CPG 7909 in phosphate. Peak antibody levels in the groups vaccinated at a 0,2 month interval were 2.52-fold higher than those vaccinated at a 0,1 month interval (p=0.037, 95% CI 1.03, 4.28). In vitro growth inhibition followed the antibody level: median inhibition was 51% (0,1 month interval) versus 85% (0,2 month interval) in antibody from samples taken 2 weeks post-second vaccination (p=0.056). PMID:19410624

  19. Efficacy of a Plasmodium vivax malaria vaccine using ChAd63 and modified vaccinia Ankara expressing thrombospondin-related anonymous protein as assessed with transgenic Plasmodium berghei parasites.

    PubMed

    Bauza, Karolis; Malinauskas, Tomas; Pfander, Claudia; Anar, Burcu; Jones, E Yvonne; Billker, Oliver; Hill, Adrian V S; Reyes-Sandoval, Arturo

    2014-03-01

    Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America. Despite this dramatic burden, very few vaccines have been assessed in humans. The clinically relevant vectors modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAd63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to induce protective immune responses against Plasmodium falciparum thrombospondin-related anonymous protein (TRAP) in clinical trials. Here, we describe the development of new recombinant ChAd63 and MVA vectors expressing P. vivax TRAP (PvTRAP) and show their ability to induce high antibody titers and T cell responses in mice. In addition, we report a novel way of assessing the efficacy of new candidate vaccines against P. vivax using a fully infectious transgenic Plasmodium berghei parasite expressing P. vivax TRAP to allow studies of vaccine efficacy and protective mechanisms in rodents. Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.

  20. Immunological Cross-Reactivity between Malaria Vaccine Target Antigen P48/45 in Plasmodium vivax and P. falciparum and Cross-Boosting of Immune Responses.

    PubMed

    Cao, Yi; Bansal, Geetha P; Merino, Kristen; Kumar, Nirbhay

    2016-01-01

    In general, malaria immunity has been suggested to be species specific with very little, if any, known cross-reactivity between Plasmodium vivax and P. falciparum, both of which are responsible for >90% of human malaria, and co-endemic in many countries. It is therefore believed that species-specific immunity may be needed to target different species of Plasmodium. Pfs48/45 and Pvs48/45 are well established targets in the sexual stages of the malaria parasites, and are being pursued for the development of transmission blocking vaccines. Comparison of their sequences reveals 61% and 55% identity at the DNA and protein level, respectively raising the possibility that these two target antigens might share cross-reacting epitopes. Having succeeded in expressing recombinant Pfs48/45 and Pvs48/45 proteins, we hypothesized that these proteins will not only exhibit immunological cross-reactivity but also cross-boost immune responses. Mice were immunized with purified recombinant proteins using CFA, Montanide ISA-51 and alum as adjuvants, and the sera were analyzed by ELISA, Western blotting and indirect fixed and live IFA to address the hypothesis. Our studies revealed that Pvs48/45-immune sera showed strong cross-reactivity to full length Pfs48/45 protein, and the majority of this cross reactivity was in the amino-terminal and carboxyl-terminal sub-fragments of Pfs48/45. In cross-boosting experiments Pfs48/45 and Pvs48/45 antigens were able to cross-boost each other in mouse immunization studies. Additionally we also noticed an effect of adjuvants in the overall magnitude of observed cross-reactivity. These studies may have significant implications for immunity targeting transmission of both the species of malaria parasites. PMID:27438603

  1. Immunological Cross-Reactivity between Malaria Vaccine Target Antigen P48/45 in Plasmodium vivax and P. falciparum and Cross–Boosting of Immune Responses

    PubMed Central

    Cao, Yi; Bansal, Geetha P.; Merino, Kristen; Kumar, Nirbhay

    2016-01-01

    In general, malaria immunity has been suggested to be species specific with very little, if any, known cross-reactivity between Plasmodium vivax and P. falciparum, both of which are responsible for >90% of human malaria, and co-endemic in many countries. It is therefore believed that species-specific immunity may be needed to target different species of Plasmodium. Pfs48/45 and Pvs48/45 are well established targets in the sexual stages of the malaria parasites, and are being pursued for the development of transmission blocking vaccines. Comparison of their sequences reveals 61% and 55% identity at the DNA and protein level, respectively raising the possibility that these two target antigens might share cross-reacting epitopes. Having succeeded in expressing recombinant Pfs48/45 and Pvs48/45 proteins, we hypothesized that these proteins will not only exhibit immunological cross–reactivity but also cross-boost immune responses. Mice were immunized with purified recombinant proteins using CFA, Montanide ISA-51 and alum as adjuvants, and the sera were analyzed by ELISA, Western blotting and indirect fixed and live IFA to address the hypothesis. Our studies revealed that Pvs48/45-immune sera showed strong cross-reactivity to full length Pfs48/45 protein, and the majority of this cross reactivity was in the amino-terminal and carboxyl-terminal sub-fragments of Pfs48/45. In cross-boosting experiments Pfs48/45 and Pvs48/45 antigens were able to cross-boost each other in mouse immunization studies. Additionally we also noticed an effect of adjuvants in the overall magnitude of observed cross-reactivity. These studies may have significant implications for immunity targeting transmission of both the species of malaria parasites. PMID:27438603

  2. The Synthetic Plasmodium falciparum Circumsporozoite Peptide PfCS102 as a Malaria Vaccine Candidate: A Randomized Controlled Phase I Trial

    PubMed Central

    Audran, Régine; Lurati-Ruiz, Floriana; Genton, Blaise; Blythman, Hildur E.; Ofori-Anyinam, Opokua; Reymond, Christophe; Corradin, Giampietro; Spertini, François

    2009-01-01

    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 µg) 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-γ production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-γ secreting CD8+ T cell responses. Responses were only marginally boosted after the 3rd vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 µg was less immunogenic in comparison to 30 and 100 µg that induced similar responses. AS02A formulations with 30 µg or 100 µg PfCS102 induced about 10-folds higher antibody and IFN-γ responses than Montanide formulations. Conclusions/Significance PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations

  3. In silico Identification and Validation of a Linear and Naturally Immunogenic B-Cell Epitope of the Plasmodium vivax Malaria Vaccine Candidate Merozoite Surface Protein-9

    PubMed Central

    Rodrigues-da-Silva, Rodrigo Nunes; Martins da Silva, João Hermínio; Singh, Balwan; Jiang, Jianlin; Meyer, Esmeralda V. S.; Santos, Fátima; Banic, Dalma Maria; Moreno, Alberto; Galinski, Mary R.; Oliveira-Ferreira, Joseli; Lima-Junior, Josué da Costa

    2016-01-01

    Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly-available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9. We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and

  4. Randomized Controlled Trial of RTS,S/AS02D and RTS,S/AS01E Malaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

    PubMed Central

    Owusu-Agyei, Seth; Ansong, Daniel; Asante, Kwaku; Kwarteng Owusu, Sandra; Owusu, Ruth; Wireko Brobby, Naana Ayiwa; Dosoo, David; Osei Akoto, Alex; Osei-Kwakye, Kingsley; Adjei, Emmanuel Asafo; Boahen, Kwadwo Owusu; Sylverken, Justice; Adjei, George; Sambian, David; Apanga, Stephen; Kayan, Kingsley; Vekemans, Johan; Ofori-Anyinam, Opokua; Leach, Amanda; Lievens, Marc; Demoitie, Marie-Ange; Dubois, Marie-Claude; Cohen, Joe; Ballou, W. Ripley; Savarese, Barbara; Chandramohan, Daniel; Gyapong, John Owusu; Milligan, Paul; Antwi, Sampson; Agbenyega, Tsiri; Greenwood, Brian; Evans, Jennifer

    2009-01-01

    Background 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/AS01E and RTS,S/AS02D in infants and young children 5–17 months of age in Ghana. Methodology 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/AS01E or rabies vaccine at one center and RTS,S/AS01E or RTS,S/AS02D at the other. For the other schedules at both study sites, they received RTS,S/AS01E or RTS,S/AS02D. The primary outcome measure was the occurrence of serious adverse events until 10 months post dose 1. Results 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/AS01E 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/AS01E than RTS,S/AS02D. Both candidate vaccines were highly immunogenic for anti-circumsporozoite and anti-Hepatitis B Virus surface antigen antibodies. Recipients of RTS,S/AS01E compared to RTS,S/AS02D 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/AS01E schedules

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

    PubMed Central

    2011-01-01

    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(OH)3-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 malaria vaccine and influenza

  6. Malaria Research

    MedlinePlus

    ... Malaria > Research Malaria Understanding Research NIAID Role Basic Biology Prevention and Control Strategies Strategic Partnerships and Research ... the malaria parasite. Related Links Global Research​ Vector Biology International Centers of Excellence for Malaria Research (ICEMR) ...

  7. Vaccines

    MedlinePlus Videos and Cool Tools

    Vaccinations are injections of antigens into the body. Once the antigens enter the blood, they circulate along ... suppressor T cells stop the attack. After a vaccination, the body will have a memory of an ...

  8. Enhanced immunogenicity for CD8+ T cell induction and complete protective efficacy of malaria DNA vaccination by boosting with modified vaccinia virus Ankara.

    PubMed

    Schneider, J; Gilbert, S C; Blanchard, T J; Hanke, T; Robson, K J; Hannan, C M; Becker, M; Sinden, R; Smith, G L; Hill, A V

    1998-04-01

    Immunization with irradiated sporozoites can protect against malaria infection and intensive efforts are aimed at reproducing this effect with subunit vaccines. A particular sequence of subunit immunization with pre-erythrocytic antigens of Plasmodium berghei, consisting of single dose priming with plasmid DNA followed by a single boost with a recombinant modified vaccinia virus Ankara (MVA) expressing the same antigen, induced unprecedented complete protection against P. berghei sporozoite challenge in two strains of mice. Protection was associated with very high levels of splenic peptide-specific interferon-gamma-secreting CD8+ T cells and was abrogated when the order of immunization was reversed. DNA priming followed by MVA boosting may provide a general immunization regime for induction of high levels of CD8+ T cells.

  9. Safety, immunogenicity and protective effect of the SPf66 malaria synthetic vaccine against Plasmodium falciparum infection in a randomized double-blind placebo-controlled field trial in an endemic area of Ecuador.

    PubMed

    Sempértegui, F; Estrella, B; Moscoso, J; Piedrahita, L; Hernández, D; Gaybor, J; Naranjo, P; Mancero, O; Arias, S; Bernal, R

    1994-03-01

    A total of 537 subjects were randomized to receive either SPf66 malaria vaccine against Plasmodium falciparum or placebo in three doses (days 0, 30 and 180). Subjects completing the course of vaccination (230 in the vaccine and 238 in the placebo group) were followed up for a further 12 months. Case detection surveillance was implemented by parasitological cross-sectional surveys every 2 months and by monthly household visits to each participant. Symptomatic subjects were also diagnosed in a local health centre. Minor local side-effects were observed mainly after the second dose in about 19% of the vaccinated subjects and in 3.7% of the placebo group. Thirty days after the third dose the prevalence of anti-SPf66 antibodies was 57% in the vaccine and 8.8% in the placebo groups. The prevaccination prevalence of antibodies measured by indirect immunofluorescence assay increased with age and seemed to be inversely related to anti-SPf66 antibody production. Immune response to SPf66 was independent of age. Vaccine efficacy was calculated based on person-time of exposure. The protective effect considering any malaria episode was 66.8% (95% confidence interval = -2.7-89.3%) and considering only one episode per individual was 60.2% (95% confidence interval = -26-87.5%).

  10. Newer approaches to malaria control

    PubMed Central

    Damodaran, SE; Pradhan, Prita; Pradhan, Suresh Chandra

    2011-01-01

    Malaria is the third leading cause of death due to infectious diseases affecting around 243 million people, causing 863,000 deaths each year, and is a major public health problem. Most of the malarial deaths occur in children below 5 years and is a major contributor of under-five mortality. As a result of environmental and climatic changes, there is a change in vector population and distribution, leading to resurgence of malaria at numerous foci. Resistance to antimalarials is a major challenge to malaria control and there are new drug developments, new approaches to treatment strategies, combination therapy to overcome resistance and progress in vaccine development. Now, artemisinin-based combination therapy is the first-line therapy as the malarial parasite has developed resistance to other antimalarials. Reports of artemisinin resistance are appearing and identification of new drug targets gains utmost importance. As there is a shift from malaria control to malaria eradication, more research is focused on malaria vaccine development. A malaria vaccine, RTS,S, is in phase III of development and may become the first successful one. Due to resistance to insecticides and lack of environmental sanitation, the conventional methods of vector control are turning out to be futile. To overcome this, novel strategies like sterile insect technique and transgenic mosquitoes are pursued for effective vector control. As a result of the global organizations stepping up their efforts with continued research, eradication of malaria can turn out to be a reality. PMID:23508211

  11. Newer approaches to malaria control.

    PubMed

    Damodaran, Se; Pradhan, Prita; Pradhan, Suresh Chandra

    2011-07-01

    Malaria is the third leading cause of death due to infectious diseases affecting around 243 million people, causing 863,000 deaths each year, and is a major public health problem. Most of the malarial deaths occur in children below 5 years and is a major contributor of under-five mortality. As a result of environmental and climatic changes, there is a change in vector population and distribution, leading to resurgence of malaria at numerous foci. Resistance to antimalarials is a major challenge to malaria control and there are new drug developments, new approaches to treatment strategies, combination therapy to overcome resistance and progress in vaccine development. Now, artemisinin-based combination therapy is the first-line therapy as the malarial parasite has developed resistance to other antimalarials. Reports of artemisinin resistance are appearing and identification of new drug targets gains utmost importance. As there is a shift from malaria control to malaria eradication, more research is focused on malaria vaccine development. A malaria vaccine, RTS,S, is in phase III of development and may become the first successful one. Due to resistance to insecticides and lack of environmental sanitation, the conventional methods of vector control are turning out to be futile. To overcome this, novel strategies like sterile insect technique and transgenic mosquitoes are pursued for effective vector control. As a result of the global organizations stepping up their efforts with continued research, eradication of malaria can turn out to be a reality. PMID:23508211

  12. [VACCINES].

    PubMed

    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.

  13. Functional Analysis of the Leading Malaria Vaccine Candidate AMA-1 Reveals an Essential Role for the Cytoplasmic Domain in the Invasion Process

    PubMed Central

    Treeck, Moritz; Zacherl, Sonja; Herrmann, Susann; Cabrera, Ana; Kono, Maya; Struck, Nicole S.; Engelberg, Klemens; Haase, Silvia; Frischknecht, Friedrich; Miura, Kota; Spielmann, Tobias; Gilberger, Tim W.

    2009-01-01

    A key process in the lifecycle of the malaria parasite Plasmodium falciparum is the fast invasion of human erythrocytes. Entry into the host cell requires the apical membrane antigen 1 (AMA-1), a type I transmembrane protein located in the micronemes of the merozoite. Although AMA-1 is evolving into the leading blood-stage malaria vaccine candidate, its precise role in invasion is still unclear. We investigate AMA-1 function using live video microscopy in the absence and presence of an AMA-1 inhibitory peptide. This data reveals a crucial function of AMA-1 during the primary contact period upstream of the entry process at around the time of moving junction formation. We generate a Plasmodium falciparum cell line that expresses a functional GFP-tagged AMA-1. This allows the visualization of the dynamics of AMA-1 in live parasites. We functionally validate the ectopically expressed AMA-1 by establishing a complementation assay based on strain-specific inhibition. This method provides the basis for the functional analysis of essential genes that are refractory to any genetic manipulation. Using the complementation assay, we show that the cytoplasmic domain of AMA-1 is not required for correct trafficking and surface translocation but is essential for AMA-1 function. Although this function can be mimicked by the highly conserved cytoplasmic domains of P. vivax and P. berghei, the exchange with the heterologous domain of the microneme protein EBA-175 or the rhoptry protein Rh2b leads to a loss of function. We identify several residues in the cytoplasmic tail that are essential for AMA-1 function. We validate this data using additional transgenic parasite lines expressing AMA-1 mutants with TY1 epitopes. We show that the cytoplasmic domain of AMA-1 is phosphorylated. Mutational analysis suggests an important role for the phosphorylation in the invasion process, which might translate into novel therapeutic strategies. PMID:19283086

  14. Malaria in Children

    PubMed Central

    Schumacher, Richard-Fabian; Spinelli, Elena

    2012-01-01

    This review is focused on childhood specific aspects of malaria, especially in resource-poor settings. We summarise the actual knowledge in the field of epidemiology, clinical presentation, diagnosis, management and prevention. These aspects are important as malaria is responsible for almost a quarter of all child death in sub-Saharan Africa. Malaria control is thus one key intervention to reduce childhood mortality, especially as malaria is also an important risk factor for other severe infections, namely bacteraemia. In children symptoms are more varied and often mimic other common childhood illness, particularly gastroenteritis, meningitis/encephalitis, or pneumonia. Fever is the key symptom, but the characteristic regular tertian and quartan patterns are rarely observed. There are no pathognomonic features for severe malaria in this age group. The well known clinical (fever, impaired consciousness, seizures, vomiting, respiratory distress) and laboratory (severe anaemia, thrombocytopenia, hypoglycaemia, metabolic acidosis, and hyperlactataemia) features of severe falciparum malaria in children, are equally typical for severe sepsis. Appropriate therapy (considering species, resistance patterns and individual patient factors) – possibly a drug combination of an artemisinin derivative with a long-acting antimalarial drug - reduces treatment duration to only three days and should be urgently started. While waiting for the results of ongoing vaccine trials, all effort should be made to better implement other malaria-control measures like the use of treated bed-nets, repellents and new chemoprophylaxis regimens. PMID:23205261

  15. Cerebral malaria.

    PubMed

    Postels, Douglas G; Birbeck, Gretchen L

    2013-01-01

    Malaria, the most significant parasitic disease of man, kills approximately one million people per year. Half of these deaths occur in those with cerebral malaria (CM). The World Health Organization (WHO) defines CM as an otherwise unexplained coma in a patient with malarial parasitemia. Worldwide, CM occurs primarily in African children and Asian adults, with the vast majority (greater than 90%) of cases occurring in children 5 years old or younger in sub-Saharan Africa. The pathophysiology of the disease is complex and involves infected erythrocyte sequestration, cerebral inflammation, and breakdown of the blood-brain barrier. A recently characterized malarial retinopathy is visual evidence of Plasmodium falciparum's pathophysiological processes occurring in the affected patient. Treatment consists of supportive care and antimalarial administration. Thus far, adjuvant therapies have not been shown to improve mortality rates or neurological outcomes in children with CM. For those who survive CM, residual neurological abnormalities are common. Epilepsy, cognitive impairment, behavioral disorders, and gross neurological deficits which include motor, sensory, and language impairments are frequent sequelae. Primary prevention strategies, including bed nets, vaccine development, and chemoprophylaxis, are in varied states of development and implementation. Continuing efforts to find successful primary prevention options and strategies to decrease neurological sequelae are needed. PMID:23829902

  16. Long term stability of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Montanide® ISA 720 and stabilized with Glycine

    PubMed Central

    Zhu, Daming; McClellan, Holly; Dai, Weili; Gebregeorgis, Elizabeth; Kidwell, Mary Anne; Aebig, Joan; Rausch, Kelly M.; Martin, Laura B.; Ellis, Ruth D.; Miller, Louis; Wu, Yimin

    2011-01-01

    Plasmodium falciparum apical membrane antigen 1 (AMA1) is an asexual blood-stage vaccine candidate against the malaria parasite. AMA1-C1/ISA720 refers to a mixture of recombinant AMA1 proteins representing the FVO and 3D7 alleles in 1:1 mass ratio, formulated with Montanide® ISA 720 as a water-in oil emulsion. In order to develop the AMA1-C1/ISA720 vaccine for human use, it was important to determine the shelf life of this formulation. Previously it was found 267mM glycine stabilized the proteins in Montanide® ISA 720 formulations for a short period of time at 2-8°C[25], we now test the long term stability of AMA1-C1 at 10 and 40 μg/ml formulated with Montanide® ISA 720 with 50 mM glycine as a stabilizer. Stability of AMA1-C1/ISA720 at different time points following formulation (0, 5, 12 or 18 months) was evaluated by determining the mean particle size (diameter of the mean droplet volume), total protein content by a Modified Lowry assay, identity and integrity using western blot and SDS-PAGE. Our results showed that the mean particle size of these emulsions increased over time, whereas protein content, as determined by an ELISA method using a monoclonal antibody against penta-his, decreased over time. For the 10 μg/ml AMA1-C1/ISA720 vaccine, the protein content with was 6.5 ± 2.2 μg/ml, and for the 40 μg/ml AMA1-C1/ISA720 vaccine, the protein content was only 8.2 ± 2.3 μg/ml after 18 months of storage at 2-8°C. These results suggest that the integrity of the protein was affected by long-term storage. The results of the present study indicate that the AMA1-C1/ISA720 emulsion was unstable after 12 months of storage, after which AMA1-C1 proteins were partially degraded. PMID:21440641

  17. An Open Source Business Model for Malaria

    PubMed Central

    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

  18. An open source business model for malaria.

    PubMed

    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

  19. A randomized and controlled Phase 1 study of the safety and immunogenicity of the AMA1-C1/Alhydrogel + CPG 7909 vaccine for Plasmodium falciparum malaria in semi-immune Malian adults.

    PubMed

    Sagara, Issaka; Ellis, Ruth D; Dicko, Alassane; Niambele, Mohamed B; Kamate, Beh; Guindo, Ousmane; Sissoko, Mahamadou S; Fay, Michael P; Guindo, Merepen A; Kante, Ousmane; Saye, Renion; Miura, Kazutoyo; Long, Carole; Mullen, Gregory E D; Pierce, Mark; Martin, Laura B; Rausch, Kelly; Dolo, Amagana; Diallo, Dapa A; Miller, Louis H; Doumbo, Ogobara K

    2009-12-01

    A double blind, randomized and controlled Phase 1 clinical trial was conducted to assess the safety and immunogenicity in malaria-exposed adults of the Plasmodium falciparum blood stage vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with and without the novel adjuvant CPG 7909. Participants were healthy adults 18-45 years old living in the village of Donéguébougou, Mali. A total of 24 participants received 2 doses one month apart of either 80 microg AMA1-C1/Alhydrogel or 80 microg AMA1-C1/Alhydrogel + 564 microg CPG 7909. The study started in October 2007 and completed follow up in May 2008. Both vaccines were well tolerated, with only mild local adverse events and no systemic adverse events judged related to vaccination. The difference in antibody responses were over 2-fold higher in the group receiving CPG 7909 for all time points after second vaccination and the differences are statistically significant (all p<0.05). This is the first use of the novel adjuvant CPG 7909 in a malaria-exposed population. PMID:19874925

  20. Antibody responses to a novel Plasmodium falciparum merozoite surface protein vaccine correlate with protection against experimental malaria infection in Aotus monkeys.

    PubMed

    Cavanagh, David R; Kocken, Clemens H M; White, John H; Cowan, Graeme J M; Samuel, Kay; Dubbeld, Martin A; Voorberg-van der Wel, Annemarie; Thomas, Alan W; McBride, Jana S; Arnot, David E

    2014-01-01

    The Block 2 region of the merozoite surface protein-1 (MSP-1) of Plasmodium falciparum has been identified as a target of protective immunity by a combination of seroepidemiology and parasite population genetics. Immunogenicity studies in small animals and Aotus monkeys were used to determine the efficacy of recombinant antigens derived from this region of MSP-1 as a potential vaccine antigen. Aotus lemurinus griseimembra monkeys were immunized three times with a recombinant antigen derived from the Block 2 region of MSP-1 of the monkey-adapted challenge strain, FVO of Plasmodium falciparum, using an adjuvant suitable for use in humans. Immunofluorescent antibody assays (IFA) against erythrocytes infected with P. falciparum using sera from the immunized monkeys showed that the MSP-1 Block 2 antigen induced significant antibody responses to whole malaria parasites. MSP-1 Block 2 antigen-specific enzyme-linked immunosorbent assays (ELISA) showed no significant differences in antibody titers between immunized animals. Immunized animals were challenged with the virulent P. falciparum FVO isolate and monitored for 21 days. Two out of four immunized animals were able to control their parasitaemia during the follow-up period, whereas two out of two controls developed fulminating parasitemia. Parasite-specific serum antibody titers measured by IFA were four-fold higher in protected animals than in unprotected animals. In addition, peptide-based epitope mapping of serum antibodies from immunized Aotus showed distinct differences in epitope specificities between protected and unprotected animals. PMID:24421900

  1. Antibody Responses to a Novel Plasmodium falciparum Merozoite Surface Protein Vaccine Correlate with Protection against Experimental Malaria Infection in Aotus Monkeys

    PubMed Central

    Cavanagh, David R.; Kocken, Clemens H. M.; White, John H.; Cowan, Graeme J. M.; Samuel, Kay; Dubbeld, Martin A.; der Wel, Annemarie Voorberg-van; Thomas, Alan W.; McBride, Jana S.; Arnot, David E.

    2014-01-01

    The Block 2 region of the merozoite surface protein-1 (MSP-1) of Plasmodium falciparum has been identified as a target of protective immunity by a combination of seroepidemiology and parasite population genetics. Immunogenicity studies in small animals and Aotus monkeys were used to determine the efficacy of recombinant antigens derived from this region of MSP-1 as a potential vaccine antigen. Aotus lemurinus griseimembra monkeys were immunized three times with a recombinant antigen derived from the Block 2 region of MSP-1 of the monkey-adapted challenge strain, FVO of Plasmodium falciparum, using an adjuvant suitable for use in humans. Immunofluorescent antibody assays (IFA) against erythrocytes infected with P. falciparum using sera from the immunized monkeys showed that the MSP-1 Block 2 antigen induced significant antibody responses to whole malaria parasites. MSP-1 Block 2 antigen-specific enzyme-linked immunosorbent assays (ELISA) showed no significant differences in antibody titers between immunized animals. Immunized animals were challenged with the virulent P. falciparum FVO isolate and monitored for 21 days. Two out of four immunized animals were able to control their parasitaemia during the follow-up period, whereas two out of two controls developed fulminating parasitemia. Parasite-specific serum antibody titers measured by IFA were four-fold higher in protected animals than in unprotected animals. In addition, peptide-based epitope mapping of serum antibodies from immunized Aotus showed distinct differences in epitope specificities between protected and unprotected animals. PMID:24421900

  2. Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid A, and squalane in malaria circumsporozoite protein vaccine.

    PubMed

    Rickman, L S; Gordon, D M; Wistar, R; Krzych, U; Gross, M; Hollingdale, M R; Egan, J E; Chulay, J D; Hoffman, S L

    1991-04-27

    Human immune responses to modern synthetic and recombinant peptide vaccines administered with the standard adjuvant, aluminum hydroxide, tend to be poor, hence the search for better adjuvants. Antibody responses to a Plasmodium falciparum circumsporozoite (CS) protein vaccine, R32NS1(81), administered with an adjuvant containing cell-wall skeleton of mycobacteria and monophosphoryl lipid A in squalane (MPL/CWS) have been compared to responses to the same immunogen administered with aluminum hydroxide. 2 weeks after the third dose the following indices were greater in the 5 patients who received MPL/CWS than in controls (p less than 0.05): the geometric mean concentration (2.0 vs 25.4 microgram/ml) and avidity index of antibodies to the P falciparum CS protein by ELISA, the geometric mean titre to P falciparum sporozoites by IFAT (1/115 vs 1/1600), and the geometric mean inhibition of sporozoite invasion of hepatoma cells in vitro (37.6 vs 90.3%). For R32NS1(81) MPL/CWS is superior to aluminum hydroxide as an adjuvant, and the data support the evaluation of this complex as an adjuvant for other vaccines.

  3. Human Vaccines and Immunotherapeutics: News

    PubMed Central

    2013-01-01

    Two studies on optimal timing for measles vaccination Chinese scientists develop bird flu vaccine Influenza vaccination reduces risk of heart attack and stroke Two-dose vaccination program shows positive impact on varicella incidence WHO prequalifies Chinese-produced Japanese encephalitis vaccine Phase 3: RTS,S almost halves malaria cases in young children Herd immunity protects babies against whooping cough New developments in nanoparticle-based vaccination

  4. Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate

    PubMed Central

    Morales, Rodrigo A. V.; MacRaild, Christopher A.; Seow, Jeffrey; Krishnarjuna, Bankala; Drinkwater, Nyssa; Rouet, Romain; Anders, Robin F.; Christ, Daniel; McGowan, Sheena; Norton, Raymond S.

    2015-01-01

    Merozoite surface protein 2 (MSP2) is an intrinsically disordered, membrane-anchored antigen of the malaria parasite Plasmodium falciparum. MSP2 can elicit a protective, albeit strain-specific, antibody response in humans. Antibodies are generated to the conserved N- and C-terminal regions but many of these react poorly with the native antigen on the parasite surface. Here we demonstrate that recognition of a conserved N-terminal epitope by mAb 6D8 is incompatible with the membrane-bound conformation of that region, suggesting a mechanism by which native MSP2 escapes antibody recognition. Furthermore, crystal structures and NMR spectroscopy identify transient, strain-specific interactions between the 6D8 antibody and regions of MSP2 beyond the conserved epitope. These interactions account for the differential affinity of 6D8 for the two allelic families of MSP2, even though 6D8 binds to a fully conserved epitope. These results highlight unappreciated mechanisms that may modulate the specificity and efficacy of immune responses towards disordered antigens. PMID:25965408

  5. Malaria Facts

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  6. Malaria diagnostics in clinical trials.

    PubMed

    Murphy, Sean C; Shott, Joseph P; Parikh, Sunil; Etter, Paige; Prescott, William R; Stewart, V Ann

    2013-11-01

    Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests.

  7. T Cell Responses to the RTS,S/AS01E and RTS,S/AS02D Malaria Candidate Vaccines Administered According to Different Schedules to Ghanaian Children

    PubMed Central

    Ansong, Daniel; Asante, Kwaku P.; Vekemans, Johan; Owusu, Sandra K.; Owusu, Ruth; Brobby, Naana A. W.; Dosoo, David; Osei-Akoto, Alex; Osei-Kwakye, Kingsley; Asafo-Adjei, Emmanuel; Boahen, Kwadwo O.; Sylverken, Justice; Adjei, George; Sambian, David; Apanga, Stephen; Kayan, Kingsley; Janssens, Michel H.; Lievens, Marc J. J.; Olivier, Aurelie C.; Jongert, Erik; Dubois, Patrice; Savarese, Barbara M.; Cohen, Joe; Antwi, Sampson; Greenwood, Brian M.; Evans, Jennifer A.; Agbenyega, Tsiri; Moris, Philippe J.; Owusu-Agyei, Seth

    2011-01-01

    Background The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub-Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01E or the oil-in-water based adjuvant AS02D induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults. Methods This study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2- and 0,1,7-month) of RTS,S/AS01E and RTS,S/AS02D in children aged 5–17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites. Results Whole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01E induced CSP specific CD4 T cells producing IL-2, TNF-α, and IFN-γ. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1- or 0,1,2-month schedule. RTS,S/AS01E induced higher CD4 T cell responses as compared to RTS,S/AS02D when given on a 0,1,7-month schedule. Conclusions These findings support further Phase III evaluation of RTS,S/AS01E. The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation. Trial Registration ClinicalTrials.gov NCT00360230 PMID:21556142

  8. Malaria (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Malaria KidsHealth > For Parents > Malaria Print A A A ... Prevention Diagnosis and Treatment en español Malaria About Malaria Malaria is a common infection in hot, tropical ...

  9. Production, Quality Control, Stability and Pharmacotoxicity of a Malaria Vaccine Comprising Three Highly Similar PfAMA1 Protein Molecules to Overcome Antigenic Variation

    PubMed Central

    Houard, Sophie; Havelange, Nicolas; Drossard, Jürgen; Mertens, Hubert; Croon, Alexander; Kastilan, Robin; Byrne, Richard; van der Werff, Nicole; van der Eijk, Marjolein; Thomas, Alan W.; Kocken, Clemens H. M.; Remarque, Edmond J.

    2016-01-01

    Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading asexual blood stage vaccine candidate for malaria. In preparation for clinical trials, three Diversity Covering (DiCo) PfAMA1 ectodomain proteins, designed to overcome the intrinsic polymorphism that is present in PfAMA1, were produced under Good Manufacturing Practice (GMP) in Pichia pastoris. Using identical methodology, the 3 strains were cultivated in 70-L scale fed-batch fermentations and PfAMA1-DiCos were purified by two chromatography steps, an ultrafiltration/diafiltration procedure and size exclusion chromatography, resulting in highly pure (>95%) PfAMA1-DiCo1, PfAMA1 DiCo2 and PfAMA1 DiCo3, with final yields of 1.8, 1.9 and 1.3 gram, respectively. N-terminal determinations showed that approximately 50% of each of the proteins lost 12 residues from their N-terminus, in accordance with SDS-PAGE (2 main bands) and MS-data. Under reducing conditions a site of limited proteolytic cleavage within a disulphide bonded region became evident. The three proteins quantitatively bound to the mAb 4G2 that recognizes a conformational epitope, suggesting proper folding of the proteins. The lyophilized Drug Product (1:1:1 mixture of PfAMA1-DiCo1, DiCo2, DiCo3) fulfilled all pre-set release criteria (appearance, dissolution rate, identity, purity, protein content, moisture content, sub-visible particles, immuno-potency (after reconstitution with adjuvant), abnormal toxicity, sterility and endotoxin), was stable in accelerated and real-time stability studies at -20°C for over 24 months. When formulated with adjuvants selected for clinical phase I evaluation, the Drug Product did not show adverse effect in a repeated-dose toxicity study in rabbits. The Drug Product has entered a phase Ia/Ib clinical trial. PMID:27695087

  10. The role of vitamin D in malaria.

    PubMed

    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.

  11. In vivo microscopy of hemozoin: towards a needle free diagnostic for malaria

    PubMed Central

    Burnett, Jennifer L.; Carns, Jennifer L.; Richards-Kortum, Rebecca

    2015-01-01

    Clinical diagnosis of malaria suffers from poor specificity leading to overtreatment with antimalarial medications. Alternatives, like blood smear microscopy or antigen-based tests, require a blood sample. We investigate in vivo microscopy as a needle-free malaria diagnostic. Two optical signatures, birefringence and absorbance, of the endogenous malaria by-product hemozoin were evaluated as in vivo optical biomarkers. Hemozoin birefringence was difficult to detect in highly scattering tissue; however, hemozoin absorbance was observed in increasingly complex biological environments and detectable over a clinically-relevant range of parasitemia in vivo in a P. yoelii-infected mouse model of malaria. PMID:26417515

  12. In vivo microscopy of hemozoin: towards a needle free diagnostic for malaria.

    PubMed

    Burnett, Jennifer L; Carns, Jennifer L; Richards-Kortum, Rebecca

    2015-09-01

    Clinical diagnosis of malaria suffers from poor specificity leading to overtreatment with antimalarial medications. Alternatives, like blood smear microscopy or antigen-based tests, require a blood sample. We investigate in vivo microscopy as a needle-free malaria diagnostic. Two optical signatures, birefringence and absorbance, of the endogenous malaria by-product hemozoin were evaluated as in vivo optical biomarkers. Hemozoin birefringence was difficult to detect in highly scattering tissue; however, hemozoin absorbance was observed in increasingly complex biological environments and detectable over a clinically-relevant range of parasitemia in vivo in a P. yoelii-infected mouse model of malaria. PMID:26417515

  13. Antigen-based immunotherapy for autoimmune disease: current status

    PubMed Central

    Hirsch, Darren Lowell; Ponda, Punita

    2015-01-01

    Autoimmune diseases are common chronic disorders that not only have a major impact on the quality of life but are also potentially life-threatening. Treatment modalities that are currently favored have conferred significant clinical benefits, but they may have considerable side effects. An optimal treatment strategy for autoimmune disease would specifically target disease-associated antigens and limit systemic side effects. Similar to allergen-specific immunotherapy for allergic rhinitis, antigen-specific immunotherapy for autoimmune disease aims to induce immune deviation and promote tolerance to specific antigens. In this review, we present the current status of studies and clinical trials in both human and animal hosts that use antigen-based immunotherapy for autoimmune disease. PMID:27471707

  14. Emerging Vaccine Technologies

    PubMed Central

    Loomis, Rebecca J.; Johnson, Philip R.

    2015-01-01

    Vaccination has proven to be an invaluable means of preventing infectious diseases by reducing both incidence of disease and mortality. However, vaccines have not been effectively developed for many diseases including HIV-1, hepatitis C virus (HCV), tuberculosis and malaria, among others. The emergence of new technologies with a growing understanding of host-pathogen interactions and immunity may lead to efficacious vaccines against pathogens, previously thought impossible. PMID:26343196

  15. Ethical aspects of malaria control and research.

    PubMed

    Jamrozik, Euzebiusz; de la Fuente-Núñez, Vânia; Reis, Andreas; Ringwald, Pascal; Selgelid, Michael J

    2015-01-01

    Malaria currently causes more harm to human beings than any other parasitic disease, and disproportionally affects low-income populations. The ethical issues raised by efforts to control or eliminate malaria have received little explicit analysis, in comparison with other major diseases of poverty. While some ethical issues associated with malaria are similar to those that have been the subject of debate in the context of other infectious diseases, malaria also raises distinct ethical issues in virtue of its unique history, epidemiology, and biology. This paper provides preliminary ethical analyses of the especially salient issues of: (i) global health justice, (ii) universal access to malaria control initiatives, (iii) multidrug resistance, including artemisinin-based combination therapy (ACT) resistance, (iv) mandatory screening, (v) mass drug administration, (vi) benefits and risks of primaquine, and (vii) malaria in the context of blood donation and transfusion. Several ethical issues are also raised by past, present and future malaria research initiatives, in particular: (i) controlled infection studies, (ii) human landing catches, (iii) transmission-blocking vaccines, and (iv) genetically-modified mosquitoes. This article maps the terrain of these major ethical issues surrounding malaria control and elimination. Its objective is to motivate further research and discussion of ethical issues associated with malaria--and to assist health workers, researchers, and policy makers in pursuit of ethically sound malaria control practice and policy. PMID:26693920

  16. Ethical aspects of malaria control and research.

    PubMed

    Jamrozik, Euzebiusz; de la Fuente-Núñez, Vânia; Reis, Andreas; Ringwald, Pascal; Selgelid, Michael J

    2015-12-22

    Malaria currently causes more harm to human beings than any other parasitic disease, and disproportionally affects low-income populations. The ethical issues raised by efforts to control or eliminate malaria have received little explicit analysis, in comparison with other major diseases of poverty. While some ethical issues associated with malaria are similar to those that have been the subject of debate in the context of other infectious diseases, malaria also raises distinct ethical issues in virtue of its unique history, epidemiology, and biology. This paper provides preliminary ethical analyses of the especially salient issues of: (i) global health justice, (ii) universal access to malaria control initiatives, (iii) multidrug resistance, including artemisinin-based combination therapy (ACT) resistance, (iv) mandatory screening, (v) mass drug administration, (vi) benefits and risks of primaquine, and (vii) malaria in the context of blood donation and transfusion. Several ethical issues are also raised by past, present and future malaria research initiatives, in particular: (i) controlled infection studies, (ii) human landing catches, (iii) transmission-blocking vaccines, and (iv) genetically-modified mosquitoes. This article maps the terrain of these major ethical issues surrounding malaria control and elimination. Its objective is to motivate further research and discussion of ethical issues associated with malaria--and to assist health workers, researchers, and policy makers in pursuit of ethically sound malaria control practice and policy.

  17. Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA

    PubMed Central

    Richie, Thomas L.; Charoenvit, Yupin; Wang, Ruobing; Epstein, Judith E.; Hedstrom, Richard C.; Kumar, Sanjai; Luke, Thomas C.; Freilich, Daniel A.; Aguiar, Joao C.; Sacci, Jr., John B.; Sedegah, Martha; Nosek, Jr., Ronald A.; De La Vega, Patricia; Berzins, Mara P.; Majam, Victoria F.; Abot, Esteban N.; Ganeshan, Harini; Richie, Nancy O.; Banania, Jo Glenna; Baraceros, Maria Fe B.; Geter, Tanya G.; Mere, Robin; Bebris, Lolita; Limbach, Keith; Hickey, Bradley W.; Lanar, David E.; Ng, Jennifer; Shi, Meng; Hobart, Peter M.; Norman, Jon A.; Soisson, Lorraine A.; Hollingdale, Michael R.; Rogers, William O.; Doolan, Denise L.; Hoffman, Stephen L.

    2012-01-01

    When introduced in the 1990s, immunization with DNA plasmids was considered potentially revolutionary for vaccine development, particularly for vaccines intended to induce protective CD8 T cell responses against multiple antigens. We conducted, in 1997−1998, the first clinical trial in healthy humans of a DNA vaccine, a single plasmid encoding Plasmodium falciparum circumsporozoite protein (PfCSP), as an initial step toward developing a multi-antigen malaria vaccine targeting the liver stages of the parasite. As the next step, we conducted in 2000–2001 a clinical trial of a five-plasmid mixture called MuStDO5 encoding pre-erythrocytic antigens PfCSP, PfSSP2/TRAP, PfEXP1, PfLSA1 and PfLSA3. Thirty-two, malaria-naïve, adult volunteers were enrolled sequentially into four cohorts receiving a mixture of 500 μg of each plasmid plus escalating doses (0, 20, 100 or 500 μg) of a sixth plasmid encoding human granulocyte macrophage-colony stimulating factor (hGM-CSF). Three doses of each formulation were administered intramuscularly by needle-less jet injection at 0, 4 and 8 weeks, and each cohort had controlled human malaria infection administered by five mosquito bites 18 d later. The vaccine was safe and well-tolerated, inducing moderate antigen-specific, MHC-restricted T cell interferon-γ responses but no antibodies. Although no volunteers were protected, T cell responses were boosted post malaria challenge. This trial demonstrated the MuStDO5 DNA and hGM-CSF plasmids to be safe and modestly immunogenic for T cell responses. It also laid the foundation for priming with DNA plasmids and boosting with recombinant viruses, an approach known for nearly 15 y to enhance the immunogenicity and protective efficacy of DNA vaccines. PMID:23151451

  18. Malaria in Brazil: an overview

    PubMed Central

    2010-01-01

    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. Averting a malaria disaster: will insecticide resistance derail malaria control?

    PubMed

    Hemingway, Janet; Ranson, Hilary; Magill, Alan; Kolaczinski, Jan; Fornadel, Christen; Gimnig, John; Coetzee, Maureen; Simard, Frederic; Roch, Dabiré K; Hinzoumbe, Clément Kerah; Pickett, John; Schellenberg, David; Gething, Peter; Hoppé, Mark; Hamon, Nicholas

    2016-04-23

    World Malaria Day 2015 highlighted the progress made in the development of new methods of prevention (vaccines and insecticides) and treatment (single dose drugs) of the disease. However, increasing drug and insecticide resistance threatens the successes made with existing methods. Insecticide resistance has decreased the efficacy of the most commonly used insecticide class of pyrethroids. This decreased efficacy has increased mosquito survival, which is a prelude to rising incidence of malaria and fatalities. Despite intensive research efforts, new insecticides will not reach the market for at least 5 years. Elimination of malaria is not possible without effective mosquito control. Therefore, to combat the threat of resistance, key stakeholders need to rapidly embrace a multifaceted approach including a reduction in the cost of bringing new resistance management methods to market and the streamlining of associated development, policy, and implementation pathways to counter this looming public health catastrophe. PMID:26880124

  20. Averting a malaria disaster: will insecticide resistance derail malaria control?

    PubMed

    Hemingway, Janet; Ranson, Hilary; Magill, Alan; Kolaczinski, Jan; Fornadel, Christen; Gimnig, John; Coetzee, Maureen; Simard, Frederic; Roch, Dabiré K; Hinzoumbe, Clément Kerah; Pickett, John; Schellenberg, David; Gething, Peter; Hoppé, Mark; Hamon, Nicholas

    2016-04-23

    World Malaria Day 2015 highlighted the progress made in the development of new methods of prevention (vaccines and insecticides) and treatment (single dose drugs) of the disease. However, increasing drug and insecticide resistance threatens the successes made with existing methods. Insecticide resistance has decreased the efficacy of the most commonly used insecticide class of pyrethroids. This decreased efficacy has increased mosquito survival, which is a prelude to rising incidence of malaria and fatalities. Despite intensive research efforts, new insecticides will not reach the market for at least 5 years. Elimination of malaria is not possible without effective mosquito control. Therefore, to combat the threat of resistance, key stakeholders need to rapidly embrace a multifaceted approach including a reduction in the cost of bringing new resistance management methods to market and the streamlining of associated development, policy, and implementation pathways to counter this looming public health catastrophe.

  1. Interactions between malaria parasites and the host immune system.

    PubMed

    Engwerda, Christian R; Good, Michael F

    2005-08-01

    Malaria remains one of the greatest impediments to development in many tropical regions of the world. Understanding host immune responses to malaria parasites is crucial for the effective design and implementation of new vaccines and drugs. Recent research has seen the identification of the first pattern recognition receptor (TLR9) on dendritic cells for a defined product of malaria infection (hemozoin). In addition, progress has been made in understanding the role of dendritic cell subsets in malaria, and how they promote specific components of the host immune response. Potentially important advances in vaccine design have also been made by inserting a Plasmodium sporozoite epitope into the yellow fever vaccine 17D, as well as using a whole, live-attenuated sporozoite vaccine. PMID:15950450

  2. Recent developments in the assessment of the immune response to malaria, especially as related to vaccination: Lethal Plasmodium yoelii malaria: the role of macrophages in normal and immunized mice

    PubMed Central

    Playfair, J. H. L.

    1979-01-01

    Mice were injected with silica or Corynebacterium parvum, which, respectively, inhibit and stimulate macrophages in vivo, in an attempt to study the role of macrophages in lethal Plasmodium yoelii infection and in mice protected by immunization. In the normal infection, macrophages were able to control parasitaemia for up to 1 week, whereas in immunized mice they appeared to inhibit the sterilizing immune response. A model is proposed in which this dual role of activated macrophages may account for the chronic non-sterilizing course of natural malaria infections. PMID:317443

  3. Rabies, tetanus, leprosy, and malaria.

    PubMed

    Murthy, J M K; Dastur, Faram D; Khadilkar, Satish V; Kochar, Dhanpat K

    2014-01-01

    The developing world is still endemic to rabies, tetanus, leprosy, and malaria. Globally more than 55000 people die of rabies each year, about 95% in Asia and Africa. Annually, more than 10 million people, mostly in Asia, receive postexposure vaccination against the disease. World Health Organization estimated tetanus-related deaths at 163000 in 2004 worldwide. Globally, the annual detection of new cases of leprosy continues to decline and the global case detection declined by 3.54% during 2008 compared to 2007. Malaria is endemic in most countries, except the US, Canada, Europe, and Russia. Malaria accounts for 1.5-2.7 million deaths annually. Much of the disease burden related to these four infections is preventable.

  4. Clinical immunity to malaria.

    PubMed

    Schofield, Louis; Mueller, Ivo

    2006-03-01

    Under appropriate conditions of transmission intensity, functional immunity to malaria appears to be acquired in distinct stages. The first phase reduces the likelihood of severe or fatal disease; the second phase limits the clinical impact of 'mild' malaria; and the third provides partial but incomplete protection against pathogen burden. These findings suggest clinical immunity to mortality and morbidity is acquired earlier, with greater ease, and via distinct mechanisms as compared to anti-parasite immunity, which is more difficult to achieve, takes longer and is only ever partially efficacious. The implications of this view are significant in that current vaccination strategies aim predominantly to achieve anti-parasite immunity, although imparting clinical immunity is the public health objective. Despite enormous relevance for global public health, the mechanisms governing these processes remain obscure. Four candidate mechanisms might mediate clinical immunity, namely immunity to cytoadherence determinants, tolerance to toxins, acquired immunity to toxins, and immunoregulation. This review addresses the targets and determinants of clinical immunity, and considers the implications for vaccine development.

  5. Host defenses in murine malaria: induction of a protracted state of immunity with a formalin-killed Plasmodium berghei blood parasite vaccine.

    PubMed Central

    Murphy, J R; Lefford, M J

    1978-01-01

    Random-bred mice were immunized with a nonliving antigen prepared from mixed-blood forms of Plasmodium berghei, strain NYU-2, in combination with Corynebacterium parvum and/or living BCG. A high proportion of intravenously immunized mice survived virulent challenge, but subcutaneous vaccination was less effective. Vaccinated mice developed a patent infection after challenge similar to that observed in normal controls. However, between days 12 to 20 postchallenge, infections in some vaccinated mice became subpatent, whereas infections in all normal controls progressed until death. The incidence of recrudescent infection was low and, eventually, a state of sterile immunity was established. The capacity of vaccinated mice to withstand P. berghei challenge was sustained at a fairly stable level for the 6-month period of observation. Mice that had survived a primary infection with P. berghei almost completely suppressed a second and larger challenge with the same organism. PMID:365770

  6. Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines: randomized, double-blind study in malaria-naïve adults.

    PubMed

    Leroux-Roels, Geert; Leroux-Roels, Isabel; Clement, Frédéric; Ofori-Anyinam, Opokua; Lievens, Marc; Jongert, Erik; Moris, Philippe; Ballou, W Ripley; Cohen, Joe

    2014-01-01

    This phase II, randomized, double-blind study evaluated the immunogenicity of RTS,S vaccines containing Adjuvant System AS01 or AS02 as compared with non-adjuvanted RTS,S in healthy, malaria-naïve adults (NCT00443131). Thirty-six subjects were randomized (1:1:1) to receive RTS,S/AS01, RTS,S/AS02, or RTS,S/saline at months 0, 1, and 2. Antibody responses to Plasmodium falciparum circumsporozoite (CS) and hepatitis B surface (HBs) antigens were assessed and cell-mediated immune responses evaluated by flow cytometry using intracellular cytokine staining on peripheral blood mononuclear cells. Anti-CS antibody avidity was also characterized. Safety and reactogenicity after each vaccine dose were monitored. One month after the third vaccine dose, RTS,S/AS01 (160.3 EU/mL [95%CI: 114.1-225.4]) and RTS,S/AS02 (77.4 EU/mL (95%CI: 47.3-126.7)) recipients had significantly higher anti-CS antibody geometric mean titers (GMTs) than recipients of RTS,S/saline (12.2 EU/mL (95%CI: 4.8-30.7); P < 0.0001 and P = 0.0011, respectively). The anti-CS antibody GMT was significantly higher with RTS,S/AS01 than with RTS,S/AS02 (P = 0.0135). Anti-CS antibody avidity was in the same range in all groups. CS- and HBs-specific CD4(+) T cell responses were greater for both RTS,S/AS groups than for the RTS,S/saline group. Reactogenicity was in general higher for RTS,S/AS compared with RTS,S/saline. Most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups. No serious adverse events were reported. In conclusion, in comparison with non-adjuvanted RTS,S, both RTS,S/AS vaccines exhibited better CS-specific immune responses. The anti-CS antibody response was significantly higher with RTS,S/AS01 than with RTS,S/AS02. The adjuvanted vaccines had acceptable safety profiles.

  7. Vaccination: The Present and the Future

    PubMed Central

    Sadanand, Saheli

    2011-01-01

    Vaccines have undoubtedly saved the lives of millions, and along with improved sanitation, they remain one of the cornerstones of modern medicine. Many diseases that were once widespread are now eradicated, but vaccine programs face ongoing challenges. Safety concerns as well as limited funding have led to pockets of reduced vaccine coverage around the world ― including in developed countries. Chronic and recurrent diseases such as human immunodeficiency virus (HIV), tuberculosis, and malaria remain without effective vaccines. This review will briefly describe vaccines and the two major issues faced by modern vaccination programs: insufficient vaccine coverage and developing effective vaccines for chronic and recurrent diseases. PMID:22180673

  8. 75 FR 59729 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-28

    ... HUMAN SERVICES Food and Drug Administration Vaccines and Related Biological Products Advisory Committee... portion of the meeting will be closed to the public. Name of Committee: Vaccines and Related Biological... for protective antigen-based anthrax vaccines for a post-exposure prophylaxis indication using...

  9. Vaccines against poverty.

    PubMed

    MacLennan, Calman A; Saul, Allan

    2014-08-26

    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.

  10. Protecting capacity against malaria of chemically defined tetramer forms based on the Plasmodium falciparum apical sushi protein as potential vaccine components.

    PubMed

    Vanegas, Magnolia; Bermúdez, Adriana; Guerrero, Yuly Andrea; Cortes-Vecino, Jesús Alfredo; Curtidor, Hernando; Patarroyo, Manuel Elkin; Lozano, José Manuel

    2014-08-15

    Developing novel generations of subunit-based antimalarial vaccines in the form of chemically-defined macromolecule systems for multiple antigen presentation represents a classical problem in the field of vaccine development. Many efforts involving synthesis strategies leading to macromolecule constructs have been based on dendrimer-like systems, the condensation of large building blocks and conventional asymmetric double dimer constructs, all based on lysine cores. This work describes novel symmetric double dimer and condensed linear constructs for presenting selected peptide multi-copies from the apical sushi protein expressed in Plasmodium falciparum. These molecules have been proved to be safe and innocuous, highly antigenic and have shown strong protective efficacy in rodents challenged with two Plasmodium species. Insights into systematic design, synthesis and characterisation have led to such novel antigen systems being used as potential platforms for developing new anti-malarial vaccine candidates.

  11. Protecting capacity against malaria of chemically defined tetramer forms based on the Plasmodium falciparum apical sushi protein as potential vaccine components.

    PubMed

    Vanegas, Magnolia; Bermúdez, Adriana; Guerrero, Yuly Andrea; Cortes-Vecino, Jesús Alfredo; Curtidor, Hernando; Patarroyo, Manuel Elkin; Lozano, José Manuel

    2014-08-15

    Developing novel generations of subunit-based antimalarial vaccines in the form of chemically-defined macromolecule systems for multiple antigen presentation represents a classical problem in the field of vaccine development. Many efforts involving synthesis strategies leading to macromolecule constructs have been based on dendrimer-like systems, the condensation of large building blocks and conventional asymmetric double dimer constructs, all based on lysine cores. This work describes novel symmetric double dimer and condensed linear constructs for presenting selected peptide multi-copies from the apical sushi protein expressed in Plasmodium falciparum. These molecules have been proved to be safe and innocuous, highly antigenic and have shown strong protective efficacy in rodents challenged with two Plasmodium species. Insights into systematic design, synthesis and characterisation have led to such novel antigen systems being used as potential platforms for developing new anti-malarial vaccine candidates. PMID:25063026

  12. Assessment in mice of a synthetic peptide-based vaccine against the sporozoite stage of the human malaria parasite, P. falciparum.

    PubMed Central

    Etlinger, H M; Heimer, E P; Trzeciak, A; Felix, A M; Gillessen, D

    1988-01-01

    The anti-P. falciparum sporozoite vaccine consisting of the synthetic peptide, Ac-Cys-(NANP)3, conjugated to the protein tetanus toxoid (TT), [Ac-Cys-(NANP)3]25-TT, is currently undergoing human trials. The purpose of the present study was to assess various immunological parameters of this vaccine in mice, which have practical implications in humans. Two injections of [Ac-Cys-(NANP)3]25-TT adsorbed to Al(OH)3 were required to elicit a high antibody response against both Ac-Cys-(NANP)3 and TT. The vaccine initiated equivalent Ac-Cys-(NANP)3 priming for a secondary IgG response in 1-week-old and adult mice. Immunization of female mice with TT or [Ac-Cys-(NANP)3]23-TT prior to mating resulted in offspring that passively received anti-Ac-Cys-(NANP)3 and/or anti-TT antibody and that had reduced secondary responses to Ac-Cys-(NANP)3 and TT. Tertiary challenge with vaccine could substantially overcome such inhibition. Preimmunization of adult mice with TT resulted in a specific inhibition of the anti-Ac-Cys-(NANP)3 antibody response that disappeared following tertiary challenge with the vaccine. The conjugate initiated an antibody response against Ac-Cys-(NANP)3 and TT in mice of 16 different genotypes; only very low T-cell proliferative responses to (NANP)3 were observed for some of these strains. Mice injected with (NANP)3 coupled to protein demonstrated a secondary response to Ac-Cys-(NANP)3 when challenged with (NANP)3 on a heterologous carrier, indicating that B-cell priming alone may be sufficient for a secondary antibody response. These results demonstrate that the vaccine has favourable and unfavourable characteristics in mice; the potential for both exists in humans. PMID:3044983

  13. Robert Koch redux: malaria immunology in Papua New Guinea.

    PubMed

    Stanisic, D I; Mueller, I; Betuela, I; Siba, P; Schofield, L

    2010-08-01

    Over a century ago, the malaria expedition of the brilliant microbiologist Robert Koch to the Dutch East Indies (Indonesia) and German New Guinea (now Papua New Guinea, or PNG), resulted in profound observations that are still central to our current understanding of the epidemiology and acquisition of immunity to the malaria parasite Plasmodium. The tradition of malaria research in PNG pioneered by Koch continues to this day, with a number of recent studies still continuing to elucidate his original concepts and hypotheses. These include age and exposure-related acquisition of immunity, species-specific and cross-species immunity, correlates of protective immunity and determining the prospects for anti-malaria vaccines.

  14. Malaria tolerance--for whom the cell tolls?

    PubMed

    Boutlis, Craig S; Yeo, Tsin W; Anstey, Nicholas M

    2006-08-01

    How is it that individuals exposed to intense malaria transmission can tolerate the presence of malaria parasites in their blood at levels that would produce fever in others? In light of evidence discounting a role for nitric oxide or antibodies to plasmodial glycosylphosphatidylinositols in maintaining this tolerant state, refractoriness to toxin-induced Toll-like receptor-mediated signalling has emerged as a likely explanation that links malarial and bacterial endotoxin tolerance. Understanding the mechanisms underlying tolerance and the potential for cross-tolerization has significant implications for understanding the potential for antitoxic vaccine strategies, as well as interactions between different malaria species and between malaria and other human parasites.

  15. Malaria drives T cells to exhaustion

    PubMed Central

    Wykes, Michelle N.; Horne-Debets, Joshua M.; Leow, Chiuan-Yee; Karunarathne, Deshapriya S.

    2014-01-01

    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. PMID:24904561

  16. Structure of the DBL3X-DBL4ε region of the VAR2CSA placental malaria vaccine candidate: insight into DBL domain interactions.

    PubMed

    Gangnard, Stéphane; Lewit-Bentley, Anita; Dechavanne, Sébastien; Srivastava, Anand; Amirat, Faroudja; Bentley, Graham A; Gamain, Benoît

    2015-01-01

    The human malaria parasite, Plasmodium falciparum, is able to evade spleen-mediated clearing from blood stream by sequestering in peripheral organs. This is due to the adhesive properties conferred by the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family exported by the parasite to the surface of infected erythrocytes. Expression of the VAR2CSA variant of PfEMP1 leads to pregnancy-associated malaria, which occurs when infected erythrocytes massively sequester in the placenta by binding to low-sulfated Chondroitin Sulfate A (CSA) present in the intervillous spaces. VAR2CSA is a 350 kDa protein that carries six Duffy-Binding Like (DBL) domains, one Cysteine-rich Inter-Domain Regions (CIDR) and several inter-domain regions. In the present paper, we report for the first time the crystal structure at 2.9 Å of a VAR2CSA double domain, DBL3X-DBL4ε, from the FCR3 strain. DBL3X and DBL4ε share a large contact interface formed by residues that are invariant or highly conserved in VAR2CSA variants, which suggests that these two central DBL domains (DBL3X-DBL4ε) contribute significantly to the structuring of the functional VAR2CSA extracellular region. We have also examined the antigenicity of peptides corresponding to exposed loop regions of the DBL4ε structure. PMID:26450557

  17. Structure of the DBL3X-DBL4ε region of the VAR2CSA placental malaria vaccine candidate: insight into DBL domain interactions

    PubMed Central

    Gangnard, Stéphane; Lewit-Bentley, Anita; Dechavanne, Sébastien; Srivastava, Anand; Amirat, Faroudja; Bentley, Graham A.; Gamain, Benoît

    2015-01-01

    The human malaria parasite, Plasmodium falciparum, is able to evade spleen-mediated clearing from blood stream by sequestering in peripheral organs. This is due to the adhesive properties conferred by the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family exported by the parasite to the surface of infected erythrocytes. Expression of the VAR2CSA variant of PfEMP1 leads to pregnancy-associated malaria, which occurs when infected erythrocytes massively sequester in the placenta by binding to low-sulfated Chondroitin Sulfate A (CSA) present in the intervillous spaces. VAR2CSA is a 350 kDa protein that carries six Duffy-Binding Like (DBL) domains, one Cysteine-rich Inter-Domain Regions (CIDR) and several inter-domain regions. In the present paper, we report for the first time the crystal structure at 2.9 Å of a VAR2CSA double domain, DBL3X-DBL4ε, from the FCR3 strain. DBL3X and DBL4ε share a large contact interface formed by residues that are invariant or highly conserved in VAR2CSA variants, which suggests that these two central DBL domains (DBL3X-DBL4ε) contribute significantly to the structuring of the functional VAR2CSA extracellular region. We have also examined the antigenicity of peptides corresponding to exposed loop regions of the DBL4ε structure. PMID:26450557

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

    PubMed

    Hemingway, Janet; Shretta, Rima; Wells, Timothy N C; Bell, David; Djimdé, Abdoulaye A; Achee, Nicole; Qi, Gao

    2016-03-01

    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.

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

    PubMed Central

    Hemingway, Janet; Shretta, Rima; Wells, Timothy N. C.; Bell, David; Djimdé, Abdoulaye A.; Achee, Nicole; Qi, Gao

    2016-01-01

    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. PMID:26934361

  20. Malaria and the Millennium Development Goals.

    PubMed

    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. PMID:25613970

  1. Recent advances in oral vaccine development

    PubMed Central

    De Smet, Rebecca; Allais, Liesbeth; Cuvelier, Claude A

    2014-01-01

    Oral vaccination is the most challenging vaccination method due to the administration route. However, oral vaccination has socio-economic benefits and provides the possibility of stimulating both humoral and cellular immune responses at systemic and mucosal sites. Despite the advantages of oral vaccination, only a limited number of oral vaccines are currently approved for human use. During the last decade, extensive research regarding antigen-based oral vaccination methods have improved immunogenicity and induced desired immunological outcomes. Nevertheless, several factors such as the harsh gastro-intestinal environment and oral tolerance impede the clinical application of oral delivery systems. To date, human clinical trials investigating the efficacy of these systems are still lacking. This review addresses the rationale and key biological and physicochemical aspects of oral vaccine design and highlights the use of yeast-derived β-glucan microparticles as an oral vaccine delivery platform. PMID:24553259

  2. Radar Monitoring of Wetlands for Malaria Control

    NASA Technical Reports Server (NTRS)

    Pope, Kevin O.

    1997-01-01

    Malaria is the most important vector-borne tropical disease (Collins and Paskewitz, 1995) and there is no simple and universally applicable form of vector control. While new methods such as malaria vaccine or genetic manipulation of mosquitoes are being explored in the laboratories, the need for more field research on malaria transmission remains very strong. For the foreseeable future many malaria programs must focus on controlling the vector, the anopheline mosquito, often under the specter of shrinking budgets. Therefore information on which human populations are at the greatest risk is especially valuable when allocating scarce resources. The goal of the Radar Monitoring of Wetlands for Malaria Control Project is to demonstrate the feasibility of using Radarsat or other comparable satellite radar imaging systems to determine where and when human populations are at greatest risk for contracting malaria. The study area is northern Belize, a region with abundant wetlands and a potentially serious malaria problem. A key aspect of this study is the analysis of multi-temporal satellite imagery to track seasonal flooding of anopheline mosquito breeding sites. Radarsat images of the test site in Belize have been acquired one to three times a month over the last year, however,, to date only one processed image has been received from the Alaska SAR Facility for analysis. Therefore analysis at this stage is focussed on determining the radar backscatter characteristics of known anopheline breeding sites, with future work to be dedicated toward seasonal changes.

  3. How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria

    PubMed Central

    Kwiatkowski, Dominic P.

    2005-01-01

    Malaria is a major killer of children worldwide and the strongest known force for evolutionary selection in the recent history of the human genome. The past decade has seen growing evidence of ethnic differences in susceptibility to malaria and of the diverse genetic adaptations to malaria that have arisen in different populations: epidemiological confirmation of the hypotheses that G6PD deficiency, α+ thalassemia, and hemoglobin C protect against malaria mortality; the application of novel haplotype-based techniques demonstrating that malaria-protective genes have been subject to recent positive selection; the first genetic linkage maps of resistance to malaria in experimental murine models; and a growing number of reported associations with resistance and susceptibility to human malaria, particularly in genes involved in immunity, inflammation, and cell adhesion. The challenge for the next decade is to build the global epidemiological infrastructure required for statistically robust genomewide association analysis, as a way of discovering novel mechanisms of protective immunity that can be used in the development of an effective malaria vaccine. PMID:16001361

  4. [Vaccinations for international travelers].

    PubMed

    Berens-Riha, N; Alberer, M; Löscher, T

    2014-03-01

    Vaccinations are a prominent part of health preparations before international travel. They can avoid or significantly reduce the risk of numerous infectious diseases. Until recently, vaccination against yellow fever was the only obligatory vaccination. However, according to updated international health regulations, other vaccinations and prophylactic measures may be required at entry from certain countries. For all routine vaccinations as recommended in Germany, necessary revaccination and catch-up of missed vaccinations should be administered before travel. At most destinations the risk of infection is higher than in Germany. Hepatitis A vaccine is generally recommended for travelers to areas of increased risk, polio vaccine for all destinations where eradication is not yet confirmed (Asia and Africa). The indications for other travel vaccines must take into consideration travel destination and itinerary, type and duration of travel, individual risk of exposure as well as the epidemiology of the disease to be prevented. Several vaccines of potential interest for travel medicine, e.g., new vaccines against malaria and dengue fever, are under development.

  5. [New approaches of malaria prevention for travelers].

    PubMed

    Voumard, Rachel; Berthod, Delphine; Rochat, Laurence; D'Acremont, Valérie; Genton, Blaise; De Vallière, Serge

    2016-05-01

    Malaria is declining in many tropical countries. This reduction challenges our usual preventive strategies. In moderate to low risk areas, the Swiss guidelines recommend a stand-by emergency treatment. Controversies between experts are numerous though. Professionals at the Travel Clinic in Lausanne has explored shared-decision making through three clinical studies. The first showed that travelers visiting moderate to low risk malaria areas prefer a standby emergency treatment rather than chemoprophylaxis. The second study investigates the use of rapid diagnostic tests by travelers. The third focuses on the prospects of tropical telemedicine. Involving the traveler into the debate is a priority, until a vaccine becomes available.

  6. Integrated Approach to Malaria Control

    PubMed Central

    Shiff, Clive

    2002-01-01

    Malaria draws global attention in a cyclic manner, with interest and associated financing waxing and waning according to political and humanitarian concerns. Currently we are on an upswing, which should be carefully developed. Malaria parasites have been eliminated from Europe and North America through the use of residual insecticides and manipulation of environmental and ecological characteristics; however, in many tropical and some temperate areas the incidence of disease is increasing dramatically. Much of this increase results from a breakdown of effective control methods developed and implemented in the 1960s, but it has also occurred because of a lack of trained scientists and control specialists who live and work in the areas of endemic infection. Add to this the widespread resistance to the most effective antimalarial drug, chloroquine, developing resistance to other first-line drugs such as sulfadoxine-pyrimethamine, and resistance of certain vector species of mosquito to some of the previously effective insecticides and we have a crisis situation. Vaccine research has proceeded for over 30 years, but as yet there is no effective product, although research continues in many promising areas. A global strategy for malaria control has been accepted, but there are critics who suggest that the single strategy cannot confront the wide range of conditions in which malaria exists and that reliance on chemotherapy without proper control of drug usage and diagnosis will select for drug resistant parasites, thus exacerbating the problem. An integrated approach to control using vector control strategies based on the biology of the mosquito, the epidemiology of the parasite, and human behavior patterns is needed to prevent continued upsurge in malaria in the endemic areas. PMID:11932233

  7. Sequence polymorphism in two novel Plasmodium vivax ookinete surface proteins, Pvs25 and Pvs28, that are malaria transmission-blocking vaccine candidates.

    PubMed Central

    Tsuboi, T.; Kaslow, D. C.; Gozar, M. M.; Tachibana, M.; Cao, Y. M.; Torii, M.

    1998-01-01

    BACKGROUND: For many malarious regions outside of Africa, development of effective transmission-blocking vaccines will require coverage against both Plasmodium falciparum and P. vivax. Work on P. vivax transmission-blocking vaccines has been hampered by the inability to clone the vaccine candidate genes from this parasite. Materials and METHODS: To search for genes encoding the ookinete surface proteins from P. vivax, the DNA sequences of the eight known proteins in the P25 subfamily (Pfs25, Pgs25, Pys25, Pbs25) and in the P21/28 subfamily (Pfs28, Pgs28, Pys21, Pbs21) of zygote/ookinete surface proteins were aligned. Regions of highest identity were used to design degenerate PCR oligonucleotides. Genomic DNA from the Sal I strain of P. vivax and genomic and splinkerette DNA libraries were used as PCR templates. To characterize the polymorphisms of Pvs25 and Pvs28, these two genes were PCR amplified and the DNA sequences were determined from genomic DNA extracted from patients infected with P. vivax. RESULTS: Analysis of the deduced amino acid sequence of Pvs28 revealed a secretory signal sequence, four epidermal growth factor (EGF)-like domains, six copies of the heptad amino acid repeat (GSGGE/D), and a short hydrophobic region. Because the fourth EGF-like domain has four rather than six cysteines, the gene designated Pvs28 is the presumed homologue of P21/28 subfamily members. Analysis of the deduced amino acid sequence of Pvs25 revealed a similar structure to that of Pvs28. The presence of six rather than four cysteines in the fourth EGF-like domain suggested that Pvs25 is the homologue of P25 subfamily members. Several regions of genetic polymorphisms in Pvs25 and Pvs28 were identified in field isolates of P. vivax. CONCLUSIONS: The genes encoding two ookinete surface proteins, Pvs28 and Pvs25, from P. vivax have been isolated and sequenced. Comparison of the primary structures of Pvs25, Pvs28, Pfs25, and Pfs28 suggest that there are regions of genetic

  8. MALARIA: A GENERAL MINIREVIEW WITH REFERENCE TO EGYPT.

    PubMed

    Ahmad Saleh, Ahmad Megahed; Adam, Samia Mohammad; Ibrahim, Abeer Mohammad Abdallah; Morsy, Tosson A

    2016-04-01

    The majority of world's population-live in areas at risk of malaria transmission. Malaria is a serious Anopheles-borne disease that pauses symptoms like the flu, as a high fever, chills, and muscle pain also, anemia, bloody stools, coma, convulsion, fever, headache, jaundice, nausea, sweating and vomiting. Symptoms tend to come and go in cycles. Apart from Anopheles vector, malaria could be transmitted nosocomial, blood transfusion or needle-stick injury Some types of malaria may cause more serious damage problems to heart, lungs, kidneys, or brain. These types can be deadly. The primary factors contributing to the resurgence of malaria are the appearance of drug-resistant strains of the parasite, the spread of insecticide-resistant strains of the mosquito and the lack of licensed malaria vaccines of proven efficacy. In rare cases, people can get malaria if they come into contact with infected blood as in blood transfusion or needle-stick injury also nosocomial and congenital malaria was reported. This is a mini-review of malaria with information on the lethal to humans, Plasmodium falciparum, together with other recent developments in the field. PMID:27363039

  9. Vaccines and global health.

    PubMed

    Greenwood, Brian; Salisbury, David; Hill, Adrian V S

    2011-10-12

    Vaccines have made a major contribution to global health in recent decades but they could do much more. In November 2011, a Royal Society discussion meeting, 'New vaccines for global health', was held in London to discuss the past contribution of vaccines to global health and to consider what more could be expected in the future. Papers presented at the meeting reviewed recent successes in the deployment of vaccines against major infections of childhood and the challenges faced in developing vaccines against some of the world's remaining major infectious diseases such as human immunodeficiency virus (HIV), malaria and tuberculosis. The important contribution that development of more effective veterinary vaccines could make to global health was also addressed. Some of the social and financial challenges to the development and deployment of new vaccines were reviewed. The latter issues were also discussed at a subsequent satellite meeting, 'Accelerating vaccine development', held at the Kavli Royal Society International Centre. Delegates at this meeting considered challenges to the more rapid development and deployment of both human and veterinary vaccines and how these might be addressed. Papers based on presentations at the discussion meeting and a summary of the main conclusions of the satellite meeting are included in this issue of Philosophical Transactions of the Royal Society B.

  10. Social Implications of Malaria and Their Relationships with Poverty

    PubMed Central

    Ricci, Francesco

    2012-01-01

    In poor countries, tragically, people die unnecessarily. Having changed our understanding about issues related to poverty, even in the fight against malaria we must keep in mind a number of issues other than simple lack of economic resources. In this article we tried to discuss the various aspects that make malaria a disease closely related to poverty and the effects of malaria on the same poverty of patients who are affected. If you want the program to "Rool Back Malaria" to succeed, you must program interventions that improve the living conditions of populations in endemic area, individually and as communities. As has become clear that the discovery of an effective vaccine will not eradicate the disease, remains a fundamental understanding of mechanisms related to poverty that cause Malaria remains one of the major killers in the world, to help communities affected and individuals to prevent, cure properly and not being afraid of this ancient disease. PMID:22973492

  11. Challenges and Approaches for Mosquito Targeted Malaria Control

    PubMed Central

    Ramirez, José L.; Garver, Lindsey S.; Dimopoulos, George

    2010-01-01

    Malaria is one of today’s most serious diseases with an enormous socioeconomic impact. While anti-malarial drugs have existed for some time and vaccines development may be underway, the most successful malaria eradication programs have thus far relied on attacking the mosquito vector that spreads the disease causing agent Plasmodium. Here we will review past, current and future perspectives of malaria vector control strategies and how these approaches have taken a promising turn thanks recent advances in functional genomics and molecular biology. PMID:19275622

  12. Ecological immunology of mosquito-malaria interactions.

    PubMed

    Tripet, Frédéric; Aboagye-Antwi, Fred; Hurd, Hilary

    2008-05-01

    More than a century after the discovery of the complex life cycle of its causative agent, malaria remains a major health problem. Understanding mosquito-malaria interactions could lead to breakthroughs in malaria control. Novel strategies, such as the design of transgenic mosquitoes refractory to Plasmodium, or design of human vaccines emulating mosquito resistance to the parasite, require extensive knowledge of processes involved in immune responses and of microevolutionary mechanisms that create and maintain variation in immune responses in wild vector populations. The recent realization of how intimately and specifically mosquitoes and Plasmodium co-evolve in Nature is driving vector molecular biologists and evolutionary ecologists to move closer to the natural setting under the common umbrella of 'Ecological immunology'.

  13. Malaria: progress, perils, and prospects for eradication

    PubMed Central

    Greenwood, Brian M.; Fidock, David A.; Kyle, Dennis E.; Kappe, Stefan H.I.; Alonso, Pedro L.; Collins, Frank H.; Duffy, Patrick E.

    2008-01-01

    There are still approximately 500 million cases of malaria and 1 million deaths from malaria each year. Yet recently, malaria incidence has been dramatically reduced in some parts of Africa by increasing deployment of anti-mosquito measures and new artemisinin-containing treatments, prompting renewed calls for global eradication. However, treatment and mosquito control currently depend on too few compounds and thus are vulnerable to the emergence of compound-resistant parasites and mosquitoes. As discussed in this Review, new drugs, vaccines, and insecticides, as well as improved surveillance methods, are research priorities. Insights into parasite biology, human immunity, and vector behavior will guide efforts to translate parasite and mosquito genome sequences into novel interventions. PMID:18382739

  14. [Development of new vaccines].

    PubMed

    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.

  15. [Development of new vaccines].

    PubMed

    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. PMID:26341041

  16. Malaria and Travelers

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  17. Malaria Treatment (United States)

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  18. Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting

    PubMed Central

    2013-01-01

    The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting. Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016–2025). Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme. PMID:23787092

  19. Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of March 2013 meeting.

    PubMed

    2013-01-01

    The Malaria Policy Advisory Committee to the World Health Organization met in Geneva, Switzerland from 13 to 15 March, 2013. This article provides a summary of the discussions, conclusions and recommendations from that meeting.Meeting sessions included: a review of the efficacy of artemisinin-based combination therapy in Guyana and Suriname; the outcomes from a consultation on non-malaria febrile illness; the outcomes from the second meeting of the Evidence Review Group on malaria burden estimation; an update on the review of the WHO Guidelines for the Treatment of Malaria; an update regarding progress on the constitution of the vector control Technical Expert Group; updates on the RTS, S/AS01 vaccine and the malaria vaccine technology roadmap; financing and resource allocation for malaria control; malaria surveillance and the need for a surveillance, monitoring and evaluation Technical Expert Group; criteria and classification related to malaria elimination; the next meeting of the Evidence Review Group on Intermittent Preventive Treatment in pregnancy; an update on the soon-to-be launched Elimination Scenario Planning Tool; and an update on the process for the Global Technical Strategy for Malaria Control and Elimination (2016-2025).Policy statements, position statements, and guidelines that arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization Member States by the World Health Organization Global Malaria Programme.

  20. Vaccine design: emerging concepts and renewed optimism.

    PubMed

    Grimm, Sebastian K; Ackerman, Margaret E

    2013-12-01

    Arguably, vaccination represents the single most effective medical intervention ever developed. Yet, vaccines have failed to provide any or adequate protection against some of the most significant global diseases. The pathogens responsible for these vaccine-recalcitrant diseases have properties that allow them to evade immune surveillance and misdirect or eliminate the immune response. However, genomic and systems biology tools, novel adjuvants and delivery systems, and refined molecular insight into protective immunity have started to redefine the landscape, and results from recent efficacy trials of HIV and malaria vaccines have instilled hope that another golden age of vaccines may be on the horizon.

  1. Malaria: prevention in travellers

    PubMed Central

    2007-01-01

    Introduction Malaria transmission occurs most frequently in environments with humidity over 60% and ambient temperature of 25-30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10-14 days but can be up to 18 months depending on the strain of parasite. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in adult travellers? What are the effects of drug prophylaxis in adult travellers? What are the effects of antimalaria vaccines in 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 February 2006 (BMJ 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). Results We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: acoustic buzzers, aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), doxycycline, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vaporising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines. PMID:19450348

  2. Malaria: prevention in travellers

    PubMed Central

    2010-01-01

    Introduction 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. Methods and outcomes 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). Results 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. Conclusions 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

  3. Modulation of host responses to blood-stage malaria by interleukin-12: from therapy to adjuvant activity.

    PubMed

    Stevenson, M M; Su, Z; Sam, H; Mohan, K

    2001-01-01

    This review focuses on the role of interleukin (IL)-12, a proinflammatory cytokine with pleiotropic effects as a potent immunoregulatory molecule and hematopoietic growth factor, in infection with Plasmodium parasites, the causative agents of malaria. IL-12 has been demonstrated to have profound effects on the immune response to blood-stage malaria, to induce protection, and to alleviate malarial anemia. In combination with an anti-malarial drug, IL-12 is effective in an established malaria infection. This cytokine also has potent immune effects as a malaria vaccine adjuvant. However, IL-12 can also mediate pathology during blood-stage malaria.

  4. Modulation of host responses to blood-stage malaria by interleukin-12: from therapy to adjuvant activity.

    PubMed

    Stevenson, M M; Su, Z; Sam, H; Mohan, K

    2001-01-01

    This review focuses on the role of interleukin (IL)-12, a proinflammatory cytokine with pleiotropic effects as a potent immunoregulatory molecule and hematopoietic growth factor, in infection with Plasmodium parasites, the causative agents of malaria. IL-12 has been demonstrated to have profound effects on the immune response to blood-stage malaria, to induce protection, and to alleviate malarial anemia. In combination with an anti-malarial drug, IL-12 is effective in an established malaria infection. This cytokine also has potent immune effects as a malaria vaccine adjuvant. However, IL-12 can also mediate pathology during blood-stage malaria. PMID:11226854

  5. Application of Genomics to Field Investigations of Malaria by the International Centers for Excellence in Malaria Research

    PubMed Central

    Volkman, Sarah K.; Ndiaye, Daouda; Diakite, Mahamadou; Koita, Ousmane; Nwakanma, Davis; Daniels, Rachel; Park, Danny; Neafsey, Dan; Muskavitch, Marc; Krogstad, Don; Sabeti, Pardis; Hartl, Dan; Wirth, Dyann

    2011-01-01

    Success of the global research agenda toward eradication of malaria will depend on development of new tools, including drugs, vaccines, insecticides and diagnostics. Genomic information, now available for the malaria parasites, their mosquito vectors, and human host, can be leveraged to both develop these tools and monitor their effectiveness. Although knowledge of genomic sequences for the malaria parasites, Plasmodium falciparum and P. vivax, have helped advance our understanding of malaria biology, simply knowing this sequence information has not yielded a plethora of new interventions to reduce the burden of malaria. Here we review and provide specific examples of how genomic information has increased our knowledge of parasite biology, focusing on P. falciparum malaria. We then discuss how population genetics can be applied toward the epidemiological and transmission-related goals outlined by the International Centers of Excellence in Malaria Research groups recently established by the National Institutes of Health. Finally, we propose genomics is a research area that can promote coordination and collaboration between various ICEMR groups, and that working together as a community can significantly advance the value of this information toward reduction of the global malaria burden. PMID:22182668

  6. HPV vaccine

    MedlinePlus

    ... Gardasil; Cervarix; HPV2; HPV4; Vaccine to prevent cervical cancer; Genital warts - HPV vaccine; Cervical dysplasia - HPV vaccine; Cervical cancer - HPV vaccine; Cancer of the cervix - HPV vaccine; ...

  7. Giant Host Red Blood Cell Membrane Mimicking Polymersomes Bind Parasite Proteins and Malaria Parasites.

    PubMed

    Najer, Adrian; Thamboo, Sagana; Palivan, Cornelia G; Beck, Hans-Peter; Meier, Wolfgang

    2016-01-01

    Malaria is an infectious disease that needs to be addressed using innovative approaches to counteract spread of drug resistance and to establish or optimize vaccination strategies. With our approach, we aim for a dual action with drug- and 'vaccine-like' activity against malaria. By inhibiting entry of malaria parasites into host red blood cells (RBCs) - using polymer vesicle-based (polymersome) nanomimics of RBC membranes - the life cycle of the parasite is interrupted and the exposed parasites are accessible to the host immune system. Here, we describe how host cell-sized RBC membrane mimics, formed with the same block copolymers as nanomimics, also bind the corresponding malaria parasite ligand and whole malaria parasites, similar to nanomimics. This was demonstrated using fluorescence imaging techniques and confirms the suitability of giant polymersomes (GUVs) as simple mimics for RBC membranes.

  8. Sri Lanka Malaria Maps

    PubMed Central

    Briët, Olivier JT; Gunawardena, Dissanayake M; van der Hoek, Wim; Amerasinghe, Felix P

    2003-01-01

    Background Despite a relatively good national case reporting system in Sri Lanka, detailed maps of malaria distribution have not been publicly available. Methods In this study, monthly records over the period 1995 – 2000 of microscopically confirmed malaria parasite positive blood film readings, at sub-district spatial resolution, were used to produce maps of malaria distribution across the island. Also, annual malaria trends at district resolution were displayed for the period 1995 – 2002. Results The maps show that Plasmodium vivax malaria incidence has a marked variation in distribution over the island. The incidence of Plasmodium falciparum malaria follows a similar spatial pattern but is generally much lower than that of P. vivax. In the north, malaria shows one seasonal peak in the beginning of the year, whereas towards the south a second peak around June is more pronounced. Conclusion This paper provides the first publicly available maps of both P. vivax and P. falciparum malaria incidence distribution on the island of Sri Lanka at sub-district resolution, which may be useful to health professionals, travellers and travel medicine professionals in their assessment of malaria risk in Sri Lanka. As incidence of malaria changes over time, regular updates of these maps are necessary. PMID:12914667

  9. Malaria ecotypes and stratification.

    PubMed

    Schapira, Allan; Boutsika, Konstantina

    2012-01-01

    To deal with the variability of malaria, control programmes need to stratify their malaria problem into a number of smaller units. Such stratification may be based on the epidemiology of malaria or on its determinants such as ecology. An ecotype classification was developed by the World Health Organization (WHO) around 1990, and it is time to assess its usefulness for current malaria control as well as for malaria modelling on the basis of published research. Journal and grey literature was searched for articles on malaria or Anopheles combined with ecology or stratification. It was found that all malaria in the world today could be assigned to one or more of the following ecotypes: savanna, plains and valleys; forest and forest fringe; foothill; mountain fringe and northern and southern fringes; desert fringe; coastal and urban. However, some areas are in transitional or mixed zones; furthermore, the implications of any ecotype depend on the biogeographical region, sometimes subregion, and finally, the knowledge on physiography needs to be supplemented by local information on natural, anthropic and health system processes including malaria control. Ecotyping can therefore not be seen as a shortcut to determine control interventions, but rather as a framework to supplement available epidemiological and entomological data so as to assess malaria situations at the local level, think through the particular risks and opportunities and reinforce intersectoral action. With these caveats, it does however emerge that several ecotypic distinctions are well defined and have relatively constant implications for control within certain biogeographic regions. Forest environments in the Indo-malay and the Neotropics are, with a few exceptions, associated with much higher malaria risk than in adjacent areas; the vectors are difficult to control, and the anthropic factors also often converge to impose constraints. Urban malaria in Africa is associated with lower risk than savanna

  10. [Vaccines in the year 2000].

    PubMed

    Lambert, P H

    1997-01-01

    Vaccinology nowadays is going through an explosive "evolution". This development, which is due to progress in molecular biology and immunology, is accompanied by a world-wide change of how we view vaccination strategies. Thus, the vaccination of travellers and migrants should be increasingly included in the global control of the infectious diseases. The risks linked to travelling, which thanks to extensive vaccination are now better controlled globally, should decrease as the success of these programs grows. However, risks connected to those diseases, which do not yet lend themselves to preventive mass vaccination carried out systematically, will no doubt prevail for a long time. This is the case, for example, for diarrhetic diseases, typhoid fever, malaria, severe respiratory diseases, AIDS, tuberculosis or more regional diseases such as dengue or leishmaniasis. As far as vaccination is concerned, the best approach must take into account industrial feasibility and immunological considerations, as to the nature of the "target" of these new vaccines and the desired time of protection. It is also necessary to simplify immunization protocols in order to improve conditions for those who are vaccinated. Priority is given to the search for new vaccinal formulas compatible with these objectives. Significant changes in the domain of vaccination should therefore be expected in a future near enough to have an impact on our upcoming preventive programs ... from the year 2000 onwards.

  11. Polio Vaccination

    MedlinePlus

    ... inactive polio vaccine OPV=oral polio vaccine Polio Vaccination Pronounced [PO-lee-oh] Recommend on Facebook Tweet ... handling and storage Related Pages Global Vaccines and Immunization Global Polio Also Known As & Abbreviations Polio=poliomyelitis ...

  12. [Malaria in Hungary: origin, current state and principles of prevention].

    PubMed

    Szénási, Zsuzsanna; Vass, Adám; Melles, Márta; Kucsera, István; Danka, József; Csohán, Agnes; Krisztalovics, Katalin

    2003-05-25

    Malaria was an endemic disease in Hungary for many centuries. A country-wide survey of the epidemiologic situation on malaria started in the year of 1927. That was done by the Department of Parasitology of the Royal State Institute of Hygiene (presently: Johan Béla National Center for Epidemiology). The notification of malaria was made compulsory in 1930. Free of charge laboratory examination of the blood of persons suffering from malaria or suspected of an infection have been carried out. Anti-malarial drugs were also distributed free of charge, together with appropriate medical advise given at the anti-malarial sanitary stations. Between 1933 and 1943, the actual number of malaria cases was estimated as high as 10-100,000 per year. The major breakthrough came in 1949 by the organized antimalarial campaign applying DDT for mosquito eradication. The drastic reduction of the vectors resulted in the rapid decline of malaria cases. Since 1956, there have not been reported any indigenous case in Hungary. In 1963, Hungary entered on the Official Register of the WHO to the areas where malaria eradication has been achieved. During the period of 1963-2001, 169 Hungarians acquired the malaria in abroad and 263 foreigners infected in abroad were registered in Hungary. More than half of the cases (230) were caused by Plasmodium falciparum. Further 178 cases were caused by Plasmodium vivax and 24 cases by other Plasmodium species. During that period, 7 fatal cases were reported (Plasmodium falciparum). The expansion of migration (both the increase of the number of foreigners travelling into Hungary and of Hungarians travelling abroad) favours to the appearance of imported cases. Attention is called of all the persons travelling to malaria endemic countries to the importance of malaria prevention by the International Vaccination Stations located in the National Center for Epidemiology and in the Public Health Institutes of 19 counties and of Budapest. The Johan Béla National

  13. [Malaria in Iraq].

    PubMed

    Shamo, F J

    2001-01-01

    Malaria control campaign started in Iraq in 1957. This made the country largely free of the disease. Since 1991, following the recent war, Iraq has been affected by serious epidemic of P. vivax malaria that started in 3 autonomous governorates and soon involved other parts of the country. There were 49,840 malaria cases in the country in 1995. The national malaria programme personnel did their best to contain and control the epidemic. Active and passive case detection and treatment were introduced. Free of charge drugs are provided at all levels in the endemic area. Vector control includes environmental management, distribution of Gambusia fish, larviciding, indoor residual spraying with pyrithroids. A total of 4134 malaria cases were recorded in the country in 1999. PMID:11548316

  14. Malaria parasite pre-erythrocytic stage infection: Gliding and Hiding

    PubMed Central

    Vaughan, Ashley M.; Aly, Ahmed S. I.; Kappe, Stefan H. I.

    2008-01-01

    Summary Malaria is caused by red blood cell-infectious forms of Plasmodium parasites resulting in illness and possible death of infected hosts. The mosquito-borne sporozoite stage of the parasite and the initial infection in the liver, however cause little pathology and no symptoms. Nevertheless, these pre-erythrocytic parasite stages are attracting passionate research efforts not least because they are the most promising targets for malaria vaccine development. Here, we review how the infectious sporozoite makes its way to the liver, subsequently develops in hepatocytes and the factors, both parasite and host, involved in the interactions that occur during this ‘silent’ phase of infection. PMID:18779047

  15. There is need for antigen-based rapid diagnostic tests to identify common acute tropical illnesses.

    PubMed

    Wilde, Henry; Suankratay, Chusana

    2007-01-01

    Enteric fever, typhus, leptospirosis, dengue, melioidosis, and tuberculous meningitis present urgent diagnostic problems that require experience and clinical judgment to make early evidence-based management decisions. Basic and applied research dealing with reliable antigen-based diagnostics has been published and confirmed for several of these infections. This should have initiated commercial production but has not. Established international firms see little profit in such diagnostic kits since they would be used in poor countries with little prospects for return of investment capital. We attempt to illustrate this issue, using common causes of acute febrile illnesses in the Southeast Asian region. We believe that rapid diagnostic technology could prevent significant delay in starting appropriate therapy, reduce hospital expenses, and even save lives.

  16. Vaccine hesitancy

    PubMed Central

    Dubé, Eve; Laberge, Caroline; Guay, Maryse; Bramadat, Paul; Roy, Réal; Bettinger, Julie A.

    2013-01-01

    Despite being recognized as one of the most successful public health measures, vaccination is perceived as unsafe and unnecessary by a growing number of individuals. Lack of confidence in vaccines is now considered a threat to the success of vaccination programs. Vaccine hesitancy is believed to be responsible for decreasing vaccine coverage and an increasing risk of vaccine-preventable disease outbreaks and epidemics. This review provides an overview of the phenomenon of vaccine hesitancy. First, we will characterize vaccine hesitancy and suggest the possible causes of the apparent increase in vaccine hesitancy in the developed world. Then we will look at determinants of individual decision-making about vaccination. PMID:23584253

  17. Current Status of Malaria and Potential for Control

    PubMed Central

    Phillips, R. S.

    2001-01-01

    Malaria remains one of the world's worst health problems with 1.5 to 2.7 million deaths annually; these deaths are primarily among children under 5 years of age and pregnant women in sub-Saharan Africa. Of significance, more people are dying from malaria today than 30 years ago. This review considers the factors which have contributed to this gloomy picture, including those which relate to the vector, the female anopheline mosquito; to human activity such as creating new mosquito breeding sites, the impact of increased numbers of people, and how their migratory behavior can increase the incidence and spread of malaria; and the problems of drug resistance by the parasites to almost all currently available antimalarial drugs. In a selective manner, this review describes what is being done to ameliorate this situation both in terms of applying existing methods in a useful or even crucial role in control and prevention and in terms of new additions to the antimalarial armory that are being developed. Topics covered include biological control of mosquitoes, the use of insecticide-impregnated bed nets, transgenic mosquitoes manipulated for resistance to malaria parasites, old and new antimalarial drugs, drug resistance and how best to maintain the useful life of antimalarials, immunity to malaria and the search for antimalarial vaccines, and the malaria genome project and the potential benefits to accrue from it. PMID:11148010

  18. [Clinical research on malaria: what for the future?].

    PubMed

    Cot, M

    2005-06-01

    Malaria still remains one of the main public health problems in the world. In spite of early and numerous clinical trials, the situation seems to have been worsening in the last ten years. Malaria clinical research involves several levels: Several meta-analyses have been performed on this topic (in particular, the Cochrane Database Library has published studies on malaria prevention during pregnancy, management of clinical malaria attacks, vaccine trials or impregnated bed net trials). All these studies show the uneven quality of trials (only 10% to 50% can be kept in the analysis for methodological reasons), which seldom lead to similar conclusions. Besides, as resistances of both parasites and vectors to drugs or insecticides are regularly increasing, trials have to be repeated and new molecules have to be found and evaluated. Finally, practical application of such interventions may be difficult, due to the heterogeneity of epidemiological situations and the poverty of target populations. Various initiatives aiming to develop malaria clinical research have recently been launched. Donators are public or international (Global Fund, Roll Back Malaria Initiative, NIH, EDCTP programme), as well as private (Bill & Melinda Gates Foundation). These substantial funds should enhance the research of new antimalarial drugs and large-scale, adequately designed trials. However, to make sure these trials really benefit to populations exposed to the disease, ethical principles should be co-elaborated with developing countries, within collaborative networks between laboratories from industrialized and developing countries.

  19. Malaria Early Warning: The MalarSat project

    NASA Astrophysics Data System (ADS)

    Roca, M.; Escorihuela, M. J.; Martínez, D.; Torrent, M.; Aponte, J.; Nunez, F.; Garcia, J.

    2009-04-01

    Malaria is one of the major public health challenges undermining development in the world. The aim of MalarSat Project is to provide a malaria risks infection maps at global scale using Earth Observation data to support and prevent epidemic episodes. The proposed service for creating malaria risk maps would be critically useful to improve the efficiency in insecticide programs, vaccine campaigns and the logistics epidemic treatment. Different teams have already carried out studies in order to exploit the use of Earth Observation (EO) data with epidemiology purposes. In the case of malaria risk maps, it has been shown that meteorological data is not sufficient to fulfill this objective. In particular being able to map the malaria mosquito habitat would increase the accuracy of risk maps. The malaria mosquitoes mainly reproduce in new water puddles of very reduced dimensions (about 1 meter wide). There is no instrument that could detect such small patches of water unless there are many of them spread in an area of several hundreds of meters. MalarSat aims at using the radar altimeter data from the EnviSat, RA-2, to try and build indicators of mosquitoes existence. This presentation will show the scientific objectives and principles of the MalarSat project.

  20. Optimized Malaria-antigens delivered by immunostimulating reconstituted influenza virosomes.

    PubMed

    Westerfeld, Nicole; Pluschke, Gerd; Zurbriggen, Rinaldo

    2006-01-01

    Malaria remains a serious cause of morbidity and mortality in millions of individuals each year. The development of widespread resistance of the parasite to drugs as well as resistance of the transmitting mosquito-vector to insecticides in combination with the poor economic situation of many malaria-endemic countries make the development of an effective and inexpensive treatment and prevention a main focus of research. Vaccines remain to be one of the most cost effective and feasible means of disease control and have remarkable success in the control of many infectious disease: eradication of small pox, virtual eradication of polio and the reduction of measles and diphtheria. Next generation vaccines should focus on specific antigens rather than whole inactivated or attenuated pathogens, since the requirements by regulatory authorities concerning safety are becoming more stringent over time. But sub-unit and in particular peptide-based vaccines are poorly immunogenic themselves, and alum represents only a sub-optimal adjuvant for recombinant proteins and synthetic peptides. This emphasizes the need for suitable carrier- and adjuvant systems promoting protective immune responses by delivering protein and peptide antigens in an appropriate conformation. Here, we review the development of a new approach combining peptide-based malaria vaccine candidate antigens with an immune stimulatory carrier-system based on influenza virosomes focusing on the induction of protective antibodies.

  1. Do Antenatal Parasite Infections Devalue Childhood Vaccination?

    PubMed Central

    King, Maria J.; King, Christopher L.; King, Charles H.

    2009-01-01

    On a global basis, both potent vaccine efficacy and high vaccine coverage are necessary to control and eliminate vaccine-preventable diseases. Emerging evidence from animal and human studies suggest that neglected tropical diseases (NTDs) significantly impair response to standard childhood immunizations. A review of efficacy and effectiveness studies of vaccination among individuals with chronic parasitic infections was conducted, using PUBMED database searches and analysis of data from the authors' published and unpublished studies. Both animal models and human studies suggest that chronic trematode, nematode, and protozoan infections can result in decreased vaccine efficacy. Among pregnant women, who in developing countries are often infected with multiple parasites, soluble parasite antigens have been shown to cross the placenta and prime or tolerize fetal immune responses. As a result, antenatal infections can have a significant impact on later vaccine responses. Acquired childhood parasitic infections, most commonly malaria, can also affect subsequent immune response to vaccination. Additional data suggest that antiparasite therapy can improve the effectiveness of several human vaccines. Emerging evidence demonstrates that both antenatal and childhood parasitic infections alter levels of protective immune response to routine vaccinations. Successful antiparasite treatment may prevent immunomodulation caused by parasitic antigens during pregnancy and early childhood and may improve vaccine efficacy. Future research should highlight the varied effects that different parasites (alone and in combination) can have on human vaccine-related immunity. To optimize vaccine effectiveness in developing countries, better control of chronic NTDs may prove imperative. PMID:19478847

  2. Neurological manifestations of malaria.

    PubMed

    Román, G C; Senanayake, N

    1992-03-01

    The involvement of the nervous system in malaria is reviewed in this paper. Cerebral malaria, the acute encephalopathy which complicates exclusively the infection by Plasmodium falciparum commonly affects children and adolescents in hyperendemic areas. Plugging of cerebral capillaries and venules by clumped, parasitized red cells causing sludging in the capillary circulation is one hypothesis to explain its pathogenesis. The other is a humoral hypothesis which proposes nonspecific, immune-mediated, inflammatory responses with release of vasoactive substances capable of producing endothelial damage and alterations of permeability. Cerebral malaria has a mortality rate up to 50%, and also a considerable longterm morbidity, particularly in children. Hypoglycemia, largely in patients treated with quinine, may complicate the cerebral symptomatology. Other central nervous manifestations of malaria include intracranial hemorrhage, cerebral arterial occlusion, and transient extrapyramidal and neuropsychiatric manifestations. A self-limiting, isolated cerebellar ataxia, presumably caused by immunological mechanisms, in patients recovering from falciparum malaria has been recognized in Sri Lanka. Malaria is a common cause of febrile seizures in the tropics, and it also contributes to the development of epilepsy in later life. Several reports of spinal cord and peripheral nerve involvement are also available. A transient muscle paralysis resembling periodic paralysis during febrile episodes of malaria has been described in some patients. The pathogenesis of these neurological manifestations remains unexplored, but offers excellent perspectives for research at a clinical as well as experimental level. PMID:1307475

  3. Migration and malaria.

    PubMed

    Jitthai, Nigoon

    2013-01-01

    Migration is an important global issue as poorly managed migration can result in a diversity of problems, including an increase in the transmission of diseases such as malaria. There is evidence to suggest that malaria is no longer a forest-dependent disease and may largely be affected by population movements, mostly to agricultural areas. While internal and transnational migration has different legal implications in most countries, both types of migration occur for the same reasons; economic and/ or safety. Although migration in itself is not a definitive risk for malaria, several factors can put, migrants and local communities alike, in vulnerable situations. In particular, infrastructure and rural development, deforestation for logging and economic farming, political movements, and natural disasters are some of the major factors that push and pull people in and out of malaria-endemic areas. Therefore, understanding the changing socio-environmental situation as well as population movements and their associated risks for malaria infection, is critical for malaria control, containment, and elimination. Efforts to address these issues should include advocacy, mapping exercises and expanded/ strengthened surveillance to also include migrant health information systems. Malaria related information, prevention measures, and early diagnosis and appropriate treatment should be made easily accessible for migrants regardless of their migration status; not only to ensure that they are equipped with appropriate knowledge and devices to protect themselves, but also to ensure that they are properly diagnosed and treated, to prevent further transmission, and to ensure that they are captured by the surveillance system. PMID:24159832

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

    PubMed

    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

  5. Malaria and Vascular Endothelium

    PubMed Central

    de Alencar, Aristóteles Comte; de Lacerda, Marcus Vinícius Guimarães; Okoshi, Katashi; Okoshi, Marina Politi

    2014-01-01

    Involvement of the cardiovascular system in patients with infectious and parasitic diseases can result from both intrinsic mechanisms of the disease and drug intervention. Malaria is an example, considering that the endothelial injury by Plasmodium-infected erythrocytes can cause circulatory disorders. This is a literature review aimed at discussing the relationship between malaria and endothelial impairment, especially its effects on the cardiovascular system. We discuss the implications of endothelial aggression and the interdisciplinarity that should guide the malaria patient care, whose acute infection can contribute to precipitate or aggravate a preexisting heart disease. PMID:25014058

  6. Malaria: prevention in travellers

    PubMed Central

    Croft, Ashley

    2000-01-01

    Definition Malaria is caused by a protozoan infection of red blood cells with one of four species of the genus plasmodium: P falciparum, P vivax, P ovale, or P malariae.1 Clinically, malaria may present in different ways, but it is usually characterised by fever (which may be swinging), tachycardia, rigors, and sweating. Anaemia, hepatosplenomegaly, cerebral involvement, renal failure, and shock may occur. Incidence/prevalence Each year there are 300-500 million clinical cases of malaria. About 40% of the world's population is at risk of acquiring the disease.23 Each year 25-30 million people from non-tropical countries visit areas in which malaria is endemic,4 of whom between 10 000 and 30 000 contract malaria.5 Aetiology/risk factors Malaria is mainly a rural disease, requiring standing water nearby. It is transmitted by bites6 from infected female anopheline mosquitoes,7 mainly at dusk and during the night.18 In cities, mosquito bites are usually from female culicene mosquitoes, which are not vectors of malaria.9 Malaria is resurgent in most tropical countries and the risk to travellers is increasing.10 Prognosis Ninety per cent of travellers who contract malaria do not become ill until after they return home.5 “Imported malaria” is easily treated if diagnosed promptly, and it follows a serious course in only about 12% of people.1112 The most severe form of the disease is cerebral malaria, with a case fatality rate in adult travellers of 2-6%,3 mainly because of delays in diagnosis.5 Aims To reduce the risk of infection; to prevent illness and death. Outcomes Rates of malarial illness and death, and adverse effects of treatment. Proxy measures include number of mosquito bites and number of mosquitoes in indoor areas. We found limited evidence linking number of mosquito bites and risk of malaria.13 Methods Clinical Evidence search and appraisal in November 1999. We reviewed all identified systematic reviews and randomised controlled trials (RCTs

  7. Malaria prevention in travelers.

    PubMed

    Genton, Blaise; D'Acremont, Valérie

    2012-09-01

    A common approach to malaria prevention is to follow the "A, B, C, D" rule: Awareness of risk, Bite avoidance, Compliance with chemoprophylaxis, and prompt Diagnosis in case of fever. The risk of acquiring malaria depends on the length and intensity of exposure; the risk of developing severe disease is primarily determined by the health status of the traveler. These parameters need to be assessed before recommending chemoprophylaxis and/or stand-by emergency treatment. This review discusses the different strategies and drug options available for the prevention of malaria during and post travel.

  8. The 1996 Runme Shaw Memorial Lecture: malaria--past, present and future.

    PubMed

    Warrell, D A

    1997-05-01

    Falciparum malaria may have infected Homo sapiens (and perhaps H erectus) in the Asia Pacific region for more than 100,000 years. This estimate is based on the gene frequency of alpha-thalassaemia, the protection it affords against falciparum malaria and assumptions of untreated mortality from the infection. Up until the end of the 19th century, there was a high mortality from malaria in the coastal parts of Malaya, but the malaria control campaign, begun in 1901 at Klang, was described by Sir Ronald Ross as the first successful antimalarial work in the (then) British Empire. This was extended to Singapore in 1911. When the Far Eastern Association of Tropical Medicine held its Fifth Biennial Congress in Singapore in 1923, malaria was still a major killing disease in parts of Malaya and Sarawak. The mechanism of life-threatening malaria involves cytoadherence of parasitised erythrocytes in microvascular beds, a process enhanced by the products of macrophage activation induced by malarial pyrogen. Improvements in the chemotherapy of life-threatening falciparum malaria with chloroquine and quinine have been countered by the emergence of resistant strains. Artemisinin derivatives may become the treatment of choice during the coming decade. Apart from traditional anti-mosquito methods, control of malaria now involves the use of insecticide-impregnated bed nets, new entomological strategies, including genetic manipulation of mosquitoes and selective chemoprophylaxis. Antigenic diversity and antigenic variation of the malaria parasite have so far defeated attempts to produce an effective vaccine.

  9. Malaria Modeling using Remote Sensing and GIS Technologies

    NASA Technical Reports Server (NTRS)

    Kiang, Richard

    2004-01-01

    Malaria has been with the human race since the ancient time. In spite of the advances of biomedical research and the completion of genomic mapping of Plasmodium falciparum, the exact mechanisms of how the various strains of parasites evade the human immune system and how they have adapted and become resistant to multiple drugs remain elusive. Perhaps because of these reasons, effective vaccines against malaria are still not available. Worldwide, approximately one to three millions deaths are attributed to malaria annually. With the increased availability of remotely sensed data, researchers in medical entomology, epidemiology and ecology have started to associate environmental and ecological variables with malaria transmission. In several studies, it has been shown that transmission correlates well with certain environmental and ecological parameters, and that remote sensing can be used to measure these determinants. In a NASA project, we have taken a holistic approach to examine how remote sensing and GIs can contribute to vector and malaria controls. To gain a better understanding of the interactions among the possible promoting factors, we have been developing a habitat model, a transmission model, and a risk prediction model, all using remote sensing data as input. Our objectives are: 1) To identify the potential breeding sites of major vector species and the locations for larvicide and insecticide applications in order to reduce costs, lessen the chance of developing pesticide resistance, and minimize the damage to the environment; 2) To develop a malaria transmission model characterizing the interactions among hosts, vectors, parasites, landcover and environment in order to identify the key factors that sustain or intensify malaria transmission, and 3) To develop a risk model to predict the occurrence of malaria and its transmission intensity using epidemiological data and satellite-derived or ground-measured environmental and meteorological data.

  10. Development of humanized mouse models to study human malaria parasite infection

    PubMed Central

    Vaughan, Ashley M; Kappe, Stefan HI; Ploss, Alexander; Mikolajczak, Sebastian A

    2013-01-01

    Malaria is a disease caused by infection with Plasmodium parasites that are transmitted by mosquito bite. Five different species of Plasmodium infect humans with severe disease, but human malaria is primarily caused by Plasmodium falciparum. The burden of malaria on the developing world is enormous, and a fully protective vaccine is still elusive. One of the biggest challenges in the quest for the development of new antimalarial drugs and vaccines is the lack of accessible animal models to study P. falciparum infection because the parasite is restricted to the great apes and human hosts. Here, we review the current state of research in this field and provide an outlook of the development of humanized small animal models to study P. falciparum infection that will accelerate fundamental research into human parasite biology and could accelerate drug and vaccine design in the future. PMID:22568719

  11. Scientific challenges and opportunities in developing novel vaccines for the emerging and developing markets: New Technologies in Emerging Markets, October 16th-18th 2012, World Vaccine Congress, Lyon.

    PubMed

    Kochhar, Sonali

    2013-04-01

    Vaccines have had a major role in enhancing the quality of life and increasing life expectancy. Despite these successes and the development of new vaccine technologies, there remain multiple infectious diseases including AIDS, malaria and tuberculosis that require effective prophylactic vaccines. New and traditional technologies have a role in the development and delivery of the new vaccine candidates. The scientific challenges, opportunities and funding models for developing vaccines for low resource settings are highlighted here.

  12. Challenges and prospects for dengue and malaria control in Thailand, Southeast Asia.

    PubMed

    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. PMID:24215776

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

    PubMed Central

    2011-01-01

    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 vaccines. PMID:21569599

  14. Diagnosis of placental malaria.

    PubMed

    Mockenhaupt, Frank P; Ulmen, Ulrike; von Gaertner, Christiane; Bedu-Addo, George; Bienzle, Ulrich

    2002-01-01

    In a group of 596 delivering Ghanaian women, the sensitivities of peripheral blood thick film microscopy, ICT Malaria P.f/P.v test, and PCR in detecting microscopically confirmed placental Plasmodium falciparum infection were 42, 80, and 97%, respectively. In addition to the gross underestimation of placental malaria by peripheral blood film microscopy, submicroscopic infections were found to be a risk factor for maternal anemia.

  15. Virulence in malaria: an evolutionary viewpoint.

    PubMed Central

    Mackinnon, Margaret J; Read, Andrew F

    2004-01-01

    Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs. PMID:15306410

  16. Vaccine delivery--current trends and future.

    PubMed

    Azad, Neelam; Rojanasakul, Yon

    2006-04-01

    Since its discovery in 1796 by Edward Jenner, vaccines have been an integral aspect of therapeutics, combating a number of infectious diseases with remarkable success. In recent years, due to rapid advances in proteomics, genomics, biotechnology and immunology and the plethora of knowledge amassed in related fields, it is fair to expect vaccine development to progress at an exponential pace. However, as we march on into the 21st century, we are still struggling in our efforts to eradicate fatal diseases such as AIDS, malaria and hepatitis C due, in part, to the absence of effective vaccines against these diseases. Vaccine development faces major challenges both technologically and economically. Newer vaccines that are stable, economical, require fewer doses and can be administered using needle free systems are a worldwide priority. An ideal theoretical vaccine may not be cogent unless formulated and delivered aptly. Delivery of vaccines via oral, intranasal, transcutaneous and intradermal routes will decrease the risk of needle-borne diseases and may eliminate the need for trained personnel and sterile equipment. Crucial to the success of a vaccine is the delivery strategy that is to be employed. Currently, various techniques involving DNA vaccines, adjuvants, microparticles and transgenic plants are being developed and evaluated. Although, no major breakthrough is in prospect, these systems have potential and will take immunization to a new technological level. This review will focus on the current development of some novel vaccine delivery systems and will explore the non-parenteral routes of vaccine administration. PMID:16611000

  17. Vaccine Safety

    MedlinePlus

    ... 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 ...

  18. Smallpox Vaccination

    MedlinePlus

    ... Newsletters Events Also Known As Smallpox = Vaccinia Smallpox Vaccination Recommend on Facebook Tweet Share Compartir The smallpox ... like many other vaccines. For that reason, the vaccination site must be cared for carefully to prevent ...

  19. Travel risk, malaria importation and malaria transmission in Zanzibar

    PubMed Central

    Le Menach, Arnaud; Tatem, Andrew J.; Cohen, Justin M.; Hay, Simon I.; Randell, Heather; Patil, Anand P.; Smith, David L.

    2011-01-01

    The prevalence of Plasmodium falciparum malaria in Zanzibar has reached historic lows. Improving control requires quantifying malaria importation rates, identifying high-risk travelers, and assessing onwards transmission. Estimates of Zanzibar's importation rate were calculated through two independent methodologies. First, mobile phone usage data and ferry traffic between Zanzibar and mainland Tanzania were re-analyzed using a model of heterogeneous travel risk. Second, a dynamic mathematical model of importation and transmission rates was used. Zanzibar residents traveling to malaria endemic regions were estimated to contribute 1–15 times more imported cases than infected visitors. The malaria importation rate was estimated to be 1.6 incoming infections per 1,000 inhabitants per year. Local transmission was estimated too low to sustain transmission in most places. Malaria infections in Zanzibar largely result from imported malaria and subsequent transmission. Plasmodium falciparum malaria elimination appears feasible by implementing control measures based on detecting imported malaria cases and controlling onward transmission. PMID:22355611

  20. Antibody response dynamics to the Plasmodium falciparum conserved vaccine candidate antigen, merozoite surface protein-1 C-terminal 19kD (MSP1-19kD), in Peruvians exposed to hypoendemic malaria transmission

    PubMed Central

    Torres, Katherine J; Clark, Eva H; Hernandez, Jean N; Soto-Cornejo, Katherine E; Gamboa, Dionicia; Branch, OraLee H

    2008-01-01

    Background In high-transmission areas, developing immunity to symptomatic Plasmodium falciparum infections requires 2–10 years of uninterrupted exposure. Delayed malaria-immunity has been attributed to difficult-to-develop and then short-lived antibody responses. Methods In a study area with <0.5 P. falciparum infections/person/year, antibody responses to the MSP1-19kD antigen were evaluated and associations with P. falciparum infections in children and adults. In months surrounding and during the malaria seasons of 2003–2004, 1,772 participants received ≥6 active visits in one study-year. Community-wide surveys were conducted at the beginning and end of each malaria season, and weekly active visits were completed for randomly-selected individuals each month. There were 79 P. falciparum infections with serum samples collected during and approximately one month before and after infection. Anti-MSP1-19kD IgG levels were measured by ELISA. Results The infection prevalence during February-July was similar in children (0.02–0.12 infections/person/month) and adults (0.03–0.14 infections/person/month) and was negligible in the four-month dry season. In children and adults, the seroprevalence was maintained in the beginning (children = 28.9%, adults = 61.8%) versus ending malaria-season community survey (children = 26.7%, adults = 64.6%). Despite the four-month non-transmission season, the IgG levels in Plasmodium-negative adults were similar to P. falciparum-positive adults. Although children frequently responded upon infection, the transition from a negative/low level before infection to a high level during/after infection was slower in children. Adults and children IgG-positive before infection had reduced symptoms and parasite density. Conclusion Individuals in low transmission areas can rapidly develop and maintain αMSP1-19kD IgG responses for >4 months, unlike responses reported in high transmission study areas. A greater immune capacity might contribute

  1. Diabetes vaccines: a future to be realized.

    PubMed

    Lin-Su, K; Kukreja, A; Maclaren, N K

    2001-01-01

    Immune-mediated (type 1) diabetes mellitus (IMD) is an autoimmune disease resulting from the chronic destruction of pancreatic islet cells by autoreactive T lymphocytes. Although there has been much advancement in diabetes management, targeting the precise etiology of the disease process has remained elusive. Recent progress in the understanding of the immunopathogenesis of IMD, however, has led to new intervention strategies, especially antigen-based therapies given as altered peptide ligands (APLs) or as vaccines. Instead of using immunosuppressive agents to suppress an already dysfunctional immune system, antigen specific vaccines or even non-antigen specific immunostimulants present a unique opportunity to boost regulatory function and thereby regain tolerance to self. We discuss here the pathogenesis of IMD as it relates to therapeutic possibilities, review various intervention strategies that have been successful in rodent models, and then present recent progress in human trials of diabetes intervention and prevention through vaccine prototypes.

  2. Recombinant hexon antigen based single serum dilution ELISA for rapid serological profiling against fowl adenovirus-4 causing hydropericardium syndrome in chickens.

    PubMed

    R, Rajasekhar; Roy, Parimal

    2014-10-01

    A recombinant hexon antigen based single serum dilution enzyme linked immunosorbent assay (ELISA) was developed to measure the specific antibody in sera of chickens against Fowl adenovirus-4 (FAdV) causing Hydropericardium syndrome (HPS). An immunodominant partial hexon gene of 737bp was cloned into pRSET vector and expressed in Escherichia coli strain BL21 DE3 pLys S. Expression was tested by Western Blot test. The purified recombinant protein antigen was used in coating ELISA plate for FAdV-4 serology. A linear relationship was found between the predicted antibody titres at a single working dilution of 1:100 and the corresponding observed serum titres as determined by the standard serial dilution method. Regression analysis was used to determine a standard curve from which an equation was derived that allowed the demonstration of this correlation. The equation was then used to convert the corrected absorbance readings of the single working dilution directly into the predicted ELISA antibody titres. The assay proved to be sensitive, specific and accurate as compared to Q-AGID test. Recombinant antigen was also used in Dot ELISA. In an experimental vaccination of broiler chicken at 10 days old age, the geometric mean (GM) antibody titres as measured by ELISA ranged from 5.006±0.11log10 to 4.526±0.04log10 and by Dot ELISA titre were from 2.240±0.08log10 to 0.180±0.04log10 during 5th-8th weeks of age, results were compared with Q-AGID results. Field samples were collected randomly from breeder flocks, found to have antibody titre by both ELISA and Dot ELISA at 10th and only 75% samples were positive at 14th weeks of age. After revaccination at 16th weeks of age, all sera samples were found have considerably high antibody titre on 24th week but all samples were negative at 32nd weeks. Advantages of recombinant hexon antigen based ELISA and Dot ELISA in FAdV-4 serology have been discussed.

  3. Recombinant UL30 antigen-based single serum dilution ELISA for detection of duck viral enteritis.

    PubMed

    Aravind, S; Patil, B R; Dey, Sohini; Mohan, C Madhan

    2012-11-01

    A recombinant UL30 antigen-based single serum dilution enzyme linked immunosorbent assay (ELISA) was developed to measure specific antibody in the sera of ducks against duck enteritis virus (DEV). The partial UL30 gene of DEV was cloned, expressed, purified and tested for its diagnostic use by designing a single serum dilution enzyme linked immuno-sorbent assay (ELISA). A total of 226 duck sera samples were tested using the assay. A linear relationship was found between the predicted antibody titres at a single working dilution of 1:100 and the corresponding serum titres observed as determined by the standard serial dilution method. Regression analysis was used to determine a standard curve from which an equation was derived which demonstrated this correlation. The equation was then used to convert the corrected absorbance readings of the single working dilution directly into the predicted ELISA antibody titres. The assay proved to be specific, sensitive and accurate as compared to the virus neutralization test with a specificity, sensitivity and accuracy being 96%, 95% and 95% respectively.

  4. Vaccine Hesitancy.

    PubMed

    Jacobson, Robert M; St Sauver, Jennifer L; Finney Rutten, Lila J

    2015-11-01

    Vaccine refusal received a lot of press with the 2015 Disneyland measles outbreak, but vaccine refusal is only a fraction of a much larger problem of vaccine delay and hesitancy. Opposition to vaccination dates back to the 1800 s, Edward Jenner, and the first vaccine ever. It has never gone away despite the public's growing scientific sophistication. A variety of factors contribute to modern vaccine hesitancy, including the layperson's heuristic thinking when it comes to balancing risks and benefits as well as a number of other features of vaccination, including falling victim to its own success. Vaccine hesitancy is pervasive, affecting a quarter to a third of US parents. Clinicians report that they routinely receive requests to delay vaccines and that they routinely acquiesce. Vaccine rates vary by state and locale and by specific vaccine, and vaccine hesitancy results in personal risk and in the failure to achieve or sustain herd immunity to protect others who have contraindications to the vaccine or fail to generate immunity to the vaccine. Clinicians should adopt a variety of practices to combat vaccine hesitancy, including a variety of population health management approaches that go beyond the usual call to educate patients, clinicians, and the public. Strategies include using every visit to vaccinate, the creation of standing orders or nursing protocols to provide vaccination without clinical encounters, and adopting the practice of stating clear recommendations. Up-to-date, trusted resources exist to support clinicians' efforts in adopting these approaches to reduce vaccine hesitancy and its impact. PMID:26541249

  5. [Vaccination perspectives].

    PubMed

    Saliou, P; Plotkin, S

    1994-01-01

    The aim of vaccinology is to improve the available vaccines and to develop new ones in the light of progress in immunology, molecular biology and biotechnologies. But it must go beyond this, and aim to protect all populations and control diseases, even eradicate them where possible. New vaccine strategies must be developed taking into account the epidemiology of diseases and the inherent logistic problems of implementing these strategies under local conditions. There are three major thrusts to the progress of the discipline. The improvement of the vaccines available. One of the drives of vaccinology is not only to deliver vaccines of increasing safety (replacement of the current vaccine for whooping cough with an acellular vaccine for example), but also to improve vaccine efficacy and immunogenicity (in particular for flu, tuberculosis, cholera and rabies vaccines). The optimisation of vaccination programmes and strategies for vaccinations. The ideal is to protect against the greatest possible number of diseases with the smallest number of vaccinations. The development of combinations of vaccines is central to this goal. The objective for the year 2000 is a hexavalent vaccine DTPP Hib HB. The development of new vaccines. Classic techniques continue to be successfully used (inactivated hepatitis A vaccine; attenuated live vaccines for chicken pox and dengue fever; conjugated polyosidic bacterial vaccines for meningococci and Streptococcus pneumoniae). However, it will become possible to prepare vaccines against most transmissible diseases using genetic engineering techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Vaccine Hesitancy.

    PubMed

    Jacobson, Robert M; St Sauver, Jennifer L; Finney Rutten, Lila J

    2015-11-01

    Vaccine refusal received a lot of press with the 2015 Disneyland measles outbreak, but vaccine refusal is only a fraction of a much larger problem of vaccine delay and hesitancy. Opposition to vaccination dates back to the 1800 s, Edward Jenner, and the first vaccine ever. It has never gone away despite the public's growing scientific sophistication. A variety of factors contribute to modern vaccine hesitancy, including the layperson's heuristic thinking when it comes to balancing risks and benefits as well as a number of other features of vaccination, including falling victim to its own success. Vaccine hesitancy is pervasive, affecting a quarter to a third of US parents. Clinicians report that they routinely receive requests to delay vaccines and that they routinely acquiesce. Vaccine rates vary by state and locale and by specific vaccine, and vaccine hesitancy results in personal risk and in the failure to achieve or sustain herd immunity to protect others who have contraindications to the vaccine or fail to generate immunity to the vaccine. Clinicians should adopt a variety of practices to combat vaccine hesitancy, including a variety of population health management approaches that go beyond the usual call to educate patients, clinicians, and the public. Strategies include using every visit to vaccinate, the creation of standing orders or nursing protocols to provide vaccination without clinical encounters, and adopting the practice of stating clear recommendations. Up-to-date, trusted resources exist to support clinicians' efforts in adopting these approaches to reduce vaccine hesitancy and its impact.

  7. Cross-species malaria immunity induced by chemically attenuated parasites

    PubMed Central

    Good, Michael F.; Reiman, Jennifer M.; Rodriguez, I. Bibiana; Ito, Koichi; Yanow, Stephanie K.; El-Deeb, Ibrahim M.; Batzloff, Michael R.; Stanisic, Danielle I.; Engwerda, Christian; Spithill, Terry; Hoffman, Stephen L.; Lee, Moses; McPhun, Virginia

    2013-01-01

    Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with seco-cyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4+ T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species. PMID:23863622

  8. Sterile Protective Immunity to Malaria is Associated with a Panel of Novel P. falciparum Antigens*

    PubMed Central

    Trieu, Angela; Kayala, Matthew A.; Burk, Chad; Molina, Douglas M.; Freilich, Daniel A.; Richie, Thomas L.; Baldi, Pierre; Felgner, Philip L.; Doolan, Denise L.

    2011-01-01

    The development of an effective malaria vaccine remains a global public health priority. Less than 0.5% of the Plasmodium falciparum genome has been assessed as potential vaccine targets and candidate vaccines have been based almost exclusively on single antigens. It is possible that the failure to develop a malaria vaccine despite decades of effort might be attributed to this historic focus. To advance malaria vaccine development, we have fabricated protein microarrays representing 23% of the entire P. falciparum proteome and have probed these arrays with plasma from subjects with sterile protection or no protection after experimental immunization with radiation attenuated P. falciparum sporozoites. A panel of 19 pre-erythrocytic stage antigens was identified as strongly associated with sporozoite-induced protective immunity; 16 of these antigens were novel and 85% have been independently identified in sporozoite and/or liver stage proteomic or transcriptomic data sets. Reactivity to any individual antigen did not correlate with protection but there was a highly significant difference in the cumulative signal intensity between protected and not protected individuals. Functional annotation indicates that most of these signature proteins are involved in cell cycle/DNA processing and protein synthesis. In addition, 21 novel blood-stage specific antigens were identified. Our data provide the first evidence that sterile protective immunity against malaria is directed against a panel of novel P. falciparum antigens rather than one antigen in isolation. These results have important implications for vaccine development, suggesting that an efficacious malaria vaccine should be multivalent and targeted at a select panel of key antigens, many of which have not been previously characterized. PMID:21628511

  9. The treatment of malaria.

    PubMed

    White, N J

    1996-09-12

    Increasing drug resistance in Plasmodium falciparum and a resurgence of malaria in tropical areas have effected a change in treatment of malaria in the last two decades. Symptoms of malaria are fever, chills, headache, and malaise. The prognosis worsens as the parasite counts, counts of mature parasites, and counts of neutrophils containing pigment increase. Treatment depends on severity, age of patient, degree of background immunity, likely pattern of susceptibility to antimalarial drugs, and the cost and availability of drugs. Chloroquine should be used for P. vivax, P. malariae, and P. ovale. P. vivax has shown high resistance to chloroquine in Oceania, however. Primaquine may be needed to treat P. vivax and P. ovale to rid the body of hypnozoites that survive in the liver. Chloroquine can treat P. falciparum infections acquired in North Africa, Central America north of the Panama Canal, Haiti, or the Middle East but not in most of Africa and some parts of Asia and South America. In areas of low grade resistance to chloroquine, amodiaquine can be used to effectively treat falciparum malaria. A combination of sulfadoxine-pyrimethamine is responsive to falciparum infections with high grade resistance to chloroquine. Mefloquine, halofantrine, or quinine with tetracycline can be used to treat multidrug-resistant P. falciparum. Derivatives of artemisinin obtained from qinghao or sweet wormwood developed as pharmaceuticals in China are the most rapidly acting of all antimalarial drugs. Children tend to tolerate antimalarial drugs well. Children who weigh less than 15 kg should not be given mefloquine. Health workers should not prescribe primaquine to pregnant women or newborns due to the risk of hemolysis. Chloroquine, sulfadoxine-pyrimethamine, quinine, and quinidine can be safely given in therapeutic doses throughout pregnancy. Clinical manifestations of severe malaria are hypoglycemia, convulsions, severe anemia, acute renal failure, jaundice, pulmonary edema

  10. Monkey malaria kills four humans.

    PubMed

    Galinski, Mary R; Barnwell, John W

    2009-05-01

    Four human deaths caused by Plasmodium knowlesi, a simian malaria species, are stimulating a surge of public health interest and clinical vigilance in vulnerable areas of Southeast Asia. We, and other colleagues, emphasize that these cases, identified in Malaysia, are a clear warning that health facilities and clinicians must rethink the diagnosis and treatment of malaria cases presumed to be caused by a less virulent human malaria species, Plasmodium malariae.

  11. Plasmodium vivax Sporozoite Challenge in Malaria-Naïve and Semi-Immune Colombian Volunteers

    PubMed Central

    Arévalo-Herrera, Myriam; Forero-Peña, David A.; Rubiano, Kelly; Gómez-Hincapie, José; Martínez, Nora L.; Lopez-Perez, Mary; Castellanos, Angélica; Céspedes, Nora; Palacios, Ricardo; Oñate, José Millán; Herrera, Sócrates

    2014-01-01

    Background Significant progress has been recently achieved in the development of Plasmodium vivax challenge infections in humans, which are essential for vaccine and drug testing. With the goal of accelerating clinical development of malaria vaccines, the outcome of infections experimentally induced in naïve and semi-immune volunteers by infected mosquito bites was compared. Methods Seven malaria-naïve and nine semi-immune Colombian adults (n = 16) were subjected to the bites of 2–4 P. vivax sporozoite-infected Anopheles mosquitoes. Parasitemia levels, malaria clinical manifestations, and immune responses were assessed and compared. Results All volunteers developed infections as confirmed by microscopy and RT-qPCR. No significant difference in the pre-patent period (mean 12.5 and 12.8 days for malaria-naïve and malaria-exposed, respectively) was observed but naïve volunteers developed classical malaria signs and symptoms, while semi-immune volunteers displayed minor or no symptoms at the day of diagnosis. A malaria-naïve volunteer developed a transient low submicroscopic parasitemia that cured spontaneously. Infection induced an increase in specific antibody levels in both groups. Conclusion Sporozoite infectious challenge was safe and reproducible in semi-immune and naïve volunteers. This model will provide information for simultaneous comparison of the protective efficacy of P. vivax vaccines in naïve and semi-immune volunteers under controlled conditions and would accelerate P. vivax vaccine development. Trial Registration clinicaltrials.gov NCT01585077 PMID:24963662

  12. Can plant biotechnology help break the HIV-malaria link?

    PubMed

    Vamvaka, E; Twyman, R M; Christou, P; Capell, T

    2014-01-01

    The population of sub-Saharan Africa is at risk from multiple, poverty-related endemic diseases. HIV and malaria are the most prevalent, but they disproportionately affect different groups of people, i.e. HIV predominantly affects sexually-active adults whereas malaria has a greater impact on children and pregnant women. Nevertheless, there is a significant geographical and epidemiological overlap which results in bidirectional and synergistic interactions with important consequences for public health. The immunosuppressive effects of HIV increase the risk of infection when individuals are exposed to malaria parasites and also the severity of malaria symptoms. Similarly, acute malaria can induce a temporary increase in the HIV viral load. HIV is associated with a wide range of opportunistic infections that can be misdiagnosed as malaria, resulting in the wasteful misuse of antimalarial drugs and a failure to address the genuine cause of the disease. There is also a cumulative risk of toxicity when antiretroviral and antimalarial drugs are given to the same patients. Synergistic approaches involving the control of malaria as a strategy to fight HIV/AIDS and vice versa are therefore needed in co-endemic areas. Plant biotechnology has emerged as a promising approach to tackle poverty-related diseases because plant-derived drugs and vaccines can be produced inexpensively in developing countries and may be distributed using agricultural infrastructure without the need for a cold chain. Here we explore some of the potential contributions of plant biotechnology and its integration into broader multidisciplinary public health programs to combat the two diseases in developing countries. PMID:24607600

  13. Can plant biotechnology help break the HIV-malaria link?

    PubMed

    Vamvaka, E; Twyman, R M; Christou, P; Capell, T

    2014-01-01

    The population of sub-Saharan Africa is at risk from multiple, poverty-related endemic diseases. HIV and malaria are the most prevalent, but they disproportionately affect different groups of people, i.e. HIV predominantly affects sexually-active adults whereas malaria has a greater impact on children and pregnant women. Nevertheless, there is a significant geographical and epidemiological overlap which results in bidirectional and synergistic interactions with important consequences for public health. The immunosuppressive effects of HIV increase the risk of infection when individuals are exposed to malaria parasites and also the severity of malaria symptoms. Similarly, acute malaria can induce a temporary increase in the HIV viral load. HIV is associated with a wide range of opportunistic infections that can be misdiagnosed as malaria, resulting in the wasteful misuse of antimalarial drugs and a failure to address the genuine cause of the disease. There is also a cumulative risk of toxicity when antiretroviral and antimalarial drugs are given to the same patients. Synergistic approaches involving the control of malaria as a strategy to fight HIV/AIDS and vice versa are therefore needed in co-endemic areas. Plant biotechnology has emerged as a promising approach to tackle poverty-related diseases because plant-derived drugs and vaccines can be produced inexpensively in developing countries and may be distributed using agricultural infrastructure without the need for a cold chain. Here we explore some of the potential contributions of plant biotechnology and its integration into broader multidisciplinary public health programs to combat the two diseases in developing countries.

  14. Molecular Epidemiology of Malaria

    PubMed Central

    Conway, David J.

    2007-01-01

    Malaria persists as an undiminished global problem, but the resources available to address it have increased. Many tools for understanding its biology and epidemiology are well developed, with a particular richness of comparative genome sequences. Targeted genetic manipulation is now effectively combined with in vitro culture assays on the most important human parasite, Plasmodium falciparum, and with in vivo analysis of rodent and monkey malaria parasites in their laboratory hosts. Studies of the epidemiology, prevention, and treatment of human malaria have already been influenced by the availability of molecular methods, and analyses of parasite polymorphisms have long had useful and highly informative applications. However, the molecular epidemiology of malaria is currently undergoing its most substantial revolution as a result of the genomic information and technologies that are available in well-resourced centers. It is a challenge for research agendas to face the real needs presented by a disease that largely exists in extremely resource-poor settings, but it is one that there appears to be an increased willingness to undertake. To this end, developments in the molecular epidemiology of malaria are reviewed here, emphasizing aspects that may be current and future priorities. PMID:17223628

  15. Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza.

    PubMed

    Matsuo, Kazuhiko; Hirobe, Sachiko; Yokota, Yayoi; Ayabe, Yurika; Seto, Masashi; Quan, Ying-Shu; Kamiyama, Fumio; Tougan, Takahiro; Horii, Toshihiro; Mukai, Yohei; Okada, Naoki; Nakagawa, Shinsaku

    2012-06-28

    Transcutaneous immunization (TCI) is an attractive alternative vaccination route compared to the commonly used injection systems. We previously developed a dissolving microneedle array for use as a TCI device, and reported that TCI with the dissolving microneedle array induced an immune response against model antigens. In the present study, we investigated the vaccination efficacy against tetanus and diphtheria, malaria, and influenza using this vaccination system. Our TCI system induced substantial increases in toxoid-specific IgG levels and toxin-neutralizing antibody titer and induced the production of anti-SE36 IgG, which could bind to malaria parasite. On influenza HA vaccination, robust antibody production was elicited in mice that provided complete protection against a subsequent influenza virus challenge. These findings demonstrate that TCI using a dissolving microneedle array can elicit large immune responses against infectious diseases. Based on these results, we are now preparing translational research for human clinical trials. PMID:22516091

  16. Improving vaccine delivery using novel adjuvant systems.

    PubMed

    Pichichero, Michael E

    2008-01-01

    Adjuvants have been common additions to vaccines to help facilitate vaccine delivery. With advancements in vaccine technology, several adjuvants which activate immune specific responses have emerged. Available data show these adjuvants elicit important immune responses in both healthy and immunocompromised populations, as well as the elderly. Guidelines for the use and licensure of vaccine adjuvants remain under discussion. However, there is a greater understanding of the innate and adaptive immune response, and the realization of the need for immune specific adjuvants appears to be growing. This is a focused review of four adjuvants currently in clinical trial development: ASO4, ASO2A, CPG 7907, and GM-CSF. The vaccines including these adjuvants are highly relevant today, and are expected to reduce the disease burden of cervical cancer, hepatitis B and malaria. PMID:18398303

  17. Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine.

    PubMed

    Chabot, Donald J; Ribot, Wilson J; Joyce, Joseph; Cook, James; Hepler, Robert; Nahas, Debbie; Chua, Jennifer; Friedlander, Arthur M

    2016-07-25

    The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines. PMID:27329184

  18. [Vaccinations 1979].

    PubMed

    Herzog, C; Just, M

    1980-05-17

    On the basis of the Federal Health Department's "Swiss Vaccination Scheme" of 1976, some up to data additions and alterations are proposed mainly with regard to combined measles-mumps-rubella vaccination during the second year of life together with the first tetanus, diphtheria and poliomyelitis booster. Oral vaccination against poliomyelitis is not contraindicated during pregnancy. Among the inoculations not considered in the official vaccination scheme, regular influenza vaccination is only indicated for certain chronically ill people. Whether this is also true of the pneumococcal vaccine newly licensed in Switzerland remains uncertain. The (likewise new) meningococcal vaccine is only effective against type A and C and not against the type B meningococci prevalent in Switzerland. In view of its safety, only HDC vaccine produced with human tissue cultures should be used for anti-rabies vaccination. For counselling prior to travel abroad, a simple vaccination scheme is provided and the importance of other prophylactic measures is emphasized. PMID:7394495

  19. Use of vaccines as probes to define disease burden.

    PubMed

    Feikin, Daniel R; Scott, J Anthony G; Gessner, Bradford D

    2014-05-17

    Vaccine probe studies have emerged in the past 15 years as a useful way to characterise disease. By contrast, traditional studies of vaccines focus on defining the vaccine effectiveness or efficacy. The underlying basis for the vaccine probe approach is that the difference in disease burden between vaccinated and unvaccinated individuals can be ascribed to the vaccine-specific pathogen. Vaccine probe studies can increase understanding of a vaccine's public health value. For instance, even when a vaccine has a seemingly low efficacy, a high baseline disease incidence can lead to a large vaccine-preventable disease burden and thus that population-based vaccine introduction would be justified. So far, vaccines have been used as probes to characterise disease syndromes caused by Haemophilus influenzae type b, pneumococcus, rotavirus, and early infant influenza. However, vaccine probe studies have enormous potential and could be used more widely in epidemiology, for example, to define the vaccine-preventable burden of malaria, typhoid, paediatric influenza, and dengue, and to identify causal interactions between different pathogens.

  20. Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

    PubMed

    Biswas, Sumi; Choudhary, Prateek; Elias, Sean C; Miura, Kazutoyo; Milne, Kathryn H; de Cassan, Simone C; Collins, Katharine A; Halstead, Fenella D; Bliss, Carly M; Ewer, Katie J; Osier, Faith H; Hodgson, Susanne H; Duncan, Christopher J A; O'Hara, Geraldine A; Long, Carole A; Hill, Adrian V S; Draper, Simon J

    2014-01-01

    The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases

  1. Consistent Safety and Infectivity in Sporozoite Challenge Model of Plasmodium vivax in Malaria-Naive Human Volunteers

    PubMed Central

    Herrera, Sócrates; Solarte, Yezid; Jordán-Villegas, Alejandro; Echavarría, Juan Fernando; Rocha, Leonardo; Palacios, Ricardo; Ramírez, Óscar; Vélez, Juan D.; Epstein, Judith E.; Richie, Thomas L.; Arévalo-Herrera, Myriam

    2011-01-01

    A safe and reproducible Plasmodium vivax infectious challenge method is required to evaluate the efficacy of malaria vaccine candidates. Seventeen healthy Duffy (+) and five Duffy (−) subjects were randomly allocated into three (A–C) groups and were exposed to the bites of 2–4 Anopheles albimanus mosquitoes infected with Plasmodium vivax derived from three donors. Duffy (−) subjects were included as controls for each group. Clinical manifestations of malaria and parasitemia were monitored beginning 7 days post-challenge. All Duffy (+) volunteers developed patent malaria infection within 16 days after challenge. Prepatent period determined by thick smear, was longer for Group A (median 14.5 d) than for Groups B and C (median 10 d/each). Infected volunteers recovered rapidly after treatment with no serious adverse events. The bite of as low as two P. vivax-infected mosquitoes provides safe and reliable infections in malaria-naive volunteers, suitable for assessing antimalarial and vaccine efficacy trials. PMID:21292872

  2. c-DNA vaccination against parasitic infections: advantages and disadvantages.

    PubMed

    Kofta, W; Wedrychowicz, H

    2001-09-12

    Recently developed technology for DNA vaccination appears to offer the good prospect for the development of a multivalent vaccines that will effectively activate both the humoral and cell mediated mechanisms of the immune system. Currently, DNA vaccination against such important parasitic diseases like malaria, leishmaniosis, toxoplasmosis, cryptosporidiosis, schistosomosis, fasciolosis offers several new opportunities. However, the outcome of vaccination depends very much on vaccine formulations, dose and route of vaccine delivery, and the species and even strain of the vaccinated host. To overcome these problems much research is still needed, specifically focused on cloning and testing of new c-DNA sequences in the following: genome projects: different ways of delivery: design of vectors containing appropriate immunostimulatory sequences and very detailed studies on safety. PMID:11522401

  3. Vaccines as a global imperative--a business perspective.

    PubMed

    Stéphenne, Jean

    2011-06-01

    During the past thirty years, vaccines have experienced a renaissance. Advances in science, business, and distribution have transformed the field to the point where vaccines are recognized as a "best buy" in global health, a driver of pharmaceutical industry growth, and a key instrument of international development. With many new vaccines available and others on the horizon, the global community will need to explore new ways of ensuring access to vaccines in developing nations. So-called tiered pricing, which makes vaccines available at different prices for countries at different levels of economic development; innovative financing mechanisms such as advance market commitments or offers of long-term and high-volume contracts to vaccine producers; and technology transfers such as sharing intellectual property and production techniques among companies and countries can all play a part in bringing new life-saving vaccines for pneumonia, rotavirus, malaria, and other diseases to developing countries. PMID:21653955

  4. Vaccines as a global imperative--a business perspective.

    PubMed

    Stéphenne, Jean

    2011-06-01

    During the past thirty years, vaccines have experienced a renaissance. Advances in science, business, and distribution have transformed the field to the point where vaccines are recognized as a "best buy" in global health, a driver of pharmaceutical industry growth, and a key instrument of international development. With many new vaccines available and others on the horizon, the global community will need to explore new ways of ensuring access to vaccines in developing nations. So-called tiered pricing, which makes vaccines available at different prices for countries at different levels of economic development; innovative financing mechanisms such as advance market commitments or offers of long-term and high-volume contracts to vaccine producers; and technology transfers such as sharing intellectual property and production techniques among companies and countries can all play a part in bringing new life-saving vaccines for pneumonia, rotavirus, malaria, and other diseases to developing countries.

  5. Seroreactivity to a Large Panel of Field-Derived Plasmodium falciparum Apical Membrane Antigen 1 and Merozoite Surface Protein 1 Variants Reflects Seasonal and Lifetime Acquired Responses to Malaria

    PubMed Central

    Bailey, Jason A.; Pablo, Jozelyn; Niangaly, Amadou; Travassos, Mark A.; Ouattara, Amed; Coulibaly, Drissa; Laurens, Matthew B.; Takala-Harrison, Shannon L.; Lyke, Kirsten E.; Skinner, Jeff; Berry, Andrea A.; Jasinskas, Algis; Nakajima-Sasaki, Rie; Kouriba, Bourema; Thera, Mahamadou A.; Felgner, Philip L.; Doumbo, Ogobara K.; Plowe, Christopher V.

    2015-01-01

    Parasite antigen diversity poses an obstacle to developing an effective malaria vaccine. A protein microarray containing Plasmodium falciparum apical membrane antigen 1 (AMA1, n = 57) and merozoite surface protein 1 19-kD (MSP119, n = 10) variants prevalent at a malaria vaccine testing site in Bandiagara, Mali, was used to assess changes in seroreactivity caused by seasonal and lifetime exposure to malaria. Malian adults had significantly higher magnitude and breadth of seroreactivity to variants of both antigens than did Malian children. Seroreactivity increased over the course of the malaria season in children and adults, but the difference was more dramatic in children. These results help to validate diversity-covering protein microarrays as a promising tool for measuring the breadth of antibody responses to highly variant proteins, and demonstrate the potential of this new tool to help guide the development of malaria vaccines with strain-transcending efficacy. PMID:25294612

  6. Seroreactivity to a large panel of field-derived Plasmodium falciparum apical membrane antigen 1 and merozoite surface protein 1 variants reflects seasonal and lifetime acquired responses to malaria.

    PubMed

    Bailey, Jason A; Pablo, Jozelyn; Niangaly, Amadou; Travassos, Mark A; Ouattara, Amed; Coulibaly, Drissa; Laurens, Matthew B; Takala-Harrison, Shannon L; Lyke, Kirsten E; Skinner, Jeff; Berry, Andrea A; Jasinskas, Algis; Nakajima-Sasaki, Rie; Kouriba, Bourema; Thera, Mahamadou A; Felgner, Philip L; Doumbo, Ogobara K; Plowe, Christopher V

    2015-01-01

    Parasite antigen diversity poses an obstacle to developing an effective malaria vaccine. A protein microarray containing Plasmodium falciparum apical membrane antigen 1 (AMA1, n = 57) and merozoite surface protein 1 19-kD (MSP119, n = 10) variants prevalent at a malaria vaccine testing site in Bandiagara, Mali, was used to assess changes in seroreactivity caused by seasonal and lifetime exposure to malaria. Malian adults had significantly higher magnitude and breadth of seroreactivity to variants of both antigens than did Malian children. Seroreactivity increased over the course of the malaria season in children and adults, but the difference was more dramatic in children. These results help to validate diversity-covering protein microarrays as a promising tool for measuring the breadth of antibody responses to highly variant proteins, and demonstrate the potential of this new tool to help guide the development of malaria vaccines with strain-transcending efficacy.

  7. The dynamics of malaria.

    PubMed

    Macdonald, G; Cuellar, C B; Foll, C V

    1968-01-01

    Previous studies on dynamic systems of transmission of malaria, and of eradication of infection following the interruption of transmission, have now been adapted for advanced techniques using the facilities offered by computers.The computer programmes have been designed for a deterministic model suitable for a large community and also for a stochastic model relevant to small populations in which infections reach very low finite numbers. In this model, new infections and recoveries are assessed by the daily inoculation rate and are subject to laws of chance. Such a representation is closer than previous models to natural happenings in the process of malaria eradication. Further refinements of the new approach include the seasonal transmission and simulation of mass chemotherapy aimed at a cure of P. falciparum infections.These programmes present models on which the actual or expected results of changes due to various factors can be studied by the analysis of specific malaria situations recorded in the field. The value of control methods can also be tested by the study of such hypothetical epidemiological models and by trying out various procedures.Two specific malaria situations (in a pilot project in Northern Nigeria and in an outbreak in Syria) were studied by this method and provided some interesting results of operational value. The attack measures in the pilot project in Northern Nigeria were carried out according to the theoretical model derived from the basic data obtained in the field. PMID:5303328

  8. Malaria Risk in Travelers

    PubMed Central

    Askling, Helena Hervius; Nilsson, Jenny; Tegnell, Anders; Janzon, Ragnhild

    2005-01-01

    Imported malaria has been an increasing problem in several Western countries in the last 2 decades. To calculate the risk factors of age, sex, and travel destination in Swedish travelers, we used data from the routine reporting system for malaria (mixture of patients with and without adequate prophylaxis), a database on travel patterns, and in-flight or visa data on Swedish travelers of 1997 to 2003. The crude risk for travelers varied from 1 per 100,000 travelers to Central America and the Caribbean to 357 per 100,000 in central Africa. Travelers to East Africa had the highest adjusted odds ratio (OR = 341; 95% confidence intervals [CI] 134–886) for being reported with malaria, closely followed by travelers to central Africa and West Africa. Male travelers as well as children <1–6 years of age had a higher risk of being reported with malaria (OR = 1,7; 95% CI 1.3–2.3 and OR = 4,8; 95%CI 1.5–14.8) than women and other age groups. PMID:15757560

  9. Vaccines for the 21st century

    PubMed Central

    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

  10. Vaccines for the 21st century.

    PubMed

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

    2014-05-06

    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.

  11. [Dengue vaccines].

    PubMed

    Morita, Kouichi

    2008-10-01

    Dengue is the most important mosquito borne virus infection in the tropics. Based on the effects of global warming, it is expected that dengue epidemic areas will further expand in the next decades unless effective and affordable vaccines are made available soon. At the moment, several vaccine developers have utilized live-attenuated live tetravalent vaccines and two of them have already completed phase two trials. However, the risk of antibody-dependent enhancement infection is not well elucidated and thus further and careful evaluation of the safety on proposed candidate vaccines are essential. At the moment, Bill and Melinda Gates Foundation strongly support the vaccine development through the Pediatric Dengue Vaccine Initiative.

  12. Protective CD8+ T cell responses against the pre-erythrocytic stages of malaria parasites: an overview.

    PubMed

    Oliveira-Ferreira, J; Daniel-Ribeiro, C

    2001-02-01

    CD8+ T cells have been implicated as critical effector cells in protection against the pre-erythrocytic stage of malaria in mice and humans following irradiated sporozoite immunization. Immunization experiments in animal models by several investigators have suggested different strategies for vaccination against malaria and many of the targets from liver stage malaria antigens have been shown to be immunogenic and to protect mice from the sporozoite challenge. Several prime/boost protocols with replicating vectors, such as vaccinia/influenza, with non-replicating vectors, such as recombinant particles derived from yeast transposon (Ty-particles) and modified vaccinia virus Ankara, and DNA, significantly enhanced CD8+ T cell immunogenicity and also the protective efficacy against the circumsporosoite protein of Plasmodium berghei and P. yeti. Based on these experimental results the development of a CD8+ T cell inducing vaccine has moved forward from epitope identification to planning stages of safety and immunogenicity trials of candidate vaccines.

  13. Nanomedicine against malaria.

    PubMed

    Urbán, Patricia; Fernàndez-Busquets, Xavier

    2014-01-01

    Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. Different types of encapsulating structure, targeting molecule, and antimalarial compound will be discussed for the assembly of Trojan horse nanocapsules capable of targeting with complete specificity diseased cells and of delivering inside them their antimalarial cargo with the objective of eliminating the parasite with a single dose. Nanotechnology can also be applied to the discovery of new antimalarials through single-molecule manipulation approaches for the identification of novel drugs targeting essential molecular components of the parasite. Finally, methods for the diagnosis of malaria can benefit from nanotools applied to the design of microfluidic-based devices for the accurate identification of the parasite's strain, its precise infective load, and the relative content of the different stages of its life cycle, whose knowledge is essential for the administration of adequate therapies. The benefits and drawbacks of these nanosystems will be considered in different possible scenarios, including cost-related issues that might be hampering the development of nanotechnology-based medicines against malaria with the dubious argument that they are too expensive to be used in developing areas.

  14. Advances in genetics and genomics: use and limitations in achieving malaria elimination goals

    PubMed Central

    Gunawardena, Sharmini; Karunaweera, Nadira D.

    2015-01-01

    Success of the global research agenda towards eradication of malaria will depend on the development of new tools, including drugs, vaccines, insecticides and diagnostics. Genetic and genomic information now available for the malaria parasites, their mosquito vectors and human host, can be harnessed to both develop these tools and monitor their effectiveness. Here we review and provide specific examples of current technological advances and how these genetic and genomic tools have increased our knowledge of host, parasite and vector biology in relation to malaria elimination and in turn enhanced the potential to reach that goal. We then discuss limitations of these tools and future prospects for the successful achievement of global malaria elimination goals. PMID:25943157

  15. Advances in genetics and genomics: use and limitations in achieving malaria elimination goals.

    PubMed

    Gunawardena, Sharmini; Karunaweera, Nadira D

    2015-05-01

    Success of the global research agenda towards eradication of malaria will depend on the development of new tools, including drugs, vaccines, insecticides and diagnostics. Genetic and genomic information now available for the malaria parasites, their mosquito vectors and human host, can be harnessed to both develop these tools and monitor their effectiveness. Here we review and provide specific examples of current technological advances and how these genetic and genomic tools have increased our knowledge of host, parasite and vector biology in relation to malaria elimination and in turn enhanced the potential to reach that goal. We then discuss limitations of these tools and future prospects for the successful achievement of global malaria elimination goals.

  16. Use of Integrated Malaria Management Reduces Malaria in Kenya

    PubMed Central

    Okech, Bernard A.; Mwobobia, Isaac K.; Kamau, Anthony; Muiruri, Samuel; Mutiso, Noah; Nyambura, Joyce; Mwatele, Cassian; Amano, Teruaki; Mwandawiro, Charles S.

    2008-01-01

    Background During an entomological survey in preparation for malaria control interventions in Mwea division, the number of malaria cases at the Kimbimbi sub-district hospital was in a steady decline. The underlying factors for this reduction were unknown and needed to be identified before any malaria intervention tools were deployed in the area. We therefore set out to investigate the potential factors that could have contributed to the decline of malaria cases in the hospital by analyzing the malaria control knowledge, attitudes and practices (KAP) that the residents in Mwea applied in an integrated fashion, also known as integrated malaria management (IMM). Methods Integrated Malaria Management was assessed among community members of Mwea division, central Kenya using KAP survey. The KAP study evaluated community members' malaria disease management practices at the home and hospitals, personal protection measures used at the household level and malaria transmission prevention methods relating to vector control. Concurrently, we also passively examined the prevalence of malaria parasite infection via outpatient admission records at the major referral hospital in the area. In addition we studied the mosquito vector population dynamics, the malaria sporozoite infection status and entomological inoculation rates (EIR) over an 8 month period in 6 villages to determine the risk of malaria transmission in the entire division. Results A total of 389 households in Mwea division were interviewed in the KAP study while 90 houses were surveyed in the entomological study. Ninety eight percent of the households knew about malaria disease while approximately 70% of households knew its symptoms and methods to manage it. Ninety seven percent of the interviewed households went to a health center for malaria diagnosis and treatment. Similarly a higher proportion (81%) used anti-malarial medicines bought from local pharmacies. Almost 90% of households reported owning and using an

  17. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function.

    PubMed

    Portugal, Silvia; Tipton, Christopher M; Sohn, Haewon; Kone, Younoussou; Wang, Jing; Li, Shanping; Skinner, Jeff; Virtaneva, Kimmo; Sturdevant, Daniel E; Porcella, Stephen F; Doumbo, Ogobara K; Doumbo, Safiatou; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Sanz, Inaki; Pierce, Susan K; Crompton, Peter D

    2015-05-08

    Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity.

  18. Computational Study of Quinolone Derivatives to Improve their Therapeutic Index as Anti-malaria Agents: QSAR and QSTR

    PubMed Central

    Iman, Maryam; Davood, Asghar; Khamesipour, Ali

    2015-01-01

    Malaria is a parasitic disease caused by five different species of Plasmodium. More than 40% of the world’s population is at risk and malaria annual incidence is estimated to be more than two hundred million, malaria is one of the most important public health problems especially in children of the poorest parts of the world, annual mortality is about 1 million. The epidemiological status of the disease justifies to search for control measures, new therapeutic options and development of an effective vaccine. Chemotherapy options in malaria are limited, moreover, drug resistant rate is high. In spite of global efforts to develop an effective vaccine yet there is no vaccine available. In the current study, a series of quinolone derivatives were subjected to quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR) analyses to identify the ideal physicochemical characteristics of potential anti-malaria activity and less cytotoxicity. Quinolone with desirable properties was built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Multi linear regression (MLR) was used as a chemo metric tool for quantitative structure activity relationship modeling and the developed models were shown to be statistically significant according to the validation parameters. The obtained QSAR model reveals that the descriptors PJI2, Mv, PCR, nBM, and VAR mainly affect the anti-malaria activity and descriptors MSD, MAXDP, and X1sol affect the cytotoxicity of the series of ligands. PMID:26330866

  19. Malaria on the move: human population movement and malaria transmission.

    PubMed Central

    Martens, P.; Hall, L.

    2000-01-01

    Reports of malaria are increasing in many countries and in areas thought free of the disease. One of the factors contributing to the reemergence of malaria is human migration. People move for a number of reasons, including environmental deterioration, economic necessity, conflicts, and natural disasters. These factors are most likely to affect the poor, many of whom live in or near malarious areas. Identifying and understanding the influence of these population movements can improve prevention measures and malaria control programs. PMID:10756143

  20. Sustainable development of a GCP-compliant clinical trials platform in Africa: the Malaria Clinical Trials Alliance perspective

    PubMed Central

    2010-01-01

    Background The Malaria Clinical Trials Alliance (MCTA), a programme of INDEPTH network of demographic surveillance centres, was launched in 2006 with two broad objectives: to facilitate the timely development of a network of centres in Africa with the capacity to conduct clinical trials of malaria vaccines and drugs under conditions of good clinical practice (GCP); and to support, strengthen and mentor the centres in the network to facilitate their progression towards self-sustaining clinical research centres. Case description Sixteen research centres in 10 African malaria-endemic countries were selected that were already working with the Malaria Vaccine Initiative (MVI) or the Medicines for Malaria Venture (MMV). All centres were visited to assess their requirements for research capacity development through infrastructure strengthening and training. Support provided by MCTA included: laboratory and facility refurbishment; workshops on GCP, malaria diagnosis, strategic management and media training; and training to support staff to undertake accreditation examinations of the Association of Clinical Research Professionals (ACRP). Short attachments to other network centres were also supported to facilitate sharing practices within the Alliance. MCTA also played a key role in the creation of the African Media & Malaria Research Network (AMMREN), which aims to promote interaction between researchers and the media for appropriate publicity and media reporting of research and developments on malaria, including drug and vaccine trials. Conclusion In three years, MCTA strengthened 13 centres to perform GCP-compliant drug and vaccine trials, including 11 centres that form the backbone of a large phase III malaria vaccine trial. MCTA activities have demonstrated that centres can be brought up to GCP compliance on this time scale, but the costs are substantial and there is a need for further support of other centres to meet the growing demand for clinical trial capacity. The

  1. Commitment of Roche in malaria and other tropical diseases.

    PubMed

    Stürchler, D; Mittelholzer, M L; Handschin, J

    1993-09-01

    In the absence of a suitable malaria case definition, reliable surveillance data on the impact of malaria are not available. Determinants of case loads, including population movements, environmental changes, lack of political commitment and resources, and resistance to antimalarials and residual insecticides, work towards global deterioration. Some 90% of the Plasmodium falciparum burden is carried by Africa south of the Sahara. There, in 1992, the number of children under five years of age and exposed to high risk was about 106 million. Assuming a malaria attack rate of 0.5-1.5 per child per year, and a case fatality rate of 2%, annual clinical cases and malaria deaths in this population alone come to 53-160 million and 1-3 million, respectively. Roche, a pharmaceutical company with major research efforts in tropical medicine, in collaboration with research centers and international institutions, has recently set up a tropical medicine unit that coordinates and concentrates corporate efforts in this field. The unit aims to make affordable and innovative products available which are effective against major tropical diseases. A commercial product of the unit is Lariam, a major antimalarial used alone or in simultaneous or sequential combinations. The single dose combination of Lariam plus Fansidar (Fansimef) is particularly useful for stand-by or emergency oral therapy. Artemisinine, or its derivatives, followed by one to two doses of Lariam are effective against severe and multiresistant P. falciparum malaria. A new Roche peroxide antimalarial is currently in phase II clinical trials. The unit is also involved in research and development of malaria sporozoite and asexual blood stage vaccine candidates.

  2. The distinctive features of Indian malaria parasites.

    PubMed

    Das, Aparup

    2015-03-01

    Malaria and factors driving malaria are heterogeneous in India, unlike in other countries, and the epidemiology of malaria therefore is considered 'highly complex'. This complexity is primarily attributed to several unique features of the malaria parasites, mosquito vectors, malaria-susceptible populations, and ecoclimatic variables in India. Recent research on the genetic epidemiology of Indian malaria parasites has been successful in partly unraveling the mysteries underlying these complexities.

  3. Vaccines (immunizations) - overview

    MedlinePlus

    ... mumps, and rubella (MMR) vaccine and the varicella (chickenpox) vaccine are examples. Killed (inactivated) vaccines are made from ... countries. Some countries require this record. COMMON VACCINES ... DTaP immunization (vaccine) Hepatitis A vaccine Hepatitis B ...

  4. [Place of malaria among febrile illnesses in two ethnic tribes living in sympatry in Mali from 1998 to 2008].

    PubMed

    Dolo, A; Maïga, B; Dara, V; Tapily, A; Tolo, Y; Arama, C; Daou, M; Doumbo, O

    2012-12-01

    In Africa, malaria is responsible for 25-40% of all outpatient visits and 20-50% of all hospitalizations. In malaria-endemic areas, individuals do not behave the same toward the outcome of clinical malaria. The aim of this study is to determine the prevalence of malaria in the locality among the different ethnic groups, evaluate the place of malaria among febrile illnesses, and assess the relationship between fever and parasite density of Plasmodium falciparum. Studies on susceptibility to malaria between the Fulani and Dogon groups in Mali were conducted in Mantéourou and the surrounding villages from 1998 to 2008. We carried out six cross-sectional studies during the malaria transmission and longitudinal surveys (July to December depending on the year) during the 10-year duration. In longitudinal studies, clinical data on malaria and other diseases frequently observed in the population were recorded. It appears from this work that malaria is the leading cause of febrile syndromes. We observed a significant reduction in malaria morbidity in the study population from 1998 to 2008. The pyrogenic threshold of parasitaemia was 1,000 parasites/mm(3) of blood in the Dogon and 5,000 parasites/mm(3) of blood in the Fulani.We have also found that high parasitical densities were not always associated with fever. Malaria morbidity was higher among the Dogon than in Fulani. The immunogenetic factors might account for this difference in susceptibility to malaria between Fulani and Dogon in the area under study. With regard to this study, it is important to take into account the ethnic origin of subjects when interpreting data of clinical and malarial vaccine trials.

  5. Diphtheria Vaccination

    MedlinePlus

    ... and adults - Tetanus-diphtheria-acellular Pertussis vaccine Diphtheria Vaccination Pronounced (dif-THEER-ee-a) Recommend on Facebook ... Related Pages Pertussis Tetanus Feature Story: Adults Need Immunizations, Too Abbreviations DTaP=Pediatric - Diphtheria-Tetanus-acellular Pertussis ...

  6. Rapid diagnostic tests for malaria.

    PubMed

    Visser, Theodoor; Daily, Jennifer; Hotte, Nora; Dolkart, Caitlin; Cunningham, Jane; Yadav, Prashant

    2015-12-01

    Maintaining quality, competitiveness and innovation in global health technology is a constant challenge for manufacturers, while affordability, access and equity are challenges for governments and international agencies. In this paper we discuss these issues with reference to rapid diagnostic tests for malaria. Strategies to control and eliminate malaria depend on early and accurate diagnosis. Rapid diagnostic tests for malaria require little training and equipment and can be performed by non-specialists in remote settings. Use of these tests has expanded significantly over the last few years, following recommendations to test all suspected malaria cases before treatment and the implementation of an evaluation programme to assess the performance of the malaria rapid diagnostic tests. Despite these gains, challenges exist that, if not addressed, could jeopardize the progress made to date. We discuss recent developments in rapid diagnostic tests for malaria, highlight some of the challenges and provide suggestions to address them.

  7. Rapid diagnostic tests for malaria

    PubMed Central

    Daily, Jennifer; Hotte, Nora; Dolkart, Caitlin; Cunningham, Jane; Yadav, Prashant

    2015-01-01

    Abstract Maintaining quality, competitiveness and innovation in global health technology is a constant challenge for manufacturers, while affordability, access and equity are challenges for governments and international agencies. In this paper we discuss these issues with reference to rapid diagnostic tests for malaria. Strategies to control and eliminate malaria depend on early and accurate diagnosis. Rapid diagnostic tests for malaria require little training and equipment and can be performed by non-specialists in remote settings. Use of these tests has expanded significantly over the last few years, following recommendations to test all suspected malaria cases before treatment and the implementation of an evaluation programme to assess the performance of the malaria rapid diagnostic tests. Despite these gains, challenges exist that, if not addressed, could jeopardize the progress made to date. We discuss recent developments in rapid diagnostic tests for malaria, highlight some of the challenges and provide suggestions to address them. PMID:26668438

  8. Recent advances in malaria genomics and epigenomics.

    PubMed

    Kirchner, Sebastian; Power, B Joanne; Waters, Andrew P

    2016-01-01

    Malaria continues to impose a significant disease burden on low- and middle-income countries in the tropics. However, revolutionary progress over the last 3 years in nucleic acid sequencing, reverse genetics, and post-genome analyses has generated step changes in our understanding of malaria parasite (Plasmodium spp.) biology and its interactions with its host and vector. Driven by the availability of vast amounts of genome sequence data from Plasmodium species strains, relevant human populations of different ethnicities, and mosquito vectors, researchers can consider any biological component of the malarial process in isolation or in the interactive setting that is infection. In particular, considerable progress has been made in the area of population genomics, with Plasmodium falciparum serving as a highly relevant model. Such studies have demonstrated that genome evolution under strong selective pressure can be detected. These data, combined with reverse genetics, have enabled the identification of the region of the P. falciparum genome that is under selective pressure and the confirmation of the functionality of the mutations in the kelch13 gene that accompany resistance to the major frontline antimalarial, artemisinin. Furthermore, the central role of epigenetic regulation of gene expression and antigenic variation and developmental fate in P. falciparum is becoming ever clearer. This review summarizes recent exciting discoveries that genome technologies have enabled in malaria research and highlights some of their applications to healthcare. The knowledge gained will help to develop surveillance approaches for the emergence or spread of drug resistance and to identify new targets for the development of antimalarial drugs and perhaps vaccines. PMID:27605022

  9. Advances in molecular genetic systems in malaria.

    PubMed

    de Koning-Ward, Tania F; Gilson, Paul R; Crabb, Brendan S

    2015-06-01

    Robust tools for analysing gene function in Plasmodium parasites, which are the causative agents of malaria, are being developed at an accelerating rate. Two decades after genetic technologies for use in Plasmodium spp. were first described, a range of genetic tools are now available. These include conditional systems that can regulate gene expression at the genome, transcriptional or protein level, as well as more sophisticated tools for gene editing that use piggyBac transposases, integrases, zinc-finger nucleases or the CRISPR-Cas9 system. In this Review, we discuss the molecular genetic systems that are currently available for use in Plasmodium falciparum and Plasmodium berghei, and evaluate the advantages and limitations of these tools. We examine the insights that have been gained into the function of genes that are important during the blood stages of the parasites, which may help to guide the development and improvement of drug therapies and vaccines.

  10. Concurrent meningitis and vivax malaria

    PubMed Central

    Santra, Tuhin; Datta, Sumana; Agrawal, Neha; Bar, Mita; Kar, Arnab; Adhikary, Apu; Ranjan, Kunal

    2015-01-01

    Malaria is an endemic infectious disease in India. It is often associated with other infective conditions but concomitant infection of malaria and meningitis are uncommon. We present a case of meningitis with vivax malaria infection in a 24-year-old lady. This case emphasizes the importance of high index of clinical suspicion to detect other infective conditions like meningitis when fever does not improve even after anti-malarial treatment in a patient of malaria before switching therapy suspecting drug resistance, which is quite common in this part of world. PMID:26985423

  11. Malaria elimination: surveillance and response

    PubMed Central

    Bridges, Daniel J; Winters, Anna M; Hamer, Davidson H

    2012-01-01

    In the last decade, substantial progress has been made in reducing malaria-associated morbidity and mortality across the globe. Nevertheless, sustained malaria control is essential to continue this downward trend. In some countries, where aggressive malaria control has reduced malaria to a low burden level, elimination, either nationally or subnationally, is now the aim. As countries or areas with a low malaria burden move towards elimination, there is a transition away from programs of universal coverage towards a strategy of localized detection and response to individual malaria cases. To do so and succeed, it is imperative that a strong surveillance and response system is supported, that community cadres are trained to provide appropriate diagnostics and treatment, and that field diagnostics are further developed such that their sensitivity allows for the detection and subsequent treatment of malaria reservoirs in low prevalence environments. To be certain, there are big challenges on the road to elimination, notably the development of drug and insecticide resistance. Nevertheless, countries like Zambia are making great strides towards implementing systems that support malaria elimination in target areas. Continued development of new diagnostics and antimalarial therapies is needed to support progress in malaria control and elimination. PMID:23265423

  12. Gut Microbiota Elicits a Protective Immune Response against Malaria Transmission

    PubMed Central

    Yilmaz, Bahtiyar; Portugal, Silvia; Tran, Tuan M.; Gozzelino, Raffaella; Ramos, Susana; Gomes, Joana; Regalado, Ana; Cowan, Peter J.; d’Apice, Anthony J.F.; Chong, Anita S.; Doumbo, Ogobara K.; Traore, Boubacar; Crompton, Peter D.; Silveira, Henrique; Soares, Miguel P.

    2014-01-01

    Summary Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans. PaperFlick PMID:25480293

  13. Who Needs Chickenpox Vaccine

    MedlinePlus

    ... Not Get Chickenpox Vaccine Types of Chickenpox Vaccine Child and Adult Immunization Schedules Possible Side Effects of Chickenpox Vaccine Childcare and School Vaccine Requirements Also Known As & Abbreviations ...

  14. Platform for Plasmodium vivax vaccine discovery and development.

    PubMed

    Valencia, Sócrates Herrera; Rodríguez, Diana Carolina; Acero, Diana Lucía; Ocampo, Vanessa; Arévalo-Herrera, Myriam

    2011-08-01

    Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80-100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development.

  15. Platform for Plasmodium vivax vaccine discovery and development

    PubMed Central

    Valencia/, Sócrates Herrera; Rodríguez, Diana Carolina; Acero, Diana Lucía; Ocampo, Vanessa; Arévalo-Herrera, Myriam

    2016-01-01

    Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80–100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development. PMID:21881773

  16. Malaria control in Tanzania

    SciTech Connect

    Yhdego, M.; Majura, P. )

    1988-01-01

    A review of the malaria control programs and the problem encountered in the United Republic of Tanzania since 1945 to the year 1986 is discussed. Buguruni, one of the squatter areas in the city of Dar es Salaam, is chosen as a case study in order to evaluate the economic advantage of engineering methods for the control of malaria infection. Although the initial capital cost of engineering methods may be high, the cost effectiveness requires a much lower financial burden of only about Tshs. 3 million compared with the conventional methods of larviciding and insecticiding which requires more than Tshs. 10 million. Finally, recommendations for the adoption of engineering methods are made concerning the upgrading of existing roads and footpaths in general with particular emphasis on drainage of large pools of water which serve as breeding sites for mosquitoes.

  17. Pathogenesis of malaria revisited.

    PubMed

    Dasari, Prasad; Bhakdi, Sucharit

    2012-11-01

    Plasmodium falciparum malaria claims 1 million lives around the globe every year. Parasitemia can reach remarkably high levels. The developing parasite digests hemoglobin and converts the waste product to hemozoin alias malaria pigment. These processes occur in a vesicular compartment named the digestive vacuole (DV). Each parasitized cell releases one DV upon rupture. Myriads of DVs thus gain entry into the blood, but whether they trigger pathobiological events has never been investigated. We recently discovered that the DV membrane simultaneously activates the two major enzyme cascades in blood, complement and coagulation. Activation of both is known to occur in patients with severe malaria, so discovery of the common trigger has large consequences. The DV membrane but not the merozoite has the capacity to spontaneously activate the alternative complement and intrinsic clotting pathway. Ejection of merozoites and the DV into the bloodstream, therefore, results in selective opsonization and phagocytosis of the DV, leaving merozoites free to invade new cells. The DV membrane furthermore has the capacity to assemble prothrombinase, the key convertase of the intrinsic clotting pathway. The dual capacity of the DV to activate both complement and coagulation can be suppressed by low-molecular-weight dextran sulfate. This agent protects experimental animals from the detrimental consequences, resulting from intravenous application of purified DVs. Phagocytosis of DVs not only deploys PMN away from merozoites, but also drives the cells into a state of functional exhaustion. This may be one reason for the enhanced susceptibility of patients with severe malaria toward systemic bacterial infections. Together, these findings indicate that the DV may represent a hitherto unrecognized, important determinant of parasite pathogenicity.

  18. Oxidative Stress in Malaria

    PubMed Central

    Percário, Sandro; Moreira, Danilo R.; Gomes, Bruno A. Q.; Ferreira, Michelli E. S.; Gonçalves, Ana Carolina M.; Laurindo, Paula S. O. C.; Vilhena, Thyago C.; Dolabela, Maria F.; Green, Michael D.

    2012-01-01

    Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise. In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy. PMID:23208374

  19. Local innate immune responses in the vaccine adjuvant-injected muscle

    PubMed Central

    Liang, Frank; Loré, Karin

    2016-01-01

    Inducing a high magnitude of antibodies, possibly in combination with T-cell responses that offer epitope breadth over prolonged periods of time is likely a prerequisite for effective vaccines against severe diseases such as HIV-1 infection, malaria and tuberculosis. A much better understanding of the innate immune mechanisms that are critical for inducing desired responses to vaccination would help in the design of novel vaccines. The majority of human vaccines are administered into the muscle. In this brief review, we focus on the initial innate immune events that occur locally at the site of intramuscular vaccine delivery, and how they are influenced by clinically approved vaccine adjuvants. In particular, the effects on cell mobilization, cell activation and vaccine antigen uptake are reviewed. Understanding how distinct adjuvants enhance and tailor vaccine responses would facilitate the selection of the best-suited adjuvant to improve vaccine efficacy to a given pathogen. PMID:27195117

  20. One more shot for the road: a review and update of vaccinations for pediatric international travelers.

    PubMed

    Rebaza, Andre; Lee, Paul J

    2015-04-01

    Increasing numbers of children are traveling to developing countries where they are often at a higher risk than adults of acquiring vaccine-preventable diseases. Yet, they are less likely to receive pretravel medical advice and preventive care. This article reviews the current recommendations for pediatric travel immunizations, including specific travel vaccines such as typhoid, yellow fever, Japanese encephalitis virus, and rabies as well as prospective vaccines for significant global diseases like malaria, dengue, chikungunya, and Ebola. PMID:25875985

  1. [Malaria in hominids].

    PubMed

    Snounou, Georges; Escalante, Ananias; Kasenene, John; Rénia, Laurent; Grüner, Anne-Charlotte; Krief, Sabrina

    2011-11-01

    Malaria parasites (Plasmodium spp) that infect great apes are very poorly documented Malaria was first described in gorillas, chimpanzees and orangutans in the early 20th century, but most studies were confined to a handful of chimpanzees in the 1930-1950s and a few orangutans in the 1970s. The three Plasmodium species described in African great apes were very similar to those infecting humans. The most extensively studied was P reichenowi, because of its close phylogenetic relation to P. falciparum, the predominant parasite in Africa and the most dangerous for humans. In the last three years, independent molecular studies of various chimpanzee and gorilla populations have revealed an unexpected diversity in the Plasmodium species they harbor, which are also phylogenetically close to P falciparum. In addition, cases of non human primate infection by human malaria parasites have been observed. These observations shed fresh light on the origin and evolutionary history of P. falciparum and provide a unique opportunity to probe the biological specificities of this major human parasite.

  2. Artemether for severe malaria

    PubMed Central

    Esu, Ekpereonne; Effa, Emmanuel E; Opie, Oko N; Uwaoma, Amirahobu; Meremikwu, Martin M

    2014-01-01

    Background In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation, many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. This review evaluates intramuscular artemether compared with both quinine and artesunate. Objectives To assess the efficacy and safety of intramuscular artemether versus any other parenteral medication in treating severe malaria in adults and children. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS, ISI Web of Science, conference proceedings and reference lists of articles. We also searched the WHO clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 9 April 2014. Selection criteria Randomized controlled trials (RCTs) comparing intramuscular artemether with intravenous or intramuscular antimalarial for treating severe malaria. Data collection and analysis The primary outcome was all-cause death.Two authors independently assessed trial eligibility, risk of bias and extracted data. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), and presented both measures with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses and assessed the quality of the evidence using the GRADE approach. Main results We included 18 RCTs, enrolling 2662 adults and children with severe malaria, carried out in Africa (11) and in Asia (7). Artemether versus quinine For children in Africa, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.96, 95% CI 0.76 to 1.20; 12 trials, 1447 participants, moderate quality evidence). Coma recovery may be about five hours shorter with

  3. DNA vaccines

    NASA Astrophysics Data System (ADS)

    Gregersen, Jens-Peter

    2001-12-01

    Immunization by genes encoding immunogens, rather than with the immunogen itself, has opened up new possibilities for vaccine research and development and offers chances for new applications and indications for future vaccines. The underlying mechanisms of antigen processing, immune presentation and regulation of immune responses raise high expectations for new and more effective prophylactic or therapeutic vaccines, particularly for vaccines against chronic or persistent infectious diseases and tumors. Our current knowledge and experience of DNA vaccination is summarized and critically reviewed with particular attention to basic immunological mechanisms, the construction of plasmids, screening for protective immunogens to be encoded by these plasmids, modes of application, pharmacokinetics, safety and immunotoxicological aspects. DNA vaccines have the potential to accelerate the research phase of new vaccines and to improve the chances of success, since finding new immunogens with the desired properties is at least technically less demanding than for conventional vaccines. However, on the way to innovative vaccine products, several hurdles have to be overcome. The efficacy of DNA vaccines in humans appears to be much less than indicated by early studies in mice. Open questions remain concerning the persistence and distribution of inoculated plasmid DNA in vivo, its potential to express antigens inappropriately, or the potentially deleterious ability to insert genes into the host cell's genome. Furthermore, the possibility of inducing immunotolerance or autoimmune diseases also needs to be investigated more thoroughly, in order to arrive at a well-founded consensus, which justifies the widespread application of DNA vaccines in a healthy population.

  4. Cross-border malaria: a major obstacle for malaria elimination.

    PubMed

    Wangdi, Kinley; Gatton, Michelle L; Kelly, Gerard C; Clements, Archie C A

    2015-06-01

    Movement of malaria across international borders poses a major obstacle to achieving malaria elimination in the 34 countries that have committed to this goal. In border areas, malaria prevalence is often higher than in other areas due to lower access to health services, treatment-seeking behaviour of marginalized populations that typically inhabit border areas, difficulties in deploying prevention programmes to hard-to-reach communities, often in difficult terrain, and constant movement of people across porous national boundaries. Malaria elimination in border areas will be challenging and key to addressing the challenges is strengthening of surveillance activities for rapid identification of any importation or reintroduction of malaria. This could involve taking advantage of technological advances, such as spatial decision support systems, which can be deployed to assist programme managers to carry out preventive and reactive measures, and mobile phone technology, which can be used to capture the movement of people in the border areas and likely sources of malaria importation. Additionally, joint collaboration in the prevention and control of cross-border malaria by neighbouring countries, and reinforcement of early diagnosis and prompt treatment are ways forward in addressing the problem of cross-border malaria.

  5. Clinical development of intramuscular electroporation: providing a "boost" for DNA vaccines.

    PubMed

    Khan, Amir S; Broderick, Kate E; Sardesai, Niranjan Y

    2014-01-01

    The development of effective vaccines has helped to eradicate or control the spread of numerous infectious diseases. However, there are many more diseases that have proved more difficult to eliminate using conventional vaccines. The recent innovation of DNA vaccines may provide a "boost" to the development efforts. While the early efforts of DNA vaccines in the clinic were disappointing, the use of in vivo electroporation has helped to provide some basis for optimism. Now, there are several ongoing clinical studies of vaccines against such diseases as malaria, HIV, hepatitis C, and even various types of cancer. This review will highlight three recently published clinical studies using intramuscular DNA administration with electroporation.

  6. Highly active ozonides selected against drug resistant malaria

    PubMed Central

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  7. Immunity to malaria in an era of declining malaria transmission.

    PubMed

    Fowkes, Freya J I; Boeuf, Philippe; Beeson, James G

    2016-02-01

    With increasing malaria control and goals of malaria elimination, many endemic areas are transitioning from high-to-low-to-no malaria transmission. Reductions in transmission will impact on the development of naturally acquired immunity to malaria, which develops after repeated exposure to Plasmodium spp. However, it is currently unclear how declining transmission and malaria exposure will affect the development and maintenance of naturally acquired immunity. Here we review the key processes which underpin this knowledge; the amount of Plasmodium spp. exposure required to generate effective immune responses, the longevity of antibody responses and the ability to mount an effective response upon re-exposure through memory responses. Lastly we identify research priorities which will increase our understanding of how changing transmission will impact on malarial immunity.

  8. Malaria risk perception, knowledge and prophylaxis practices among travellers of African ethnicity living in Paris and visiting their country of origin in sub-Saharan Africa.

    PubMed

    Pistone, T; Guibert, P; Gay, F; Malvy, D; Ezzedine, K; Receveur, M C; Siriwardana, M; Larouzé, B; Bouchaud, O

    2007-10-01

    An observational prospective cohort study assessed malaria risk perception, knowledge and prophylaxis practices among individuals of African ethnicity living in Paris and travelling to their country of origin to visit friends or relatives (VFR). The study compared two groups of VFR who had visited a travel clinic (TC; n=122) or a travel agency (TA; n=69) before departure. Of the 47% of VFR citing malaria as a health concern, 75% knew that malaria is mosquito-borne and that bed nets are an effective preventive measure. Perception of high malaria risk was greater in the TA group (33%) than in the TC group (7%). The availability of a malaria vaccine was mentioned by 35% of VFR, with frequent confusion between yellow fever vaccine and malaria prevention. Twenty-nine percent took adequate chemoprophylaxis with complete adherence, which was higher among the TC group (41%) than the TA group (12%). Effective antivector protection measures used were bed nets (16%), wearing long clothes at night (14%) and air conditioning (8%), with no differences between the study groups except in the use of impregnated bed nets (11% of the TC group and none of the TA group). Media coverage, malaria chemoprophylaxis repayment and cultural adaptation of preventive messages should be improved to reduce the high rate of inadequate malaria prophylaxis in VFR.

  9. Hepatitis Vaccines

    PubMed Central

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

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

  10. Using rainfall estimates to predict malaria transmission

    NASA Astrophysics Data System (ADS)

    Tretkoff, Ernie

    2011-05-01

    Malaria kills nearly a million people each year, mostly in rural Africa. The disease is spread by mosquitoes, which thrive in wet areas, so malaria transmission is closely linked to rainfall. Rainfall estimates could therefore be used to help predict potential malaria transmission. However, rain gauge networks are sparse in many of the rural areas that are hit hardest by malaria.

  11. Large-scale growth of the Plasmodium falciparum malaria parasite in a wave bioreactor.

    PubMed

    Dalton, John P; Demanga, Corine G; Reiling, Sarah J; Wunderlich, Juliane; Eng, Jenny W L; Rohrbach, Petra

    2012-01-01

    We describe methods for the large-scale in vitro culturing of synchronous and asynchronous blood-stage Plasmodium falciparum parasites in sterile disposable plastic bioreactors controlled by wave-induced motion (wave bioreactor). These cultures perform better than static flask cultures in terms of preserving parasite cell cycle synchronicity and reducing the number of multiple-infected erythrocytes. The straight-forward methods described here will facilitate the large scale production of malaria parasites for antigen and organelle isolation and characterisation, for the high throughput screening of compound libraries with whole cells or extracts, and the development of live- or whole-cell malaria vaccines under good manufacturing practice compliant standards.

  12. Economics of Malaria Prevention in US Travelers to West Africa

    PubMed Central

    Adachi, Kenji; Coleman, Margaret S.; Khan, Nomana; Jentes, Emily S.; Arguin, Paul; Rao, Sowmya R.; LaRocque, Regina C.; Sotir, Mark J.; Brunette, Gary; Ryan, Edward T.; Meltzer, Martin I.

    2014-01-01

    Background. Pretravel health consultations help international travelers manage travel-related illness risks through education, vaccination, and medication. This study evaluated costs and benefits of that portion of the health consultation associated with malaria prevention provided to US travelers bound for West Africa. Methods. The estimated change in disease risk and associated costs and benefits resulting from traveler adherence to malaria chemoprophylaxis were calculated from 2 perspectives: the healthcare payer's and the traveler's. We used data from the Global TravEpiNet network of US travel clinics that collect de-identified pretravel data for international travelers. Disease risk and chemoprophylaxis effectiveness were estimated from published medical reports. Direct medical costs were obtained from the Nationwide Inpatient Sample and published literature. Results. We analyzed 1029 records from January 2009 to January 2011. Assuming full adherence to chemoprophylaxis regimens, consultations saved healthcare payers a per-traveler average of $14 (9-day trip) to $372 (30-day trip). For travelers, consultations resulted in a range of net cost of $20 (9-day trip) to a net savings of $32 (30-day trip). Differences were mostly driven by risk of malaria in the destination country. Conclusions. Our model suggests that healthcare payers save money for short- and longer-term trips, and that travelers save money for longer trips when travelers adhere to malaria recommendations and prophylactic regimens in West Africa. This is a potential incentive to healthcare payers to offer consistent pretravel preventive care to travelers. This financial benefit complements the medical benefit of reducing the risk of malaria. PMID:24014735

  13. Meningococcal Vaccinations.

    PubMed

    Crum-Cianflone, Nancy; Sullivan, Eva

    2016-06-01

    Neisseria meningitidis, a gram-negative diplococcal bacterium, is a common asymptomatic nasopharyngeal colonizer that may infrequently lead to invasive disease in the form of meningitis or bacteremia. Six serogroups (A, B, C, W, X and Y) are responsible for the majority of invasive infections. Increased risk of disease occurs in specific population groups including infants, adolescents, those with asplenia or complement deficiencies, and those residing in crowded living conditions such as in college dormitories. The incidence of invasive meningococcal disease varies geographically with some countries (e.g., in the African meningitis belt) having both high endemic disease rates and ongoing epidemics, with annual rates reaching 1000 cases per 100,000 persons. Given the significant morbidity and mortality associated with meningococcal disease, it remains a major global health threat best prevented by vaccination. Several countries have implemented vaccination programs with the selection of specific vaccine(s) based on locally prevalent serogroup(s) of N. meningitidis and targeting population groups at highest risk. Polysaccharide meningococcal vaccines became available over 40 years ago, but are limited by their inability to produce immunologic memory responses, poor immunogenicity in infants/children, hyporesponsiveness after repeated doses, and lack of efficacy against nasopharyngeal carriage. In 1999, the first meningococcal conjugate vaccines were introduced and have been successful in overcoming many of the shortcomings of polysaccharide vaccines. The implementation of meningococcal conjugate vaccination programs in many areas of the world (including the massive campaign in sub-Saharan Africa using a serogroup A conjugate vaccine) has led to dramatic reductions in the incidence of meningococcal disease by both individual and population protection. Progressive advances in vaccinology have led to the recent licensure of two effective vaccines against serogroup B

  14. Varicella (Chickenpox) Vaccine

    MedlinePlus

    ... product containing Measles Vaccine, Mumps Vaccine, Rubella Vaccine, Varicella Vaccine) ... Why get vaccinated?Chickenpox (also called varicella) is a common childhood disease. It is usually mild, but it can be serious, especially in ...

  15. Vaccine Adverse Events

    MedlinePlus

    ... Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Vaccines, Blood & Biologics Home Vaccines, Blood & Biologics Safety & Availability ( ... Center for Biologics Evaluation & Research Vaccine Adverse Events Vaccine Adverse Events Share Tweet Linkedin Pin it More ...

  16. Serological testing in malaria*

    PubMed Central

    1974-01-01

    The main purpose of this paper is to evaluate, in a critical manner, various serological tests with general emphasis on their value in the epidemiological assessment of malaria. Several tests have been employed in the past. However, the present memorandum will deal only with the methods that have been widely used recently—i.e., indirect immunofluorescence (IFA), passive haemagglutination (IHA), and gel-diffusion. The three immunoglobulins most commonly involved in these tests are IgG, IgM, and—to a lesser extent—IgA. PMID:4218506

  17. [Fake malaria drugs].

    PubMed

    Bygbjerg, Ib Christian

    2009-03-01

    The literature on fake medicaments is sparse, even if approximately 15% of all medicaments are fake, a figure that for antimalarials in particular reaches 50% in parts of Africa and Asia. Sub-standard and fake medicines deplete the public's confidence in health systems, health professionals and in the pharmaceutical industry - and increase the risk that resistance develops. For a traveller coming from a rich Western country, choosing to buy e.g. preventive antimalarials over the internet or in poor malaria-endemic areas, the consequences may be fatal. International trade-, control- and police-collaboration is needed to manage the problem, as is the fight against poverty and poor governance.

  18. Bioorganometallic Chemistry and Malaria

    NASA Astrophysics Data System (ADS)

    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.

  19. Backward bifurcation and optimal control of Plasmodium Knowlesi malaria

    NASA Astrophysics Data System (ADS)

    Abdullahi, Mohammed Baba; Hasan, Yahya Abu; Abdullah, Farah Aini

    2014-07-01

    A deterministic model for the transmission dynamics of Plasmodium Knowlesi malaria with direct transmission is developed. The model is analyzed using dynamical system techniques and it shows that the backward bifurcation occurs for some range of parameters. The model is extended to assess the impact of time dependent preventive (biological and chemical control) against the mosquitoes and vaccination for susceptible humans, while treatment for infected humans. The existence of optimal control is established analytically by the use of optimal control theory. Numerical simulations of the problem, suggest that applying the four control measure can effectively reduce if not eliminate the spread of Plasmodium Knowlesi in a community.

  20. Vaccination Using Gene-Gun Technology.

    PubMed

    Bergmann-Leitner, Elke S; Leitner, Wolfgang W

    2015-01-01

    DNA vaccines against infection with Plasmodium have been highly successful in rodent models of malaria and have shown promise in the very limited number of clinical trials conducted so far. The vaccine platform is highly attractive for numerous reasons, such as low cost and a very favorable safety profile. Gene gun delivery of DNA plasmids drastically reduces the vaccine dose and does not only have the potential to make vaccines more accessible and affordable, but also simplifies (a) the testing of novel antigens as vaccine candidates, (b) the testing of antigen combinations, and (c) the co-delivery of antigens with molecular adjuvants such as cytokines or costimulatory molecules. Described in this chapter are the preparation of the inoculum (i.e., DNA plasmids attached to gold particles, coating to the inside of plastic tubing also referred to as gene gun "bullets" or cartridges), the gene gun vaccination procedure, and the challenge of mice with Plasmodium berghei parasites to test the efficacy of the experimental vaccine.

  1. New Vaccines for the World's Poorest People.

    PubMed

    Hotez, Peter J; Bottazzi, Maria Elena; Strych, Ulrich

    2016-01-01

    The 2000 Millennium Development Goals helped stimulate the development of life-saving childhood vaccines for pneumococcal and rotavirus infections while greatly expanding coverage of existing vaccines. However, there remains an urgent need to develop new vaccines for HIV/AIDS, malaria, and tuberculosis, as well as for respiratory syncytial virus and those chronic and debilitating (mostly parasitic) infections known as neglected tropical diseases (NTDs). The NTDs represent the most common diseases of people living in extreme poverty and are the subject of this review. The development of NTD vaccines, including those for hookworm infection, schistosomiasis, leishmaniasis, and Chagas disease, is being led by nonprofit product development partnerships (PDPs) working in consortia of academic and industrial partners, including vaccine manufacturers in developing countries. NTD vaccines face unique challenges with respect to their product development and manufacture, as well as their preclinical and clinical testing. We emphasize global efforts to accelerate the development of NTD vaccines and some of the hurdles to ensuring their availability to the world's poorest people.

  2. A primate model for human cerebral malaria: Plasmodium coatneyi-infected rhesus monkeys.

    PubMed

    Aikawa, M; Brown, A; Smith, C D; Tegoshi, T; Howard, R J; Hasler, T H; Ito, Y; Perry, G; Collins, W E; Webster, K

    1992-04-01

    A major factor in the pathogenesis of human cerebral malaria is blockage of cerebral microvessels by the sequestration of parasitized human red blood cells (PRBC). In vitro studies indicate that sequestration of PRBC in the microvessels is mediated by the attachment of knobs on PRBC to receptors on the endothelial cell surface such as CD36, thrombospondin (TSP), and intercellular adhesion molecule-1 (ICAM-1). However, it is difficult to test this theory in vivo because fresh human brain tissues from cerebral malarial autopsy cases are not easy to obtain. Although several animal models for human cerebral malaria have been proposed, none have shown pathologic findings that are similar to those seen in humans. In order to develop an animal model for human cerebral malaria, we studied brains of rhesus monkeys infected with the primate malaria parasite, Plasmodium coatneyi. Our study demonstrated PRBC sequestration and cytoadherence of knobs on PRBC to endothelial cells in the cerebral microvessels of these monkeys. Cerebral microvessels with sequestered PRBC were shown by immunohistochemical analysis to possess CD36, TSP, and ICAM-1. These proteins were not evident in the cerebral microvessels of uninfected control monkeys. Thus, our study indicates, for the first time, that rhesus monkeys infected with P. coatneyi can be used as a primate model to study human cerebral malaria. By using this animal model, we may be able to evaluate strategies for the development of vaccines to prevent human cerebral malaria. PMID:1374220

  3. Fya/Fyb antigen polymorphism in human erythrocyte Duffy antigen affects susceptibility to Plasmodium vivax malaria

    PubMed Central

    King, Christopher L.; Adams, John H.; Xianli, Jia; Grimberg, Brian T.; McHenry, Amy M.; Greenberg, Lior J.; Siddiqui, Asim; Howes, Rosalind E.; da Silva-Nunes, Monica; Ferreira, Marcelo U.; Zimmerman, Peter A.

    2011-01-01

    Plasmodium vivax (Pv) is a major cause of human malaria and is increasing in public health importance compared with falciparum malaria. Pv is unique among human malarias in that invasion of erythrocytes is almost solely dependent on the red cell's surface receptor, known as the Duffy blood-group antigen (Fy). Fy is an important minor blood-group antigen that has two immunologically distinct alleles, referred to as Fya or Fyb, resulting from a single-point mutation. This mutation occurs within the binding domain of the parasite's red cell invasion ligand. Whether this polymorphism affects susceptibility to clinical vivax malaria is unknown. Here we show that Fya, compared with Fyb, significantly diminishes binding of Pv Duffy binding protein (PvDBP) at the erythrocyte surface, and is associated with a reduced risk of clinical Pv in humans. Erythrocytes expressing Fya had 41–50% lower binding compared with Fyb cells and showed an increased ability of naturally occurring or artificially induced antibodies to block binding of PvDBP to their surface. Individuals with the Fya+b− phenotype demonstrated a 30–80% reduced risk of clinical vivax, but not falciparum malaria in a prospective cohort study in the Brazilian Amazon. The Fya+b− phenotype, predominant in Southeast Asian and many American populations, would confer a selective advantage against vivax malaria. Our results also suggest that efficacy of a PvDBP-based vaccine may differ among populations with different Fy phenotypes. PMID:22123959

  4. [HPV vaccination].

    PubMed

    Stronski Huwiler, Susanne; Spaar, Anne

    2016-01-01

    Human Papilloma Viruses are associated with genital carcinoma (of the cervix, anus, vulva, vagina and the penis) as well as with non-genital carcinoma (oropharyngeal carcinoma) and genital warts. In Switzerland two highly efficient and safe vaccines are available. The safety of these vaccines has been repeatedly subject of controversial discussions, however so far post marketing surveillance has always been able to confirm the safety. In Switzerland girls and young women have been offered the HPV vaccination within cantonal programmes since 2008. 2015 the recommendation for the HPV-vaccination for boys and young men was issued, and starting July 1, 2016 they as well will be offered vaccination free of charge within the cantonal programmes. This article discusses the burden of disease, efficacy and safety of the vaccines and presents facts which are important for vaccinating these young people. Specifically, aspects of the decisional capacity of adolescents to consent to the vaccination are presented. Finally, the future perspective with a focus on a new vaccine with an enlarged spectrum of HPV-types is discussed. PMID:27268446

  5. Algae-Produced Pfs25 Elicits Antibodies That Inhibit Malaria Transmission

    PubMed Central

    Gregory, James A.; Li, Fengwu; Tomosada, Lauren M.; Cox, Chesa J.; Topol, Aaron B.; Vinetz, Joseph M.; Mayfield, Stephen

    2012-01-01

    Subunit vaccines are significantly more expensive to produce than traditional vaccines because they are based primarily on recombinant proteins that must be purified from the expression system. Despite the increased cost, subunit vaccines are being developed because they are safe, effective, and can elicit antibodies that confer protection against diseases that are not currently vaccine-preventable. Algae are an attractive platform for producing subunit vaccines because they are relatively inexpensive to grow, genetically tractable, easily scaled to large volumes, have a short generation time, and are devoid of inflammatory, viral, or prion contaminants often present in other systems. We tested whether algal chloroplasts can produce malaria transmission blocking vaccine candidates, Plasmodium falciparum surface protein 25 (Pfs25) and 28 (Pfs28). Antibodies that recognize Pfs25 and Pfs28 disrupt the sexual development of parasites within the mosquito midgut, thus preventing transmission of malaria from one human host to the next. These proteins have been difficult to produce in traditional recombinant systems because they contain tandem repeats of structurally complex epidermal growth factor-like domains, which cannot be produced in bacterial systems, and because they are not glycosylated, so they must be modified for production in eukaryotic systems. Production in algal chloroplasts avoids these issues because chloroplasts can fold complex eukaryotic proteins and do not glycosylate proteins. Here we demonstrate that algae are the first recombinant system to successfully produce an unmodified and aglycosylated version of Pfs25 or Pfs28. These antigens are structurally similar to the native proteins and antibodies raised to these recombinant proteins recognize Pfs25 and Pfs28 from P. falciparum. Furthermore, antibodies to algae-produced Pfs25 bind the surface of in-vitro cultured P. falciparum sexual stage parasites and exhibit transmission blocking activity. Thus

  6. Conquering the intolerable burden of malaria: what's new, what's needed: a summary.

    PubMed

    Breman, Joel G; Alilio, Martin S; Mills, Anne

    2004-08-01

    approach for countering the spread and intensity of Plasmodium falciparum resistance to chloroquine, sulfadoxine/pyrimethamine, and other antimalarial drugs. Although costly, ACT ($1.20-2.50 per adult treatment) becomes more cost-effective as resistance to alternative drugs increases; early use of ACT may delay development of resistance to these drugs and prevent the medical toll associated with use of ineffective drugs. The burden of malaria in one district in Tanzania has not decreased since the primary health care approach replaced the vertical malaria control efforts of the 1960s. Despite decentralization, this situation resulted, in part, from weak district management capacity, poor coordination, inadequate monitoring, and lack of training of key staff. Experience in the Solomon Islands showed that spraying with DDT, use of insecticide-treated bed nets (ITNs), and health education were all associated with disease reduction. The use of nets permitted a reduction in DDT spraying, but could not replace it without an increased malaria incidence. Baseline data and reliable monitoring of key outcome indicators are needed to measure whether the ambitious goals for the control of malaria and other diseases has occurred. Such systems are being used for evidence-based decision making in Tanzania and several other countries. Baseline cluster sampling surveys in several countries across Africa indicate that only 53% of the children with febrile illness in malarious areas are being treated; chloroquine (CQ) is used 84% of the time, even where the drug may be ineffective. Insecticide-treated bed nets were used only 2% of the time by children less than five years of age. Progress in malaria vaccine research has been substantial over the past five years; 35 candidate malaria vaccines are in development, many of which are in clinical trials. Development of new vaccines and drugs has been the result of increased investments and formation of public-private partnerships. Before malaria

  7. Conquering the intolerable burden of malaria: what's new, what's needed: a summary.

    PubMed

    Breman, Joel G; Alilio, Martin S; Mills, Anne

    2004-08-01

    approach for countering the spread and intensity of Plasmodium falciparum resistance to chloroquine, sulfadoxine/pyrimethamine, and other antimalarial drugs. Although costly, ACT ($1.20-2.50 per adult treatment) becomes more cost-effective as resistance to alternative drugs increases; early use of ACT may delay development of resistance to these drugs and prevent the medical toll associated with use of ineffective drugs. The burden of malaria in one district in Tanzania has not decreased since the primary health care approach replaced the vertical malaria control efforts of the 1960s. Despite decentralization, this situation resulted, in part, from weak district management capacity, poor coordination, inadequate monitoring, and lack of training of key staff. Experience in the Solomon Islands showed that spraying with DDT, use of insecticide-treated bed nets (ITNs), and health education were all associated with disease reduction. The use of nets permitted a reduction in DDT spraying, but could not replace it without an increased malaria incidence. Baseline data and reliable monitoring of key outcome indicators are needed to measure whether the ambitious goals for the control of malaria and other diseases has occurred. Such systems are being used for evidence-based decision making in Tanzania and several other countries. Baseline cluster sampling surveys in several countries across Africa indicate that only 53% of the children with febrile illness in malarious areas are being treated; chloroquine (CQ) is used 84% of the time, even where the drug may be ineffective. Insecticide-treated bed nets were used only 2% of the time by children less than five years of age. Progress in malaria vaccine research has been substantial over the past five years; 35 candidate malaria vaccines are in development, many of which are in clinical trials. Development of new vaccines and drugs has been the result of increased investments and formation of public-private partnerships. Before malaria

  8. Elimination of the cold-chain dependence of a nanoemulsion adjuvanted vaccine against tuberculosis by lyophilization

    PubMed Central

    Orr, Mark T.; Kramer, Ryan M.; Barnes, Lucien V; Dowling, Quinton M.; Desbien, Anthony L.; Beebe, Elyse A.; Laurance, John D.; Fox, Christopher B.; Reed, Steven G.; Coler, Rhea N.; Vedvick, Thomas S.

    2014-01-01

    Next-generation rationally-designed vaccine adjuvants represent a significant breakthrough to enable development of vaccines against challenging diseases including tuberculosis, HIV, and malaria. New vaccine candidates often require maintenance of a cold-chain process to ensure long-term stability and separate vials to enable bedside mixing of antigen and adjuvant. This presents a significant financial and technological barrier to worldwide implementation of such vaccines. Herein we describe the development and characterization of a tuberculosis vaccine comprised of both antigen and adjuvant components that are stable in a single vial at sustained elevated temperatures. Further this vaccine retains the ability to elicit both antibody and TH1 responses against the vaccine antigen and protect against experimental challenge with Mycobacterium tuberculosis. These results represent a significant breakthrough in the development of vaccine candidates that can be implemented throughout the world without being hampered by the necessity of a continuous cold chain or separate adjuvant and antigen vials. PMID:24382398

  9. Malaria in pregnancy: current issues.

    PubMed

    Brabin, B

    1997-01-01

    Though not known why, pregnant women are far more susceptible to Plasmodium falciparum malaria during their first pregnancies. Therefore, in sub-Saharan African countries endemic for malaria, almost half of all primigravidae will be parasitemic at their first antenatal visit. Some estimate that up to half of all low birth weight babies born to primigravidae in malaria-endemic areas may be attributable to malaria. Intrauterine growth in the context of maternal parasitemia therefore has major adverse implications for child survival. For the mothers, the prevalence of anemia among pregnant women is greatly increased in malarious areas, and iron-deficiency anemia in pregnant women in developed countries has been associated with pre-term birth and low birth weight. These adverse health and developmental consequences of malaria infection among mothers and their babies is compounded by the absence of any widely-applied recommendation for malaria control in pregnant women in Africa. Current control strategies are nonetheless described. The influence of HIV infection in relation to the effectiveness of malaria drug control during pregnancy has not been assessed.

  10. Healthy malaria control.

    PubMed

    Mathen, K

    1998-01-01

    According to an article in the May 27, 1998, issue of the Times of India, Dr. Menno Jan Bouma, an epidemiologist from the London School of Hygiene and Tropical Medicine, has suggested spraying India's cows, goats, and buffaloes with insecticide in a bid to combat malaria. This strategy, however, fails to fully consider what is currently known about insect behavior, insecticides' modes of action, and the interaction between the two in the environment. A population of insects can ultimately develop resistance and adapt to the repeated onslaught of insecticides. Furthermore, each type of insecticide which could potentially be used has its own set of problems with regard to the environment, the products into which they break down, and how they affect wildlife and humans. The once commonplace spraying of livestock in the West led to Mad Cow Disease, Chicken Flu, and other problems. India's meat and dairy products will definitely be contaminated should the country's livestock be sprayed with insecticides. In the long-term interest of humankind, efforts must be made to contain, not eradicate, mosquitoes and malaria. PMID:12348880

  11. Ungulate malaria parasites

    PubMed Central

    Templeton, Thomas J.; Asada, Masahito; Jiratanh, Montakan; Ishikawa, Sohta A.; Tiawsirisup, Sonthaya; Sivakumar, Thillaiampalam; Namangala, Boniface; Takeda, Mika; Mohkaew, Kingdao; Ngamjituea, Supawan; Inoue, Noboru; Sugimoto, Chihiro; Inagaki, Yuji; Suzuki, Yasuhiko; Yokoyama, Naoaki; Kaewthamasorn, Morakot; Kaneko, Osamu

    2016-01-01

    Haemosporida parasites of even-toed ungulates are diverse and globally distributed, but since their discovery in 1913 their characterization has relied exclusively on microscopy-based descriptions. In order to bring molecular approaches to bear on the identity and evolutionary relationships of ungulate malaria parasites, we conducted Plasmodium cytb-specific nested PCR surveys using blood from water buffalo in Vietnam and Thailand, and goats in Zambia. We found that Plasmodium is readily detectable from water buffalo in these countries, indicating that buffalo Plasmodium is distributed in a wider region than India, which is the only area in which buffalo Plasmodium has been reported. Two types (I and II) of Plasmodium sequences were identified from water buffalo and a third type (III) was isolated from goat. Morphology of the parasite was confirmed in Giemsa-reagent stained blood smears for the Type I sample. Complete mitochondrial DNA sequences were isolated and used to infer a phylogeny in which ungulate malaria parasites form a monophyletic clade within the Haemosporida, and branch prior to the clade containing bird, lizard and other mammalian Plasmodium. Thus it is likely that host switching of Plasmodium from birds to mammals occurred multiple times, with a switch to ungulates independently from other mammalian Plasmodium. PMID:26996979

  12. Ungulate malaria parasites.

    PubMed

    Templeton, Thomas J; Asada, Masahito; Jiratanh, Montakan; Ishikawa, Sohta A; Tiawsirisup, Sonthaya; Sivakumar, Thillaiampalam; Namangala, Boniface; Takeda, Mika; Mohkaew, Kingdao; Ngamjituea, Supawan; Inoue, Noboru; Sugimoto, Chihiro; Inagaki, Yuji; Suzuki, Yasuhiko; Yokoyama, Naoaki; Kaewthamasorn, Morakot; Kaneko, Osamu

    2016-01-01

    Haemosporida parasites of even-toed ungulates are diverse and globally distributed, but since their discovery in 1913 their characterization has relied exclusively on microscopy-based descriptions. In order to bring molecular approaches to bear on the identity and evolutionary relationships of ungulate malaria parasites, we conducted Plasmodium cytb-specific nested PCR surveys using blood from water buffalo in Vietnam and Thailand, and goats in Zambia. We found that Plasmodium is readily detectable from water buffalo in these countries, indicating that buffalo Plasmodium is distributed in a wider region than India, which is the only area in which buffalo Plasmodium has been reported. Two types (I and II) of Plasmodium sequences were identified from water buffalo and a third type (III) was isolated from goat. Morphology of the parasite was confirmed in Giemsa-reagent stained blood smears for the Type I sample. Complete mitochondrial DNA sequences were isolated and used to infer a phylogeny in which ungulate malaria parasites form a monophyletic clade within the Haemosporida, and branch prior to the clade containing bird, lizard and other mammalian Plasmodium. Thus it is likely that host switching of Plasmodium from birds to mammals occurred multiple times, with a switch to ungulates independently from other mammalian Plasmodium.

  13. Ungulate malaria parasites.

    PubMed

    Templeton, Thomas J; Asada, Masahito; Jiratanh, Montakan; Ishikawa, Sohta A; Tiawsirisup, Sonthaya; Sivakumar, Thillaiampalam; Namangala, Boniface; Takeda, Mika; Mohkaew, Kingdao; Ngamjituea, Supawan; Inoue, Noboru; Sugimoto, Chihiro; Inagaki, Yuji; Suzuki, Yasuhiko; Yokoyama, Naoaki; Kaewthamasorn, Morakot; Kaneko, Osamu

    2016-01-01

    Haemosporida parasites of even-toed ungulates are diverse and globally distributed, but since their discovery in 1913 their characterization has relied exclusively on microscopy-based descriptions. In order to bring molecular approaches to bear on the identity and evolutionary relationships of ungulate malaria parasites, we conducted Plasmodium cytb-specific nested PCR surveys using blood from water buffalo in Vietnam and Thailand, and goats in Zambia. We found that Plasmodium is readily detectable from water buffalo in these countries, indicating that buffalo Plasmodium is distributed in a wider region than India, which is the only area in which buffalo Plasmodium has been reported. Two types (I and II) of Plasmodium sequences were identified from water buffalo and a third type (III) was isolated from goat. Morphology of the parasite was confirmed in Giemsa-reagent stained blood smears for the Type I sample. Complete mitochondrial DNA sequences were isolated and used to infer a phylogeny in which ungulate malaria parasites form a monophyletic clade within the Haemosporida, and branch prior to the clade containing bird, lizard and other mammalian Plasmodium. Thus it is likely that host switching of Plasmodium from birds to mammals occurred multiple times, with a switch to ungulates independently from other mammalian Plasmodium. PMID:26996979

  14. Vaccines 85: Molecular and chemical basis of resistance to parasitic, bacterial, and viral diseases

    SciTech Connect

    Lerner, R.A.; Chanock, R.M.; Brown, F.

    1985-01-01

    This book contains 70 selections. Some of the selection titles are: Structure of the Gene Encoding of Immunodominant Surface Antigen on the Sprozoite of the Human Malaria Parasite Plasmodium falciparum; Cloning and Expression in Bacteria of the Genes for Merozite-specific Antigens from the Malaria Parasite Plasmodium falciparum; A Major Surface Antigen of Plasmodium falciparum in Merozoites: Studies on the Protein and its Gene; Genetic Construction of Cholera Vaccine Prototypes; and Viral Genes, Cytotoxic T Lymphocytes and Immunity.

  15. Biologic Vaccines

    PubMed Central

    ADAMS, KATHERINE T.

    2009-01-01

    The threat of new disease pandemics has spurred the development of biologic vaccines, which promise tremendous improvements in global and local health. Several lend themselves to the prevention or treatment of chronic diseases. But the uncertainties of whom to vaccinate raise the question of whether the health care system can make these promising products viable. PMID:22478749

  16. [Pretravel vaccination].

    PubMed

    Koch, Claus

    2005-10-17

    Vaccination is a simple and effective way to protect against certain infectious diseases and is nearly always to be recommended when one is travelling to countries with lesser hygienic standards. This report provides guidance on immunization concerns and describes the individual vaccines most commonly used in travel medicine.

  17. HPV Vaccine

    MedlinePlus

    ... can cause problems like genital warts and some kinds of cancer, a vaccine is an important step in preventing infection and protecting against the spread of HPV. That's why doctors recommend that all girls and guys get the vaccine at these ages: ...

  18. Rotavirus Vaccine

    MedlinePlus

    Why get vaccinated?Rotavirus is a virus that causes diarrhea, mostly in babies and young children. The diarrhea can be severe, and lead ... and fever are also common in babies with rotavirus.Before rotavirus vaccine, rotavirus disease was a common ...

  19. Typhoid Vaccine

    MedlinePlus

    ... should be given at least 2 weeks before travel to allow the vaccine time to work. A booster dose is needed every ... should be given at least 1 week before travel to allow the vaccine time to work. Swallow each dose about an hour ...

  20. Dengue vaccine.

    PubMed

    Simasathien, Sriluck; Watanaveeradej, Veerachai

    2005-11-01

    Dengue is an expanding health problem. About two-fifths of the world population are at risk for acquiring dengue with 50-100 million cases of acute febrile illness yearly including about 500,000 cases of DHF/DSS. No antiviral drugs active against the flavivirus exist. Attempts to control mosquito vector has been largely unsuccessful. Vaccination remains the most hopeful preventive measure. Dengue vaccine has been in development for more than 30 years, yet none has been licensed. The fact that enhancing antibody from previous infection and high level of T cell activation during secondary infection contribute to immunopathology of DHF, the vaccine must be able to induce protective response to four dengue serotypes simultaneously. Inactivated vaccine is safe but needs a repeated booster thus, development is delayed. Tetravalent live attenuated vaccine and chimeric vaccine using yellow fever or dengue viruses as a backbone are being carried out in human trials. DNA vaccine and subunit vaccine are being carried out in animal trials.

  1. Combination Vaccines

    PubMed Central

    Skibinski, David AG; Baudner, Barbara C; Singh, Manmohan; O’Hagan, Derek T

    2011-01-01

    The combination of diphtheria, tetanus, and pertussis vaccines into a single product has been central to the protection of the pediatric population over the past 50 years. The addition of inactivated polio, Haemophilus influenzae, and hepatitis B vaccines into the combination has facilitated the introduction of these vaccines into recommended immunization schedules by reducing the number of injections required and has therefore increased immunization compliance. However, the development of these combinations encountered numerous challenges, including the reduced response to Haemophilus influenzae vaccine when given in combination; the need to consolidate the differences in the immunization schedule (hepatitis B); and the need to improve the safety profile of the diphtheria, tetanus, and pertussis combination. Here, we review these challenges and also discuss future prospects for combination vaccines. PMID:21572611

  2. Anti-Infectious Human Vaccination in Historical Perspective.

    PubMed

    D'Amelio, Enrico; Salemi, Simonetta; D'Amelio, Raffaele

    2016-05-01

    A brief history of vaccination is presented since the Jenner's observation, through the first golden age of vaccinology (from Pasteur's era to 1938), the second golden age (from 1940 to 1970), until the current period. In the first golden age, live, such as Bacille Calmette Guérin (BCG), and yellow fever, inactivated, such as typhoid, cholera, plague, and influenza, and subunit vaccines, such as tetanus and diphtheria toxoids, have been developed. In the second golden age, the cell culture technology enabled polio, measles, mumps, and rubella vaccines be developed. In the era of modern vaccines, in addition to the conjugate polysaccharide, hepatitis A, oral typhoid, and varicella vaccines, the advent of molecular biology enabled to develop hepatitis B, acellular pertussis, papillomavirus, and rotavirus recombinant vaccines. Great successes have been achieved in the fight against infectious diseases, including the smallpox global eradication, the nearly disappearance of polio, the control of tetanus, diphtheria, measles, rubella, yellow fever, and rabies. However, much work should still be done for improving old vaccines, such as BCG, anthrax, smallpox, plague, or for developing effective vaccines against old or emerging infectious threats, such as human-immunodeficiency-virus, malaria, hepatitis C, dengue, respiratory-syncytial-virus, cytomegalovirus, multiresistant bacteria, Clostridium difficile, Ebola virus. In addition to search for innovative and effective vaccines and global infant coverage, even risk categories should adequately be protected. Despite patients under immunosuppressive therapy are globally increasing, their vaccine coverage is lower than recommended, even in developed and affluent countries.

  3. Applications of nanoparticles for DNA based rabies vaccine.

    PubMed

    Shah, Muhammad Ali A; Khan, Sajid Umar; Ali, Zeeshan; Yang, Haowen; Liu, Keke; Mao, Lanlan

    2014-01-01

    Rabies is a fatal encephalomyelitis. Most cases occur in developing countries and are transmitted by dogs. The cell culture vaccines as associated with high cost; therefore, have not replaced the unsafe brain-derived vaccines. In the developing countries these brain-derived rabies vaccines still can be seen in action. Moreover, there will be a need for vaccines against rabies-related viruses against which classical vaccines are not always effective. The worldwide incidence of rabies and the inability of currently used vaccination strategies to provide highly potent and cost-effective therapy indicate the need for alternate control strategies. DNA vaccines have emerged as the safest vaccines and best remedy for complicated diseases like hepatitis, HIV, and rabies. A number of recombinant DNA vaccines are now being developed against several diseases such as AIDS and malaria. Therefore, it can be a valuable alternative for the production of cheaper rabies vaccines against its larger spectrum of viruses. In this review we report published data on DNA-based immunization with sequences encoding rabies with special reference to nanotechnology. PMID:24730305

  4. Anti-Infectious Human Vaccination in Historical Perspective.

    PubMed

    D'Amelio, Enrico; Salemi, Simonetta; D'Amelio, Raffaele

    2016-05-01

    A brief history of vaccination is presented since the Jenner's observation, through the first golden age of vaccinology (from Pasteur's era to 1938), the second golden age (from 1940 to 1970), until the current period. In the first golden age, live, such as Bacille Calmette Guérin (BCG), and yellow fever, inactivated, such as typhoid, cholera, plague, and influenza, and subunit vaccines, such as tetanus and diphtheria toxoids, have been developed. In the second golden age, the cell culture technology enabled polio, measles, mumps, and rubella vaccines be developed. In the era of modern vaccines, in addition to the conjugate polysaccharide, hepatitis A, oral typhoid, and varicella vaccines, the advent of molecular biology enabled to develop hepatitis B, acellular pertussis, papillomavirus, and rotavirus recombinant vaccines. Great successes have been achieved in the fight against infectious diseases, including the smallpox global eradication, the nearly disappearance of polio, the control of tetanus, diphtheria, measles, rubella, yellow fever, and rabies. However, much work should still be done for improving old vaccines, such as BCG, anthrax, smallpox, plague, or for developing effective vaccines against old or emerging infectious threats, such as human-immunodeficiency-virus, malaria, hepatitis C, dengue, respiratory-syncytial-virus, cytomegalovirus, multiresistant bacteria, Clostridium difficile, Ebola virus. In addition to search for innovative and effective vaccines and global infant coverage, even risk categories should adequately be protected. Despite patients under immunosuppressive therapy are globally increasing, their vaccine coverage is lower than recommended, even in developed and affluent countries. PMID:26606466

  5. Designing vaccines based on biology of human dendritic cell subsets

    PubMed Central

    Palucka, Karolina; Banchereau, Jacques; Mellman, Ira

    2010-01-01

    The effective vaccines developed against a variety of infectious agents, including polio, measles and Hepatitis B, represent major achievements in medicine. These vaccines, usually composed of microbial antigens, are often associated with an adjuvant that activates dendritic cells (DCs). Many infectious diseases are still in need of an effective vaccine including HIV, malaria, hepatitis C and tuberculosis. In some cases, the induction of cellular rather than humoral responses may be more important as the goal is to control and eliminate the existing infection rather than to prevent it. Our increased understanding of the mechanisms of antigen presentation, particularly with the description of DC subsets with distinct functions, as well as their plasticity in responding to extrinsic signals, represent opportunities to develop novel vaccines. In addition, we foresee that this increased knowledge will permit us to design vaccines that will reprogram the immune system to intervene therapeutically in cancer, allergy and autoimmunity. PMID:21029958

  6. Malaria ecology and climate change

    NASA Astrophysics Data System (ADS)

    McCord, G. C.

    2016-05-01

    Understanding the costs that climate change will exact on society is crucial to devising an appropriate policy response. One of the channels through while climate change will affect human society is through vector-borne diseases whose epidemiology is conditioned by ambient ecology. This paper introduces the literature on malaria, its cost on society, and the consequences of climate change to the physics community in hopes of inspiring synergistic research in the area of climate change and health. It then demonstrates the use of one ecological indicator of malaria suitability to provide an order-of-magnitude assessment of how climate change might affect the malaria burden. The average of Global Circulation Model end-of-century predictions implies a 47% average increase in the basic reproduction number of the disease in today's malarious areas, significantly complicating malaria elimination efforts.

  7. Malaria Prophylaxis: A Comprehensive Review

    PubMed Central

    Castelli, Francesco; Odolini, Silvia; Autino, Beatrice; Foca, Emanuele; Russo, Rosario

    2010-01-01

    The flow of international travellers to and from malaria-endemic areas, especially Africa, has increased in recent years. Apart from the very high morbidity and mortality burden imposed on malaria-endemic areas, imported malaria is the main cause of fever possibly causing severe disease and death in travellers coming from tropical and subtropical areas, particularly Sub-Saharan Africa. The importance of behavioural preventive measures (bed nets, repellents, etc.), adequate chemoprophylaxis and, in selected circumstances, stand-by emergency treatment may not be overemphasized. However, no prophylactic regimen may offer complete protection. Expert advice is needed to tailor prophylactic advice according to traveller (age, baseline clinical conditions, etc.) and travel (destination, season, etc.) characteristics in order to reduce malaria risk.

  8. Comparison of Current Regulatory Status for Gene-Based Vaccines in the U.S., Europe and Japan.

    PubMed

    Nakayama, Yoshikazu; Aruga, Atsushi

    2015-01-01

    Gene-based vaccines as typified by plasmid DNA vaccines and recombinant viral-vectored vaccines are expected as promising solutions against infectious diseases for which no effective prophylactic vaccines exist such as HIV, dengue virus, Ebola virus and malaria, and for which more improved vaccines are needed such as tuberculosis and influenza virus. Although many preclinical and clinical trials have been conducted to date, no DNA vaccines or recombinant viral-vectored vaccines expressing heterologous antigens for human use have yet been licensed in the U.S., Europe or Japan. In this research, we describe the current regulatory context for gene-based prophylactic vaccines against infectious disease in the U.S., Europe, and Japan. We identify the important considerations, in particular, on the preclinical assessments that would allow these vaccines to proceed to clinical trials, and the differences on the regulatory pathway for the marketing authorization in each region. PMID:26344953

  9. Comparison of Current Regulatory Status for Gene-Based Vaccines in the U.S., Europe and Japan

    PubMed Central

    Nakayama, Yoshikazu; Aruga, Atsushi

    2015-01-01

    Gene-based vaccines as typified by plasmid DNA vaccines and recombinant viral-vectored vaccines are expected as promising solutions against infectious diseases for which no effective prophylactic vaccines exist such as HIV, dengue virus, Ebola virus and malaria, and for which more improved vaccines are needed such as tuberculosis and influenza virus. Although many preclinical and clinical trials have been conducted to date, no DNA vaccines or recombinant viral-vectored vaccines expressing heterologous antigens for human use have yet been licensed in the U.S., Europe or Japan. In this research, we describe the current regulatory context for gene-based prophylactic vaccines against infectious disease in the U.S., Europe, and Japan. We identify the important considerations, in particular, on the preclinical assessments that would allow these vaccines to proceed to clinical trials, and the differences on the regulatory pathway for the marketing authorization in each region. PMID:26344953

  10. Comparison of Current Regulatory Status for Gene-Based Vaccines in the U.S., Europe and Japan.

    PubMed

    Nakayama, Yoshikazu; Aruga, Atsushi

    2015-03-18

    Gene-based vaccines as typified by plasmid DNA vaccines and recombinant viral-vectored vaccines are expected as promising solutions against infectious diseases for which no effective prophylactic vaccines exist such as HIV, dengue virus, Ebola virus and malaria, and for which more improved vaccines are needed such as tuberculosis and influenza virus. Although many preclinical and clinical trials have been conducted to date, no DNA vaccines or recombinant viral-vectored vaccines expressing heterologous antigens for human use have yet been licensed in the U.S., Europe or Japan. In this research, we describe the current regulatory context for gene-based prophylactic vaccines against infectious disease in the U.S., Europe, and Japan. We identify the important considerations, in particular, on the preclinical assessments that would allow these vaccines to proceed to clinical trials, and the differences on the regulatory pathway for the marketing authorization in each region.

  11. Lessons from malaria control to help meet the rising challenge of dengue

    PubMed Central

    Anders, Katherine L; Hay, Simon I

    2012-01-01

    Summary Achievements in malaria control could inform efforts to control the increasing global burden of dengue. Better methods for quantifying dengue endemicity—equivalent to parasite prevalence surveys and endemicity mapping used for malaria—would help target resources, monitor progress, and advocate for investment in dengue prevention. Success in controlling malaria has been attributed to widespread implementation of interventions with proven efficacy. An improved evidence base is needed for large-scale delivery of existing and novel interventions for vector control, alongside continued investment in dengue drug and vaccine development. Control of dengue is unlikely to be achieved without coordinated international financial and technical support for national programmes, which has proven effective in reducing the global burden of malaria. PMID:23174383

  12. Prevalence of Plasmodium falciparum transmission reducing immunity among primary school children in a malaria moderate transmission region in Zimbabwe.

    PubMed

    Paul, Noah H; Vengesai, Arthur; Mduluza, Takafira; Chipeta, James; Midzi, Nicholas; Bansal, Geetha P; Kumar, Nirbhay

    2016-11-01

    Malaria continues to cause alarming morbidity and mortality in more than 100 countries worldwide. Antigens in the various life cycle stages of malaria parasites are presented to the immune system during natural infection and it is widely recognized that after repeated malaria exposure, adults develop partially protective immunity. Specific antigens of natural immunity represent among the most important targets for the development of malaria vaccines. Immunity against the transmission stages of the malaria parasite represents an important approach to reduce malaria transmission and is believed to become an important tool for gradual elimination of malaria. Development of immunity against Plasmodium falciparum sexual stages was evaluated in primary school children aged 6-16 years in Makoni district of Zimbabwe, an area of low to modest malaria transmission. Malaria infection was screened by microscopy, rapid diagnostic tests and finally using nested PCR. Plasma samples were tested for antibodies against recombinant Pfs48/45 and Pfs47 by ELISA. Corresponding serum samples were used to test for P. falciparum transmission reducing activity in Anopheles stephensi and An. gambiae mosquitoes using the membrane feeding assay. The prevalence of malaria diagnosed by rapid diagnostic test kit (Paracheck)™ was 1.7%. However, of the randomly tested blood samples, 66% were positive by nested PCR. ELISA revealed prevalence (64% positivity at 1:500 dilution, in randomly selected 66 plasma samples) of antibodies against recombinant Pfs48/45 (mean A 405nm=0.53, CI=0.46-0.60) and Pfs47 (mean A405nm=0.91, CI=0.80-1.02); antigens specific to the sexual stages. The mosquito membrane feeding assay demonstrated measurable transmission reducing ability of the samples that were positive for Pfs48/45 antibodies by ELISA. Interestingly, 3 plasma samples revealed enhancement of infectivity of P. falciparum in An. stephensi mosquitoes. These studies revealed the presence of antibodies with

  13. Re-emergence of malaria in India.

    PubMed

    Sharma, V P

    1996-01-01

    Malaria was nearly eradicated from India in the early 1960s but the disease has re-emerged as a major public health problem. Early set backs in malaria eradication coincided with DDT shortages. Later in the 1960s and 1970s malaria resurgence was the result of technical, financial and operational problems. In the late 1960s malaria cases in urban areas started to multiply, and upsurge of malaria was widespread. As a result in 1976, 6.45 million cases were recorded by the National Malaria Eradication Programme (NMEP), highest since resurgence. The implementation of urban malaria scheme (UMS) in 1971-72 and the modified plan of operation (MPO) in 1977 improved the malaria situation for 5-6 yr. Malaria cases were reduced to about 2 million. The impact was mainly on vivax malaria. Easy availability of drugs under the MPO prevented deaths due to malaria and reduced morbidity, a peculiar feature of malaria during the resurgence. The Plasmodium falciparum containment programme (PfCP) launched in 1977 to contain the spread of falciparum malaria reduced falciparum malaria in the areas where the containment programme was operated but its general spread could not be contained. P. falciparum showed a steady upward trend during the 1970s and thereafter. Rising trend of malaria was facilitated by developments in various sectors to improve the national economy under successive 5 year plans. Malaria at one time a rural disease, diversified under the pressure of developments into various ecotypes. These ecotypes have been identified as forest malaria, urban malaria, rural malaria, industrial malaria, border malaria and migration malaria; the latter cutting across boundaries of various epidemiological types. Further, malaria in the 1990s has returned with new features not witnessed during the pre-eradication days. These are the vector resistance to insecticide(s); pronounced exophilic vector behaviour; extensive vector breeding grounds created principally by the water resource

  14. Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

    PubMed

    Carlton, Jane M; Adams, John H; Silva, Joana C; Bidwell, Shelby L; Lorenzi, Hernan; Caler, Elisabet; Crabtree, Jonathan; Angiuoli, Samuel V; Merino, Emilio F; Amedeo, Paolo; Cheng, Qin; Coulson, Richard M R; Crabb, Brendan S; Del Portillo, Hernando A; Essien, Kobby; Feldblyum, Tamara V; Fernandez-Becerra, Carmen; Gilson, Paul R; Gueye, Amy H; Guo, Xiang; Kang'a, Simon; Kooij, Taco W A; Korsinczky, Michael; Meyer, Esmeralda V-S; Nene, Vish; Paulsen, Ian; White, Owen; Ralph, Stuart A; Ren, Qinghu; Sargeant, Tobias J; Salzberg, Steven L; Stoeckert, Christian J; Sullivan, Steven A; Yamamoto, Marcio M; Hoffman, Stephen L; Wortman, Jennifer R; Gardner, Malcolm J; Galinski, Mary R; Barnwell, John W; Fraser-Liggett, Claire M

    2008-10-01

    The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.

  15. Dendritic cells and the malaria pre-erythrocytic stage.

    PubMed

    Mauduit, Marjorie; See, Peter; Peng, Kaitian; Rénia, Laurent; Ginhoux, Florent

    2012-09-01

    Malaria remains one of the main infectious diseases in intertropical regions. The malaria parasite has a complex life cycle in its mammalian host, switching between variable forms as it traverses through different tissues and anatomic locations, either intra- or intercellularly. During its journey, the parasite encounters and interacts with the host immune system, which functions to prevent infections and limit ensuing pathologies. One important component of the host immune system is the dendritic cells (DC) network. DC form a heterogeneous group of pathogen-sensing and antigen-presenting cells that play a crucial role in the initiation of adaptive immunity. Here, we review the known and unknown interactions between the malaria parasites and the DC system, starting from the inoculation of the parasite in the skin up to its exit from the liver, also known as the pre-erythrocytic stage of the infection, and discuss how deciphering these interactions may contribute to our understanding of the Plasmodium parasite biology as well as to the induction of immune protection via vaccination. PMID:22418726

  16. Are multilateral malaria research and control programs the most successful? Lessons from the past 100 years in Africa.

    PubMed

    Alilio, Martin S; Bygbjerg, Ib C; Breman, Joel G

    2004-08-01

    Multilateral malaria research and control programs in Africa have regained prominence recently as bilateral assistance has diminished. The transnational nature of the threat and the need for inspired leadership, good coordination, and new discoveries to decrease the impact of the disease has led to the founding of the Multilateral Initiative on Malaria, the Roll Back Malaria Project, Global Fund for HIV, Tuberculosis and Malaria (Global Fund), the Medicines for Malaria Venture, and the Malaria Vaccine Initiative, among other groups. Historically, the most striking feature of malaria control and elimination activities was the connectedness and balance between malaria research and control especially, from 1892 to 1949. A combination of scientific originality, perseverance in research, integrated approaches, and social concern were the keys for success. The elimination of Anopheles gambiae from Upper Egypt in 1942 using integrated vector control methods is a prime example of malaria control during the first half of the 20th century where those factors were brought together. After 1949, there were three decades of great optimism. Four notable landmarks characterized this period: the Kampala Conference in 1950; the Global Malaria Eradication Program beginning in 1955; the primary health care strategies adopted by most African States after attaining their political independence in the 1960s, and accelerating in the 1980s; and creation of the Special Program in Training and Research in Tropical Diseases at the World Health Organization in 1975. The initial highly encouraging operational results, largely obtained in temperate or subtropical areas where transmission was unstable, engendered undue expectations for the success of identical antimalarial measures elsewhere. Many were convinced that the eradication was in sight, such that support for malaria research virtually ceased. Young, bright scientists were discouraged from seeking a career in a discipline that appeared

  17. [Malaria and intestinal protozoa].

    PubMed

    Rojo-Marcos, Gerardo; Cuadros-González, Juan

    2016-03-01

    Malaria is life threatening and requires urgent diagnosis and treatment. Incidence and mortality are being reduced in endemic areas. Clinical features are unspecific so in imported cases it is vital the history of staying in a malarious area. The first line treatments for Plasmodium falciparum are artemisinin combination therapies, chloroquine in most non-falciparum and intravenous artesunate if any severity criteria. Human infections with intestinal protozoa are distributed worldwide with a high global morbid-mortality. They cause diarrhea and sometimes invasive disease, although most are asymptomatic. In our environment populations at higher risk are children, including adopted abroad, immune-suppressed, travelers, immigrants, people in contact with animals or who engage in oral-anal sex. Diagnostic microscopic examination has low sensitivity improving with antigen detection or molecular methods. Antiparasitic resistances are emerging lately. PMID:26832999

  18. [Malaria and intestinal protozoa].

    PubMed

    Rojo-Marcos, Gerardo; Cuadros-González, Juan

    2016-03-01

    Malaria is life threatening and requires urgent diagnosis and treatment. Incidence and mortality are being reduced in endemic areas. Clinical features are unspecific so in imported cases it is vital the history of staying in a malarious area. The first line treatments for Plasmodium falciparum are artemisinin combination therapies, chloroquine in most non-falciparum and intravenous artesunate if any severity criteria. Human infections with intestinal protozoa are distributed worldwide with a high global morbid-mortality. They cause diarrhea and sometimes invasive disease, although most are asymptomatic. In our environment populations at higher risk are children, including adopted abroad, immune-suppressed, travelers, immigrants, people in contact with animals or who engage in oral-anal sex. Diagnostic microscopic examination has low sensitivity improving with antigen detection or molecular methods. Antiparasitic resistances are emerging lately.

  19. Climate change and malaria transmission.

    PubMed

    Lindsay, S W; Birley, M H

    1996-12-01

    There is a consensus among climatologists that our planet is experiencing a progressive rise in surface temperature due to the increased production of "greenhouse" gases. Some of the possible consequences of elevated temperature on malaria transmission are examined in the present review. A simple mathematical model is first used to examine the effect of temperature on the ability of Anopheles maculipennis to transmit vivax malaria. This indicates that small increases in temperature at low temperatures may increase the risk of transmission substantially. This is important, since vulnerable communities, poorly protected by health services, in areas of unstable or no malaria are likely to be at increased risk of future outbreaks. In contrast, areas of stable transmission may be little affected by rising temperature. It is thought that global warming will lead to coastal flooding, changes in precipitation and, indirectly, changes in land use. Just how these changes will effect transmission at a regional level requires an understanding of the ecology of local vectors, since environmental changes which favour malaria transmission in one vector species may reduce it in another. Methods for predicting future changes in malaria in different regions are discussed, highlighting the need for further research in this area. Most importantly, there is a need for researchers to validate the accuracy of the models used for predicting malaria and to confirm the assumptions on which the models are based.

  20. Rotavirus vaccines.

    PubMed

    Barnes, G

    1998-01-01

    Encouraging results have been reported from several large trials of tetravalent rhesus rotavirus vaccine, with efficacy of 70-80% against severe disease. A recent Venezuelan study showed similar results to trials in USA and Europe. The vaccine may soon be licensed in USA. It provides the exciting prospect of a strategy to prevent one of the world's major child killers. Other candidate vaccines are under development including human-bovine reassortants, neonatal strains, non-replicating rotaviruses, vector vaccines and other genetically engineered products. Second and third generation rotavirus vaccines are on the horizon. The need for a rotavirus vaccine is well accepted by paediatricians, but public health authorities need to be lobbied. Other issues which need to be addressed include relative importance of non-group A rotaviruses, possible administration with OPV, the influence of breast feeding, and most importantly, cost. It is essential that rotavirus vaccine is somehow made available to all of the world's children, not just those in developed countries. PMID:9553287

  1. Vaccines and future global health needs.

    PubMed

    Nossal, G J V

    2011-10-12

    Increased international support for both research into new vaccines and their deployment in developing countries has been evident over the past decade. In particular, the GAVI Alliance has had a major impact in increasing uptake of the six common infant vaccines as well as those against hepatitis B and yellow fever. It further aims to introduce pneumococcal and rotavirus vaccines in the near future and several others, including those against human papillomavirus, meningococcal disease, rubella and typhoid not long after that. In addition, there is advanced research into vaccines against malaria, HIV/AIDS and tuberculosis. By 2030, we may have about 20 vaccines that need to be used in the developing world. Finding the requisite funds to achieve this will pose a major problem. A second and urgent question is how to complete the job of global polio eradication. The new strategic plan calls for completion by 2013, but both pre-eradication and post-eradication challenges remain. Vaccines will eventually become available beyond the field of infectious diseases. Much interesting work is being done in both autoimmunity and cancer. Cutting across disease groupings, there are issues in methods of delivery and new adjuvant formulations. PMID:21893548

  2. Vaccines and future global health needs

    PubMed Central

    Nossal, G. J. V.

    2011-01-01

    Increased international support for both research into new vaccines and their deployment in developing countries has been evident over the past decade. In particular, the GAVI Alliance has had a major impact in increasing uptake of the six common infant vaccines as well as those against hepatitis B and yellow fever. It further aims to introduce pneumococcal and rotavirus vaccines in the near future and several others, including those against human papillomavirus, meningococcal disease, rubella and typhoid not long after that. In addition, there is advanced research into vaccines against malaria, HIV/AIDS and tuberculosis. By 2030, we may have about 20 vaccines that need to be used in the developing world. Finding the requisite funds to achieve this will pose a major problem. A second and urgent question is how to complete the job of global polio eradication. The new strategic plan calls for completion by 2013, but both pre-eradication and post-eradication challenges remain. Vaccines will eventually become available beyond the field of infectious diseases. Much interesting work is being done in both autoimmunity and cancer. Cutting across disease groupings, there are issues in methods of delivery and new adjuvant formulations. PMID:21893548

  3. Meningococcal Vaccinations.

    PubMed

    Crum-Cianflone, Nancy; Sullivan, Eva

    2016-06-01

    Neisseria meningitidis, a gram-negative diplococcal bacterium, is a common asymptomatic nasopharyngeal colonizer that may infrequently lead to invasive disease in the form of meningitis or bacteremia. Six serogroups (A, B, C, W, X and Y) are responsible for the majority of invasive infections. Increased risk of disease occurs in specific population groups including infants, adolescents, those with asplenia or complement deficiencies, and those residing in crowded living conditions such as in college dormitories. The incidence of invasive meningococcal disease varies geographically with some countries (e.g., in the African meningitis belt) having both high endemic disease rates and ongoing epidemics, with annual rates reaching 1000 cases per 100,000 persons. Given the significant morbidity and mortality associated with meningococcal disease, it remains a major global health threat best prevented by vaccination. Several countries have implemented vaccination programs with the selection of specific vaccine(s) based on locally prevalent serogroup(s) of N. meningitidis and targeting population groups at highest risk. Polysaccharide meningococcal vaccines became available over 40 years ago, but are limited by their inability to produce immunologic memory responses, poor immunogenicity in infants/children, hyporesponsiveness after repeated doses, and lack of efficacy against nasopharyngeal carriage. In 1999, the first meningococcal conjugate vaccines were introduced and have been successful in overcoming many of the shortcomings of polysaccharide vaccines. The implementation of meningococcal conjugate vaccination programs in many areas of the world (including the massive campaign in sub-Saharan Africa using a serogroup A conjugate vaccine) has led to dramatic reductions in the incidence of meningococcal disease by both individual and population protection. Progressive advances in vaccinology have led to the recent licensure of two effective vaccines against serogroup B

  4. [Rabbies vaccination].

    PubMed

    Jelinek, Tomas

    2016-01-01

    With very few exceptions, rabies is occurring around the globe. The clinical course of this mammal-transmitted infection is almost universally fatal. Thus, the disease is causing more human deaths than any other zoonosis. Due to the lack of effective therapeutic options, pre- or post-exposure vaccination remains the only effective means to avoid development of fatal disease. Save and highly effective cell culture vaccines which have been available for decades provide long-lasting protection. Various vaccination schedules have been tested and are being recommended. PMID:27268449

  5. Malaria Parasite Survival Depends on Conserved Binding Peptides' Critical Biological Functions.

    PubMed

    Patarroyo, Manuel E; Arevalo-Pinzon, Gabriela; Reyes, Cesar; Moreno-Vranich, Armando; Patarroyo, Manuel A

    2016-01-01

    Biochemical, structural and single amino acid level analysis of 49 Plasmodium falciparum protein regions (13 sporozoite and 36 merozoite proteins) has highlighted the functional role of each conserved high activity binding peptide (cHABP) in cell host-microbe interaction, involving biological functions such as gliding motility, traversal activity, binding invasion, reproduction, nutrient ion transport and the development of severe malaria. Each protein's key function in the malaria parasite's asexual lifecycle (pre-erythrocyte and erythro-cyte) is described in terms of cHABPs; their sequences were located in elegant work published by other groups regarding critical binding regions implicated in malarial parasite invasion. Such cHABPs represent the starting point for developing a logical and rational methodology for selecting an appropriate mixture of modified cHABPs to be used in a completely effective, synthetic antimalarial vaccine. Such methodology could be used for developing vaccines against diseases scourging humanity. PMID:26317369

  6. Protective efficacy and safety of liver stage attenuated malaria parasites

    PubMed Central

    Kumar, Hirdesh; Sattler, Julia Magdalena; Singer, Mirko; Heiss, Kirsten; Reinig, Miriam; Hammerschmidt-Kamper, Christiane; Heussler, Volker; Mueller, Ann-Kristin; Frischknecht, Friedrich

    2016-01-01

    During the clinically silent liver stage of a Plasmodium infection the parasite replicates from a single sporozoite into thousands of merozoites. Infection of humans and rodents with large numbers of sporozoites that arrest their development within the liver can cause sterile protection from subsequent infections. Disruption of genes essential for liver stage development of rodent malaria parasites has yielded a number of attenuated parasite strains. A key question to this end is how increased attenuation relates to vaccine efficacy. Here, we generated rodent malaria parasite lines that arrest during liver stage development and probed the impact of multiple gene deletions on attenuation and protective efficacy. In contrast to P. berghei strain ANKA LISP2(–) or uis3(–) single knockout parasites, which occasionally caused breakthrough infections, the double mutant lacking both genes was completely attenuated even when high numbers of sporozoites were administered. However, different vaccination protocols showed that LISP2(–) parasites protected better than uis3(–) and double mutants. Hence, deletion of several genes can yield increased safety but might come at the cost of protective efficacy. PMID:27241521

  7. Pulmonary pathology in pediatric cerebral malaria.

    PubMed

    Milner, Danny; Factor, Rachel; Whitten, Rich; Carr, Richard A; Kamiza, Steve; Pinkus, Geraldine; Molyneux, Malcolm; Taylor, Terrie

    2013-12-01

    Respiratory signs are common in African children where malaria is highly endemic, and thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 children from an autopsy series in Blantyre, Malawi, many of whom death was attributed to Plasmodium falciparum malaria. Our aim was to describe the pathologic manifestations of fatal malaria; to understand the role of parasites, pigment, and macrophages; and to catalog comorbidities. From available patients, which included 55 patients with cerebral malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that, in patients with cerebral malaria, large numbers of malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with cerebral malaria, noncerebral malaria, and nonmalarial diagnoses. Comorbidities found in some cerebral malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with cerebral malaria does not appear to be anatomic in origin but that increasing malaria pigment is strongly associated with cerebral malaria at autopsy.

  8. Malaria at Christmas: risks of prophylaxis versus risks of malaria.

    PubMed

    Reid, A J; Whitty, C J; Ayles, H M; Jennings, R M; Bovill, B A; Felton, J M; Behrens, R H; Bryceson, A D; Mabey, D C

    1998-11-28

    A large increase in the number of falciparum malaria cases imported into the UK was reported to the malaria reference laboratory in the first quarter of 1998. Contributory factors were unusually heavy rains in east Africa and a reduction in the use of the most effective antimalarial drug, mefloquine. There was also an increase in the number of cases of severe malaria in the UK. During December 1997 and January 1998, the Hospital for Tropical Diseases, London, treated 5 patients for severe malaria and gave advice on 20 more patients with malaria who had been admitted to intensive care units throughout England. 4 of the severe cases treated at the hospital are reported. In 3 of those 4 cases, incorrect, misleading, or inadequate advice was given by health care professionals. Media coverage of the adverse effects of antimalarial drugs has contributed to confusion about prophylactic regimens among both health care professionals and the public. The incidence of falciparum malaria among travellers who do not take prophylactic drugs is about 0.6% in east Africa and 3.5% in west Africa over a 2-week travel period. Travellers need to take measures to avoid being bitten by mosquitoes and should be taught to promptly seek medical help if they develop a fever while abroad or after they return. Moreover, using any one of the recommended prophylactic regimens is better than not using a potent regimen or no prophylaxis at all. Mefloquine is 90% protective against malaria in sub-Saharan Africa. While the efficacy of proguanil and chloroquine in 1987 was about 70% in west Africa and 50% in east Africa, those levels are now probably lower. The side effects of antimalarial drugs are discussed.

  9. [Current malaria situation in Turkey].

    PubMed

    Gockchinar, T; Kalipsi, S

    2001-01-01

    Geographically, Turkey is situated in an area where malaria is very risky. The climatic conditions in the region are suitable for the malaria vector to proliferate. Due to agricultural infrastructural changes, GAP and other similar projects, insufficient environmental conditions, urbanization, national and international population moves, are a key to manage malaria control activities. It is estimated that malaria will be a potential danger for Turkey in the forthcoming years. The disease is located largely in south-eastern Anatolia. The Diyarbakir, Batman, Sanliurfa, Siirt, and Mardin districts are the most affected areas. In western districts, like Aydin and Manisa, an increase in the number of indigenous cases can be observed from time to time. This is due to workers moving from malaria districts to western parts to final work. Since these workers cannot be controlled, the population living in these regions get infected from indigenous cases. There were 84,345 malaria cases in 1994 and 82,096 in 1995, they decreased to 60,884 in 1996 and numbered 35,456 in 1997. They accounted for 36,842 and 20,963 in 1998 and 1999, respectively. In Turkey there are almost all cases of P. vivax malaria. There are also P. vivax and P. falciparum malaria cases coming from other countries: There were 321 P. vivax cases, including 2 P. falciparum ones, arriving to Turkey from Iraq in 1995. The P. vivax malaria cases accounted for 229 in 1996, and 67, cases P. vivax including 12 P. falciparum cases, in 1997, and 4 P. vivax cases in 1998 that came from that country. One P. vivax case entered Turkey from Georgia in 1998. The cause of higher incidence of P. vivax cases in 1995, it decreasing in 1999, is the lack of border controls over workers coming to Turkey. The other internationally imported cases are from Syria, Sudan, Pakistan, Afghanistan, Nigeria, India, Azerbaijan, Malaysia, Ghana, Indonesia, Yemen. Our examinations have shown that none of these internationally imported cases

  10. [Current malaria situation in Turkmenistan].

    PubMed

    Amangel'diev, K A

    2001-01-01

    Malaria is one of the main health problems facing most developing countries having a hot climate. It is a problem in Turkmenistan. The country is situated in Central Asia, north of the Kopetdag mountains, between the Caspian Sea to the west and the Amu-Darya river to the east. Turkmenistan stretches for a distance of 1,100 km from west to east and 650 km from north to south. It borders Kazakhstan in the north, Uzbekistan in the east and north-east, Iran in the south, and Afghanistan in the south-east. Seven malaria vector species are found in Turkmenistan, the main ones being Anopheles superpictus, An. pulcherrimus, and An. martinius. The potentially endemic area consists of the floodplains of the Tejen and Murgab rivers, with a long chain of reservoirs built along them. In 1980 most cases of imported malaria were recorded in military personnel who had returned from service in Afghanistan. In the past years, only tertian (Plasmodium vivax) malaria has been recorded and there have been no death from malaria over that period. In the Serkhetabad (Gushgi) district there are currently 5 active foci of malaria infection, with a population of 22,000 people. In 1999, forty nine cases of P. vivax malaria were recorded in Turkmenistan. Of them, 36 cases, including 4 children under 14 years were diagnosed for the first time while 13 were relapses. There were 88 fewer cases than those in the previous year (by a factor of 2.8). There were 17 more cases of imported malaria than those in 1998 (by a factor of 1.7), most of which occurred in the foci of malaria infection (Serkhetabad, Tagtabazar, and Kerki districts), in the city of Ashkhabat and in Lebap, Dashkhovuz and Akhal Regions. The emergence of indigenous malaria in the border areas was due to the importation of the disease at intervals by infected mosquitoes flying in from neighbouring countries (e.g. Afghanistan), the lack of drugs to treat the first cases and the lack of alternative insecticides. Most patients suffer

  11. [Current malaria situation in Turkmenistan].

    PubMed

    Amangel'diev, K A

    2001-01-01

    Malaria is one of the main health problems facing most developing countries having a hot climate. It is a problem in Turkmenistan. The country is situated in Central Asia, north of the Kopetdag mountains, between the Caspian Sea to the west and the Amu-Darya river to the east. Turkmenistan stretches for a distance of 1,100 km from west to east and 650 km from north to south. It borders Kazakhstan in the north, Uzbekistan in the east and north-east, Iran in the south, and Afghanistan in the south-east. Seven malaria vector species are found in Turkmenistan, the main ones being Anopheles superpictus, An. pulcherrimus, and An. martinius. The potentially endemic area consists of the floodplains of the Tejen and Murgab rivers, with a long chain of reservoirs built along them. In 1980 most cases of imported malaria were recorded in military personnel who had returned from service in Afghanistan. In the past years, only tertian (Plasmodium vivax) malaria has been recorded and there have been no death from malaria over that period. In the Serkhetabad (Gushgi) district there are currently 5 active foci of malaria infection, with a population of 22,000 people. In 1999, forty nine cases of P. vivax malaria were recorded in Turkmenistan. Of them, 36 cases, including 4 children under 14 years were diagnosed for the first time while 13 were relapses. There were 88 fewer cases than those in the previous year (by a factor of 2.8). There were 17 more cases of imported malaria than those in 1998 (by a factor of 1.7), most of which occurred in the foci of malaria infection (Serkhetabad, Tagtabazar, and Kerki districts), in the city of Ashkhabat and in Lebap, Dashkhovuz and Akhal Regions. The emergence of indigenous malaria in the border areas was due to the importation of the disease at intervals by infected mosquitoes flying in from neighbouring countries (e.g. Afghanistan), the lack of drugs to treat the first cases and the lack of alternative insecticides. Most patients suffer

  12. Standardization of the antibody-dependent respiratory burst assay with human neutrophils and Plasmodium falciparum malaria.

    PubMed

    Llewellyn, David; Miura, Kazutoyo; Fay, Michael P; Williams, Andrew R; Murungi, Linda M; Shi, Jianguo; Hodgson, Susanne H; Douglas, Alexander D; Osier, Faith H; Fairhurst, Rick M; Diakite, Mahamadou; Pleass, Richard J; Long, Carole A; Draper, Simon J

    2015-09-16

    The assessment of naturally-acquired and vaccine-induced immunity to blood-stage Plasmodium falciparum malaria is of long-standing interest. However, the field has suffered from a paucity of in vitro assays that reproducibly measure the anti-parasitic activity induced by antibodies in conjunction with immune cells. Here we optimize the antibody-dependent respiratory burst (ADRB) assay, which assesses the ability of antibodies to activate the release of reactive oxygen species from human neutrophils in response to P. falciparum blood-stage parasites. We focus particularly on assay parameters affecting serum preparation and concentration, and importantly assess reproducibility. Our standardized protocol involves testing each serum sample in singlicate with three independent neutrophil donors, and indexing responses against a standard positive control of pooled hyper-immune Kenyan sera. The protocol can be used to quickly screen large cohorts of samples from individuals enrolled in immuno-epidemiological studies or clinical vaccine trials, and requires only 6 μL of serum per sample. Using a cohort of 86 samples, we show that malaria-exposed individuals induce higher ADRB activity than malaria-naïve individuals. The development of the ADRB assay complements the use of cell-independent assays in blood-stage malaria, such as the assay of growth inhibitory activity, and provides an important standardized cell-based assay in the field.

  13. Immune protection-inducing protein structures (IMPIPS) against malaria: the weapons needed for beating Odysseus.

    PubMed

    Patarroyo, Manuel E; Patarroyo, Manuel A; Pabón, Laura; Curtidor, Hernando; Poloche, Luis A

    2015-12-22

    The review covers the functional and structural approach followed by our group for more than 34 years in the search for a methodology that allows the rational design of chemically synthesised vaccines. An analogy between Odysseus, the cunning hero of the epic poem Odyssey by Homer, and the elusive Plasmodium parasite has been made, to review our research group's main considerations when developing a rational methodology for designing second generation, modified peptide-based, minimal subunit, multi-antigen, multi-stage, chemically synthesised vaccines against Plasmodium falciparum malaria.

  14. Changing landscape of malaria in China: progress and feasibility of malaria elimination.

    PubMed

    Diouf, Gorgui; Kpanyen, Patrick N; Tokpa, Augustine F; Nie, Shaofa

    2014-01-01

    Large-scale malaria control activities in China have been conducted with significant success, since the launch of the nationwide malaria control program. This study investigated the malaria distribution in China, particularly in provinces with high risks. Spatial and temporal data were assembled for all endemic or historically endemic areas and combined to identify common patterns and to investigate the actual changes in the burden of malaria in the country. Data were analyzed and the progress in malaria elimination feasibility was discussed. The results indicated that the current distribution of malaria and vectors associated could provide evidence on the assessment of the feasibility of the malaria elimination in China.

  15. Impact of malaria on genetic polymorphism and genetic diseases in Africans and African Americans.

    PubMed Central

    Miller, L H

    1994-01-01

    The high mortality from malaria in sub-Sahara Africa selected multiple genes that give the population a selective advantage. Identification of the genetic basis for resistance may suggest unusual approaches to development of malarial vaccines and antimalarial drugs. Some of these genes may be deleterious, although of selective advantage within the African setting, and need to be identified for counseling for disease prevention. PMID:8146132

  16. [Historical outline on malaria and the struggle against it in Venezuela].

    PubMed

    López Ramírez, T

    1992-12-01

    The paper presents a synthesis of the history of malaria: the ancient origins of disease, the parasites which produce it, and its vectors. Emphasis is given to its existence in Venezuela, the struggle against its endemic character during the decades of the XXth century and its almost total eradication from malarial areas during the fifties. Reference is also made to current research of an anti-malarial vaccine and its application in a rural area of this country.

  17. Typhoid Vaccine

    MedlinePlus

    ... serious disease. It is caused by bacteria called Salmonella Typhi. Typhoid causes a high fever, fatigue, weakness, ... a typhoid carrier. • Laboratory workers who work with Salmonella Typhi bacteria. Inactivated typhoid vaccine (shot) • One dose ...

  18. Mapping residual transmission for malaria elimination.

    PubMed

    Reiner, Robert C; Le Menach, Arnaud; Kunene, Simon; Ntshalintshali, Nyasatu; Hsiang, Michelle S; Perkins, T Alex; Greenhouse, Bryan; Tatem, Andrew J; Cohen, Justin M; Smith, David L

    2015-12-29

    Eliminating malaria from a defined region involves draining the endemic parasite reservoir and minimizing local malaria transmission around imported malaria infections . In the last phases of malaria elimination, as universal interventions reap diminishing marginal returns, national resources must become increasingly devoted to identifying where residual transmission is occurring. The needs for accurate measures of progress and practical advice about how to allocate scarce resources require new analytical methods to quantify fine-grained heterogeneity in malaria risk. Using routine national surveillance data from Swaziland (a sub-Saharan country on the verge of elimination), we estimated individual reproductiv