Malaria vaccine development has focused on antigens expressed during various stages of the life cycle of the parasite. Malaria transmission depends upon the development of intraerythrocytic sexual stages, ingestion by female anopheline mosquitoes and subsequent sexual development in mosquitoes leading to formation of sporozoites. An infected Anopheles mosquito initiates malaria infection cycle by injecting sporozoites which invade hepatocytes. Hence immune interventions aimed at blocking development of both the liver stage (pre-erythrocytic phase - PE) and sexual stage are expected to provide more effective strategy to protect against malaria. A transmission blocking vaccine (TBV) approach targeting antigens in the sexual stages (i.e. male and female gametocytes and gametes) and the mosquito stages of the parasite (i.e. zygote and ookinete) is believed to be of central importance in malaria elimination efforts. In Plasmodium falciparum, TBV target antigens include Pfs25, Pfs48/45 and Pfs230, with known orthologs in P. vivax. While a PE stage vaccine will prevent or reduce the development of blood stage parasites including gametocytes in an infected person, a TBV will block sexual reproduction of the gametocytes in the mosquito. A combination of vaccines targeting both PE and sexual/midgut stages, is expected to provide effective ways for interruption of malaria transmission, critical for elimination goal. Using knowledge gained from our published studies on Pfs25, Pvs28 and Pfs48/45, it is now possible to systematically evaluate a combination of these antigens along with PfCSP, an already well-established PE stage vaccine antigen. We propose to rationally develop and evaluate multi-stage (PE and sexual), multi-antigen (Pfs25, Pvs25, Pfs48/45, Pvs48/45 and PfCSP) and multi-species (P. falciparum and P. vivax) vaccine combinations to interrupt malaria transmission, a long-term and ultimate goal of our research. Using recombinant proteins, and DNA vaccines delivered by in vivo electroporation (EP), we will determine the potency of vaccine combinations comprised of target antigens from PE and sexual stages of P. falciparum (aim 1).
In aim 2, we will evaluate and compare combination of vaccines targeting transmission of the two major Plasmodium spp. (P. falciparum and P. vivax). The goal of studies in aim 3 is to determine outcome and immune potency of DNA vaccines by enhancing delivery of DNA plasmids and uptake of antigen by antigen presenting cells in vivo. The proposed studies are expected to identify most potent vaccine combination(s) and provide a rational approach for advancing effective combination(s) to interrupt transmission of malaria, an important goal of malaria elimination strategies.

Public Health Relevance

Malaria ranks among the top serious public health problems in the world with nearly half the world's population living in malaria endemic areas, resulting in as many as 214 million new infections and ~438,000 reported deaths in 2015. Significant gains achieved during the last decade from the use of insecticide-treated bednet and artemisinin combination therapies are being threatened by newly emergent resistance to artemisinin-related drugs. Vaccines have played a central role in the control of many and eradication of a few infectious diseases. Likewise, vaccines against malaria currently under development will provide the most effective way to control and eliminate the disease. We are proposing a novel strategy to combine multiple vaccine antigens for targeting interruption of malaria transmission from multiple species. Such a vaccine is expected to aid in the control and elimination of malaria via effective interruption of malaria transmission.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases Study Section (VMD)
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MO, Annie X Y
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George Washington University
Schools of Public Health
United States
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