Plasmodium vivax is responsible for 132-391 million cases of clinical malaria each year causing about 12% of infections in Africa and more than 70% of infections in Asia and the Americas. Vivax malaria is known to incapacitate individuals of all ages resulting in repeated febrile episodes, severe anemia, respiratory distress and poor outcomes in pregnancy. Exclusion of P. vivax from much of Africa is associated with high prevalence of Duffy blood group negativity while the parasite's strong preference for reticulocytes has limited our ability to conduct experimental research in the laboratory. Both of these biological characteristics can be attributed to ligands expressed by invasive blood-stage merozoites. Humoral immunity to P. vivax invasion ligands is believed to play a critical role in controlling the blood-stage infection thereby limiting clinical disease. Therefore, the Duffy binding protein, which binds its cognate receptor the Duffy blood group antigen, has become a leading candidate against vivax malaria with the primary focus on the cysteine-rich ligand domain, or region II (DBPII). The major obstacle for developing this antigen as an effective vaccine is its high degree of polymorphism within the receptor-binding site that makes ineffective the weak strain-specific immunity that typically results from infection. We hypothesize that dominant B-cell epitopes of DBPII are polymorphic as an evasion mechanism that diverts the immune response away from the more conserved, functionally important neutralizing epitopes similar to other microbial ligands. Data generated from our initial funding period supported this underlying hypothesis that guide our project and the methodological approaches pursued.
The specific aims will define the immunological properties of DBPII and identify functionally conserved determinants that are targets of strain-transcending inhibitory antibodies. Our long-term goal is to optimize efficacy of DBPII as a broadly effective vaccine that elicits antibodies to conserved strain-transcending neutralizing epitopes.
Malaria is a significant global health problem and Plasmodium vivax is the major cause of non-African malaria, causing 132-391 million cases of clinical malaria each year at an estimated cost of $1.4 - $4 billion per year. Widespread drug resistance, the relapsing nature of P. vivax, and emerging virulent forms of P. vivax emphasizes the critical need for development of a vaccine against P. vivax. Our goal is to develop a vaccine to eliminate vivax malaria as a major health problem.
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