The major goal of this proposal is to understand the nature of the conformational constraints that determine the vaccine efficacy of two asexual blood-stage antigens of P. falciparum. These antigens, apical membrane antigen 1 (AMA1) and merozoite surface protein 2 (MSP2), are both in the early stages of clinical development as potential components of a malaria vaccine. The fine specificity of the immune response to these and other proteins is critical in conferring protection against malaria infection, since only a proportion of the antibodies generated to a particular malaria antigen are protective. Understanding the antigenic features responsible for distinguishing between one antibody, which inhibits erythrocyte invasion, and another which is non-inhibitory is a central issue of this work.
The specific aims are: (1) to determine the solution structure of the individual domains of AMA1 and the 3D structure of the complete AMA1 ectodomain. Mapping the polymorphic residues onto these structures will aid in our understanding of immune evasion in malaria at the atomic level. (2) to map the sites on AMA1 that bind a range of inhibitory molecules and localize regions of importance. The solution structures of a range of molecules that bind to AMA1 and inhibit merozoite invasion, including peptides and antibodies, will be determined and their locations on the AMA1 surface mapped. The solution structures of peptides that mimic important inhibitory epitopes on AMA1 will also be determined and the ability of these peptides to act as surrogate markers for providing in vitro correlates of immunity will be examined. (3) to determine the biological and immunological relevance of the recently identified oligomeric forms of MSP2. A structural, biochemical and immunological characterization of the different forms of MSP2 will inform efforts to design a vaccine based on this antigen. This work builds on considerable expertise and novel reagents from extensive preliminary work. As this proposal addresses a fundamental aspect of malaria vaccine efficacy it should enhance our understanding of the nature of the protective immune response and inform the malaria vaccine effort.
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