Kemri-Wellcome Trust Research Programme: A novel strategy for understanding the functional impact of variation in Plasmodium falciparum merozoite vaccine candidates.

Plasmodium falciparum merozoite proteins are required for the invasion of erythrocytes, an essential step for parasite survival and malaria pathogenesis. These proteins are also targets of naturally acquired immunity, making them potential vaccine targets. However, vaccine trials have shown the host often generates allele-specific responses which are not protective against heterologous non-vaccine alleles. This problem has been attributed to the polymorphisms in these antigens, but the actual fu nctional impact of polymorphism has not been systematically studied. I therefore propose to study the impact of variation in two merozoite antigens. I will assess their temporal allele frequency and naturally acquired immune response distribution over 20 years in the Kilifi population. I will use antibodies targeting the conserved and polymorphic regions of each antigen to determine the functional impact of polymorphisms on erythrocyte recognition and invasion in vitro. Finally, I will use a rec ently developed transfection strategy to develop a novel barcoded parallel phenotyping assay. This assay will mimic natural infections, which often contain multiple parasite variants invading erythrocytes in the presence of antibodies, allowing me to determine whether variation has an impact on immune evasion. This research will provide a set of assays to study other merozoite antigens in the future.

Programme: International Intermediate Fellowship

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