Once Bitten: Acquisition of Malaria Adaptive Immunity (OBAMA - Immunity)

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Plasmodium falciparum control has stalled, and further progress reducing infections and deaths will require a highly-effective malaria vaccine. Individuals exposed to malaria develop protective immune responses gradually over several infections. Studies of immune responses to P. falciparum have consistently demonstrated that targets which exhibit very high diversity are critical for these protective responses. However, immunity to these antigens is dominated by strain-specific responses, which confer partial but imperfect protection to heterologous strains. This is a challenge for current vaccine candidates, including the first licensed malaria vaccine RTS,S, which are based on a single antigenic variant for a protein target and suffer from reduced efficacy to non-vaccine strains. There is evidence for strain-transcendent immunity in naturally exposed populations where individuals mount broadly protective responses after a few infections, despite the presence of dozens if not hundreds of different strains. Understanding how to elicit strain-transcendent immunity towards key, diverse antigenic targets has the potential to transform the next generation of vaccine products. Prior longitudinal studies of infection and disease are unable to furnish this insight mainly because they suffer from the inability to distinguish protection from lack of exposure in naturally exposed populations. As a consequence, there is no clear phenotype of protection, producing an incomplete understanding of the acquisition of protective immunity. Using our unique, longstanding cohort encompassing ~600 people in 75 households (initiated in 2017) in a high-transmission community in Western Kenya, we are able to pinpoint parasite transmission events to the individual-level, characterize the variant composition of multi-strain P. falciparum exposures, and document the outcome (no infection or protected vs. infected with or without symptoms) at the variant level. By leveraging known exposures to clearly define protection phenotypes within a natural system that encompasses a high degree of parasite diversity, we are uniquely-positioned to answer longstanding questions about protective immune responses. The goal of the proposed work is to use our unique system to advance multi-variant vaccine design. In our first Aim, we will quantify the strain-specific risk of malaria infection following a confirmed infectious bite (exposure). In the second Aim, we will leverage peri- exposure and post-exposure samples to correlate strain-specific protection following an infectious bite with strain-specific immune responses in order to identify strain-transcendent responses, and then identify variants that most effectively promote strain-transcendent responses. Our hypothesis is that a minimum set of strain- specific immune responses will be associated with strain-transcendent protection from infection after exposure. By exploring heterologous versus homologous strain-specific responses to elucidate a minimum set of antigenic variants required to confer strain-transcendent protection, we can facilitate the development and delivery of the next generation of P. falciparum vaccines.