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

Plasmodium falciparum control has stalled, and further progress in reducing infections and deaths will require a highly-effective malaria vaccine. Individuals exposed to malaria gradually develop protective immune responses over several infections. Studies of immune responses to P. falciparum have consistently demonstrated that targets exhibiting very high diversity are critical for these protective responses. However, immunity to these antigens is dominated by strain-specific responses, conferring partial but imperfect protection to heterologous strains. This presents a challenge for current vaccine candidates, including the first licensed malaria vaccine RTS,S, which is based on a single antigenic variant for a protein target and suffers from reduced efficacy against non-vaccine strains. Evidence suggests strain-transcendent immunity in naturally exposed populations, where individuals mount broadly protective responses after a few infections despite the presence of numerous strains. Understanding how to elicit strain-transcendent immunity toward key, diverse antigenic targets has the potential to transform the next generation of vaccine products. Previous longitudinal studies of infection and disease have been unable to provide this insight, mainly due to their inability to distinguish protection from a lack of exposure in naturally exposed populations. As a result, a clear phenotype of protection has not been established, leading to an incomplete understanding of the acquisition of protective immunity. By using a unique, longstanding cohort of approximately 600 people in 75 households (initiated in 2017) in a high-transmission community in Western Kenya, individual parasite transmission events can be pinpointed, the variant composition of multi-strain P. falciparum exposures can be characterized, and outcomes (no infection or protection vs. infection with or without symptoms) can be documented at the variant level. Known exposures are leveraged to clearly define protection phenotypes within a natural system that encompasses a high degree of parasite diversity, allowing for the answering of longstanding questions about protective immune responses. The goal of the proposed work is to use this unique system to advance multi-variant vaccine design. In the first aim, the strain-specific risk of malaria infection following a confirmed infectious bite (exposure) will be quantified. In the second aim, peri-exposure and post-exposure samples will be used to correlate strain-specific protection following an infectious bite with strain-specific immune responses, in order to identify strain-transcendent responses and the variants that most effectively promote these responses. The 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 the minimum set of antigenic variants required for strain-transcendent protection, the development and delivery of the next generation of P. falciparum vaccines can be facilitated.

NIH project details

Immunology

Jul 2023 — Jun 2028

$2.08M

Kenya