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McLeod, Brandon Robert
01/2023Dissertation
Malaria is an ongoing global health crisis with cases and resistance to treatments on the rise. Only one malaria vaccine is currently recommended for use in endemic regions in Africa by the WHO, which has middling efficacy that drops to approximately 35% protection against clinical disease after a year. Novel approaches are urgently needed. Transmission-blocking vaccines aim to inhibit the malaria parasite, Plasmodium falciparum, while in the mosquito vector, so the parasite is not viable to transmit to the human host. However, both biological and biophysical understanding is lacking for most target antigens within the field. This thesis establishes the groundwork for the molecular understanding of antibody recognition of leading transmission-blocking antigens Pfs25 and Pfs48/45 by solving multiple crystal structures of Fabs bound in complex to the antigens. Herein is described the first atomic resolution structure of Pfs25, as well as the molecular characterizations of both murine and human monoclonal antibody epitopes of high and low potency, providing a comprehensive map of the immunogenicity and potency of Pfs25. This thesis also leverages molecular blueprints of Pfs48/45 to stabilize its structure using integrative structural biology approaches leading to increases in recombinant expression (~30x), thermostability (>25°C improvement in melting temperature from wild-type), and potency (1-2 log) of the antibody response elicited through immunization. Overall, this work provides foundational molecular understandings and improvements to two of the most high- priority transmission-blocking vaccine targets against malaria.
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