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Project Topic
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Malaria transmission blocking vaccines (PfTBV) halt parasite transmission to mosquitoes, and are needed for elimination. The most advanced PfTBV (Pfs230D1M-EPA/AS01) induces high and durable functional serum activity in African adults, providing an essential benchmark for our partnership to rapidly identify the optimal candidate for Phase 3 trials. PfTBV address WHO Goal 3 Target 3.3, aiming to “end the epidemic of malaria diseases” by 2030 since a highly effective malaria vaccine is currently unavailable. Malaria vaccine development has been thwarted by the stepwise approach to assess one protein in the clinic at a time, thereby delaying evaluations and diverting resources from other targets. We circumvent these challenges by directly comparing lead vaccine candidates, delivery platforms and adjuvants, providing definitive down-selection of optimal candidates for later efficacy trials. The resulting PfTBV could be used alongside RTS,S, or “anti-infection” vaccine components (outside this proposal). Multi-stage vaccines would directly protect and halt onward parasite transmission. Four African, two European, and one US institution will liase with the NIH as third party and form the PfTBV consortium, leveraging past/current investments. The primary proposal objective comparatively tests three well-established sexual stage antigens in human: Pfs48/45 (first-in-human testing), Pfs230 (clinical benchmark), and a Pfs230-Pfs48/45 chimeric antigen. In the first year, while Pfs48/45 vaccine materials are manufactured, an experimental medicine community trial of Pfs230D1M-EPA/AS01 will qualify/establish assays and endpoints for future Phase 2 trials, a first-of-its-kind trial to enroll children and qualify efficacy endpoints. In the first comparative clinical trials, antigens will be tested individually with various adjuvant formulations in African adults for induction of antibodies that block parasite transmission ex vivo. For products that are well-tolerated, safe, and elicit functional antibodies, a second comparative clinical trial will test superiority of a multi-component vaccine (combining the individual antigens), The CHMI model of controlled human malaria infection will be employed for studies of malaria transmission (CHMI-trans) in Africa. Circulating mature gametocytes induced in vaccinees are taken up by mosquitoes together with vaccine-specific antibodies, resulting in reduced numbers of infected mosquitoes as the measure of vaccine efficacy. A final Phase 2 field trial of the lead candidate in adults will establish activity that blocks transmission of naturally circulating parasites. The second objective is to strengthen capacity for vaccine trials, training, networking, and experience sharing (year 1). The third objective uses trial samples and data to identify immune correlates of vaccine efficacy, and compiles a African biobank for future study.
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