Targeting the Conserved Fusion Loop of HAP2 Inhibits the Transmission of Plasmodium berghei and falciparum

Summary Inhibiting transmission of Plasmodium is a central strategy in malarial eradication, and the biological process of gamete fusion during fertilization is a proven target for this approach. The lack of a structure or known molecular function of current anti-malarial vaccine targets has previously been a hindrance in the development of transmission-blocking vaccines. Structure/function studies have indicated that the conserved gamete membrane fusion protein HAP2 is a class II viral fusion protein. Here, we demonstrate that targeting a function-critical site of the fusion/ cd loop with species-specific antibodies reduces Plasmodium berghei transmission in vivo by 58.9% and in vitro fertilization by up to 89.9%. A corresponding reduction in P. falciparum transmission (75.5%/36.4% reductions in intensity/prevalence) is observed in complimentary field studies. These results emphasize conserved mechanisms of fusion in Apicomplexa , while highlighting an approach to design future anti-malarial transmission-blocking vaccines. Graphical Abstract Highlights • Plasmodium HAP2 is a class II fusion protein • Class II proteins are targetable to inhibit fertilization/transmission • A short synthetically generated peptide can induce transmission-blocking immunity Angrisano et al. find that the HAP2 cd -loop can be targeted as an anti-malarial intervention, is immunogenic across multiple plasmodial species, can induce antibodies that specifically recognize the sexual stages of the parasitic life cycle, and can mediate transmission-blocking immunity in the lab and the field.