Plasmodium falciparum is a major parasitic pathogen resulting in over 600,000 deaths annually. Within the mosquito host, the malaria parasite undergoes fertilisation and sexual reproduction critical for onwards transmission of the parasite to humans. Preventing parasite fertilisation in the mosquito midgut can halt malaria transmission. Pfs230 and Pfs48/45 are the current leading transmission-blocking vaccine candidates, which are present as a complex on the surface of sexual stage parasites and are essential for male gamete fertility.
We present a cryo-EM structure of the endogenous Pfs230-Pfs48/45 complex from P. falciparum sexual stage parasites. Our structure identified Pfs230 domains 13 and 14 as interaction site with Pfs48/45. We used transgenic parasites with a deletion of these domains to show they are crucial for localisation of Pfs230 on the gamete surface and their absence greatly reduces parasite transmission within the female Anopheles mosquito. Nanobodies against domains 13 and 14 are able to disrupt the endogenous Pfs230-Pfs48/45 complex, reduce transmission and structural analyses reveal their epitopes. Furthermore, domains 13 and 14 are targets of naturally acquired immunity and mRNA-LNP vaccination of mice with these domains elicits transmission-reducing antibodies. This work shows that Pfs230 domains 13 and 14 are new vaccine candidates for blocking malaria transmission.