Structural elucidation of full-length Pfs48/45 in complex with potent mAbs isolated from a naturally exposed individual

Abstract

Abstract Biomedical interventions capable of preventing the transmission of malaria-causing Plasmodium falciparum (Pf) between the human host and mosquito vector could prove a valuable tool in malaria elimination efforts. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a key component of clinical-stage transmission-blocking vaccines. Antibodies against this antigen have been demonstrated to efficiently reduce Pf transmission from humans to mosquitoes. Potent human monoclonal antibodies (mAbs) against Domain 3 (D3) of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a 3.3 Å resolution cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent mAbs targeting Domain 1 (D1) and D3, and a moderately potent mAb targeting Domain 2 (D2). Our data indicate that while Pfs48/45 D1 and D2 are rigidly coupled, there is substantial conformational flexibility between D2 and D3. Characterization of mAbs against D1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by highly potent antibodies. Our study provides comprehensive insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria transmission-blocking vaccines and antibodies.