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

I. Kucharska,Danton Ivanochko,Sophia Hailemariam,Maartje R. Inklaar,Hee Ryung Kim,K. Teelen,Rianne Stoter,M. van de Vegte-Bolmer,G. van Gemert,Anthony Semesi,B. McLeod,Ahyoung Ki,Won-Kyu Lee,J. Rubinstein,M. Jore,Jean-Philippe Julien

Published 2025 in Nature Structural & Molecular Biology

ABSTRACT

Biomedical interventions that block the transmission of Plasmodium falciparum (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a target of clinical-stage transmission-blocking vaccines and monoclonal antibodies (mAbs) that disrupt Pf transmission to mosquitoes. Antibodies directed to domain 3 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 cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent human mAbs targeting all three domains. Our data indicate that although Pfs48/45 domains 1 and 2 are rigidly coupled, there is substantial conformational flexibility between domains 2 and 3. Characterization of mAbs against domain 1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by potent antibodies. Our study provides insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria interventions. Kucharska, Ivanochko and Hailemariam and colleagues solved cryo-EM structures of Pfs48/45, needed for Plasmodium falciparum development, with potent antibodies. The work revealed conformational epitopes, with implications for design of therapies against malaria.

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