Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9

Gregory M. Martin, Monica L. Fernández-Quintero, Wen-Hsin Lee, Tossapol Pholcharee, Lisa Eshun-Wilson, Klaus R. Liedl, Marie Pancera, Robert A. Seder, Ian A. Wilson and Andrew B. Ward ()
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Gregory M. Martin: The Scripps Research Institute
Monica L. Fernández-Quintero: The University of Innsbruck; Innrain 80-82/III
Wen-Hsin Lee: The Scripps Research Institute
Tossapol Pholcharee: The Scripps Research Institute
Lisa Eshun-Wilson: The Scripps Research Institute
Klaus R. Liedl: The University of Innsbruck; Innrain 80-82/III
Marie Pancera: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
Robert A. Seder: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Ian A. Wilson: The Scripps Research Institute
Andrew B. Ward: The Scripps Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure of the highly potent anti-PfCSP antibody L9 in complex with recombinant PfCSP. We found that L9 Fab binds multivalently to the minor (NPNV) repeat domain, which is stabilized by a unique set of affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed a critical role of the L9 light chain in integrity of the homotypic interface, which likely impacts PfCSP affinity and protective efficacy. These findings reveal the molecular mechanism of the unique NPNV selectivity of L9 and emphasize the importance of anti-homotypic affinity maturation in protective immunity against P. falciparum.

Date: 2023
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DOI: 10.1038/s41467-023-38509-2

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