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Affinity-matured homotypic interactions induce spectrum of PfCSP-antibody structures that influence protection from malaria infection

Gregory M. Martin,J. Torres,T. Pholcharee,D. Oyen,Yevel Flores-Garcia,Grace Gibson,Re’em Moskovitz,N. Beutler,Diana D. Jung,Jeffrey Copps,W. Lee,G. González-Páez,D. Emerling,R. MacGill,Emily Locke,C. King,F. Zavala,I. Wilson,A. Ward

Published 2022 in bioRxiv

ABSTRACT

The generation of high-quality antibody responses to PfCSP, the primary surface antigen of Plasmodium falciparum sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the IGHV3-33 germline gene, which is among the most prevalent and potent antibody families induced in the anti-CSP immune response and targets the NANP repeat region. Cryo-EM reveals a remarkable spectrum of helical Fab-CSP structures stabilized by homotypic interactions between tightly packed Fabs, many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to CSP and in protection from P. falciparum malaria infection. These data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies, advance our understanding of the mechanism(s) of antibody-mediated protection, and inform next generation CSP vaccine design.

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