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

Abstract

SummaryThe generation of high-quality antibody responses to PfCSP, the primary surface antigen ofPlasmodium falciparumsporozoites, 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 theIGHV3-33germline 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 fromP. falciparummalaria infection. These data emphasize the importance of anti-homotypic affinity maturation in the frequent selection ofIGHV3-33antibodies, advance our understanding of the mechanism(s) of antibody-mediated protection, and inform next generation CSP vaccine design.