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

Martin, Gregory M.; Torres, Jonathan L.; Pholcharee, Tossapol; Oyen, David; Flores-Garcia, Yevel; Gibson, Grace; Moskovitz, Re’em; Beutler, Nathan; Jung, Diana D.; Copps, Jeffrey; Lee, Wen-Hsin; Gonzalez-Paez, Gonzalo; Emerling, Daniel; MacGill, Randall S.; Locke, Emily; King, C. Richter; Zavala, Fidel; Wilson, Ian A.; Ward, Andrew B.

doi:10.1038/s41467-023-40151-x

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

Journal Article · 28 July 2023 · Nature Communications

DOI: https://doi.org/10.1038/s41467-023-40151-x · OSTI ID:2423882

Martin, Gregory M. ^[1];

^[1];

^[2]; Oyen, David ^[3]; Flores-Garcia, Yevel ^[4]; Gibson, Grace ^[1]; Moskovitz, Re’em ^[1];

^[1]; Jung, Diana D. ^[1];

^[1];

^[1]; Gonzalez-Paez, Gonzalo ^[1];

^[5];

^[6]; Locke, Emily ^[6]; King, C. Richter ^[6];

^[4];

^[7];

^[1]

The Scripps Research Inst., La Jolla, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States); Univ. of Oxford (United Kingdom)
The Scripps Research Inst., La Jolla, CA (United States); Pfizer Inc., San Diego, CA (United States)
Johns Hopkins Univ., Baltimore, MD (United States)
Atreca Inc., San Carlos, CA (United States)
PATH's Malaria Vaccine Initiative, Washington, DC (United States)
The Scripps Research Inst., La Jolla, CA (United States); The Scripps Research Inst., La Jolla, CA (United States). Skaggs Institute for Chemical Biology

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf 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 immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3–33 antibodies and highlight key features underlying the potent protection of this antibody family.

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Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: Bill & Melinda Gates Foundation; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2423882

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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