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

Author

Listed:
  • Gregory M. Martin

    (The Scripps Research Institute)

  • Jonathan L. Torres

    (The Scripps Research Institute)

  • Tossapol Pholcharee

    (The Scripps Research Institute
    University of Oxford)

  • David Oyen

    (The Scripps Research Institute
    Pfizer Inc)

  • Yevel Flores-Garcia

    (Johns Hopkins Bloomberg School of Public Health)

  • Grace Gibson

    (The Scripps Research Institute)

  • Re’em Moskovitz

    (The Scripps Research Institute)

  • Nathan Beutler

    (The Scripps Research Institute)

  • Diana D. Jung

    (The Scripps Research Institute)

  • Jeffrey Copps

    (The Scripps Research Institute)

  • Wen-Hsin Lee

    (The Scripps Research Institute)

  • Gonzalo Gonzalez-Paez

    (The Scripps Research Institute)

  • Daniel Emerling

    (Atreca Inc)

  • Randall S. MacGill

    (PATH’s Malaria Vaccine Initiative)

  • Emily Locke

    (PATH’s Malaria Vaccine Initiative)

  • C. Richter King

    (PATH’s Malaria Vaccine Initiative)

  • Fidel Zavala

    (Johns Hopkins Bloomberg School of Public Health)

  • Ian A. Wilson

    (The Scripps Research Institute
    The Scripps Research Institute)

  • Andrew B. Ward

    (The Scripps Research Institute)

Abstract

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.

Suggested Citation

  • Gregory M. Martin & Jonathan L. Torres & Tossapol Pholcharee & David Oyen & Yevel Flores-Garcia & Grace Gibson & Re’em Moskovitz & Nathan Beutler & Diana D. Jung & Jeffrey Copps & Wen-Hsin Lee & Gonza, 2023. "Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40151-x
    DOI: 10.1038/s41467-023-40151-x
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    References listed on IDEAS

    as
    1. Tossapol Pholcharee & David Oyen & Yevel Flores-Garcia & Gonzalo Gonzalez-Paez & Zhen Han & Katherine L. Williams & Wayne Volkmuth & Daniel Emerling & Emily Locke & C. Richter King & Fidel Zavala & Ia, 2021. "Structural and biophysical correlation of anti-NANP antibodies with in vivo protection against P. falciparum," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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    Cited by:

    1. Elena Ethel Vidal-Calvo & Anne Martin-Salazar & Swati Choudhary & Robert Dagil & Sai Sundar Rajan Raghavan & Lara Duvnjak & Mie Anemone Nordmaj & Thomas Mandel Clausen & Ann Skafte & Jan Oberkofler & , 2024. "Tumor-agnostic cancer therapy using antibodies targeting oncofetal chondroitin sulfate," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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