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Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

Author

Listed:
  • Matthew Gagne

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Barbara J. Flynn

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Christopher Cole Honeycutt

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Dillon R. Flebbe

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Shayne F. Andrew

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Samantha J. Provost

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Lauren McCormick

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Alex Ry

    (Bioqual Inc.)

  • Elizabeth McCarthy

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health
    Fred Hutch Cancer Center)

  • John-Paul M. Todd

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Saran Bao

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • I-Ting Teng

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Shir Marciano

    (Weizmann Institute of Science)

  • Yinon Rudich

    (Weizmann Institute of Science)

  • Chunlin Li

    (Weizmann Institute of Science)

  • Shilpi Jain

    (Emory University School of Medicine
    Emory University
    Emory National Primate Research Center)

  • Bushra Wali

    (Emory University School of Medicine
    Emory University
    Emory National Primate Research Center)

  • Laurent Pessaint

    (Bioqual Inc.)

  • Alan Dodson

    (Bioqual Inc.)

  • Anthony Cook

    (Bioqual Inc.)

  • Mark G. Lewis

    (Bioqual Inc.)

  • Hanne Andersen

    (Bioqual Inc.)

  • Jiří Zahradník

    (Weizmann Institute of Science)

  • Mehul S. Suthar

    (Emory University School of Medicine
    Emory University
    Emory National Primate Research Center
    Emory University)

  • Martha C. Nason

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Kathryn E. Foulds

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Peter D. Kwong

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Mario Roederer

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Gideon Schreiber

    (Weizmann Institute of Science)

  • Robert A. Seder

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Daniel C. Douek

    (National Institute of Allergy and Infectious Diseases, National Institutes of Health)

Abstract

SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta—the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Suggested Citation

  • Matthew Gagne & Barbara J. Flynn & Christopher Cole Honeycutt & Dillon R. Flebbe & Shayne F. Andrew & Samantha J. Provost & Lauren McCormick & Alex Ry & Elizabeth McCarthy & John-Paul M. Todd & Saran , 2024. "Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51046-w
    DOI: 10.1038/s41467-024-51046-w
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    References listed on IDEAS

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