Abstract

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Yiska Weisblum

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    Yiska Weisblum, Rockefeller University has applied for a patent relating to the replication compentent VSV/SARS-CoV-2 chimeric virus on which YW is listed as an inventor (US patent 63/036,124).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9249-1745
  2. Fabian Schmidt

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    Fabian Schmidt, Rockefeller University has applied for a patent relating to the replication compentent VSV/SARS-CoV-2 chimeric virus on which FS is listed as an inventor (US patent 63/036,124).
  3. Fengwen Zhang

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  4. Justin DaSilva

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  5. Daniel Poston

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  6. Julio CC Lorenzi

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  7. Frauke Muecksch

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0132-5101
  8. Magdalena Rutkowska

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  9. Hans-Heinrich Hoffmann

    Laboratory of Vorology and Infectious Disease, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  10. Eleftherios Michailidis

    Laboratory of Vorology and Infectious Disease, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9907-4346
  11. Christian Gaebler

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  12. Marianna Agudelo

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  13. Alice Cho

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  14. Zijun Wang

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  15. Anna Gazumyan

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  16. Melissa Cipolla

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  17. Larry Luchsinger

    Lindsley F. Kimball Research Institute, New York Blood Center, New York City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0063-1764
  18. Christopher D Hillyer

    Lindsley F. Kimball Research Institute, New York Blood Center, New York, United States
    Competing interests
    No competing interests declared.
  19. Marina Caskey

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  20. Davide F Robbiani

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    Davide F Robbiani, Rockefeller University has applied for a patent relating to SARS-CoV-2 monoclonal antibodies on which DFR is listed as an inventor.
  21. Charles M Rice

    Laboratory of Vorology and Infectious Disease, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3087-8079
  22. Michel C Nussenzweig

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    Michel C Nussenzweig, Rockefeller University has applied for a patent relating to SARS-CoV-2 monoclonal antibodies on which MCN is listed as an inventor.
  23. Theodora Hatziioannou

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    For correspondence
    thatziio@rockefeller.edu
    Competing interests
    Theodora Hatziioannou, Rockefeller University has applied for a patent relating to the replication compentent VSV/SARS-CoV-2 chimeric virus on which TH is listed as an inventor (US patent 63/036,124).
  24. Paul D Bieniasz

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    For correspondence
    pbieniasz@rockefeller.edu
    Competing interests
    Paul D Bieniasz, Rockefeller University has applied for a patent relating to the replication compentent VSV/SARS-CoV-2 chimeric virus on which PDB is listed as an inventor (US patent 63/036,124).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2368-3719

Funding

National Institute of Allergy and Infectious Diseases (R37AI64003)

  • Paul D Bieniasz

National Institute of Allergy and Infectious Diseases (R01AI078788)

  • Theodora Hatziioannou

National Institute of Allergy and Infectious Diseases (P01AI138398-S1,2U19AI111825)

  • Charles M Rice
  • Michel C Nussenzweig

National Institute of Allergy and Infectious Diseases (R01AI091707-10S1)

  • Charles M Rice

George Mason University (Fast Grant)

  • Davide F Robbiani
  • Charles M Rice

European ATAC Consortium (EC101003650)

  • Davide F Robbiani

National Institutes of Health (UL1 TR001866)

  • Christian Gaebler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Human plasma samples were obtained from volunteers at the New York Blood Center and Rockefeller University Hospital. Informed consent, and consent to publishers obtained. De-identified Plasma samples from the New York Blood Center were obtained under protocols approved by Institutional Review Boards at the New York Blood Center and authorized by donors under informed consent in accordance with federal, state and local laws and regulations which address protection of human subjects in research, including 45 CFR part 46. Plasma samples at the Rockefeller University were collected with Informed consent, and consent to publishers after review by the Rockefeller University IRB protocol number DRO-1006.

Reviewing Editor

  1. Mark Marsh, University Coillege London, United Kingdom

Publication history

  1. Received: July 22, 2020
  2. Accepted: October 27, 2020
  3. Accepted Manuscript published: October 28, 2020 (version 1)
  4. Version of Record published: December 8, 2020 (version 2)

Copyright

© 2020, Weisblum et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yiska Weisblum
  2. Fabian Schmidt
  3. Fengwen Zhang
  4. Justin DaSilva
  5. Daniel Poston
  6. Julio CC Lorenzi
  7. Frauke Muecksch
  8. Magdalena Rutkowska
  9. Hans-Heinrich Hoffmann
  10. Eleftherios Michailidis
  11. Christian Gaebler
  12. Marianna Agudelo
  13. Alice Cho
  14. Zijun Wang
  15. Anna Gazumyan
  16. Melissa Cipolla
  17. Larry Luchsinger
  18. Christopher D Hillyer
  19. Marina Caskey
  20. Davide F Robbiani
  21. Charles M Rice
  22. Michel C Nussenzweig
  23. Theodora Hatziioannou
  24. Paul D Bieniasz
(2020)
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants
eLife 9:e61312.
https://doi.org/10.7554/eLife.61312
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