1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
Download icon

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Research Article
  • Cited 0
  • Views 2,434
  • Annotations
Cite this article as: eLife 2020;9:e61312 doi: 10.7554/eLife.61312

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.

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)

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.

Metrics

  • 2,434
    Page views
  • 539
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Immunology and Inflammation
    Cristina Alarcón-Vila et al.
    Research Article Updated

    P2X7 receptor activation induces the release of different cellular proteins, such as CD14, a glycosylphosphatidylinositol (GPI)-anchored protein to the plasma membrane important for LPS signaling via TLR4. Circulating CD14 has been found at elevated levels in sepsis, but the exact mechanism of CD14 release in sepsis has not been established. Here, we show for first time that P2X7 receptor induces the release of CD14 in extracellular vesicles, resulting in a net reduction in macrophage plasma membrane CD14 that functionally affects LPS, but not monophosphoryl lipid A, pro-inflammatory cytokine production. Also, we found that during a murine model of sepsis, P2X7 receptor activity is important for maintaining elevated levels of CD14 in biological fluids and a decrease in its activity results in higher bacterial load and exacerbated organ damage, ultimately leading to premature deaths. Our data reveal that P2X7 is a key receptor for helping to clear sepsis because it maintains elevated concentrations of circulating CD14 during infection.

    1. Evolutionary Biology
    2. Immunology and Inflammation
    Damilola Pinheiro et al.
    Research Article

    Neutrophils constitute the largest population of phagocytic granulocytes in the blood of mammals. The development and function of neutrophils and monocytes is primarily governed by the granulocyte colony-stimulating factor receptor family (CSF3R/CSF3) and macrophage colony-stimulating factor receptor family (CSF1R/IL34/CSF1) respectively. Using various techniques this study considered how the emergence of receptor:ligand pairings shaped the distribution of blood myeloid cell populations. Comparative gene analysis supported the ancestral pairings of CSF1R/IL34 and CSF3R/CSF3, and the emergence of CSF1 later in lineages after the advent of Jawed/Jawless fish. Further analysis suggested that the emergence of CSF3 lead to reorganisation of granulocyte distribution between amphibian and early reptiles. However, the advent of endothermy likely contributed to the dominance of the neutrophil/heterophil in modern-day mammals and birds. In summary, we show that the emergence of CSF3R/CSF3 was a key factor in the subsequent evolution of the modern-day mammalian neutrophil.