Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants
- The Rockefeller University, United States
- New York Blood Center, United States
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
Eleftherios Michailidis
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
- Mark Marsh, University Coillege London, United Kingdom
Publication history
- Received: July 22, 2020
- Accepted: October 27, 2020
- Accepted Manuscript published: October 28, 2020 (version 1)
- 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.
Metrics
-
- 32,843
- Page views
-
- 3,505
- Downloads
-
- 598
- Citations
Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, 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)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants
eLife 9:e61312.
https://doi.org/10.7554/eLife.61312
Further reading
-
- Epidemiology and Global Health
- Medicine
- Microbiology and Infectious Disease
eLife has published the following articles on SARS-CoV-2 and COVID-19.
-
- Immunology and Inflammation
- Structural Biology and Molecular Biophysics
Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors, IL-27Rα and gp130, results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.
