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Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies

Greaney, Allison J. and Starr, Tyler N. and Barnes, Christopher O. and Weisblum, Yiska and Schmidt, Fabian and Caskey, Marina and Gaebler, Christian and Cho, Alice and Agudelo, Marianna and Finkin, Shlomo and Wang, Zijun and Poston, Daniel and Muecksch, Frauke and Hatziioannou, Theodora and Bieniasz, Paul D. and Robbiani, Davide F. and Nussenzweig, Michel C. and Bjorkman, Pamela J. and Bloom, Jesse D. (2021) Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies. Nature Communications, 12 . Art. No. 4196. ISSN 2041-1723. PMCID PMC8263750; PMC7987015. doi:10.1038/s41467-021-24435-8.

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Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.

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URLURL TypeDescription ReadCube access Paper ItemCode ItemCode CentralDiscussion Paper CentralArticle
Greaney, Allison J.0000-0001-7202-3349
Starr, Tyler N.0000-0001-6713-6904
Barnes, Christopher O.0000-0003-2754-5951
Weisblum, Yiska0000-0002-9249-1745
Caskey, Marina0000-0003-1727-8693
Gaebler, Christian0000-0001-7295-8128
Agudelo, Marianna0000-0003-3924-6449
Finkin, Shlomo0000-0003-4474-2658
Wang, Zijun0000-0002-2095-2151
Hatziioannou, Theodora0000-0002-7889-0766
Bieniasz, Paul D.0000-0002-2368-3719
Robbiani, Davide F.0000-0001-7379-3484
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Bloom, Jesse D.0000-0003-1267-3408
Alternate Title:Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies
Additional Information:© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 18 May 2021; Accepted 11 June 2021; Published 07 July 2021. We thank Andrea Loes for experimental assistance and Cathy Lin for administrative support; Dolores Covarrubias, Andy Marty, and the Genomics and Flow Cytometry core facilities at the Fred Hutchinson Cancer Research Center for experimental support; J. Vielmetter, P. Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance. This work was supported by the NIAID/NIH (R01AI141707 and R01AI127893 to J.D.B., T32AI083203 to A.J.G., P01 AI138398-S1 to M.C.N. and P.J.B.) and the Gates Foundation (INV-004949). Support was also provided by the Caltech Merkin Institute for Translational Research (P.J.B.), a George Mason University Fast Grant (P.J.B.), and ATAC consortium EC 101003650 (D.F.R.); NIH grants U19 AI111825 and NIH U01 AI151698 for the United World Antiviral Research Network, UWARN (M.C.N. and D.F.R.). The Scientific Computing Infrastructure at Fred Hutch is funded by ORIP grant S10OD028685. T.N.S. is a Washington Research Foundation Innovation Fellow at the University of Washington Institute for Protein Design and a Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation (DRG-2381-19). C.O.B. was supported by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund. J.D.B., P.D.B., and M.C.N. are Investigators of the Howard Hughes Medical Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US government or the other sponsors. Code availability: The complete custom code computational pipeline for escape-mapping data analysis is available at and archived in the Zenodo repository ( Markdown summaries of the escape-mapping data analysis steps are at Author Contributions: Conceptualization: A.J.G., C.O.B., M.C.N., P.J.B. and J.D.B.; methodology: A.J.G., T.N.S. and J.D.B.; investigation: A.J.G.; software: A.J.G., T.N.S. and J.D.B.; formal analysis: A.J.G. and J.D.B.; VSV escape data: Y.W., F.S. and D.P.; resources: M.C.N., D.F.R., M.C., C.G., A.C., M.A., S.F., Z.W. and F.M.; writing—original draft: A.J.G. and J.D.B.; writing—review and editing: all authors; supervision: T.H., P.D.B., M.C.N., P.J.B. and J.D.B. Competing interests: Subsequent to completion and submission of the initial version of this study, J.D.B. began consulting for Moderna on viral evolution and epidemiology. J.D.B. has the potential to receive a share of IP revenue as an inventor on a Fred Hutch optioned technology/patent (application WO2020006494) related to deep mutational scanning of viral proteins. The Rockefeller University has filed a provisional patent application related to SARS-CoV-2 monoclonal antibodies on which D.F.R. and M.C.N. are inventors. The Rockefeller University has applied for a patent relating to the replication-competent VSV/SARS-CoV-2 chimeric virus on which Y.W, F.S., T.H. and P.B. are inventors (US patent 63/036,124). The remaining authors declare no competing interests. Peer review information: Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.
Group:COVID-19, Richard N. Merkin Institute for Translational Research
Funding AgencyGrant Number
NIHP01 AI138398-S1
Bill and Melinda Gates FoundationINV-004949
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
George Mason UniversityUNSPECIFIED
ATAC ConsortiumEC 101003650
NIHU19 AI111825
NIHU01 AI151698
Washington Research FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Damon Runyon Cancer Research FoundationDRG-2381-19
Burroughs Wellcome FundUNSPECIFIED
Subject Keywords:SARS-CoV-2; Viral evolution; Viral infection
PubMed Central ID:PMC8263750; PMC7987015
Record Number:CaltechAUTHORS:20210322-133440105
Persistent URL:
Official Citation:Greaney, A.J., Starr, T.N., Barnes, C.O. et al. Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies. Nat Commun 12, 4196 (2021).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108512
Deposited By: Tony Diaz
Deposited On:24 Mar 2021 19:50
Last Modified:26 Aug 2021 18:55

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