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Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class 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) Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. . (Unpublished)

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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 plasma, including plasma from individuals from whom some of the antibodies were isolated. The plasma-escape maps most closely 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 dominated by a single class of antibodies targeting an epitope that is already undergoing rapid evolution.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemData/Code ItemData/Code
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
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. This version posted March 18, 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., 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. 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., D.P.; Resources, M.C.N., D.F.R., M.C., C.G., A.C., M.A., S.F., Z.W., 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. Declarations of Interests: 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 other authors declare no competing interests.
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
Record Number:CaltechAUTHORS:20210322-133440105
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Official Citation:Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. Allison J. Greaney, Tyler N. Starr, Christopher O. Barnes, Yiska Weisblum, Fabian Schmidt, Marina Caskey, Christian Gaebler, Alice Cho, Marianna Agudelo, Shlomo Finkin, Zijun Wang, Daniel Poston, Frauke Muecksch, Theodora Hatziioannou, Paul D. Bieniasz, Davide F. Robbiani, Michel C. Nussenzweig, Pamela J. Bjorkman, Jesse D. Bloom. bioRxiv 2021.03.17.435863; doi:
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:19 Apr 2021 22:05

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