Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity
- PMID: 33621484
- PMCID: PMC7843029
- DOI: 10.1016/j.cell.2021.01.037
Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity
Abstract
SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.
Keywords: COVID-19; N439K; SARS-CoV-2; Spike; monoclonal antibody escape; mutation; protein structure; receptor binding motif; variant.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests L.E.R., R. Spreafico, J.A.W., L.P., J.D., N.C., M.M., A.D.M., J.B., D.P., K.C., F.Z., S.J., M.B., M.P., E.C., J.D.I., H.W.V., A.T., D.C., and G.S. are or were employees of Vir Biotechnology and may hold shares in Vir Biotechnology. C.G. is an external scientific advisor for Humabs BioMed SA. J. Nix and T.I.C. are consultants with Vir Biotechnology. M.G.S. declares interest in Integrum Scientific, Greensboro, NC, outside the scope of this work. J.D.C. is a current member of the Scientific Advisory Board of OpenEye Scientific Software and is a scientific consultant to Foresite Labs. The Chodera laboratory (I.Z., W.G.G., and J.D.C.) receives or has received funding from multiple sources, including the NIH, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, XtalPi, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at https://www.choderalab.org/funding. The other authors declare no competing interests.
Figures
Comment in
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Do rogue antibodies make the difference between mild versus severe COVID-19?Nat Rev Immunol. 2021 Mar;21(3):136. doi: 10.1038/s41577-021-00511-4. Nat Rev Immunol. 2021. PMID: 33542500 Free PMC article. No abstract available.
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SARS-CoV-2 variant evades antibodies whilst maintaining fitness.Nat Rev Immunol. 2021 Mar;21(3):136. doi: 10.1038/s41577-021-00510-5. Nat Rev Immunol. 2021. PMID: 33542501 Free PMC article. No abstract available.
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