Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

The ISARIC4C Investigators, COVID-19 Genomics UK (COG-UK) Consortium, Andrew Beggs

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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.
Original languageEnglish
Pages (from-to)1171-1187.e20
Number of pages38
Issue number5
Early online date28 Jan 2021
Publication statusPublished - 4 Mar 2021


  • COVID-19
  • N439K
  • SARS-CoV-2
  • Spike
  • monoclonal antibody escape
  • mutation
  • protein structure
  • receptor binding motif
  • variant


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