Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Cell Host Microbe. 2021 Mar 10;29(3):477-488.e4. doi: 10.1016/j.chom.2021.01.014. Epub 2021 Jan 27.


Neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics. However, viral escape mutants could compromise efficacy. To define immune-selected mutations in the S protein, we exposed a VSV-eGFP-SARS-CoV-2-S chimeric virus, in which the VSV glycoprotein is replaced with the S protein, to 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) and generated 50 different escape mutants. Each mAb had a unique resistance profile, although many shared residues within an epitope of the RBD. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera. Additionally, sequential selection identified mutants that escape neutralization by antibody cocktails. Comparing these antibody-mediated mutations with sequence variation in circulating SARS-CoV-2 revealed substitutions that may attenuate neutralizing immune responses in some humans and thus warrant further investigation.

Keywords: ACE2 receptor decoys; COVID-19 vaccines; SARS-CoV-2 escape mutants; convalescent sera; coronaviruses; monoclonal antibodies; receptor-binding domain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Angiotensin-Converting Enzyme 2 / genetics
  • Animals
  • Antibodies, Monoclonal / blood*
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Antibodies, Viral / blood*
  • Antibodies, Viral / immunology
  • COVID-19 / virology
  • COVID-19 Vaccines / immunology
  • Chlorocebus aethiops
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Mutation*
  • Neutralization Tests / methods*
  • Protein Binding
  • Receptors, Virus / metabolism
  • SARS-CoV-2 / genetics*
  • SARS-CoV-2 / immunology
  • Spike Glycoprotein, Coronavirus / genetics*
  • Spike Glycoprotein, Coronavirus / immunology
  • Vero Cells


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2