An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies

Cell. 2021 Jun 24;184(13):3452-3466.e18. doi: 10.1016/j.cell.2021.05.032. Epub 2021 May 24.


Antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from coronavirus disease 2019 (COVID-19) patients and found that some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all of the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients. Moreover, we identified antibodies against the infectivity-enhancing site in uninfected donors, albeit at a lower frequency. These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection.

Keywords: ADE; angiotensin converting enzyme 2; antibody-dependent enhancement; cryo-EM; cryo-electron microscopy; docking model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology*
  • COVID-19 / immunology
  • Cell Line
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Protein Binding / immunology
  • Protein Domains / immunology
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vero Cells


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2