A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction

Nat Biotechnol. 2020 Sep;38(9):1073-1078. doi: 10.1038/s41587-020-0631-z. Epub 2020 Jul 23.


A robust serological test to detect neutralizing antibodies to SARS-CoV-2 is urgently needed to determine not only the infection rate, herd immunity and predicted humoral protection, but also vaccine efficacy during clinical trials and after large-scale vaccination. The current gold standard is the conventional virus neutralization test requiring live pathogen and a biosafety level 3 laboratory. Here, we report a SARS-CoV-2 surrogate virus neutralization test that detects total immunodominant neutralizing antibodies targeting the viral spike (S) protein receptor-binding domain in an isotype- and species-independent manner. Our simple and rapid test is based on antibody-mediated blockage of the interaction between the angiotensin-converting enzyme 2 (ACE2) receptor protein and the receptor-binding domain. The test, which has been validated with two cohorts of patients with COVID-19 in two different countries, achieves 99.93% specificity and 95-100% sensitivity, and differentiates antibody responses to several human coronaviruses. The surrogate virus neutralization test does not require biosafety level 3 containment, making it broadly accessible to the wider community for both research and clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Betacoronavirus / genetics
  • Betacoronavirus / pathogenicity*
  • COVID-19
  • Coronavirus Infections / genetics*
  • Coronavirus Infections / immunology
  • Coronavirus Infections / pathology
  • Coronavirus Infections / virology
  • Humans
  • Neutralization Tests
  • Pandemics
  • Peptidyl-Dipeptidase A / genetics*
  • Pneumonia, Viral / genetics*
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • Protein Interaction Domains and Motifs / genetics
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / genetics*


  • Antibodies
  • Spike Glycoprotein, Coronavirus
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2