Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers

Cell Host Microbe. 2022 Jan 12;30(1):69-82.e10. doi: 10.1016/j.chom.2021.12.010. Epub 2021 Dec 18.


A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both "up" and "down" conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.

Keywords: COVID-19; SARS-CoV-2; broadly neutralizing antibodies; cryo-EM; emerging variants; ultrapotent monoclonal antibodies; variants of concern.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Viral / immunology*
  • Broadly Neutralizing Antibodies / immunology*
  • COVID-19 / immunology*
  • COVID-19 / virology
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cross Reactions / immunology
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Middle Aged
  • Neutralization Tests / methods
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology
  • Vero Cells


  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • Spike Glycoprotein, Coronavirus

Supplementary concepts

  • SARS-CoV-2 variants