Cell Host & Microbe
Volume 30, Issue 1, 12 January 2022, Pages 69-82.e10
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Article
Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers

https://doi.org/10.1016/j.chom.2021.12.010Get rights and content
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Highlights

  • SARS-CoV-2 elite neutralizers are a source for highly potent antibodies

  • Isolated bNAbs are highly active against VOCs and emerging variants

  • The majority of isolated bNAbs utilized a IGHV3-53/IGKV1-9 gene segment combination

  • R40-1G8 is a class-1 RBD bNAb that binds to both “up” and “down” RBD

Summary

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
variants of concern
emerging variants
ultrapotent monoclonal antibodies

Data and code availability

  • All data has been included in main figures or supplementary information.

  • SARS-CoV-2 antibody sequences are available at GenBank with accession numbers OL741060 - OL741311. The atomic coordinate and 3D EM reconstruction for SARS-CoV-2 S 6P in complex with R40-1G8 Fab has been deposited in the Protein Data Bank (PDB) with PDB ID 7SC1 and the Electron Microscopy Data Bank (EMDB) with EMDB 25008, respectively.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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