Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers
• 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 combination.
• R40-1G8 is a class-1 RBD bNAb that binds to both ‘up’ and ‘down’ RBD.
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, B1.351, B.1.429, B.1.617, 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.