Cell Host Microbe
. 2021 Dec 18;S1931-3128(21)00581-3.
doi: 10.1016/j.chom.2021.12.010. Online ahead of print.
Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers
Kanika Vanshylla 1 , Chengcheng Fan 2 , Marie Wunsch 1 , Nareshkumar Poopalasingam 1 , Matthijs Meijers 3 , Christoph Kreer 1 , Franziska Kleipass 1 , Denis Ruchnewitz 3 , Meryem S Ercanoglu 1 , Henning Gruell 1 , Friederike Münn 4 , Kai Pohl 4 , Hanna Janicki 1 , Tobias Nolden 5 , Simone Bartl 6 , Saskia C Stein 7 , Max Augustin 8 , Felix Dewald 1 , Lutz Gieselmann 1 , Philipp Schommers 9 , Thomas F Schulz 7 , Leif Erik Sander 4 , Manuel Koch 10 , Marta Łuksza 11 , Michael Lässig 3 , Pamela J Bjorkman 2 , Florian Klein 12
Affiliations
- PMID: 34973165
- DOI: 10.1016/j.chom.2021.12.010
Abstract
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.