Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies.

Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.

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Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests D.J.S. has consulted for AstraZeneca AB on topics related to viral evolution and the use of monoclonal antibodies for SARS-CoV-2. P.P. is currently employed by BioNTech. A.J.G. and J.D.B. have the potential to receive a share of IP revenue as inventors on the Fred Hutch-optioned technology related to deep mutational scanning of the receptor-binding domain of the SARS-CoV-2 spike protein. J.D.B. consults for Apriori Bio, Aerium Therapeutics, Invivyd, and the Vax Company on topics related to viral evolution. B.M.H. is founder and owner of Macrostruct Consulting AB. M.C. and G.B.K.H. are co-founders and co-owners of ImmuneDiscover Sweden AB.