1. Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry
- Author
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Barbara Guarino, Young-Jun Park, Tyler N. Starr, Herbert W. Virgin, Florian A. Lempp, Matteo Samuele Pizzuto, Anshu Joshi, Sean P. J. Whelan, Gyorgy Snell, Alexandra C. Walls, Zhuoming Liu, Jesse D. Bloom, Johan Neyts, Julia Noack, Fabrizia Zatta, Davide Corti, Martina Giurdanella, Samantha K Zepeda, Dora Pinto, Rana Abdelnabi, Fabio Benigni, John E. Bowen, Kaitlin S Sprouse, David Veesler, Anna De Marco, and Shi-Yan Caroline Foo
- Subjects
Models, Molecular ,Protein Conformation ,medicine.drug_class ,viruses ,Mutant ,Antibody Affinity ,Cross Reactions ,Antibodies, Viral ,medicine.disease_cause ,Monoclonal antibody ,Article ,Epitope ,Neutralization ,Betacoronavirus ,Epitopes ,Protein Domains ,Immunity ,medicine ,Animals ,Humans ,Binding site ,Immune Evasion ,Multidisciplinary ,Mesocricetus ,biology ,SARS-CoV-2 ,Cryoelectron Microscopy ,Molecular Mimicry ,Antibodies, Monoclonal ,COVID-19 ,Virology ,Molecular mimicry ,Mutation ,Spike Glycoprotein, Coronavirus ,biology.protein ,Angiotensin-Converting Enzyme 2 ,Antibody ,Broadly Neutralizing Antibodies ,Receptors, Coronavirus - Abstract
Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV– and SARS-CoV-2–related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta variant challenge in hamsters, and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.
- Published
- 2022