Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against 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 b...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2022-01, Vol.375 (6579), p.449-454
Main Authors: Park, Young-Jun, De Marco, Anna, Starr, Tyler N, Liu, Zhuoming, Pinto, Dora, Walls, Alexandra C, Zatta, Fabrizia, Zepeda, Samantha K, Bowen, John E, Sprouse, Kaitlin R, Joshi, Anshu, Giurdanella, Martina, Guarino, Barbara, Noack, Julia, Abdelnabi, Rana, Foo, Shi-Yan Caroline, Rosen, Laura E, Lempp, Florian A, Benigni, Fabio, Snell, Gyorgy, Neyts, Johan, Whelan, Sean P J, Virgin, Herbert W, Bloom, Jesse D, Corti, Davide, Pizzuto, Matteo Samuele, Veesler, David
Format: Article
Language:English
Subjects:
ACE2
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - chemistry
Angiotensin-Converting Enzyme 2 - metabolism
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - metabolism
Antibodies, Monoclonal - therapeutic use
Antibodies, Viral - chemistry
Antibodies, Viral - immunology
Antibodies, Viral - metabolism
Antibody Affinity
Betacoronavirus - immunology
Binding
Broadly Neutralizing Antibodies - chemistry
Broadly Neutralizing Antibodies - immunology
Broadly Neutralizing Antibodies - metabolism
Broadly Neutralizing Antibodies - therapeutic use
Coronaviruses
COVID-19 - immunology
COVID-19 - therapy
Cross Reactions
Cryoelectron Microscopy
Epitopes
Humans
Immune Evasion
Mesocricetus
Mimicry
Models, Molecular
Molecular Mimicry
Monoclonal antibodies
Mutation
Neutralization
Neutralizing
Protein Conformation
Protein Domains
Proteins
Receptors
Receptors, Coronavirus - chemistry
Receptors, Coronavirus - metabolism
SARS-CoV-2 - immunology
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - chemistry
Spike Glycoprotein, Coronavirus - genetics
Spike Glycoprotein, Coronavirus - immunology
Spike Glycoprotein, Coronavirus - metabolism
Spike protein
Vaccination
Viral diseases
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Summary:Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against 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 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 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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abm8143