Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology

Luca Piccoli; Young-Jun Park; M Alejandra Tortorici; Nadine Czudnochowski; Alexandra C Walls; Martina Beltramello; Chiara Silacci-Fregni; Dora Pinto; Laura E Rosen; John E Bowen; Oliver J Acton; Stefano Jaconi; Barbara Guarino; Andrea Minola; Fabrizia Zatta; Nicole Sprugasci; Jessica Bassi; Alessia Peter; Anna De Marco; Jay C Nix; Federico Mele; Sandra Jovic; Blanca Fernandez Rodriguez; Sneha V Gupta; Feng Jin; Giovanni Piumatti; Giorgia Lo Presti; Alessandra Franzetti Pellanda; Maira Biggiogero; Maciej Tarkowski; Matteo S Pizzuto; Elisabetta Cameroni; Colin Havenar-Daughton; Megan Smithey; David Hong; Valentino Lepori; Emiliano Albanese; Alessandro Ceschi; Enos Bernasconi; Luigia Elzi; Paolo Ferrari; Christian Garzoni; Agostino Riva; Gyorgy Snell; Federica Sallusto; Katja Fink; Herbert W Virgin; Antonio Lanzavecchia; Davide Corti; David Veesler

doi:10.1016/j.cell.2020.09.037

Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology

Cell. 2020 Nov 12;183(4):1024-1042.e21. doi: 10.1016/j.cell.2020.09.037. Epub 2020 Sep 16.

Authors

Luca Piccoli¹, Young-Jun Park², M Alejandra Tortorici³, Nadine Czudnochowski⁴, Alexandra C Walls², Martina Beltramello¹, Chiara Silacci-Fregni¹, Dora Pinto¹, Laura E Rosen⁴, John E Bowen², Oliver J Acton², Stefano Jaconi¹, Barbara Guarino¹, Andrea Minola¹, Fabrizia Zatta¹, Nicole Sprugasci¹, Jessica Bassi¹, Alessia Peter¹, Anna De Marco¹, Jay C Nix⁵, Federico Mele⁶, Sandra Jovic⁶, Blanca Fernandez Rodriguez⁶, Sneha V Gupta⁴, Feng Jin⁴, Giovanni Piumatti⁷, Giorgia Lo Presti⁸, Alessandra Franzetti Pellanda⁸, Maira Biggiogero⁸, Maciej Tarkowski⁹, Matteo S Pizzuto¹, Elisabetta Cameroni¹, Colin Havenar-Daughton⁴, Megan Smithey⁴, David Hong⁴, Valentino Lepori¹⁰, Emiliano Albanese¹¹, Alessandro Ceschi¹², Enos Bernasconi¹³, Luigia Elzi¹⁴, Paolo Ferrari¹⁵, Christian Garzoni⁸, Agostino Riva⁹, Gyorgy Snell⁴, Federica Sallusto⁶, Katja Fink¹, Herbert W Virgin⁴, Antonio Lanzavecchia¹, Davide Corti¹⁶, David Veesler¹⁷

Affiliations

¹ Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
² Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
³ Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institut Pasteur and CNRS UMR 3569, Unité de Virologie Structurale, 75015 Paris, France.
⁴ Vir Biotechnology, San Francisco, CA 94158, USA.
⁵ Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
⁶ Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
⁷ Division of Primary Care, Geneva University Hospitals, 1205 Geneva, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland.
⁸ Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland.
⁹ III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy.
¹⁰ Independent Physician, 6500 Bellinzona, Switzerland.
¹¹ Institute of Public Health, Università della Svizzera italiana, 6900 Lugano, Switzerland.
¹² Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland; Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, 6900 Lugano, Switzerland; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, 8091 Zurich, Switzerland.
¹³ Division of Infectious Diseases, Ente Ospedaliero Cantonale, Ospedale Civico and Ospedale Italiano, 6900 Lugano, Switzerland.
¹⁴ Division of Infectious Diseases, Ente Ospedaliero Cantonale, Ospedale Regionale Bellinzona e Valli and Ospedale Regionale, 6600 Locarno, Switzerland.
¹⁵ Department of Nephrology, Ospedale Civico Lugano, Ente Ospedaliero Cantonale, 6900 Lugano, Switzerland; Prince of Wales Hospital Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
¹⁶ Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland. Electronic address: dcorti@vir.bio.
¹⁷ Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: dveesler@uw.edu.

Abstract

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

Keywords: COVID-19; SARS-CoV-2; coronaviruses; effector functions; immunity; neutralizing antibodies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2
Antibodies, Monoclonal / chemistry
Antibodies, Monoclonal / genetics
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing / blood
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / immunology*
Antibodies, Viral / blood
Antibodies, Viral / chemistry
Antibodies, Viral / immunology
Antigen-Antibody Reactions
Betacoronavirus / immunology
Betacoronavirus / isolation & purification
Betacoronavirus / metabolism
Binding Sites
COVID-19
Coronavirus Infections / pathology
Coronavirus Infections / virology
Epitope Mapping / methods*
Epitopes / chemistry
Epitopes / immunology
Humans
Immunoglobulin A / blood
Immunoglobulin A / immunology
Immunoglobulin G / blood
Immunoglobulin G / immunology
Immunoglobulin M / blood
Immunoglobulin M / immunology
Kinetics
Molecular Dynamics Simulation
Pandemics
Peptidyl-Dipeptidase A / chemistry
Peptidyl-Dipeptidase A / metabolism
Pneumonia, Viral / pathology
Pneumonia, Viral / virology
Protein Binding
Protein Domains / immunology
Protein Structure, Quaternary
SARS-CoV-2
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology*
Spike Glycoprotein, Coronavirus / metabolism

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Epitopes
Immunoglobulin A
Immunoglobulin G
Immunoglobulin M
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Peptidyl-Dipeptidase A
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding