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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.Cell

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.

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Authors+Show Affiliations

Piccoli L
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Park YJ
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Tortorici MA
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institut Pasteur and CNRS UMR 3569, Unité de Virologie Structurale, 75015 Paris, France.
Czudnochowski N
Vir Biotechnology, San Francisco, CA 94158, USA.
Walls AC
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Beltramello M
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Silacci-Fregni C
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Pinto D
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Rosen LE
Vir Biotechnology, San Francisco, CA 94158, USA.
Bowen JE
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Acton OJ
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Jaconi S
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Guarino B
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Minola A
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Zatta F
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Sprugasci N
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Bassi J
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Peter A
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
De Marco A
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Nix JC
Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Mele F
Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
Jovic S
Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
Rodriguez BF
Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
Gupta SV
Vir Biotechnology, San Francisco, CA 94158, USA.
Jin F
Vir Biotechnology, San Francisco, CA 94158, USA.
Piumatti G
Division of Primary Care, Geneva University Hospitals, 1205 Geneva, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland.
Lo Presti G
Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland.
Pellanda AF
Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland.
Biggiogero M
Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland.
Tarkowski M
III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy.
Pizzuto MS
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Cameroni E
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Havenar-Daughton C
Vir Biotechnology, San Francisco, CA 94158, USA.
Smithey M
Vir Biotechnology, San Francisco, CA 94158, USA.
Hong D
Vir Biotechnology, San Francisco, CA 94158, USA.
Lepori V
Independent Physician, 6500 Bellinzona, Switzerland.
Albanese E
Institute of Public Health, Università della Svizzera italiana, 6900 Lugano, Switzerland.
Ceschi A
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.
Bernasconi E
Division of Infectious Diseases, Ente Ospedaliero Cantonale, Ospedale Civico and Ospedale Italiano, 6900 Lugano, Switzerland.
Elzi L
Division of Infectious Diseases, Ente Ospedaliero Cantonale, Ospedale Regionale Bellinzona e Valli and Ospedale Regionale, 6600 Locarno, Switzerland.
Ferrari P
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.
Garzoni C
Clinic of Internal Medicine and Infectious Diseases, Clinica Luganese Moncucco, 6900 Lugano, Switzerland.
Riva A
III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy.
Snell G
Vir Biotechnology, San Francisco, CA 94158, USA.
Sallusto F
Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland.
Fink K
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Virgin HW
Vir Biotechnology, San Francisco, CA 94158, USA.
Lanzavecchia A
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland.
Corti D
Humabs BioMed SA, Vir Biotechnology, 6500 Bellinzona, Switzerland. Electronic address: dcorti@vir.bio.
Veesler D
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: dveesler@uw.edu.

MeSH

Angiotensin-Converting Enzyme 2Antibodies, MonoclonalAntibodies, NeutralizingAntibodies, ViralAntigen-Antibody ReactionsBetacoronavirusBinding SitesCOVID-19Coronavirus InfectionsEpitope MappingEpitopesHumansImmunoglobulin AImmunoglobulin GImmunoglobulin MKineticsMolecular Dynamics SimulationPandemicsPeptidyl-Dipeptidase APneumonia, ViralProtein BindingProtein DomainsProtein Structure, QuaternarySARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

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

Language

eng

PubMed ID

32991844

Clinical Trial Links

Change in Antibody Levels Following SARS-CoV-2 (Covid-19) Vaccinations
Phase II Study of AVX/COVID-12 Vaccine in Subjects With Prior SARS-CoV-2 Immunity Evidence
Clinical and Immunological Responses After SARS-CoV-2 Infection Causing COVID-19

Citation

Piccoli, Luca, et al. "Mapping Neutralizing and Immunodominant Sites On the SARS-CoV-2 Spike Receptor-Binding Domain By Structure-Guided High-Resolution Serology." Cell, vol. 183, no. 4, 2020, pp. 1024-1042.e21.
Piccoli L, Park YJ, Tortorici MA, et al. Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology. Cell. 2020;183(4):1024-1042.e21.
Piccoli, L., Park, Y. J., Tortorici, M. A., Czudnochowski, N., Walls, A. C., Beltramello, M., Silacci-Fregni, C., Pinto, D., Rosen, L. E., Bowen, J. E., Acton, O. J., Jaconi, S., Guarino, B., Minola, A., Zatta, F., Sprugasci, N., Bassi, J., Peter, A., De Marco, A., ... Veesler, D. (2020). Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology. Cell, 183(4), 1024-e21. https://doi.org/10.1016/j.cell.2020.09.037
Piccoli L, et al. 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. PubMed PMID: 32991844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology. AU - Piccoli,Luca, AU - Park,Young-Jun, AU - Tortorici,M Alejandra, AU - Czudnochowski,Nadine, AU - Walls,Alexandra C, AU - Beltramello,Martina, AU - Silacci-Fregni,Chiara, AU - Pinto,Dora, AU - Rosen,Laura E, AU - Bowen,John E, AU - Acton,Oliver J, AU - Jaconi,Stefano, AU - Guarino,Barbara, AU - Minola,Andrea, AU - Zatta,Fabrizia, AU - Sprugasci,Nicole, AU - Bassi,Jessica, AU - Peter,Alessia, AU - De Marco,Anna, AU - Nix,Jay C, AU - Mele,Federico, AU - Jovic,Sandra, AU - Rodriguez,Blanca Fernandez, AU - Gupta,Sneha V, AU - Jin,Feng, AU - Piumatti,Giovanni, AU - Lo Presti,Giorgia, AU - Pellanda,Alessandra Franzetti, AU - Biggiogero,Maira, AU - Tarkowski,Maciej, AU - Pizzuto,Matteo S, AU - Cameroni,Elisabetta, AU - Havenar-Daughton,Colin, AU - Smithey,Megan, AU - Hong,David, AU - Lepori,Valentino, AU - Albanese,Emiliano, AU - Ceschi,Alessandro, AU - Bernasconi,Enos, AU - Elzi,Luigia, AU - Ferrari,Paolo, AU - Garzoni,Christian, AU - Riva,Agostino, AU - Snell,Gyorgy, AU - Sallusto,Federica, AU - Fink,Katja, AU - Virgin,Herbert W, AU - Lanzavecchia,Antonio, AU - Corti,Davide, AU - Veesler,David, Y1 - 2020/09/16/ PY - 2020/8/3/received PY - 2020/8/28/revised PY - 2020/9/11/accepted PY - 2020/9/30/pubmed PY - 2020/11/26/medline PY - 2020/9/29/entrez KW - COVID-19 KW - SARS-CoV-2 KW - coronaviruses KW - effector functions KW - immunity KW - neutralizing antibodies SP - 1024 EP - 1042.e21 JF - Cell JO - Cell VL - 183 IS - 4 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32991844/Mapping_Neutralizing_and_Immunodominant_Sites_on_the_SARS_CoV_2_Spike_Receptor_Binding_Domain_by_Structure_Guided_High_Resolution_Serology_ DB - PRIME DP - Unbound Medicine ER -