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

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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Affiliated Institutions

• Luigi Sacco Hospital IT
• Centre National de la Recherche Scientifique FR
• Università della Svizzera italiana CH
• Lawrence Berkeley National Laboratory US
• University Hospital of Zurich CH
• Ente Ospedaliero Cantonale CH
• VIR Biotechnology (United States) US
• Vir Biotechnology (Switzerland) CH
• University Hospital of Geneva CH
• Clinica Luganese Moncucco CH
• ASST Fatebenefratelli Sacco IT
• Molecular Biology Consortium US
• Institut Pasteur FR
• University of Washington US
• Ospedale regionale di Lugano CH
• Prince of Wales Hospital AU
• UNSW Sydney AU

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