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. NixFederico 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

Research output: Contribution to journalArticlepeer-review

378 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1024-1042.e21
JournalCell
Volume183
Issue number4
DOIs
StatePublished - Nov 12 2020

Keywords

  • COVID-19
  • SARS-CoV-2
  • coronaviruses
  • effector functions
  • immunity
  • neutralizing antibodies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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