Neutralization, effector function and immune imprinting of Omicron variants

Amin Addetia, Luca Piccoli, James Brett Case, Young-Jun Park, Martina Beltramello, Barbara Guarino, Ha Dang, Guilherme Dias de Melo, Dora Pinto, Kaitlin Sprouse, Suzanne M. Scheaffer, Jessica Bassi, Chiara Silacci-Fregni, Francesco Muoio, Marco Dini, Lucia Vincenzetti, Rima Acosta, Daisy Johnson, Sambhavi Subramanian, Christian Saliba, Martina Giurdanella, Gloria Lombardo, Giada Leoni, Katja Culap, Carley McAlister, Anushka Rajesh, Exequiel Dellota, Jiayi Zhou, Nisar Farhat, Dana Bohan, Julia Noack, Alex Chen, Florian A. Lempp, Joel Quispe, Lauriane Kergoat, Florence Larrous, Elisabetta Cameroni, Bradley Whitener, Olivier Giannini, Pietro Cippà, Alessandro Ceschi, Paolo Ferrari, Alessandra Franzetti-Pellanda, Maira Biggiogero, Christian Garzoni, Stephanie Zappi, Luca Bernasconi, Min Jeong Kim, Laura E. Rosen, Gretja Schnell, Nadine Czudnochowski, Fabio Benigni, Nicholas Franko, Jennifer K. Logue, Courtney Yoshiyama, Cameron Stewart, Helen Chu, Hervé Bourhy, Michael A. Schmid, Lisa A. Purcell, Gyorgy Snell, Antonio Lanzavecchia, Michael S. Diamond (), Davide Corti () and David Veesler ()
Additional contact information
Amin Addetia: University of Washington
Luca Piccoli: Humabs BioMed
James Brett Case: Washington University School of Medicine
Young-Jun Park: University of Washington
Martina Beltramello: Humabs BioMed
Barbara Guarino: Humabs BioMed
Ha Dang: Vir Biotechnology
Guilherme Dias de Melo: Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit
Dora Pinto: Humabs BioMed
Kaitlin Sprouse: University of Washington
Suzanne M. Scheaffer: Washington University School of Medicine
Jessica Bassi: Humabs BioMed
Chiara Silacci-Fregni: Humabs BioMed
Francesco Muoio: Humabs BioMed
Marco Dini: Humabs BioMed
Lucia Vincenzetti: Humabs BioMed
Rima Acosta: Vir Biotechnology
Daisy Johnson: Vir Biotechnology
Sambhavi Subramanian: Vir Biotechnology
Christian Saliba: Humabs BioMed
Martina Giurdanella: Humabs BioMed
Gloria Lombardo: Humabs BioMed
Giada Leoni: Humabs BioMed
Katja Culap: Humabs BioMed
Carley McAlister: Vir Biotechnology
Anushka Rajesh: Vir Biotechnology
Exequiel Dellota: Vir Biotechnology
Jiayi Zhou: Vir Biotechnology
Nisar Farhat: Vir Biotechnology
Dana Bohan: Vir Biotechnology
Julia Noack: Vir Biotechnology
Alex Chen: Vir Biotechnology
Florian A. Lempp: Vir Biotechnology
Joel Quispe: University of Washington
Lauriane Kergoat: Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit
Florence Larrous: Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit
Elisabetta Cameroni: Humabs BioMed
Bradley Whitener: Washington University School of Medicine
Olivier Giannini: Università della Svizzera italiana
Pietro Cippà: Università della Svizzera italiana
Alessandro Ceschi: Università della Svizzera italiana
Paolo Ferrari: Università della Svizzera italiana
Alessandra Franzetti-Pellanda: Clinica Luganese Moncucco
Maira Biggiogero: Clinica Luganese Moncucco
Christian Garzoni: Clinica Luganese Moncucco
Stephanie Zappi: Cantonal Hospital Aarau
Luca Bernasconi: Cantonal Hospital Aarau
Min Jeong Kim: Cantonal Hospital Aarau
Laura E. Rosen: Vir Biotechnology
Gretja Schnell: Vir Biotechnology
Nadine Czudnochowski: Vir Biotechnology
Fabio Benigni: Humabs BioMed
Nicholas Franko: University of Washington
Jennifer K. Logue: University of Washington
Courtney Yoshiyama: University of Washington
Cameron Stewart: University of Washington
Helen Chu: University of Washington
Hervé Bourhy: Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit
Michael A. Schmid: Humabs BioMed
Lisa A. Purcell: Vir Biotechnology
Gyorgy Snell: Vir Biotechnology
Antonio Lanzavecchia: Humabs BioMed
Michael S. Diamond: Washington University School of Medicine
Davide Corti: Humabs BioMed
David Veesler: University of Washington

Nature, 2023, vol. 621, issue 7979, 592-601

Abstract: Abstract Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.

Date: 2023
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DOI: 10.1038/s41586-023-06487-6

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