A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.
Authors
- Fabrizia Zatta (ORCID: https://orcid.org/0000-0003-4945-8058)
- Ivy Zhang (ORCID: https://orcid.org/0000-0003-0628-6276)
- Matteo Samuele Pizzuto
- M. Alejandra Tortorici (ORCID: https://orcid.org/0000-0002-2260-2577)
- Laura E. Rosen (ORCID: https://orcid.org/0000-0002-8030-0219)
- William Foreman (ORCID: https://orcid.org/0000-0003-0784-214X)
- Anushka Rajesh (ORCID: https://orcid.org/0000-0002-7729-0865)
- Tyler N. Starr (ORCID: https://orcid.org/0000-0001-6713-6904)
- Lauriane Kergoat (ORCID: https://orcid.org/0000-0002-5609-4398)
- Michael Schmid (ORCID: https://orcid.org/0000-0002-1137-9322)
- Qiqing Tao (ORCID: https://orcid.org/0000-0001-7360-409X)
- Florian A. Lempp (ORCID: https://orcid.org/0000-0001-6103-8078)
- Hervé Bourhy (ORCID: https://orcid.org/0000-0002-2608-5589)
- Amin Addetia (ORCID: https://orcid.org/0000-0001-6703-3841)
- Lisa A. Purcell (ORCID: https://orcid.org/0000-0002-9565-2030)
- Tyson A. Rietz (ORCID: https://orcid.org/0000-0003-4670-5279)
- Kaitlin R. Sprouse (ORCID: https://orcid.org/0000-0003-0007-2226)
- Ashley L. Taylor (ORCID: https://orcid.org/0000-0001-9975-7596)
- Kevin Hauser (ORCID: https://orcid.org/0000-0002-4579-4794)
- Christian Saliba (ORCID: https://orcid.org/0000-0003-0100-6976)
- Zhuoming Liu (ORCID: https://orcid.org/0000-0001-8198-0976)
- Barbara Guarino (ORCID: https://orcid.org/0000-0003-3759-3252)
- Young‐Jun Park (ORCID: https://orcid.org/0000-0003-2901-6949)
- Anna De Marco (ORCID: https://orcid.org/0000-0001-9641-4838)
- Martina Giurdanella
- Fabio Benigni (ORCID: https://orcid.org/0000-0002-1974-5606)
- Julia Noack (ORCID: https://orcid.org/0000-0002-9113-8181)
- Jimin Lee (ORCID: https://orcid.org/0000-0001-5849-7732)
- Antonio Lanzavecchia (ORCID: https://orcid.org/0000-0002-3041-7240)
- Dora Pinto
- Ha V. Dang (ORCID: https://orcid.org/0000-0003-1173-9241)
- Amalio Telenti (ORCID: https://orcid.org/0000-0001-6290-7677)
- Samantha K. Zepeda (ORCID: https://orcid.org/0000-0003-0005-9793)
- John M. Errico (ORCID: https://orcid.org/0000-0002-4452-8152)
- Brian V. Tsu (ORCID: https://orcid.org/0000-0003-0268-8323)
- Dana Bohan (ORCID: https://orcid.org/0000-0002-9239-3053)
- Guilherme Dias de Melo (ORCID: https://orcid.org/0000-0003-0747-7760)
- Exequiel Dellota (ORCID: https://orcid.org/0000-0002-2006-3880)
- Gretja Schnell
- Sean P. J. Whelan (ORCID: https://orcid.org/0000-0003-1564-8590)
- Elisabetta Cameroni (ORCID: https://orcid.org/0000-0002-9102-8943)
- Rima Acosta (ORCID: https://orcid.org/0000-0002-0255-9487)
- Jessica L. Miller (ORCID: https://orcid.org/0000-0001-6080-6143)
- David Veesler (ORCID: https://orcid.org/0000-0002-6019-8675)
- Julia di Iulio (ORCID: https://orcid.org/0000-0001-9343-127X)
- Justin W. Chartron (ORCID: https://orcid.org/0000-0003-1734-3424)
- Gyorgy Snell
- Nadine Czudnochowski
- Davide Corti (ORCID: https://orcid.org/0000-0003-4046-7222)
- Yvonne DaCosta
- Jack Brown
- Sambhavi Subramanian
- Giuseppe Cusumano
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Institut Pasteur (FR)
- University of Washington (US)
- Washington University in St. Louis (US)
- Université Paris Cité (FR)
- Cornell University (US)
- University of Utah (US)
- University of Washington Medical Center (US)
- Kettering University (US)
- Vir Biotechnology (Switzerland) (CH)
- Tri-Institutional PhD Program in Chemical Biology (US)
- VIR Biotechnology (United States) (US)
Publication Details
- Journal
- Cell
- Published
- 2024-10-08
- DOI
- https://doi.org/10.1016/j.cell.2024.09.026
- Citations
- 56
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 21.40
Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy
- Burroughs Wellcome Fund
- Pew Charitable Trusts
- Damon Runyon Cancer Research Foundation
- Searle Scholars Program
- Vir Biotechnology
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- Basic Energy Sciences
- Biological and Environmental Research
- SLAC National Accelerator Laboratory