OmniVira

A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification.

Laura E Rosen1 M Alejandra Tortorici2 Anna De Marco3 Dora Pinto3 William B Foreman4 Ashley L Taylor4 Young-Jun Park5,6 Dana Bohan1 Tyson Rietz1 John M Errico1 Kevin Hauser1 Ha V Dang1 Justin W Chartron7 Martina Giurdanella3 Giuseppe Cusumano3 Christian Saliba3 Fabrizia Zatta3 Kaitlin R Sprouse2 Amin Addetia2 Samantha K Zepeda2 Jack Brown2 Jimin Lee2 Exequiel Dellota1 Anushka Rajesh1 Julia Noack1 Qiqing Tao1 Yvonne DaCosta1 Brian Tsu1 Rima Acosta1 Sambhavi Subramanian1 Guilherme Dias de Melo8 Lauriane Kergoat8 Ivy Zhang9,10 Zhuoming Liu11 Barbara Guarino3 Michael A Schmid3 Gretja Schnell1 Jessica L Miller1 Florian A Lempp12,3 Nadine Czudnochowski1 Elisabetta Cameroni3 Sean P J Whelan11 Hervé Bourhy8 Lisa A Purcell1 Fabio Benigni3 Julia di Iulio1 Matteo Samuele Pizzuto3 Antonio Lanzavecchia3 Amalio Telenti1 Gyorgy Snell1 Davide Corti13 David Veesler5,14 Tyler N Starr15
Affiliations 15 institutions
  1. Vir Biotechnology, San Francisco, CA 94158, USA.
  2. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  3. Humabs BioMed SA, a Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
  4. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  5. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
  6. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
  7. ProtaBody, Pasadena, CA 91105, USA.
  8. Institut Pasteur, Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit, F-75015 Paris, France.
  9. Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
  10. Tri-Institutional PhD Program in Computational Biology and Medicine, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
  11. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  12. Vir Biotechnology, San Francisco, CA 94158, USA
  13. Humabs BioMed SA, a Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland. Electronic address: [email protected].
  14. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
  15. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: [email protected].
PMID39383863 DOI10.1016/j.cell.2024.09.026 Year2024 Journal Cell Languageeng Statusppublish

Abstract

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.

Supporting text Virus Host Location
broadly neutralizing antibody 1 monoclonal antibody 2 sarbecovirus 19 SARS-CoV-2 550 viral antibody escape 1 Antibodies, Monoclonal 26 Antibodies, Neutralizing 80 Antibodies, Viral 212 Epitopes 17 SARS-CoV-2 453 Angiotensin-Converting Enzyme 2 177 Animals 1948 Chiroptera 371 COVID-19 425 Cross Reactions 21 Humans 1440 Spike Glycoprotein, Coronavirus 274 SARS-CoV-2 variants 86 spike protein, SARS-CoV-2 157

Evidence records

1 total
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE8452 Molecular Adaptation
Key finding

SARS-CoV-2 escape mutants selected under VIR-7229 antibody pressure are rare and show reduced viral fitness, indicating a molecular adaptation barrier and fitness cost.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

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. 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.

Genes or proteins
receptor-binding motif (RBM) | spike protein
Receptors
ACE2
Host factors
VIR-7229 neutralizing antibody
Mechanism types
immune escape | transmission fitness