Epitope-focused discovery of SARS-CoV-2 antibodies that potently neutralize Omicron variants
The emergence of SARS-CoV-2 Omicron variants has led to viral escape from many clinically approved monoclonal antibodies (mAbs) due to rapid evolution of the receptor-binding domain (RBD). Co-circulation of SARS-CoV-2 variants with unique sets of antigenic substitutions has further complicated therapeutic mAb discovery. New approaches are needed to rapidly discover and characterize mAbs with preferred specificity and functional characteristics. Here we describe and perform epitope-focused mAb discovery using glycan-masked antigens. We isolated and expressed a panel of 303 mAbs, some of which potently neutralize divergent Omicron subvariants by targeting the class 3 antigenic site on SARS-CoV-2 RBD. Epitope mapping of these antibodies revealed a spectrum of cross-reactivity and differential recognition of the class 3 site, validating the utility of this enrichment approach for targeted mAb discovery. Together, this work rationally designs glycan-masked engineered RBDs and uses them to isolate mAbs that potently neutralize antigenically divergent SARS-CoV-2 variants.
Authors
- Laura S. Handal (ORCID: https://orcid.org/0000-0001-8658-4411)
- Doan C. Nguyen (ORCID: https://orcid.org/0000-0002-5389-6731)
- Lauren E. Williamson
- Nathaniel S. Chapman
- James E. Crowe (ORCID: https://orcid.org/0000-0002-0049-1079)
- Stacey A. Rutherford
- Elad Binshtein (ORCID: https://orcid.org/0000-0003-2745-104X)
- Naveenchandra Suryadevara (ORCID: https://orcid.org/0000-0003-2571-1290)
- Andrew Trivette
- Seth J. Zost (ORCID: https://orcid.org/0000-0001-6712-5076)
- Suzanne M. Scheaffer (ORCID: https://orcid.org/0009-0001-0459-0816)
- Ajit R. Ramamohan (ORCID: https://orcid.org/0009-0005-9778-5987)
- Cameron D. Buchman
- Luke Myers
- James R. Martinez
- F. Eun-Hyung Lee
- Silvia Ravera
- Robert H. Carnahan
- Eduardo Villalobos
- Jason S. McLellan
- Ralph S. Baric
- Nicole V. Johnson
- Michael S. Diamond
- Alexandra Schäfer
- Nicholas J. Catanzaro
Institutions
- University of North Carolina at Chapel Hill (US)
- Emory University (US)
- Washington University in St. Louis (US)
- The University of Texas at Austin (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1038/s41564-026-02282-x
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Energy
- Vanderbilt University
- Emory University
- University of Wisconsin-Madison
- Johns Hopkins University
- European Synchrotron Radiation Facility
- National Institutes of Health
- Defense Advanced Research Projects Agency
- Office of Science
- Advanced Research Projects Agency
- Michigan Technology Tri-Corridor
- National Institute of Allergy and Infectious Diseases
- Argonne National Laboratory