Clonotype-enriched somatic hypermutations drive affinity maturation of a public human antibody targeting an occluded sarbecovirus epitope
Investigating public antibodies that recognize conserved epitopes is critical for vaccine development. Identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public antibodies is key to guiding vaccine design for better protection against pathogens. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes but with different epitope specificities. Using M15, a human IGHV4-59/IGKV3-20 public antibody as a model, we compare SHM signatures in antibodies that use the same V genes but recognize other epitopes. We identified clonotype-enriched mutations in the light chain of M15 and showed that, in combination, these SHMs enhance binding to a previously uncharacterized Sarbecovirus epitope, with antibody responses to it increasing after sequential vaccination. Our findings identify convergence and clonotype enrichment as features of affinity-enhancing SHMs in public antibodies, which can help guide vaccine design aimed at eliciting such antibodies.
Authors
- Yuexing Chen
- Hallie Cohn (ORCID: https://orcid.org/0009-0008-3846-0666)
- Dongwan Yoo (ORCID: https://orcid.org/0000-0002-6730-9729)
- Duane R. Wesemann (ORCID: https://orcid.org/0000-0002-6690-944X)
- Iden A. Sapse (ORCID: https://orcid.org/0000-0001-8788-7107)
- Jordan J. Clark (ORCID: https://orcid.org/0000-0003-1790-7883)
- Vishal N. Rao (ORCID: https://orcid.org/0000-0003-3545-4267)
- Komal Srivastava
- Goran Bajic (ORCID: https://orcid.org/0000-0003-0480-4324)
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Pei Tong (ORCID: https://orcid.org/0000-0003-4301-6857)
- Camila H. Coelho (ORCID: https://orcid.org/0000-0002-7885-9996)
- Viviana Simon (ORCID: https://orcid.org/0000-0002-6416-5096)
- Bailey Bozarth
- Gagandeep Singh
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Mount Sinai Hospital (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116122
- Citations
- 5
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 6.80
Funders
- Simons Foundation
- Irma T. Hirschl Trust
- Icahn School of Medicine at Mount Sinai
- Monique Weill-Caulier Trust
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences