Delineating the functional activity of antibodies with cross-reactivity to SARS-CoV-2, SARS-CoV-1 and related sarbecoviruses
Open accessPublished version of a preprint
Abstract
The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.
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- Authors
- Ruiz, F., Foreman, W. B., Lilly, M., Baharani, V. A., Depierreux, D. M., Chohan, V., Taylor, A. L., Guenthoer, J., Ralph, D., Matsen IV, F. A., Chu, H. Y., Bieniasz, P. D., Côté, M., Starr, T. N., & Overbaugh, J.
- Affiliations
- University of Washington (US)
- University of Utah (US)
- Fred Hutch Cancer Center (US)
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- University of Ottawa (CA)
- Corresponding author
- Starr, Tyler N.
- Overbaugh, Julie
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2024-10-28
- Volume
- 20
- Issue
- 10
- Pages
- e1012650
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC11542851
- OpenAlex
- W4403826528
- Cited by
- 7
- References
- 12
- Citations by year
- 2026: 6 · 2025: 1
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Update notices
- new_version (2024-11-07)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (AI38709, P01AI167966, DP2AI177890)
- National Science Foundation Graduate Research Fellowship Program (DGE-2140004)
- National Institute of Allergy and Infectious Diseases (P01 AI165075, R01 AI146028)
- Boehringer Ingelheim
- Howard Hughes Medical Institute Investigators
- Damon Runyon Cancer Research Foundation
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- SARS-CoV-2, SARS-CoV-1, sarbecoviruses, cross-reactive antibodies, neutralizing antibodies, spike protein receptor-binding domain, conserved epitopes, escape variants, Fc effector functions, pandemic preparedness, immunogen design
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