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Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection
Open accessPublished version of a preprint
Abstract
SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.
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“Thus, residual SARS-CoV-2-specific non-neutralizing antibodies following infection may confer some protective benefit during reinfection, even when serum neutralizing activity has declined below the threshold of protection25–27.”
From Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection (2021) · cites this paper as [27]
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“this measurement does not account for Fc effector functions; Fcγ receptor or complement protein engagement by non-, weakly-, or strongly- neutralizing antibodies that bind the SARS-CoV-2 spike protein on the surface of infected cells could confer substantial protection39–41.”
From Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies (2021) · cites this paper as [39]
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Dong, E., Du, H., & Gardner, L. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(20)30120-1 · Cited by 10,048
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Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody
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Self-citationConvergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals
Robbiani, D. F., Gaebler, C., Muecksch, F., Lorenzi, J. C. C., Wang, Z., Cho, A., Agudelo, M., Barnes, C. O., Gazumyan, A., Finkin, S., et al. (2020) · Nature · doi:10.1038/s41586-020-2456-9 · Cited by 1,853
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Self-citationVanBlargan, L. A., Errico, J. M., Halfmann, P., Zost, S. J., Crowe, J. E., Purcell, L. A., Kawaoka, Y., Corti, D., Fremont, D. H., & Diamond, M. (2022) · Nature Medicine · doi:10.1038/s41591-021-01678-y · Cited by 690
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Metadata
- Authors
- Winkler, E. S., Gilchuk, P., Yu, J., Bailey, A. L., Chen, R. E., Chong, Z., Zost, S. J., Jang, H., Huang, Y., Allen, J. D., Case, J. B., Sutton, R. E., Carnahan, R. H., Darling, T. L., Boon, A. C. M., Mack, M., Head, R. D., Ross, T. M., Crowe, J. E., & Diamond, M. S.
- Affiliations
- Washington University in St. Louis (US)
- Vanderbilt University Medical Center (US)
- University of Georgia (US)
- University Hospital Regensburg (DE)
- Corresponding author
- Crowe, James E.
- Diamond, Michael S.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 184
- Issue
- 7
- Pages
- 1804-1820.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7879018
- OpenAlex
- W3132982761
- Cited by
- 366
- References
- 101
- Citations by year
- 2026: 13 · 2025: 34 · 2024: 40 · 2023: 69 · 2022: 99 · 2021: 109
- FWCI
- 25.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- NIAID
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, neutralizing monoclonal antibodies, Fc effector functions, passive immunotherapy, COVID-19 pandemic, pulmonary infection, monocytes, CD8+ T cells, innate immune signaling, tissue repair, inflammation, correlates of protection
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