IgV somatic mutation of human anti–SARS-CoV-2 monoclonal antibodies governs neutralization and breadth of reactivity
Open accessAbstract
Abs that neutralize SARS-CoV-2 are thought to provide the most immediate and effective treatment for those severely afflicted by this virus. Because coronavirus potentially diversifies by mutation, broadly neutralizing Abs are especially sought. Here, we report a possibly novel approach to rapid generation of potent broadly neutralizing human anti–SARS-CoV-2 Abs. We isolated SARS-CoV-2 spike protein–specific memory B cells by panning from the blood of convalescent subjects after infection with SARS-CoV-2 and sequenced and expressed Ig genes from individual B cells as human mAbs. All of 43 human mAbs generated in this way neutralized SARS-CoV-2. Eighteen of the forty-three human mAbs exhibited half-maximal inhibitory concentrations (IC 50 ) of 6.7 × 10 –12 M to 6.7 × 10 –15 M for spike-pseudotyped virus. Seven of the human mAbs also neutralized (with IC 50 < 6.7 × 10 –12 M) viruses pseudotyped with mutant spike proteins (including receptor-binding domain mutants and the S1 C-terminal D614G mutant). Neutralization of the Wuhan Hu-1 founder strain and of some variants decreased when coding sequences were reverted to germline, suggesting that potency of neutralization was acquired by somatic hypermutation and selection of B cells. These results indicate that infection with SARS-CoV-2 evokes high-affinity B cell responses, some products of which are broadly neutralizing and others highly strain specific. We also identify variants that would potentially resist immunity evoked by infection with the Wuhan Hu-1 founder strain or by vaccines developed with products of that strain, suggesting evolutionary courses that SARS-CoV-2 could take.
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These findings are consistent with earlier work that has suggested that SHM and affinity maturation are important for the acquisition of broader neutralization activity of RBD-binding antibodies that are formed in response to SARS-CoV-2 infection.
“These findings are consistent with earlier work that has suggested that SHM and affinity maturation are important for the acquisition of broader neutralization activity of RBD-binding antibodies that are formed in response to SARS-CoV-2 infection (48, 49).”
From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [49]
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- Authors
- de Mattos Barbosa, M. G., Liu, H., Huynh, D., Shelley, G., Keller, E. T., Emmer, B. T., Sherman, E., Ginsburg, D., Kennedy, A. A., Tai, A. W., Wobus, C., Mirabeli, C., Lanigan, T. M., Samaniego, M., Meng, W., Rosenfeld, A. M., Prak, E. T. L., Platt, J. L., & Cascalho, M.
- Affiliations
- Department of Surgery,
- Department of Urology,
- Department of Internal Medicine,
- Howard Hughes Medical Institute (US)
- Department of Microbiology and Immunology, and
- University of Michigan (US)
- Henry Ford Health (US)
- University of Pennsylvania (US)
- Corresponding author
- Platt, Jeffrey L.
- ORCID
- Venue
- JCI Insight
- Published
- 2021-05-10
- Volume
- 6
- Issue
- 9
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8262290
- OpenAlex
- W3139030566
- Cited by
- 14
- References
- 46
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 4
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Michigan (48109, P30CA046592, U069943)
- National Institutes of Health (U069943, COVID-19, CA093900, CA046592)
- College of Pharmacy, University of Michigan
- Michigan Institute for Clinical and Health Research (U069943)
- National Heart, Lung, and Blood Institute (K08HL148552, R35HL135793)
- National Cancer Institute (P01CA093900, P30CA046592)
- National Institute of Allergy and Infectious Diseases (R01AI051588)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- SARS-CoV-2, broadly neutralizing antibodies, human monoclonal antibodies, spike protein, somatic hypermutation, memory B cells, neutralization breadth, D614G mutation, vaccine escape variants, convalescent donors, B cell selection
- MeSH terms
- Broadly Neutralizing Antibodies, COVID-19, SARS-CoV-2, Adult, Aged, Antibodies, Monoclonal, Antibodies, Viral, Antibody Specificity, B-Lymphocytes, Humans, Immunoglobulin Variable Region, Immunoglobulin Heavy Chains, Immunologic Memory, Middle Aged, Neutralization Tests, Somatic Hypermutation, Immunoglobulin, Antibodies, Neutralizing, Pandemics, Spike Glycoprotein, Coronavirus
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