Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination
Neutralizing antibodies correlate with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also correlate with protection against disease progression. Non-neutralizing antibodies cannot directly protect against infection but may recruit effector cells and thus contribute to the clearance of infected cells. Additionally, they often bind conserved epitopes across multiple variants. Here, we characterize 42 human monoclonal antibodies (mAbs) from coronavirus disease 2019 (COVID-19)-vaccinated individuals. Most of these antibodies exhibit no neutralizing activity in vitro, but several non-neutralizing antibodies provide protection against lethal challenge with SARS-CoV-2 in different animal models. A subset of those mAbs shows a clear dependence on Fc-mediated effector functions. We have determined the structures of three non-neutralizing antibodies, with two targeting the receptor-binding domain and one that binds the subdomain 1 region. Our data confirm the real-world observation in humans that non-neutralizing antibodies to SARS-CoV-2 can be protective.
Authors
- Weina Sun (ORCID: https://orcid.org/0000-0002-2435-5047)
- Daniel C. Adelsberg (ORCID: https://orcid.org/0000-0003-0591-7136)
- Juan Manuel Carreño (ORCID: https://orcid.org/0000-0002-9039-9275)
- Stylianos Bournazos (ORCID: https://orcid.org/0000-0001-5466-5620)
- Ali H. Ellebedy (ORCID: https://orcid.org/0000-0002-6129-2532)
- Iden A. Sapse (ORCID: https://orcid.org/0000-0001-8788-7107)
- Irene Hoxie
- Fatima Amanat (ORCID: https://orcid.org/0000-0002-8029-8227)
- Ariel Raskin (ORCID: https://orcid.org/0000-0001-9110-8217)
- Goran Bajic (ORCID: https://orcid.org/0000-0003-0480-4324)
- Johnstone Tcheou (ORCID: https://orcid.org/0000-0003-2733-4687)
- Gagandeep Singh (ORCID: https://orcid.org/0000-0001-5848-2741)
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Robert Andreata‐Santos (ORCID: https://orcid.org/0000-0002-4506-3756)
- Irene González‐Domínguez (ORCID: https://orcid.org/0000-0002-7920-5505)
- Viviana Simon (ORCID: https://orcid.org/0000-0002-6416-5096)
- Jordan J Clark
- Jeremy S. Yong
- Julia E. Edgar
Institutions
- Washington University in St. Louis (US)
- Medical University of Vienna (AT)
- Rockefeller University (US)
- Universidade Federal de São Paulo (BR)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-11-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114922
- Citations
- 30
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 11.67
Funders
- U.S. Department of Health and Human Services
- Icahn School of Medicine at Mount Sinai
- Monique Weill-Caulier Trust
- Georgia Clinical and Translational Science Alliance
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences
- Common Fund