Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

Wenwei Li; Yaozong Chen; Jérémie Prévost; Irfan Ullah; Maolin Lu; Shang Yu Gong; Alexandra Tauzin; Romain Gasser; Dani Vézina; Sai Priya Anand; Guillaume Goyette; Debashree Chaterjee; Shilei Ding; William D Tolbert; Michael W Grunst; Yuxia Bo; Shijian Zhang; Jonathan Richard; Fei Zhou; Rick K Huang; Lothar Esser; Allison Zeher; Marceline Côté; Priti Kumar; Joseph Sodroski; Di Xia; Pradeep D Uchil; Marzena Pazgier; Andrés Finzi; Walther Mothes

doi:10.1016/j.celrep.2021.110210

Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern

Cell Rep. 2022 Jan 11;38(2):110210. doi: 10.1016/j.celrep.2021.110210. Epub 2021 Dec 15.

Authors

Wenwei Li¹, Yaozong Chen², Jérémie Prévost³, Irfan Ullah⁴, Maolin Lu¹, Shang Yu Gong⁵, Alexandra Tauzin³, Romain Gasser³, Dani Vézina³, Sai Priya Anand⁵, Guillaume Goyette⁶, Debashree Chaterjee⁶, Shilei Ding⁶, William D Tolbert², Michael W Grunst¹, Yuxia Bo⁷, Shijian Zhang⁸, Jonathan Richard³, Fei Zhou⁹, Rick K Huang⁹, Lothar Esser⁹, Allison Zeher⁹, Marceline Côté⁷, Priti Kumar⁴, Joseph Sodroski⁸, Di Xia⁹, Pradeep D Uchil¹, Marzena Pazgier¹⁰, Andrés Finzi¹¹, Walther Mothes¹²

Affiliations

¹ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520, USA.
² Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.
³ Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada.
⁴ Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
⁵ Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
⁶ Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada.
⁷ Department of Biochemistry, Microbiology and Immunology, and Center for Infection, Immunity, and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁸ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
⁹ Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁰ Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA. Electronic address: marzena.pazgier@usuhs.edu.
¹¹ Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: andres.finzi@umontreal.ca.
¹² Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: walther.mothes@yale.edu.

Abstract

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

Keywords: COVID-19; SARS-CoV-2; emerging variants of concern; epitopes; neutralizing antibodies; receptor-binding domain; β-coronaviruses.

Abstract

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