iScience (Jan 2023)
Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD
- Yaozong Chen,
- Jérémie Prévost,
- Irfan Ullah,
- Hugo Romero,
- Veronique Lisi,
- William D. Tolbert,
- Jonathan R. Grover,
- Shilei Ding,
- Shang Yu Gong,
- Guillaume Beaudoin-Bussières,
- Romain Gasser,
- Mehdi Benlarbi,
- Dani Vézina,
- Sai Priya Anand,
- Debashree Chatterjee,
- Guillaume Goyette,
- Michael W. Grunst,
- Ziwei Yang,
- Yuxia Bo,
- Fei Zhou,
- Kathie Béland,
- Xiaoyun Bai,
- Allison R. Zeher,
- Rick K. Huang,
- Dung N. Nguyen,
- Rebekah Sherburn,
- Di Wu,
- Grzegorz Piszczek,
- Bastien Paré,
- Doreen Matthies,
- Di Xia,
- Jonathan Richard,
- Priti Kumar,
- Walther Mothes,
- Marceline Côté,
- Pradeep D. Uchil,
- Vincent-Philippe Lavallée,
- Martin A. Smith,
- Marzena Pazgier,
- Elie Haddad,
- Andrés Finzi
Affiliations
- Yaozong Chen
- Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA
- Jérémie Prévost
- 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
- Irfan Ullah
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
- Hugo Romero
- Centre de Recherche du CHU Ste-Justine, Montreal, QC H3T 1C5, Canada
- Veronique Lisi
- Centre de Recherche du CHU Ste-Justine, Montreal, QC H3T 1C5, Canada
- William D. Tolbert
- Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA
- Jonathan R. Grover
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA
- Shilei Ding
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada
- Shang Yu Gong
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
- Guillaume Beaudoin-Bussières
- 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
- Romain Gasser
- 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
- Mehdi Benlarbi
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada
- Dani Vézina
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada
- Sai Priya Anand
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
- Debashree Chatterjee
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada
- Guillaume Goyette
- Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada
- Michael W. Grunst
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA
- Ziwei Yang
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA
- Yuxia Bo
- Department of Biochemistry, Microbiology and Immunology, Center for Infection, Immunity, and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Fei Zhou
- Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
- Kathie Béland
- Centre de Recherche du CHU Ste-Justine, Montreal, QC H3T 1C5, Canada
- Xiaoyun Bai
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Allison R. Zeher
- Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Rick K. Huang
- Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Dung N. Nguyen
- Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA
- Rebekah Sherburn
- Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA
- Di Wu
- Biophysics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Grzegorz Piszczek
- Biophysics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Bastien Paré
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Doreen Matthies
- Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
- Di Xia
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Jonathan Richard
- 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
- Priti Kumar
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
- Walther Mothes
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA
- Marceline Côté
- Department of Biochemistry, Microbiology and Immunology, Center for Infection, Immunity, and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Pradeep D. Uchil
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA
- Vincent-Philippe Lavallée
- Centre de Recherche du CHU Ste-Justine, Montreal, QC H3T 1C5, Canada; Division of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, QC, Canada; Département de Pédiatrie, Université de Montréal, Montreal, QC H3T 1C5, Canada
- Martin A. Smith
- Centre de Recherche du CHU Ste-Justine, Montreal, QC H3T 1C5, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Marzena Pazgier
- Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA; Corresponding author
- Elie Haddad
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada; Département de Pédiatrie, Université de Montréal, Montreal, QC H3T 1C5, Canada; Corresponding author
- Andrés Finzi
- 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; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 1
p. 105783
Abstract
Summary: Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.
