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

doi:10.1016/j.isci.2022.105783

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

iScience. 2023 Jan 20;26(1):105783. doi: 10.1016/j.isci.2022.105783. Epub 2022 Dec 9.

Authors

Yaozong Chen¹, Jérémie Prévost^{2

3}, Irfan Ullah⁴, Hugo Romero⁵, Veronique Lisi⁵, William D Tolbert¹, Jonathan R Grover⁶, Shilei Ding², Shang Yu Gong^{2

7}, Guillaume Beaudoin-Bussières^{2

3}, Romain Gasser^{2

3}, Mehdi Benlarbi², Dani Vézina², Sai Priya Anand^{2

7}, Debashree Chatterjee², Guillaume Goyette², Michael W Grunst⁶, Ziwei Yang⁶, Yuxia Bo⁸, Fei Zhou⁹, Kathie Béland⁵, Xiaoyun Bai¹⁰, Allison R Zeher^{9

10}, Rick K Huang^{9

10}, Dung N Nguyen¹, Rebekah Sherburn¹, Di Wu¹¹, Grzegorz Piszczek¹¹, Bastien Paré¹², Doreen Matthies⁹, Di Xia¹⁰, Jonathan Richard^{2

3}, Priti Kumar⁴, Walther Mothes⁶, Marceline Côté⁸, Pradeep D Uchil⁶, Vincent-Philippe Lavallée^{5

13

14}, Martin A Smith^{5

12}, Marzena Pazgier¹, Elie Haddad^{3

14}, Andrés Finzi^{2

3

7}

Affiliations

¹ Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.
² Centre de Recherche du CHUM (CRCHUM), Montreal, QC H2X 0A9, Canada.
³ 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 CHU Ste-Justine, Montreal, QC H3T 1C5, Canada.
⁶ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA.
⁷ Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
⁸ Department of Biochemistry, Microbiology and Immunology, Center for Infection, Immunity, and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
⁹ 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.
¹⁰ Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ Biophysics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹² Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montreal, QC H3T 1J4, Canada.
¹³ Division of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montréal, QC, Canada.
¹⁴ Département de Pédiatrie, Université de Montréal, Montreal, QC H3T 1C5, Canada.

Abstract

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.

Keywords: Immunology; Virology.

Abstract

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