Krithika Muthuraman, The Hospital for Sick Children

Krithika Muthuraman (a), Matthew Jackman (a), Yu Liang (b), Meghan E. Garrett (b), Hong Cui (a), Loan Vu Hong Nguyen (a), Danton Ivanochko (a), Chengjin Ye (c), Paula A. Pino (c), Amberlee Hicks (c), Billie Maingot (c), Erik Yusko (b), Sharon Benzeno (b), Luis Martinez Sobrido (c,d), Jordi B Torrelles (c,d), Amy E. Gilbert (b), Benjamin Evan Russell Rubin (b), Gladys Keitany (b), Arif Jetha (a) and Jean-Philippe Julien (a,e); a-Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada ; b-Adaptive Biotechnologies, Seattle, Washington, USA; c-Population Health Program, Texas Biomedical Research Institute, San Antonio, Texas, USA; d-International Center for Advancement of Research & Education (I· CARE), San Antonio, Texas, USA; e-Department of Immunology, University of Toronto, Canada

Fighting & Responding

Over the past two decades, betacoronaviruses (β-CoVs) have caused two epidemics and a pandemic and remain a high risk for future outbreaks through zoonotic transmissions, highlighting the need for broad biomedical countermeasures. Here, we describe a convalescent human monoclonal antibody (mAb 1871) that targets the S2 subunit of the coronavirus spike protein, with broad β-CoVs binding and sarbecovirus neutralization. Cryo-electron microscopy analysis revealed that mAb 1871 binds the upstream helix of the S2 subunit, interacting with partially conserved residues, providing a molecular basis for its cross reactivity. Though less potent than receptor-binding domain directed antibodies, mAb 1871 provides protective efficacy in a mouse model. Notably, Fc effector functions are critical for its in vivo protection. This study highlights the Fc dependence of S2 directed antibodies for in vivo protection and identifies a conserved epitope in the S2 subunit as a potential target for broad-β-CoVs countermeasures.