Discovery and characterization of a pan-betacoronavirus S2-binding antibody

• DOI: 10.1016/j.str.2024.08.022
• Publication Date: 2024-09-25T14:37:29Z
• Authors: Nicole V. Johnson; Steven C. Wall; Kevin J. Kramer; Clinton M. Holt; Sivakumar Periasamy; Simone I. Richardson; Nelia P. Manamela; Naveenchandra Sur...; Emanuele Andreano; Ida Paciello; Giulio Pierleoni; Giulia Piccini; Ying Huang; Pan Ge; James D. Allen; Naoko Uno; Andrea R. Shiakolas; Kelsey A. Pilewski; Rachel S. Nargi; Rachel E. Sutton; Alexandria A. Abu...; Robert Parks; Barton F. Haynes; Robert H. Carnahan; James E. Crowe; Emanuele Montomoli; Rino Rappuoli; Alexander Bukreyev; Ted M. Ross; Giuseppe A. Sautto; Jason S. McLellan; Ivelin S. Georgiev

The continued emergence of deadly human coronaviruses from animal reservoirs highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq), we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryoelectron microscopy (cryo-EM) structure of 54043-5 bound to the prefusion S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses in vitro, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.