Discovery and Characterization of a Pan-betacoronavirus S2-binding antibody

Nicole V. Johnson; Steven C. Wall; Kevin J. Kramer; Clinton Holt; Sivakumar Periasamy; Simone I. Richardson; Nelia P. Manamela; Naveenchandra Suryadevara; 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-Shmais; Robert Parks; Barton F. Haynes; Robert H. Carnahan; James E. Crowe; Emanuele Montomoli; Rino Rappuoli; Alexander A. Bukreyev; Ted M. Ross; Giuseppe Andrea Sautto

doi:10.1016/j.str.2024.08.022

Molecular BiologyStructureSep 25, 2024

Peer-reviewed journal article

Discovery and Characterization of a Pan-betacoronavirus S2-binding antibody

Nicole V. Johnson iD, Steven C. Wall iD, Kevin J. Kramer, Clinton Holt iD, Sivakumar Periasamy iD, Simone I. Richardson iD, Nelia P. Manamela iD, Naveenchandra Suryadevara iD, Emanuele Andreano iD, Ida Paciello iD, Giulio Pierleoni iD, Giulia Piccini iD, Ying Huang iD, Pan Ge iD, James D. Allen iD, Naoko Uno iD, Andrea R. Shiakolas iD, Kelsey A. Pilewski iD, Rachel S. Nargi, Rachel E. Sutton, Alexandria A. Abu-Shmais, Robert Parks iD, Barton F. Haynes iD, Robert H. Carnahan iD, James E. Crowe iD, , Ivelin S. Georgiev iD

Abstract

SUMMARY/ABSTRACTThree coronaviruses have spilled over from animal reservoirs into the human population and caused deadly epidemics or pandemics. The continued emergence of coronaviruses highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using LIBRA-seq, we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these antibodies, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryo-EM structure of 54043-5 bound to the pre-fusion S2 subunit of the 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, including ADCC and 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.

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