Discovery and characterization of a pan-betacoronavirus S2-binding antibody.
Johnson, N.V., Wall, S.C., Kramer, K.J., Holt, C.M., Periasamy, S., Richardson, S.I., Manamela, N.P., Suryadevara, N., Andreano, E., Paciello, I., Pierleoni, G., Piccini, G., Huang, Y., Ge, P., Allen, J.D., Uno, N., Shiakolas, A.R., Pilewski, K.A., Nargi, R.S., Sutton, R.E., Abu-Shmais, A.A., Parks, R., Haynes, B.F., Carnahan, R.H., Crowe Jr., J.E., Montomoli, E., Rappuoli, R., Bukreyev, A., Ross, T.M., Sautto, G.A., McLellan, J.S., Georgiev, I.S.(2024) Structure 32: 1893
- PubMed: 39326419
- DOI: https://doi.org/10.1016/j.str.2024.08.022
- Primary Citation of Related Structures:
8VCR - PubMed Abstract:
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.
Organizational Affiliation:
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.