Submission history

Received: 8 April 2021

Accepted: 31 January 2022

Acknowledgments

We thank all of the human cohort participants for donating samples.

Funding: This work was supported by NIH NIAID CHAVD (UM1 AI44462 to D.R.B.), IAVI Neutralizing Antibody Center, the Bill and Melinda Gates Foundation (OPP 1170236 and INV-004923 to I.A.W. and D.R.B.), and the Translational Virology Core of the San Diego Center for AIDS Research (CFAR) AI036214. D.H., L.P., and D.N. were supported by R01AI132317. S.A.R. was supported by NIH 5T32AI007384). This work was also supported by the John and Mary Tu Foundation and the James B. Pendleton Charitable Trust (to D.M.S. and D.R.B.). X-ray diffraction data were collected at Stanford Synchrotron Radiation Lightsource (SSRL). SSRL is a Directorate of SLAC National Accelerator Laboratory, and an Office of Science User Facility operated for the U.S. Department of Energy Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393) and the National Center for Research Resources (P41RR001209).

Author contributions: P.Z., M.Y., G.S., I.A.W., D.R.B., and R.A. conceived and designed the study. N.B., J.R., M.P., E.G., S.A.R., D.M.S., and T.F.R. recruited donors and collected and processed plasma samples. P.Z., G.S., and F.A. performed BLI, ELISA, cell binding, and virus neutralization assays. D.H. and L.P. conducted cell-cell fusion experiment. W.H., S.C., and P.Y. generated recombinant protein antigens. M.Y. and X.Z. determined the crystal structure of the antibody-antigen complex. N.B., N.S., J.R.T., and T.F.R. carried out animal studies and viral load measurements. P.Z., M.Y., G.S., N.B., N.S., D.H., W.H., D.N., J.R.T., T.F.R., I.A.W., D.R.B., and R.A. designed the experiments and analyzed the data. R.A., P.Z., G.S., M.Y., I.A.W., and D.R.B. wrote the paper, and all authors reviewed and edited the paper.

Competing interests: R.A., G.S., W.H., T.F.R., and D.R.B. are listed as inventors on pending patent applications describing the SARS-CoV-2 and HCoV-HKU1 S cross-reactive antibodies. P.Z., G.S., M.Y., I.A.W., D.R.B. and R.A. are listed as inventors on a pending patent application describing the S2 stem epitope immunogens identified in this study. D.R.B. is a consultant for IAVI, Mabloc and Adagio. All other authors have no competing interests to declare.

Data Availability: All data associated with this study are in the paper or supplementary materials. The structure of CC40.8 antibody Fab in complex with SARS-CoV-2 stem-helix peptide is available under the accession code PDB ID 7SJS. CC40.8 antibody plasmids are available from Raiees Andrabi or Dennis R. Burton under a standard MTA with The Scripps Research Institute.

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