Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 28, Issue 6, Pages 478-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-021-00596-4
Keywords
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Funding
- National Institute of General Medical Sciences [R01GM120553]
- National Institute of Allergy and Infectious Diseases [DP1AI158186, HHSN272201700059C]
- Pew Biomedical Scholars Award
- Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund
- Swiss National Science Foundation [P400PB_183942]
- M.J. Murdock Charitable Trust
- US DOE Office of Science User Facility [DE-AC02-05CH11231]
- University of Washington Arnold and Mabel Beckman cryoEM center
- Pasteur Institute
- Fast Grant
- Swiss National Science Foundation (SNF) [P400PB_183942] Funding Source: Swiss National Science Foundation (SNF)
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The study identified a monoclonal antibody, B6, that can cross-react with eight beta-coronavirus spike proteins from three viral lineages, targeting a conserved cryptic epitope for potential broad coronavirus neutralization, marking a potential breakthrough in pan-beta-coronavirus vaccine design.
Three highly pathogenic beta-coronaviruses have crossed the animal-to-human species barrier in the past two decades: SARS-CoV, MERS-CoV and SARS-CoV-2. To evaluate the possibility of identifying antibodies with broad neutralizing activity, we isolated a monoclonal antibody, termed B6, that cross-reacts with eight beta-coronavirus spike glycoproteins, including all five human-infecting beta-coronaviruses. B6 broadly neutralizes entry of pseudotyped viruses from lineages A and C, but not from lineage B, and the latter includes SARS-CoV and SARS-CoV-2. Cryo-EM, X-ray crystallography and membrane fusion assays reveal that B6 binds to a conserved cryptic epitope located in the fusion machinery. The data indicate that antibody binding sterically interferes with the spike conformational changes leading to membrane fusion. Our data provide a structural framework explaining B6 cross-reactivity with beta-coronaviruses from three lineages, along with a proof of concept for antibody-mediated broad coronavirus neutralization elicited through vaccination. This study unveils an unexpected target for next-generation structure-guided design of a pan-beta-coronavirus vaccine. Structural characterization of B6, a monoclonal antibody that cross-reacts with eight beta-coronavirus spike proteins from three viral lineages, reveals a conserved cryptic epitope that could serve as a target for structure-guided design of a pan-beta-coronavirus vaccine.
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