4.8 Article

A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection

期刊

SCIENCE TRANSLATIONAL MEDICINE
卷 14, 期 637, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abi9215

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资金

  1. NIH NIAID CHAVD [UM1 AI44462]
  2. IAVI Neutralizing Antibody Center
  3. Bill & Melinda Gates Foundation [OPP 1170236, INV-004923]
  4. Translational Virology Core of the San Diego Center for AIDS Research (CFAR) [AI036214, R01AI132317]
  5. NIH [5T32AI007384]
  6. John and Mary Tu Foundation
  7. James B. Pendleton Charitable Trust
  8. DOE Office of Biological and Environmental Research
  9. National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
  10. National Center for Research Resources [P41RR001209]

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This study describes a broadly neutralizing antibody CC40.8 that targets the spike fusion machinery of coronaviruses and demonstrates its protective efficacy against SARS-CoV-2 in animal models, indicating its potential for the development of pan-coronavirus vaccines.
Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a CoV disease 2019 (COVID-19) convalescent donor that exhibits broad reactivity with human beta-CoVs. Here, we showed that CC40.8 targets the conserved S2 stem helix region of the CoV spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem peptide at 1.6-angstrom resolution and found that the peptide adopted a mainly helical structure. Conserved residues in beta-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted that CC40.8-like bnAbs are relatively rare in human COVID-19 infection, and therefore, their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on beta- CoV spike proteins for protective antibodies that may facilitate the development of pan-beta-CoV vaccines.

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