Cell Reports
Volume 38, Issue 12, 22 March 2022, 110561
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Article
Rationally designed immunogens enable immune focusing following SARS-CoV-2 spike imprinting

https://doi.org/10.1016/j.celrep.2022.110561Get rights and content
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Highlights

  • Rationally designed immunogens using glycan engineering and epitope scaffolding

  • Immunogens focus murine antibody responses following SARS-CoV-2 spike imprinting

  • Focusing to the SARS-CoV-2 receptor binding motif yields broad, potent neutralization

  • Structural characterization of immunogen-elicited mAbs defines conserved epitopes

Summary

Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit the spread of related viruses with pandemic potential. Here we leverage rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding in boosting immunogens, we focus murine serum antibody responses to conserved receptor binding motif (RBM) and receptor binding domain (RBD) epitopes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike imprinting. Although all engineered immunogens elicit a robust SARS-CoV-2-neutralizing serum response, RBM-focusing immunogens exhibit increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV; structural characterization of representative antibodies defines a conserved epitope. RBM-focused sera confer protection against SARS-CoV-2 challenge. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses without compromising SARS-CoV-2 protection. These engineering strategies are adaptable to other viral glycoproteins for targeting conserved epitopes.

Research topic

CP: Immunology

Keywords

immunogen design
glycan
immune focusing
SARS-CoV-2
coronavirus

Data and code availability

  • CryoEM data have been deposited in the Electron Microscopy Data Base and are available as of the date of publication. X-ray crystallography data have been deposited in the Protein Data Bank (7TE1) and are available as of the date of publication. B cell receptor sequences have been deposited in Genbank. Accession numbers are listed in the key resources table.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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