Rationally designed immunogens enable immune focusing following SARS-CoV-2 spike imprinting
Blake M. Hauser,
Maya Sangesland,
Kerri J. St. Denis,
Evan C. Lam,
James Brett Case,
Ian W. Windsor,
Jared Feldman,
Timothy M. Caradonna,
Ty Kannegieter,
Michael S. Diamond,
Alejandro B. Balazs,
Daniel Lingwood,
Aaron G. Schmidt
Affiliations
Blake M. Hauser
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Maya Sangesland
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Kerri J. St. Denis
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Evan C. Lam
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
James Brett Case
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Ian W. Windsor
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
Jared Feldman
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Timothy M. Caradonna
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Ty Kannegieter
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Michael S. Diamond
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Alejandro B. Balazs
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Daniel Lingwood
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
Aaron G. Schmidt
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
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.
