National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI158186
United States
Citation
Journal: Nat Commun / Year: 2024 Title: A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines. Authors: Jimin Lee / Cameron Stewart / Alexandra Schäfer / Elizabeth M Leaf / Young-Jun Park / Daniel Asarnow / John M Powers / Catherine Treichel / Kaitlin R Sprouse / Davide Corti / Ralph Baric / ...Authors: Jimin Lee / Cameron Stewart / Alexandra Schäfer / Elizabeth M Leaf / Young-Jun Park / Daniel Asarnow / John M Powers / Catherine Treichel / Kaitlin R Sprouse / Davide Corti / Ralph Baric / Neil P King / David Veesler / Abstract: Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome ...Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.
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