A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

Author:

Lee Jimin,Stewart CameronORCID,Schäfer AlexandraORCID,Leaf Elizabeth M.,Park Young-JunORCID,Asarnow Daniel,Powers John M.ORCID,Treichel Catherine,Sprouse Kaitlin R.,Corti DavideORCID,Baric RalphORCID,King Neil P.ORCID,Veesler DavidORCID

Abstract

AbstractEvolution 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 S2 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 S2 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) S2 subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2 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.

Funder

Howard Hughes Medical Institute

Publisher

Springer Science and Business Media LLC

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