%0 Journal Article
%T A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.
%A Lee J
%A Stewart C
%A Schäfer A
%A Leaf EM
%A Park YJ
%A Asarnow D
%A Powers JM
%A Treichel C
%A Sprouse KR
%A Corti D
%A Baric R
%A King NP
%A Veesler D
%J Nat Commun
%V 15
%N 1
%D 2024 Jun 28
%M 38944664
%F 17.694
%R 10.1038/s41467-024-49656-5
%X 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 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.