A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

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 and David Veesler ()
Additional contact information
Jimin Lee: University of Washington
Cameron Stewart: University of Washington
Alexandra Schäfer: University of North Carolina
Elizabeth M. Leaf: University of Washington
Young-Jun Park: University of Washington
Daniel Asarnow: University of Washington
John M. Powers: University of North Carolina
Catherine Treichel: University of Washington
Kaitlin R. Sprouse: University of Washington
Davide Corti: a subsidiary of Vir Biotechnology
Ralph Baric: University of North Carolina
Neil P. King: University of Washington
David Veesler: University of Washington

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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 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.

Date: 2024
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DOI: 10.1038/s41467-024-49656-5

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