+Search query
-Structure paper
Title | A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines. |
---|---|
Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 5496, Year 2024 |
Publish date | Jun 28, 2024 |
![]() | 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 / ![]() ![]() |
PubMed 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. |
![]() | ![]() ![]() ![]() |
Methods | EM (single particle) |
Resolution | 2.7 - 3.5 Å |
Structure data | EMDB-43435, PDB-8vq9: EMDB-43436, PDB-8vqa: EMDB-43437, PDB-8vqb: |
Chemicals | ![]() ChemComp-NAG: |
Source |
|
![]() | VIRAL PROTEIN / Sarbecoviruses / Spike glycoprotein / fusion protein / prefusion-stabilized / Seattle Structural Genomics Center for Infectious Disease / SSGCID |