tetano
Editor, Senior Moderator
Nat Commun
. 2024 Jun 28;15(1):5496.
doi: 10.1038/s41467-024-49656-5. A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines
Jimin Lee[SUP] 1 [/SUP], Cameron Stewart[SUP] 1 [/SUP], Alexandra Schäfer[SUP] 2 [/SUP], Elizabeth M Leaf[SUP] 1 3 [/SUP], Young-Jun Park[SUP] 1 4 [/SUP], Daniel Asarnow[SUP] 1 [/SUP], John M Powers[SUP] 2 [/SUP], Catherine Treichel[SUP] 1 3 [/SUP], Kaitlin R Sprouse[SUP] 1 4 [/SUP], Davide Corti[SUP] 5 [/SUP], Ralph Baric[SUP] 2 [/SUP], Neil P King[SUP] 1 3 [/SUP], David Veesler[SUP] 6 7 [/SUP]
Affiliations
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[SUB]2[/SUB] 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[SUB]2[/SUB] 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[SUB]2[/SUB] subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S[SUB]2[/SUB] 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.
. 2024 Jun 28;15(1):5496.
doi: 10.1038/s41467-024-49656-5. A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines
Jimin Lee[SUP] 1 [/SUP], Cameron Stewart[SUP] 1 [/SUP], Alexandra Schäfer[SUP] 2 [/SUP], Elizabeth M Leaf[SUP] 1 3 [/SUP], Young-Jun Park[SUP] 1 4 [/SUP], Daniel Asarnow[SUP] 1 [/SUP], John M Powers[SUP] 2 [/SUP], Catherine Treichel[SUP] 1 3 [/SUP], Kaitlin R Sprouse[SUP] 1 4 [/SUP], Davide Corti[SUP] 5 [/SUP], Ralph Baric[SUP] 2 [/SUP], Neil P King[SUP] 1 3 [/SUP], David Veesler[SUP] 6 7 [/SUP]
Affiliations
- PMID: 38944664
- PMCID: PMC11214633
- DOI: 10.1038/s41467-024-49656-5
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[SUB]2[/SUB] 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[SUB]2[/SUB] 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[SUB]2[/SUB] subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S[SUB]2[/SUB] 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.