A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.

Autor: Lee J; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Stewart C; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Schaefer A; Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA., Leaf EM; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Park YJ; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Howard Hughes Medical Institute, Seattle, WA 98195, USA., Asarnow D; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Powers JM; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.; Howard Hughes Medical Institute, Seattle, WA 98195, USA.; Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland., Treichel C; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Corti D; Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland., Baric R; Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA., King NP; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Veesler D; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 20. Date of Electronic Publication: 2023 Dec 20.
DOI: 10.1101/2023.12.12.571160
Abstrakt: Continuous 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 monoclonal antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S 2 subunit, which folds as a spring-loaded fusion machinery. Here, we describe a protein design strategy enabling prefusion-stabilization of the SARS-CoV-2 S 2 subunit and high yield recombinant expression of trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to all sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S 2 fusion machineries. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S 2 trimer vaccine elicits broadly reactive sarbecovirus antibody responses 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 SARS-CoV-2 XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines motivating future development.
Competing Interests: Competing Interests N.P.K. and D.V. are named as inventors on patents for coronavirus nanoparticle vaccines filed by the University of Washington. N.P.K. is a co-founder, shareholder, paid consultant,and chair of the scientific advisory board of Icosavax, Inc. and has received an unrelated sponsored research agreement from Pfizer. D.C. is an employee of Vir Biotechnology and may hold shares in Vir Biotechnology.
Databáze: MEDLINE
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