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Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens
Xandra Nuqui1, Lorenzo Casalino2, Ling Zhou3
1Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
Nature Communications
|August 27, 2024
Summary
Researchers engineered a stabilized S2-only immunogen for a more universal COVID-19 vaccine. This conserved spike protein region offers broad protection against SARS-CoV-2 variants.
Area of Science:
- Virology
- Vaccinology
- Structural Biology
Background:
- The SARS-CoV-2 spike (S) protein's S1 subunit contains variant-specific epitopes, limiting current vaccine efficacy.
- The S2 subunit is highly conserved across sarbecoviruses and elicits broadly neutralizing antibodies.
- S2-only immunogens are unstable, hindering their vaccine development.
Purpose of the Study:
- To design and engineer a stabilized S2-only immunogen in its prefusion conformation.
- To enhance the stability and immunogenicity of S2 for broader vaccine applications.
Main Methods:
- Utilized simulation-driven design to identify stabilizing mutations.
- Employed molecular dynamics simulations to characterize S2 trimer dynamics.
- Applied cryo-electron microscopy (cryo-EM) for structural determination.
- Engineered tryptophan substitutions for kinetic and thermodynamic stabilization.
Main Results:
- Developed a stabilized S2 immunogen in the closed prefusion conformation.
- Achieved enhanced protein expression and superior thermostability of the S2 immunogen.
- Demonstrated preserved immunogenicity against sarbecoviruses.
Conclusions:
- An engineered S2 immunogen offers a promising alternative vaccine strategy against SARS-CoV-2 and related viruses.
- Stabilization of the S2 subunit in its prefusion conformation is key to its potential as a universal vaccine component.
