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Rabies glycoprotein engineering for improved stability and expression
Solomon English1, Sofiya Fedosyuk1, Francisco Orliacq1
1Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
Vaccine
|July 27, 2025
Summary
Developing new rabies vaccines is crucial for accessibility. Researchers engineered the rabies virus glycoprotein (RVG) to improve vaccine immunogenicity, but found wild-type RVG sufficient for current mRNA and adenovirus platforms in mice.
Area of Science:
- Vaccinology
- Molecular Biology
- Immunology
Background:
- Current rabies vaccines are costly and require multiple doses, limiting global access.
- Developing novel, low-cost vaccines that elicit a robust immune response against rabies virus glycoprotein (RVG) is a priority.
Purpose of the Study:
- To investigate structure-guided antigen engineering and transgene cassette optimization for improved rabies vaccine immunogenicity.
- To evaluate novel vaccine constructs for enhanced expression, stability, and protective antibody response against rabies virus.
Main Methods:
- Evaluated twelve candidate transgene cassette designs, including codon optimization and co-expression strategies.
- Screened 72 mutant constructs of RVG for in vitro expression and pre-fusion stability at low pH.
- Tested immunogenicity of wild-type RVG and mutant constructs using an mRNA vaccine platform in mice.
Main Results:
- Codon optimization improved in vitro expression but not immunogenicity.
- Mutant constructs showed enhanced expression and/or stability, with specific double mutants (L271Q + H419L) demonstrating the greatest expression increase.
- Neither engineered RVG mutants nor cassette optimizations improved immunogenicity compared to wild-type RVG in mRNA vaccines.
Conclusions:
- While certain mutations enhance RVG expression and stability, they did not translate to improved immunogenicity in mRNA vaccines.
- Full-length wild-type RVG appears sufficiently stable and expressed for optimal immunogenicity in adenovirus and mRNA rabies vaccines.
- Engineered RVG mutants may hold potential for future protein subunit vaccine development.
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