sa-mRNA influenza vaccine raises a higher and more durable immune response than mRNA vaccine in preclinical models

Feb 16, 2025Vaccine

Self-amplifying mRNA flu vaccine produces stronger and longer-lasting immune response than regular mRNA vaccine in animal tests

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Abstract

Self-amplifying mRNA vaccines demonstrate >100-fold greater transfection efficiency compared to modified mRNA platforms.

Self-amplifying mRNA vaccines show enhanced durability of gene expression compared to conventional mRNA vaccines.
In vivo studies indicate that self-amplifying mRNA produces >100-fold cumulative bioluminescence, suggesting superior gene expression.
A 10-fold lower dose of self-amplifying mRNA achieves similar binding and neutralizing titers against the H5N1 influenza strain in mouse and rat models.
Lower doses of self-amplifying mRNA result in reduced reactogenicity while maintaining or increasing immunogenicity compared to modified mRNA.
The findings suggest potential advantages of self-amplifying mRNA vaccines in terms of dose sparing and enhanced immune responses.

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mRNA-based vaccines can be rapidly manufactured and have been demonstrated clinically to raise robust immune responses to COVID-19 and protect against severe COVID-19 disease. The clinical immunogenicity and efficacy of self-amplifying mRNA (sa-mRNA) vaccines have also been demonstrated, along with a longer duration of action than mRNA vaccines. However, a detailed understanding of differences between sa-mRNA and conventional mRNA vaccines with modified bases is lacking. Compared with a Nψ-modified mRNA platform, when using an sa-mRNA approach, we observed a > 100-fold greater transfection efficiency for multiple antigens by sa-mRNA, all of which also showed high durability for gene-of-interest (GOI) production. The enhanced magnitude and durability of GOI expression by sa-mRNA compared with modified mRNA was also analysed in vivo using a luciferase reporter construct. In this experiment, sa-mRNA produced >100-fold cumulative bioluminescence compared with an mRNA construct. The elevation in GOI production translated into greater in vivo immunogenicity, where a 10-fold lower dose of sa-mRNA generated similar binding and neutralizing titers for the avian pandemic influenza H5N1 strain in both mouse and rat models. The sa-mRNA construct also generated comparable or higher antigen-specific CD8 T cell responses at 10-fold lower doses than mRNA. The lower doses of sa-mRNA generated a reduced elevation of reactogenic biomarkers while still generating similar or higher immunogenicity in rats and mice compared with modified mRNA. The current study suggests the potential of leveraging dose sparing, improved durability, enhanced immunogenicity, and possibly reduced reactogenicity of the sa-mRNA platform for vaccine applications. 1

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sa-mRNA influenza vaccine raises a higher and more durable immune response than mRNA vaccine in preclinical models

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