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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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sa-mRNA influenza vaccine raises a higher and more durable immune response than mRNA vaccine in preclinical models
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Journal Article
sa-mRNA influenza vaccine raises a higher and more durable immune response than mRNA vaccine in preclinical models
2025
Overview
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 N1ψ-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.
•GOI expression with sa-mRNA vaccine is more potent and durable vs. mRNA vaccine.•Antibody titers and CD8 T cell responses are greater with sa-mRNA vs. mRNA vaccines.•sa-mRNA vaccine generates similar immunogenicity as mRNA vaccine at smaller doses.•Dose-spared sa-mRNA vaccine induces lower cytokine release than mRNA vaccine.
Publisher
Elsevier Ltd,Elsevier Limited
Subject
/ Animals
/ Antibodies, Neutralizing - blood
/ Antibodies, Neutralizing - immunology
/ Antibodies, Viral - immunology
/ Antigens
/ birds
/ Blood
/ COVID-19
/ COVID-19 - prevention & control
/ Female
/ Humans
/ Influenza A Virus, H5N1 Subtype - immunology
/ Influenza Vaccines - administration & dosage
/ Influenza Vaccines - genetics
/ Influenza Vaccines - immunology
/ Kinases
/ Mice
/ mRNA
/ pandemic
/ Proteins
/ Rats
/ Severe acute respiratory syndrome coronavirus 2
/ Vaccine production of antigen
/ Vaccines
