Optimization of a liver Trm cell-inducing mRNA vaccine by reduction of type I interferon response

Optimization of a liver Trm cell-inducing mRNA vaccine by reduction of type I interferon response Abstract CD8+ tissue-resident memory T cells provide rapid frontline protection at pathogen invasion sites, making them attractive targets for vaccine-mediated immunity. We previously developed an NKT cell-adjuvanted mRNA lipoplex vaccine capable of inducing liver Trm cells and sterile protection against malaria in mice. Here, we show that type I interferon (IFN-I) signalling through dendritic cells — not T cells — is a key brake on liver Trm induction by this vaccine. Optimising mRNA manufacturing to reduce immunostimulatory contaminants substantially dampened IFN-I production, boosted antigen expression in the lymphoid tissues, and drove significantly greater Trm accumulation. These enhanced responses translated into superior protection against parasite challenge. Our findings identify DC-intrinsic IFN-I signalling as a tractable target, and mRNA manufacturing quality as a critical and underappreciated lever, for maximising Trm-based vaccine efficacy. Competing Interest Statement The authors have declared no competing interest. Subject Area - Biochemistry (17691) - Bioengineering (13892) - Bioinformatics (41937) - Biophysics (21452) - Cancer Biology (18589) - Cell Biology (25504) - Clinical Trials (138) - Developmental Biology (13378) - Ecology (19899) - Epidemiology (2067) - Evolutionary Biology (24320) - Genetics (15609) - Genomics (22506) - Immunology (17736) - Microbiology (40394) - Molecular Biology (17181) - Neuroscience (88605) - Paleontology (666) - Pathology (2832) - Pharmacology and Toxicology (4824) - Physiology (7641) - Plant Biology (15156) - Synthetic Biology (4294) - Systems Biology (9825) - Zoology (2271)