Minnell, J. J.; Ganley, M.; Lee, A. R.; Phabmixay, T.; Farrand, K. J.; Burn, O. K.; Mamum, J. C.; Lamb, E.; Draper, S. L.; Chan, S. T. S.; Palmer, O. R.; Mason, N. C.; Bilbrough, T.; Anderson, R. J.; Compton, B. J.; Cozijnsen, A.; McKenzie, R. E.; Vink, J. N. A.; Le, S.; Jayasinghe, D.; Gras, S.; McFadden, G. I.; Heath, W. R.; Beattie, L.; Painter, G. F.; Holz, L. E.; Hermans, I. F.

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.