Impact of RNA modification and IL-12 boosts on mRNA-LNP vaccine-elicited CD8+ T cell responses

Santra, S.; Lifton, M. A.; Mildenberg, B.; Morton, G.; Tran, H. N.; Sutherland, L.; Parks, R.; Edwards, W.; Korber, B.; Phan, A. T.; Hunter, C.; Dwivedi, G.; Davis, B.; Su, J.; Alameh, M.-G.; Kreider, E. F.; Pratiksha, S.; Villinger, F.; Hanke, T.; Borrow, P.; Weissman, D.; Haynes, B. F.

doi:10.64898/2026.10.26.761945

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bioRxiv · 10.64898/2026.10.26.761945

Impact of RNA modification and IL-12 boosts on mRNA-LNP vaccine-elicited CD8+ T cell responses

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Abstract

Development of effective HIV-1 vaccines requires strategies for inducing both CD8+ T cell and neutralizing antibody responses. Nucleoside-modified mRNA-lipid-nanoparticles (LNP) induce more potent antibody responses than unmodified mRNA-LNP vaccines, while unmodified mRNA is typically employed for CD8+ T cell-inducing vaccines. Here, we compared the abilities of differing ratios of unmodified versus modified mRNA expressing a SIV conserved-region CD8+ T cell immunogen co-administered with IL-12-encoding mRNA-LNP during boosting to induce CD8+ T cell and humoral responses in non-human primates, assessing responses in ChAdOx1-primed controls in parallel. Serial priming and boosting with fully-unmodified mRNA elicited higher-magnitude, more CD8-biased T cell responses than fully-modified mRNA, that were durably maintained after the IL-12-encoding mRNA boosts. Inclusion of 30% nucleoside-modified mRNA enhanced antibody titers, suggesting potential benefits to a mixed-composition vaccine.

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Santra, S., Lifton, M. A., Mildenberg, B., Morton, G., Tran, H. N., Sutherland, L., Parks, R., Edwards, W., Korber, B., Phan, A. T., Hunter, C., Dwivedi, G., Davis, B., Su, J., Alameh, M.-G., Kreider, E. F., Pratiksha, S., Villinger, F., Hanke, T., Borrow, P., Weissman, D., Haynes, B. F.. 2026-11-01. Impact of RNA modification and IL-12 boosts on mRNA-LNP vaccine-elicited CD8+ T cell responses. https://doi.org/10.64898/2026.10.26.761945

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