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

Sampa Santra; Michelle A. Lifton; Benjamin Mildenberg; Georgeanna Morton; Han Nhat Tran; Laura L. Sutherland; Robert Parks; Whitney Edwards; Bette Korber; Anthony T. Phan; Christopher A. Hunter; Garima Dwivedi; Benjamin Davis; Justin Su; Mohamad‐Gabriel Alameh; Edward F. Kreider; Susan Pratiksha; Francois J. Villinger; Tomáš Hanke; Persephone Borrow; Drew Weissman; Barton F. Haynes

doi:10.64898/2026.10.26.761945

ImmunologybioRxivNov 1, 2026

Preprint

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

Sampa Santra iD, Michelle A. Lifton iD, Benjamin Mildenberg iD, Georgeanna Morton iD, Han Nhat Tran, Laura L. Sutherland iD, Robert Parks iD, Whitney Edwards, Bette Korber iD, Anthony T. Phan iD, Christopher A. Hunter iD, Garima Dwivedi iD, Benjamin Davis iD, Justin Su iD, Mohamad‐Gabriel Alameh iD, Edward F. Kreider iD, Susan Pratiksha, Francois J. Villinger iD, Tomáš Hanke iD, Persephone Borrow iD, Drew Weissman iD, Barton F. Haynes iD

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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