An IL-12 mRNA-LNP adjuvant durably enhances the CD8+ T cell response to mRNA vaccination

Abstract The design of vaccines that can reliably induce protective CD8+ T cell activity has been considered a challenge for the vaccine field, but the use of viral vectors or mRNA encapsulated into lipid nanoparticles (LNPs) has overcome some of these issues. Because the cytokine interleukin-12 (IL-12) supports CD8+ T cell expansion and acquisition of effector functions, studies were performed to assess its contribution to the ability of mRNA vaccines to promote CD8+ T cell responses. mRNA-LNPs do not stimulate macrophage production of IL-12 in vitro nor does in vivo vaccination, and endogenous IL-12 is not required for the CD8+ T cell response to mRNA vaccination. However, the addition of IL-12 mRNA-LNPs into vaccination with LNPs that contain mRNA for the model antigen ovalbumin (OVA) results in enhanced OVA-specific CD8+ T cell expansion, improved acquisition of effector function, diversification of the CD8+ T cell effector pool through generation of a KLRG1hi effector subset and expanded effector and central memory CD8+ T cell populations. In both preventative vaccination against Listeria monocytogenes-OVA and therapeutic vaccination against B16 F0-OVA melanoma, addition of IL-12 mRNA-LNPs enhanced protection. Thus, modification of current mRNA vaccine formulations to induce IL-12 production provides a strategy to modify the CD8+ T cell response, enhance CD8+ T cell mediated protection and illustrates the utility of cytokine mRNA to tailor vaccine-induced immunity.