Type 1 Interferon Restricts mRNA Vaccine Efficacy Through Suppression of Antigen Uptake in Conventional Dendritic Cells 2309444

Abstract Introduction mRNA-based vaccines are a versatile tool reshaping vaccinology. Therefore, it is critical to understand the underlying mechanisms governing their efficacy. These vaccines transiently induce type I interferons (IFN), and studies conflict as to whether IFN is beneficial or detrimental to the vaccine-specific immune response. We sought to determine how IFN shapes the efficacy of mRNA—lipid nanoparticle (mRNA-LNP) vaccines. Methods We hypothesized that IFN inhibits the ability of dendritic cells (DCs) to acquire and express mRNA-LNPs. To test this, we administered mRNA-LNPs in vitro to bone marrow—derived dendritic cells (BMDCs) that were inhibited from signaling through the IFN alpha/beta receptor (IFNαR) using an antagonistic antibody, MAR1-5A3. In addition, we inhibited IFN signaling in vivo using MAR1-5A3 and by genetically deleting IFNαR in DCs via CD11c-specific Cre—mediated deletion of loxP-flanked Ifnar1. These mice were immunized with mRNA-LNPs and assessed for vaccine mRNA uptake and expression, as well as induction of a vaccine-specific immune response. Results We found that IFN reduces vaccine-specific mRNA expression by DCs in vitro and in vivo. Inhibition of IFNαR signaling or genetic ablation of IFNαR in DCs in vivo improved vaccine-specific CD8+ T cell responses. Additionally, IFN induction prior to vaccination reduced vaccine-specific immune responses. Thus, we find that IFN inhibits vaccine uptake by DCs, limiting their ability to mount vaccine-specific immune responses. Conclusion In conclusion, we find that DCs that had not yet acquired vaccine antigen are inhibited from antigen uptake upon IFN signaling. Inhibiting nonessential IFN signaling augmented antigen uptake and downstream vaccine-specific immune responses. These insights provide a compelling rationale for optimizing formulation strategies to transiently modulate IFNαR signaling pathways to maximize antigen acquisition, mRNA expression, T cell priming, and efficacy. Funding Source n/a Topic Categories Vaccines and Immunotherapy (VAC)