PhD Candidate Saint Louis University School of Medicine Saint Louis, Missouri, United States
Disclosure(s):
Tyson Lobb: No financial relationships to disclose
Introduction/Rationale: 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.
