mRNA Therapeutics: immunological issues (from 9th Int. Vaccines R&D Conference, Boston, Nov. 2024)

I review the key immune issues in the design and development of mRNA therapeutics for protein replacement, vs. infectious disease and cancer vaccines. I focus on the role of type I IFN, and the critical differentiation between IFN-a vs. IFN-b in driving CD8+ T cells vs. Treg. The unique role of TLR7/9, and the optimal design for their ligands in driving IFN-a production has been widely ignored in the field, and i explain how this has led to suboptimal approaches in human clinical development. I conclude with a proposed schema for the combinatorial role of PRRs in distinguishing various types of infectious and noninfectious "danger", and the rationale for mimicking retroviral replicative structures to costimulate TLR7/8/9 to induce optimal CD8+ T cell responses for cancer immunotherapy.