Understanding Mechanisms of Adjuvancy in Muscle by mRNA/Lipid Nanoparticles

Abstract Vaccines utilizing encapsulated mRNA within lipid nanoparticles (LNPs) have demonstrated unprecedented efficacy in clinical studies of mRNA-1273 and BNT162b2, two prominent vaccines developed against the S protein of SARS-CoV-2. Despite several Phase III trials offering deep clinical intuition about vaccine efficacy, the musculo-immune basis for elicitation of a strong germinal center response from mRNA/LNP vaccine remains unclear. Here, we characterize the trajectory of the immune response to an mRNA lipid nanoparticle vaccine, encapsulated in sm-102 (Moderna). Furthermore, we find that intramuscular administration of empty LNPs elicits a strong neutrophil and dendritic response within 24h. Additionally, we show that skeletal muscle may play a role in the early immune response to mRNA LNPs. Inflammatory LNPs thus contribute to the well-established role of RNA immunogenicity. Using a reporter of transduction, we show that both >10% of muscle-resident myeloid and lymphoid cells are directly transduced with mRNA vaccines, and that these cells play a crucial role in the downstream germinal center response. Transcriptomic measurements of muscle tissue reveal a direct role role of ionizable lipid operating as an adjuvant to induce this response. Using in vitro and molecular tools, these studies advance our understanding of the cellular and molecular basis for LNP-mediated inflammation and adjuvancy underpinning the exceptional clinical efficacy of mRNA/LNP vaccination.