Transcriptome atlas of injection site response reveals initial mechanisms of mRNA vaccine immunity
Precise immunological mechanisms of mRNA vaccines have still not been fully elucidated, especially the initial immune responses at the injection site. Here, by constructing a single-cell atlas of injection site responses of mRNA vaccine, we show that stromal inflammatory responses and type I interferon responses dominate initial transcriptional reactions elicited by mRNA vaccines at the injection site. Tracking down the fates of the delivered mRNA revealed that injection site fibroblasts are highly enriched with the delivered mRNA, and they express IFN-ß specifically in response to the mRNA component, not to the LNP. Accordingly, migratory dendritic cells highly expressing interferon stimulated genes (mDC_ISG) were found specifically in muscle and draining lymph nodes of mRNA vaccine injected mice, compared to the empty LNP injected mice. Co-administration of IFN-ß and LNP robustly induced mDC_ISGs at the injection site and substantially enhanced antigen-specific CD8 T cell responses. Collectively, these data elucidate earliest mechanisms of the mRNA vaccine and highlight the underappreciated immunogenic role of the mRNA component in the mRNA vaccine. Overall design: We performed single cell RNA sequencing on the mRNA vaccine or empty LNP injected muscle tissues, draining lymph nodes and peripheral blood cells.