Fig. 1: Mechanisms of immunogenicity of and reactogenicity to LNP-mRNA vaccines.
In the lymph nodes (LNs), modified RNA sensed by MDA-5 results in the production of type I interferons (IFNs). Type I interferons induce antigen-specific CD8+ T cell responses. LNPs can activate innate immune responses in lymph nodes and elicit production of IL-6 that is essential for the induction of TFH cells and GC B cells. These pathways are important for the immunogenicity of LNP-mRNA vaccines. When the mRNA is unmodified and a specific ionizable lipid (such as SM-102) is contained in the LNP, the mRNA is recognized by TLR7 and/or TLR8 and the ionizable lipid is recognized by the NLRP3 inflammasome in monocytes. Inflammasome-induced members of the IL-1 family trigger further inflammatory cytokine production. IL-1Ra is also produced as a negative feedback loop to inhibit IL-1 signaling and reduce inflammation. Unmodified mRNA is also detected by RIG-I, which results in the production of type I interferons and thus interferes with antigen translation. After booster vaccination, modified RNA–induced type I interferons also activate natural killer (NK) cells to produce IFN-γ. These signaling pathways might affect the reactogenicity of LNP-mRNA vaccines. APC, antigen-presenting cell; DC, dendritic cell; pDC, plasmacytoid dendritic cell; cDC, conventional dendritic cell; CARD, caspase-recruitment domain; PRR, proline-rich region; TM, transmembrane domain; TIR, Toll–IL-1R domain; DD, death domain; TH1 cells, type 1 helper T cells; NACHT, nucleotide-binding domain; PYD, pyrin domain; LRR, leucine-rich repeat; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain.
