Innate immune responses underlying local and systemic adverse reactions to mRNA-lipid nanoparticle vaccines

Abstract Vaccine reactogenicity refers to the capacity of a vaccine to induce transient local and systemic adverse reactions (ARs). Although these ARs are often attributed to vaccine-induced innate inflammation, accumulating evidence indicates that the inflammatory pathways causing symptoms are not necessarily identical to those required for protective immunity. mRNA-lipid nanoparticle (LNP) vaccines provide a valuable framework for examining this relationship, because both the mRNA cargo and the LNP delivery system can contribute to innate immune activation. Early inflammatory responses following mRNA-LNP vaccination appear to reflect the interplay of multiple signals, including ionizable lipid-driven signaling, mRNA-associated interferon (IFN) responses, endosomal membrane perturbation, and tissue-derived danger signals. These upstream events can be amplified through cytokine networks that promote systemic symptoms. Interleukin-1 (IL-1) has emerged as a major contributor to this process, although IL-6, tumor necrosis factor-alpha (TNF-α), type I IFN, and prostaglandin-related pathways also contribute, depending on the experimental model and context. In this review, we summarize recent evidence linking upstream sensing pathways to local and systemic ARs, and discuss how these pathways intersect with vaccine-induced adaptive immunity. We also consider booster-associated amplification of ARs as an example in which immune memory may reshape innate cytokine responses after repeated vaccination. Understanding these relationships will help delineate the shared and distinct inflammatory circuits underlying ARs and protective immunity. These mechanistic insights may also inform the rational design of low-reactogenic mRNA-LNP formulations that retain sufficient immunogenicity.