Tomohiro Takano, Keigo Kumagai, Hitoshi Iuchi, Kazutaka Terahara, Aya Mizuike, Eita Sasaki, Yu Adachi, Ryutaro Kotaki, Saya Moriyama, Shinichiro Ota, Mizuki Fujisawa, Tomoharu Mizukami, Kyoko Saito, Masanori Isogawa, Kohei Soga, Haruyo Nakajima‐Adachi, Satoshi Hachimura, Kouji Kobiyama, Ken J. Ishii, Michiaki Hamada, Masayoshi Fukasawa, Masaharu Shinkai, Takayuki Matsumura, Yoshimasa Takahashi
Lipid nanoparticle (LNP)-mRNA vaccines robustly activate immune responses, contributing to their high efficacy and frequent adverse reactions (ARs). Here, we identified an LNP-mRNA formulation with a more favorable balanced immunogenicity-reactogenicity profile. Immune profiling in a mouse model defined the reactogenic LNP-mRNA vaccine as a potent inducer of HMGB1 release, pro-inflammatory cytokine production, and concurrent neutrophil infiltration. HMGB1 induced TNF-α secretion from monocyte subsets, yet in vivo blockade studies revealed the contribution of multiple cytokines (TNF-α, IL-1, and IL-6) to reactogenicity. Among the reactogenic cytokines, IL-1 was identified as the key mediator of vaccine-induced ARs, but was dispensable for humoral immunity. The clinical relevance was confirmed in a well-controlled vaccine cohort where IL-1 pathway activation correlated with fever severity but not with neutralizing antibody titers. We dissected early innate pathways specifically linked to vaccine reactogenicity, providing a rationale for selectively reducing ARs in next-generation vaccines.