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<p>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.</p>

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A poorly reactogenic lipid nanoparticle-mRNA vaccine unveils an innate immune pathway for adverse reactions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • 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

摘要

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.