A poorly reactogenic lipid nanoparticle-mRNA vaccine unveils an innate immune pathway for adverse reactions
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.
Authors
- Yoshimasa Takahashi (ORCID: https://orcid.org/0000-0001-6342-4087)
- Tomoharu Mizukami
- Shinichiro Ota (ORCID: https://orcid.org/0000-0002-0922-8656)
- Michiaki Hamada (ORCID: https://orcid.org/0000-0001-9466-1034)
- Tomohiro Takano (ORCID: https://orcid.org/0000-0003-4267-1147)
- Masayoshi Fukasawa (ORCID: https://orcid.org/0000-0002-0702-0691)
- Yu Adachi (ORCID: https://orcid.org/0000-0002-8573-987X)
- Hitoshi Iuchi (ORCID: https://orcid.org/0000-0002-2278-3443)
- Kohei Soga (ORCID: https://orcid.org/0000-0001-7364-6724)
- Satoshi Hachimura (ORCID: https://orcid.org/0000-0002-4475-781X)
- Ken J. Ishii (ORCID: https://orcid.org/0000-0002-6728-3872)
- Takayuki Matsumura (ORCID: https://orcid.org/0000-0003-1760-3484)
- Saya Moriyama (ORCID: https://orcid.org/0000-0003-2057-9198)
- Mizuki Fujisawa (ORCID: https://orcid.org/0000-0002-9491-0886)
- Masanori Isogawa (ORCID: https://orcid.org/0000-0001-8730-4303)
- Kazutaka Terahara (ORCID: https://orcid.org/0000-0001-9876-4356)
- Keigo Kumagai (ORCID: https://orcid.org/0000-0002-1663-2905)
- Aya Mizuike (ORCID: https://orcid.org/0000-0001-6736-2987)
- Kouji Kobiyama (ORCID: https://orcid.org/0000-0002-5846-4807)
- Ryutaro Kotaki (ORCID: https://orcid.org/0000-0001-7965-1671)
- Haruyo Nakajima‐Adachi (ORCID: https://orcid.org/0000-0003-2008-2501)
- Masaharu Shinkai
- Kyoko Saito
- Eita Sasaki
Institutions
- Tokyo University of Agriculture (JP)
- Waseda University (JP)
- Tokyo Medical University (JP)
- National Institute of Infectious Diseases (JP)
- Seiwa Hospital (JP)
- New Tokyo Hospital (JP)
- Saitama International Medical Center (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- npj Vaccines
- Published
- 2026-04-16
- DOI
- https://doi.org/10.1038/s41541-026-01441-9
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science