Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions

Atsushi Kawai, Taro Shimizu, Hiroki Tanaka, Shintaro Shichinohe, Jessica Anindita, Mika Hirose, Eigo Kawahara, Kota Senpuku, Makoto Shimooka, Le Thi Quynh Mai, Ryo Suzuki, Takuto Nogimori, Takuya Yamamoto, Toshiro Hirai, Takayuki Kato, Tokiko Watanabe, Hidetaka Akita, Yasuo Yoshioka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Messenger RNA vaccines based on lipid nanoparticles (mRNA-LNPs) are promising vaccine modalities. However, mRNA-LNP vaccines frequently cause adverse reactions such as swelling and fever in humans, partly due to the inflammatory nature of LNP. Modification of the ionizable lipids used in LNPs is one approach to avoid these adverse reactions. Here, we report the development of mRNA-LNP vaccines with better protective immunity and reduced adverse reactions using LNPs, which contain a disulfide (SS)-cleavable bond and pH-activated lipid-like materials with oleic acid (ssPalmO) as an ionizable lipid (LNPssPalmO). We used mRNA expressing H5N1 subtype high-pathogenicity avian influenza virus-derived hemagglutinin or neuraminidase to generate mRNA-LNP vaccines against H5N1 influenza. Compared with conventional LNPs, mRNA-LNPssPalmO induced comparable antigen-specific antibodies and better interferon-γ (IFN-γ)-producing T helper type 1 responses in mice. Both mRNA-LNPssPalmO and conventional mRNA-LNPs conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared with conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPssPalmO induced less-inflammatory responses (e.g., inflammatory cytokine production, vascular hyperpermeability) and fewer adverse reactions (e.g., weight loss, fever) compared with conventional mRNA-LNPs. These results suggest that mRNA-LNPssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.

Original languageEnglish
Pages (from-to)529-547
Number of pages19
JournalMolecular Therapy
Volume33
Issue number2
DOIs
StatePublished - 2025/02/05

Keywords

  • adverse reaction
  • cross-protection
  • high-pathogenicity avian influenza virus
  • ionizable lipid
  • lipid nanoparticle
  • mRNA vaccine

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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