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

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

doi:https://doi.org/10.1016/j.ymthe.2024.12.032

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

Kawai, Atsushi; Shimizu, Taro; Tanaka, Hiroki et al.

Molecular Therapy, 2025, 33(2), 529-547

Number of Access:2,591（2025-07-20 13:42 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100439

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Title	Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions
Creator	CreatorName Kawai, Atsushi
	NRID 1000030749388 1000030749388 researchmap permalink mzbpeg mzbpeg CreatorName Shimizu, Taro
	CreatorName Tanaka, Hiroki
	NRID 1000080737148 1000080737148 researchmap permalink shichi_ shichi_ Scopus Author ID 54993583800 54993583800 CreatorName Shichinohe, Shintaro
	CreatorName Anindita, Jessica
	ORCID 0000-0001-8991-587X 0000-0001-8991-587X researchmap permalink mhiro_map mhiro_map Scopus Author ID 55672764900 55672764900 CreatorName Hirose, Mika
	NRID 1000091004498 1000091004498 CreatorName Kawahara, Eigo
	CreatorName Senpuku, Kota
	CreatorName Shimooka, Makoto
	CreatorName Quynh Mai, Le Thi
	NRID 1000090384784 1000090384784 CreatorName Suzuki, Ryo
	NRID 1000020870653 1000020870653 CreatorName Nogimori, Takuto
	NRID 1000060752368 1000060752368 researchmap permalink yamamotot2 yamamotot2 CreatorName Yamamoto, Takuya
	NRID 1000000895815 1000000895815 ORCID 0000-0002-9212-1664 0000-0002-9212-1664 researchmap permalink toshiro.hirai toshiro.hirai Scopus Author ID 55628552543 55628552543 CreatorName Hirai, Toshiro
	NRID 1000020423155 1000020423155 ORCID 0000-0002-8879-6685 0000-0002-8879-6685 researchmap permalink tkato_ipr tkato_ipr Scopus Author ID 55261010900 55261010900 CreatorName Kato, Takayuki
	NRID 1000060557479 1000060557479 researchmap permalink toki_watanabe toki_watanabe Scopus Author ID 8926021900 8926021900 CreatorName Watanabe, Tokiko
	NRID 1000080344472 1000080344472 researchmap permalink HideJ HideJ CreatorName Akita, Hidetaka
	NRID 1000000392308 1000000392308 ORCID 0000-0002-7265-9221 0000-0002-7265-9221 researchmap permalink read0076530 read0076530 Scopus Author ID 55502847200 55502847200 CreatorName Yoshioka, Yasuo
Subject	adverse reaction
	cross-protection
	high-pathogenicity avian influenza virus
	ionizable lipid
	lipid nanoparticle
	mRNA vaccine
Description	Kawai A., Shimizu T., Tanaka H., et al. Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions. Molecular Therapy 33, 529 (2025); https://doi.org/10.1016/j.ymthe.2024.12.032.
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.
Publisher	Cell Press
Source Title	Molecular Therapy
Volume (Issue)	33(2)
Page	529-547
Date of Issued	2025-02-01
Language	English
Handle URL	https://hdl.handle.net/11094/100439
PISSN	15250016
eISSN	15250024
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.ymthe.2024.12.032
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Molecular Therapy. 2025, 33(2), p. 529-547
DC.title	Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions
DC.creator	Kawai, Atsushi
	Shimizu, Taro
	Tanaka, Hiroki
	Shichinohe, Shintaro
	Anindita, Jessica
	Hirose, Mika
	Kawahara, Eigo
	Senpuku, Kota
	Shimooka, Makoto
	Quynh Mai, Le Thi
	Suzuki, Ryo
	Nogimori, Takuto
	Yamamoto, Takuya
	Hirai, Toshiro
	Kato, Takayuki
	Watanabe, Tokiko
	Akita, Hidetaka
	Yoshioka, Yasuo
DC.publisher	Cell Press
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-02-01
DC.identifier	https://doi.org/10.1016/j.ymthe.2024.12.032
DC.subject	adverse reaction
	cross-protection
	high-pathogenicity avian influenza virus
	ionizable lipid
	lipid nanoparticle
	mRNA vaccine
DC.description	Kawai A., Shimizu T., Tanaka H., et al. Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions. Molecular Therapy 33, 529 (2025); https://doi.org/10.1016/j.ymthe.2024.12.032.
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100439
citation_title	Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 influenza virus with reduced adverse reactions
citation_author	Kawai, Atsushi
	Shimizu, Taro
	Tanaka, Hiroki
	Shichinohe, Shintaro
	Anindita, Jessica
	Hirose, Mika
	Kawahara, Eigo
	Senpuku, Kota
	Shimooka, Makoto
	Quynh Mai, Le Thi
	Suzuki, Ryo
	Nogimori, Takuto
	Yamamoto, Takuya
	Hirai, Toshiro
	Kato, Takayuki
	Watanabe, Tokiko
	Akita, Hidetaka
	Yoshioka, Yasuo
citation_publisher	Cell Press
citation_language	English
citation_date	2025-02-01
citation_journal_title	Molecular Therapy
citation_volume	33
citation_issue	2
citation_firstpage	529
citation_lastpage	547
citation_doi	https://doi.org/10.1016/j.ymthe.2024.12.032
citation_public_url	https://hdl.handle.net/11094/100439

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

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