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

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 (LNP _ssPalmO ). 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-LNP _ssPalmO induced comparable antigen-specific antibodies and better interferon-γ (IFN-γ)-producing T helper type 1 responses in mice. Both mRNA-LNP _ssPalmO and conventional mRNA-LNPs conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNP _ssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared with conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNP _ssPalmO 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-LNP _ssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.
Competing Interests: Declaration of interests T.S., H.T., T.W., H.A., and Y.Y. filed a patent application related to the content of the manuscript (US63/515,413 and PCT/JP2024/026712). H.T. and H.A. are the named inventors on a patent (WO2019/188867). Y.Y. is an employee of The Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)