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

Dec 18, 2024Molecular therapy : the journal of the American Society of Gene Therapy

Low-inflammation lipid nanoparticle mRNA vaccine triggers protection against H5N1 flu with fewer side effects

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Abstract

mRNA-LNP vaccines with disulfide-cleavable bonds and pH-activated lipids showed better cross-protection against heterologous H5N1 virus challenges compared to conventional mRNA-LNPs.

Modified ionizable lipids in mRNA-LNPs may reduce inflammatory responses and adverse reactions like weight loss and fever.
mRNA-LNPs induced comparable levels of antigen-specific antibodies and enhanced T helper type 1 responses in mice.
Both mRNA-LNPs and conventional mRNA-LNPs provided strong protection against homologous H5N1 virus challenges.
The new mRNA-LNP formulation demonstrated improved safety profiles compared to traditional mRNA-LNPs.

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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). 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-LNPinduced comparable antigen-specific antibodies and better interferon-γ (IFN-γ)-producing T helper type 1 responses in mice. Both mRNA-LNPand conventional mRNA-LNPs conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPshowed better cross-protection against heterologous H5N1 virus challenge compared with conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPinduced 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-LNPwould be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy. ssPalmO ssPalmO ssPalmO ssPalmO ssPalmO ssPalmO

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

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