Design and lyophilization of lipid nanoparticles for mRNA vaccine and its robust immune response in mice and nonhuman primates
MOLECULAR THERAPY-NUCLEIC ACIDS(2022)
Abstract
mRNA and lipid nanoparticles have emerged as powerful sys-tems for the preparation of vaccines against severe acute respi-ratory syndrome coronavirus-2 (SARS-CoV-2) infection. The emergence of novel variants or the necessity of cold chain logis-tics for approved mRNA vaccines undermines the investigation of next-generation systems that could preserve both potency and stability. However, the correlation between lipid nanopar-ticle composition and activity is not fully explored. Here, we screened a panel of ionizable lipids in vivo and identified lead lipid nanoparticles with a branched-tail lipid structure. Buffer optimization allowed the determination of lyophilization conditions, where lipid nanoparticle-encapsulated mRNA en-coding SARS-CoV-2 spike protein could induce robust immu-nogenicity in mice after 1 month of storage at 5 degrees C and 25 degrees C. Intramuscularly injected lipid nanoparticles distributed in conventional dendritic cells in mouse lymph nodes induced balanced T helper (Th) 1/Th2 responses against SARS-CoV-2 spike protein. In nonhuman primates, two doses of 10 or 100 mg of mRNA induced higher spike-specific binding geo-metric mean titers than those from a panel of SARS-CoV-2-convalescent human sera. Immunized sera broadly inhibited the viral entry receptor angiotensin-converting enzyme 2 (ACE2) from binding to the spike protein in all six strains tested, including variants of concern. These results could pro-vide useful information for designing next-generation mRNA vaccines.
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Key words
MT: Oligonucleotides: Therapies and Applications,lipid nanoparticles,SARS-CoV-2 spike protein,mRNA,viral entry receptor,vaccines
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