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An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and non-human primates.

ABSTRACT: The mRNA vaccine technology has promising applications to fight infectious diseases as demonstrated by the licensing of two mRNA-based vaccines, Comirnaty® (Pfizer/BioNtech) and Spikevax® (Moderna), in the context of the Covid-19 crisis. Safe and effective delivery systems are essential to the performance of these vaccines and lipid nanoparticles (LNPs) able to entrap, protect and deliver the mRNA in vivo are considered by many as the current "best in class". Nevertheless, current mRNA/LNP vaccine technology has still some limitations, one of them being thermostability, as evidenced by the ultracold distribution chain required for the licensed vaccines. We found that the thermostability of mRNA/LNP, could be improved by a novel imidazole modified lipid, DOG-IM4, in combination with standard helper lipids. DOG-IM4 comprises an ionizable head group consisting of imidazole, a dioleoyl lipid tail and a short flexible polyoxyethylene spacer between the head and tail. Here we describe the synthesis of DOG-IM4 and show that DOG-IM4 LNPs confer strong immunization properties to influenza HA mRNA in mice and macaques and a remarkable stability to the encapsulated mRNA when stored liquid in phosphate buffered saline at 4 °C. We speculate the increased stability to result from some specific attributes of the lipid's imidazole head group.

SUBMITTER: Ripoll M

PROVIDER: S-EPMC9078044 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and non-human primates.

Ripoll Manon M Bernard Marie-Clotilde MC Vaure Céline C Bazin Emilie E Commandeur Sylvie S Perkov Vladimir V Lemdani Katia K Nicolaï Marie-Claire MC Bonifassi Patrick P Kichler Antoine A Frisch Benoit B Haensler Jean J

Biomaterials 20220507

The mRNA vaccine technology has promising applications to fight infectious diseases as demonstrated by the licensing of two mRNA-based vaccines, Comirnaty® (Pfizer/BioNtech) and Spikevax® (Moderna), in the context of the Covid-19 crisis. Safe and effective delivery systems are essential to the performance of these vaccines and lipid nanoparticles (LNPs) able to entrap, protect and deliver the mRNA in vivo are considered by many as the current "best in class". Nevertheless, current mRNA/LNP vacci ...[more]

PMID: 35576809

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Project description:In vitro transcribed mRNAs hold the promises of many medical applications in disease prevention and treatment, such as replacement or supplement of missing or inadequately expressed endogenous proteins and as preventive vaccines against infectious diseases, therapeutic vaccines, or other protein-based biopharmaceutics for cancer therapy. A safe and efficient delivery system for mRNA is crucial to the success of mRNA therapeutic applications. In this study, we report that InstantFECT, a liposome-based transfection reagent, can pack pseudouridine-incorporated mRNA into nanocomplexes that are highly efficient in mediating in vivo transfection in multiple organs after local delivery. High levels of expression of EGFP and luciferase reporters after intratumoral and intramuscular injections were observed, which lasted for up to 96 hrs. Immunogenicity of antigens encoded by mRNA delivered with nanocomplex was investigated by subcutaneous delivery of modified mRNAs encoding Staphylococcus aureus adenosine synthase A (AdsA) and a model tumor-associated antigen ovalbumin (OVA). Strong T cell responses were provoked by both mRNAs delivered. Therapeutic and protective treatment with the OVA mRNA-liposome nanocomplex significantly inhibited B16-OVA tumor progression and increased mouse survival. There was no sign of obvious toxicity related to the treatment both in tissue culture and in mice. An intravenous injection of the same dosage of the modified mRNA-lipid nanocomplex showed minimal transfection in major organs, indicating an excellent safety feature as the gene transfer occurred only at the injection sites, whereas intravenous (i.v.) injection with the same amount of mRNA complexed with a commercial transfection reagent Trans-IT showed luciferase expression in the spleen. In summary, InstantFECT cationic liposomes provide a safe and efficient in vivo locoregional delivery of mRNA and could be a useful tool for basic research and for the development of mRNA-based therapies.

Project description:Toxoplasma gondii, a specialized intracellular parasite, causes a widespread zoonotic disease and is a severe threat to social and economic development. There is a lack of effective drugs and vaccines against T. gondii infection. Recently, mRNA vaccines have been rapidly developed, and their packaging materials and technologies are well established. In this study, TGGT1_216200 (TG_200), a novel molecule from T. gondii, was identified using bioinformatic screening analysis. TG_200 was purified and encapsulated with a lipid nanoparticle (LNP) to produce the TG_200 mRNA-LNP vaccine. The immune protection provided by the new vaccine and its mechanisms after immunizing BABL/C mice via intramuscular injection were investigated. There was a strong immune response when mice were vaccinated with TG_200 mRNA-LNP. Elevated levels of anti-T. gondii-specific immunoglobulin G (IgG), and a higher IgG2a-to-IgG1 ratio was observed. The levels of interleukin-12 (IL-12), interferon-γ (IFN-γ), IL-4, and IL-10 were also elevated. The result showed that the vaccine induced a mixture of Th1 and Th2 cells, and Th1-dominated humoral immune response. Significantly increased antigen-specific splenocyte proliferation was induced by TG_200 mRNA-LNP immunization. The vaccine could also induce T. gondii-specific cytotoxic T lymphocytes (CTLs). The expression levels of interferon regulatory factor 8 (IRF8), T-Box 21 (T-bet), and nuclear factor kappa B (NF-κB) were significantly elevated after TG_200 mRNA-LNP immunization. The levels of CD83, CD86, MHC-I, MHC-II, CD8, and CD4 molecules were also higher. The results indicated that TG_200 mRNA-LNP produced specific cellular and humoral immune responses. Most importantly, TG_200 mRNA-LNP immunized mice survived significantly longer (19.27 ± 3.438 days) than the control mice, which died within eight days after T. gondii challenge (P< 0.001). The protective effect of adoptive transfer was also assessed, and mice receiving serum and splenocytes from mice immunized with TG_200 mRNA-LNP showed improved survival rates of 9.70 ± 1.64 days and, 13.40 ± 2.32 days, respectively (P< 0.001). The results suggested that TG_200 mRNA-LNP is a safe and promising vaccine against T. gondii infection.

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An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and non-human primates.

Publications

An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and non-human primates.

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