Alpha-galactosylceramide improves the potency of mRNA LNP vaccines against cancer and intracellular bacteria

🥉 Top 5% JournalMay 2, 2024Journal of controlled release : official journal of the Controlled Release Society

Alpha-galactosylceramide boosts the strength of mRNA nanoparticle vaccines against cancer and bacteria inside cells

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Intramuscular vaccination with ovalbumin-encoding mRNA in lipid nanoparticles adjuvanted with alpha-galactosylceramide showed the highest antibody and CD8 T cell responses.

mRNA vaccines can induce both humoral and cellular immunity through various delivery methods.
The inclusion of alpha-galactosylceramide may enhance cellular immunity in mRNA vaccines.
Signal peptides and endocytic sorting signals can improve CD8 T cell activation but may reduce IgG antibody responses.
mRNA lipid nanoparticles with the ionizable lipidoid C12-200 exhibited greater pro-inflammatory activity and T cell activation than those with SM-102.
A Listeria monocytogenes mRNA vaccine supplemented with alpha-galactosylceramide showed synergistic protective effects against listeriosis.

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Although various types of mRNA-based vaccines have been explored, the optimal conditions for induction of both humoral and cellular immunity remain rather unknown. In this study, mRNA vaccines of nucleoside-modified mRNA in lipoplexes (LPXs) or lipid nanoparticles (LNPs) were evaluated after administration in mice through different routes, assessing mRNA delivery, tolerability and immunogenicity. In addition, we investigated whether mRNA vaccines could benefit from the inclusion of the adjuvant alpha-galactosylceramide (αGC), an invariant Natural Killer T (iNKT) cell ligand. Intramuscular (IM) vaccination with ovalbumin (OVA)-encoding mRNA encapsulated in LNPs adjuvanted with αGC showed the highest antibody- and CD8T cell responses. Furthermore, we observed that addition of signal peptides and endocytic sorting signals of either LAMP1 or HLA-B7 in the OVA-encoding mRNA sequence further enhanced CD8T cell activation although reducing the induction of IgG antibody responses. Moreover, mRNA LNPs with the ionizable lipidoid C12-200 exhibited higher pro-inflammatory- and reactogenic activity compared to mRNA LNPs with SM-102, correlating with increased T cell activation and antitumor potential. We also observed that αGC could further enhance the cellular immunity of clinically relevant mRNA LNP vaccines, thereby promoting therapeutic antitumor potential. Finally, a Listeria monocytogenes mRNA LNP vaccine supplemented with αGC showed synergistic protective effects against listeriosis, highlighting a key advantage of co-activating iNKT cells in antibacterial mRNA vaccines. Taken together, our study offers multiple insights for optimizing the design of mRNA vaccines for disease applications, such as cancer and intracellular bacterial infections. + +

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