Nucleoside modified mRNA vaccines for infectious diseases

Abstract

In recent years, numerous studies have demonstrated the outstanding abilities of mRNA to elicit potent immune responses against pathogens, making it a viable new platform for vaccine development (reviewed in Weissman, Expert Rev Vaccines 14:265–281, 2015; Sahin et al., Nat Rev Drug Discov 13:759–780, 2014). The incorporation of modified nucleosides in mRNA has many advantages and is currently undergoing a renaissance in the field of therapeutic protein delivery. Its use in a vaccine against infectious diseases has only begun to be described, but offers advantages for the generation of potent and long-lived antibody responses. FPLC purification and substitution of modified nucleosides in the mRNA make it non-inflammatory and highly translatable (Kariko et al., Immunity 23:165–175, 2005; Kariko et al., Mol Ther 16:1833–1840, 2008; Kariko et al., Nucleic Acids Research 39:e142, 2011) that are crucial features for therapeutic relevance. Formulation of the mRNA in lipid nanoparticles (LNPs) protects it from degradation enabling high levels of protein production for extended periods of time (Pardi et al., J Control Release, 2015). Here, we describe a simple vaccination method using LNP-encapsulated 1-methylpseudouridine-containing FPLC purified mRNA in mice. Furthermore, we describe the evaluation of antigen-specific T and B cell responses elicited by this vaccine format.