Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles

Abstract

Dendritic cells (DC) play essential roles determining efficacy of vaccine delivery with respect to immune defence development and regulation. This renders DCs important targets for vaccine delivery, particularly RNA vaccines. While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites. Delivery of mRNA has benefitted from application of cationic entities; these offer value following endocytosis of RNA, when cationic or amphipathic properties can promote endocytic vesicle membrane perturbation to facilitate cytosolic translocation. The present review presents how such advances are being applied to the delivery of a new form of RNA vaccine, replicons (RepRNA) carrying inserted foreign genes of interest encoding vaccine antigens. Approaches have been developed for delivery to DCs, leading to the translation of the RepRNA and encoded vaccine antigens both in vitro and in vivo. Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures. The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future.

Dendritic Cell Targets for Self-Replicating RNA Vaccines

“…Nanoparticulate vehicles, which have involved primarily lipid-based and carbohydrate-based systems [8,20], can enhance the protection of the RNA, or even render the capping procedure unnecessary. Moreover, many of these delivery vehicles have a proven capacity for interacting with DCs for delivery of their cargoes; in the case of RNA delivery, this has also led to the end goal of the deliverytranslation of the encoded vaccine antigen [3,8,[19][20][21].…”

“…Self-amplifying replicon RNA are derived from what are termed "positive strand viruses" and "negative strand viruses" [3,8,38,39]. The former class of virus carries a genome with a ribosomal entry site at its 5' end, which can thus function as a mRNA to initiate translation, including its own replication machinery (polymerase complex proteins, which are non-structural).…”

“…Both positive strand and negative strand replicon RNA vaccines have been employed, based on virus replicon particles (VRP). These VRPs are produced in cell lines providing the deleted structural gene in trans for the generation of virus particles carrying replicons; VRP vaccines have proven efficacy [3,8,[34][35][36][37][38][39].…”

“…With the RNA-based vaccine now possessing a replicating characteristic, it has been referred to as self-amplifying, selfreplicating, or just simply replicon RNA vaccine [3,8]. There is the notion that these can be termed self-amplifying or self-replicating mRNA vaccines, but this is only applicable when derived from a positive strand virus, with which the genome can function as an mRNA.…”

“…Nucleic acid-based vaccines can circumvent many of the problems associated with both inactivated and live, attenuated or vector vaccines [3,8,[12][13][14][15][16]. DNA-based vaccines have a proven success, but often in murine models [8].…”