Self-Replicating RNA Vaccine Delivery to Dendritic Cells
Most current vaccines are either inactivated pathogen-derived or protein/peptide-based, although attenuated and vector vaccines have also been developed. The former induce at best moderate protection, even as multimeric antigen, due to limitations in antigen loads and therefore capacity for inducing robust immune defense. While attenuated and vector vaccines offer advantages through their replicative nature, drawbacks and risks remain with potential reversion to virulence and interference from preexisting immunity. New advances averting these problems are combining self-amplifying replicon RNA (RepRNA) technology with nanotechnology. RepRNA are large self-replicating RNA molecules (12–15 kb) derived from viral genomes defective in at least one structural protein gene. They provide sustained antigen production, effectively increasing vaccine antigen payloads over time, without the risk of producing infectious progeny. The major limitation with RepRNA is RNase-sensitivity and inefficient uptake by dendritic cells (DCs)—absolute requirements for efficacious vaccine design. We employed biodegradable delivery vehicles to protect the RepRNA and promote DC delivery. Encapsulating RepRNA into chitosan nanoparticles, as well as condensing RepRNA with polyethylenimine (PEI), cationic lipids, or chitosans, has proven effective for delivery to DCs and induction of immune responses in vivo.
KeywordsReplicon-RNA Self-replicating vaccine Universal influenza vaccine Dendritic cell delivery Chitosan nanoparticles Polyplexes Cationic lipids
We thank Markus Gerber and Samira Locher for their help and input with the RepRNA technology, and Brigitte Herrmann for helping with the DC studies. We are also grateful to Patrick Midoux and Laure Magrangeas-Janot for help with the polyplex technology, Olivier Zelphati and Florent Poulhes for help with the lipoplex technology, and Kai Schulze for the adaptive immune response profiling. The work was funded by the Marie Curie IAPP Project Replixcel (251420) and the EU FP7 Project UniVax (HEALTH-F3-2013-60173).
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