title: Self-Replicating RNA Vaccine Delivery to Dendritic Cells.
abstract: 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.
authors.affiliation: Institute of Virology and Immunology (IVI), Sensemattstrasse 293, CH-3147, Mittelhäusern, Switzerland. thomas.demoulins@ivi.admin.ch.
authors.forename: Thomas
authors.initials: T
authors.lastname: Démoulins
authors.affiliation: Institute of Virology and Immunology (IVI), Sensemattstrasse 293, CH-3147, Mittelhäusern, Switzerland.
authors.forename: Pavlos C
authors.initials: PC
authors.lastname: Englezou
authors.affiliation: Institute of Virology and Immunology (IVI), Sensemattstrasse 293, CH-3147, Mittelhäusern, Switzerland.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Milona
authors.affiliation: Institute of Virology and Immunology (IVI), Sensemattstrasse 293, CH-3147, Mittelhäusern, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ruggli
authors.affiliation: Centre of Regenerative Medicine, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tirelli
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, 45071, Orléans cedex 2, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Pichon
authors.affiliation: OzBiosciences, Parc scientifique de Luminy, Marseille, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Sapet
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
authors.affiliation: Institute of Virology and Immunology (IVI), Sensemattstrasse 293, CH-3147, Mittelhäusern, Switzerland.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: McCullough
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D016503:Drug Delivery Systems / Q000379:methods; D018014:Gene Transfer Techniques; D006801:Humans; D012313:RNA / Q000235:genetics / Q000276:immunology*; D012093:Replicon / Q000235:genetics / Q000276:immunology*; D014612:Vaccines / Q000235:genetics / Q000276:immunology*
chemical_list: D014612:Vaccines; D012313:RNA
keywords: Cationic lipids; Chitosan nanoparticles; Dendritic cell delivery; Polyplexes; Replicon-RNA; Self-replicating vaccine; Universal influenza vaccine