title: Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines.
abstract: The use of DNA and viral vector-based vaccines for the induction of cellular immune responses is increasingly gaining interest. However, concerns have been raised regarding the safety of these immunization strategies. Due to the lack of their genome integration, mRNA-based vaccines have emerged as a promising alternative. In this study, we evaluated the potency of antigen-encoding mRNA complexed with the cationic lipid 1,2-dioleoyl-3trimethylammonium-propane/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOTAP/DOPE ) as a novel vaccination approach. We demonstrate that subcutaneous immunization of mice with mRNA encoding the HIV-1 antigen Gag complexed with DOTAP/DOPE elicits antigen-specific, functional T cell responses resulting in specific killing of Gag peptide-pulsed cells and the induction of humoral responses. In addition, we show that DOTAP/DOPE complexed antigen-encoding mRNA displays immune-activating properties characterized by secretion of type I interferon (IFN) and the recruitment of proinflammatory monocytes to the draining lymph nodes. Finally, we demonstrate that type I IFN inhibit the expression of DOTAP/DOPE complexed antigen-encoding mRNA and the subsequent induction of antigen-specific immune responses. These results are of high relevance as they will stimulate the design and development of improved mRNA-based vaccination approaches.
authors.affiliation: Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium. cpollard@itg.be
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pollard
authors.forename: Joanna
authors.initials: J
authors.lastname: Rejman
authors.forename: Winni
authors.initials: W
authors.lastname: De Haes
authors.forename: Bernard
authors.initials: B
authors.lastname: Verrier
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Gulck
authors.forename: Thomas
authors.initials: T
authors.lastname: Naessens
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Smedt
authors.forename: Pieter
authors.initials: P
authors.lastname: Bogaert
authors.forename: Johan
authors.initials: J
authors.lastname: Grooten
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Koker
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects*; D007370:Interferon Type I / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000941:Antigens; D007370:Interferon Type I; D012333:RNA, Messenger