title: A New RNA-Based Adjuvant Enhances Virus-Specific Vaccine Responses by Locally Triggering TLR- and RLH-Dependent Effects.
abstract: Among innovative adjuvants conferring a Th1-shift, RNAdjuvant is a promising candidate. This adjuvant consists of a 547-nt uncapped noncoding ssRNA containing polyU repeats that is stabilized by a cationic carrier peptide. Whereas vaccination of mice with an influenza subunit vaccine induced moderate virus-specific IgG1, vaccination together with RNAdjuvant significantly enhanced this IgG1 and additionally promoted the formation of IgG2b/c, which is indicative of Th1 responses. Furthermore, such sera neutralized influenza virus, whereas this effect was not detected upon vaccination with the subunit vaccine alone. Similarly, upon vaccination with virus-like particles displaying vesicular stomatitis virus G protein, RNAdjuvant promoted the formation of virus-specific IgG2b/c and enhanced neutralizing IgG responses to an extent that mice were protected against lethal virus infection. RNAdjuvant induced dendritic cells to upregulate activation markers and produce IFN-I. Although these effects were strictly TLR7 dependent, RNAdjuvant-mediated augmentation of vaccine responses needed concurrent TLR and RIG-I-like helicase signaling. This was indicated by the absence of the adjuvant effect in vaccinated MyD88-/-Cardif-/-mice, which are devoid of TLR (with the exception of TLR3) and RIG-I-like helicase signaling, whereas in vaccinated MyD88-/-mice the adjuvant effect was reduced. Notably, i.m. RNAdjuvant injection induced local IFN-I responses and did not induce systemic effects, implying good tolerability and a favorable safety profile for RNAdjuvant.
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, D-30625 Hannover, Germany.
authors.forename: Annett
authors.identifier: 0000-0002-2033-5049
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, D-30625 Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Soldner
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, D-30625 Hannover, Germany.|Department of Molecular Immunology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany.|Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, D-30625 Hannover, Germany.
authors.forename: Julia
authors.identifier: 0000-0002-8797-3563
authors.initials: J
authors.lastname: Spanier
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Trittel
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany; and.
authors.forename: Peggy
authors.initials: P
authors.lastname: Riese
authors.affiliation: CureVac AG, D-72076 Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kramps
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: CureVac AG, D-72076 Tübingen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Heidenreich
authors.affiliation: CureVac AG, D-72076 Tübingen, Germany.
authors.forename: Edith
authors.initials: E
authors.lastname: Jasny
authors.affiliation: Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany; and.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
authors.affiliation: CureVac AG, D-72076 Tübingen, Germany.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Kallen
authors.affiliation: CureVac AG, D-72076 Tübingen, Germany.
authors.forename: Mariola
authors.initials: M
authors.lastname: Fotin-Mleczek
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, D-30625 Hannover, Germany; ulrich.kalinke@twincore.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000071457:DEAD Box Protein 58 / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D022661:RNA, Untranslated / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; C028391:G protein, vesicular stomatitis virus; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D022661:RNA, Untranslated; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D022223:Vaccines, Subunit; D058425:Vaccines, Virus-Like Particle; D014759:Viral Envelope Proteins; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58