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: Annett Ziegler, Claudia Soldner, Stefan Lienenklaus, Julia Spanier, Stephanie Trittel, Peggy Riese, Thomas Kramps, Siegfried Weiss, Regina Heidenreich, Edith Jasny, Carlos A Guzmán, Karl-Josef Kallen, Mariola Fotin-Mleczek, Ulrich Kalinke
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 198 Issue 4 Pg. 1595-1605 (02 15 2017) ISSN: 1550-6606 [Electronic] United States
• PMID: 28077601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 by The American Association of Immunologists, Inc.

Chemical References

• Adjuvants, Immunologic
• Antibodies, Viral
• G protein, vesicular stomatitis virus
• Immunoglobulin G
• Influenza Vaccines
• Membrane Glycoproteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• RNA, Untranslated
• Tlr7 protein, mouse
• Toll-Like Receptor 7
• Vaccines, Subunit
• Vaccines, Virus-Like Particle
• Viral Envelope Proteins
• Ddx58 protein, mouse
• DEAD Box Protein 58

Topics

• Adjuvants, Immunologic (adverse effects)
• Animals
• Antibodies, Viral (blood)
• DEAD Box Protein 58 (immunology, metabolism)
• Immunoglobulin G (blood, immunology)
• Influenza Vaccines (administration & dosage, immunology)
• Membrane Glycoproteins (administration & dosage, immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Myeloid Differentiation Factor 88 (deficiency, metabolism)
• RNA, Untranslated (immunology)
• Th1 Cells (immunology)
• Toll-Like Receptor 7 (immunology, metabolism)
• Vaccination
• Vaccines, Subunit (immunology)
• Vaccines, Virus-Like Particle (administration & dosage, immunology)
• Viral Envelope Proteins (administration & dosage, immunology)