Combined Intranasal Nanoemulsion and RIG-I Activating RNA Adjuvants Enhance Mucosal, Humoral, and Cellular Immunity to Influenza Virus

• DOI: 10.1021/acs.molpharmaceut.0c00315
• Publication Date: 2020-06-03T17:42:52Z
• Authors: Pamela T. Wong; Peter H. Goff; Rachel J. Sun; Matthew J. Ruge; Megan E. Ermler; Alyssa Sebring; Jessica J. O’Konek; Jeffrey J. Landers; Katarzyna W. Janczak; Weina Sun; James R. Baker
• Keywords: TLR3; Sendai virus

Current influenza virus vaccines are focused on humoral immunity and limited by the short duration of protection, narrow cross-strain efficacy, suboptimal immunogenicity. Here, we combined two chemically biologically distinct adjuvants, an oil-in-water nanoemulsion (NE) RNA-based agonists RIG-I, to determine whether diverse mechanisms these adjuvants could lead improved immunogenicity breadth protection against virus. NE activates TLRs, stimulates immunogenic apoptosis, enhances cellular antigen uptake, leading a balanced TH1/TH2/TH17 response when administered intranasally. RIG-I included RNAs derived from Sendai viral defective interfering (IVT DI, 3php, respectively) RIG-I/TLR3 agonist, poly(I:C) (pIC), which induce IFN-Is TH1-polarized responses. NE/RNA potentially allow for costimulation multiple innate immune receptor pathways, more closely mimicking patterns activation occurring during natural infection. Mice intranasally immunized with inactivated A/Puerto Rico/8/1934 (H1N1) (PR/8) adjuvanted NE/IVT DI or NE/3php (but not NE/pIC) showed synergistic enhancement systemic PR/8-specific IgG significantly greater avidity neutralization activity than individual adjuvants. Notably, induced protective neutralizing titers after single immunization. Hemagglutinin stem-specific antibodies were also improved, allowing recognition heterologous heterosubtypic hemagglutinins. All NE/RNAs elicited substantial sIgA. Finally, unique enhanced TH1/TH17 was NE/RNAs. These results demonstrate that adjuvant combinations simply additive, highlighting potential value approach improving efficacy vaccination