tetano
Editor, Senior Moderator
Mol Pharm
. 2020 Jun 3.
doi: 10.1021/acs.molpharmaceut.0c00315. Online ahead of print.
Combined Intranasal Nanoemulsion and RIG-I Activating RNA Adjuvants Enhances Mucosal, Humoral and Cellular Immunity to Influenza Virus
Pamela T Wong, Peter H Goff, Rachel J Sun, Matthew R Ruge, Megan E Ermler, Alyssa Sebring, Jessica J O'Konek, Jeffrey J Landers, Katarzyna W Janczak, Weina Sun, James R Baker
Abstract
Current influenza virus vaccines are focused on humoral immunity and are limited by short duration of protection, narrow cross-strain efficacy and sub-optimal immunogenicity. Here, we combined two chemically and biologically distinct adjuvants, an oil-in-water nanoemulsion (NE) and RNA-based agonists of RIG-I to determine whether the diverse mechanisms of these adjuvants could lead to improved immunogenicity and breadth of protection against influenza virus. NE activates TLRs, stimulates immunogenic apoptosis, and enhances cellular antigen uptake, leading to a balanced TH1/TH2/TH17 response when administered intranasally. RIG-I agonists included RNAs derived from Sendai and influenza viral defective interfering RNAs (IVT DI, 3php, respectively) and RIG-I/TLR3 agonist, poly(I:C) (pIC), which induce IFN-Is and TH1-polarized responses. NE/RNA combined adjuvants potentially allow for co-stimulation of multiple innate immune receptor pathways, more closely mimicking patterns of activation occurring during natural viral infection. Mice intranasally immunized with inactivated A/Puerto Rico/8/1934 (H1N1) (PR/8) adjuvanted with NE/IVT DI or NE/3php (but not NE/pIC) showed synergistic enhancement of systemic PR/8-specific IgG with significantly greater avidity and virus neutralization activity than the individual adjuvants. Notably, NE/IVT DI induced protective neutralizing titers after a single immunization. Hemagglutinin stem-specific antibodies were also improved, allowing recognition of heterologous and heterosubtypic hemagglutinins. All NE/RNAs elicited substantial PR/8-specific sIgA. Finally, a unique cellular response with enhanced TH1/TH17 immunity was induced with the NE/RNAs. These results demonstrate that the enhanced immunogenicity of the adjuvant combinations was synergistic and not simply additive, highlighting the potential value of a combined adjuvant approach for improving the efficacy of vaccination against influenza virus.
. 2020 Jun 3.
doi: 10.1021/acs.molpharmaceut.0c00315. Online ahead of print.
Combined Intranasal Nanoemulsion and RIG-I Activating RNA Adjuvants Enhances Mucosal, Humoral and Cellular Immunity to Influenza Virus
Pamela T Wong, Peter H Goff, Rachel J Sun, Matthew R Ruge, Megan E Ermler, Alyssa Sebring, Jessica J O'Konek, Jeffrey J Landers, Katarzyna W Janczak, Weina Sun, James R Baker
- PMID: 32491861
- DOI: 10.1021/acs.molpharmaceut.0c00315
Abstract
Current influenza virus vaccines are focused on humoral immunity and are limited by short duration of protection, narrow cross-strain efficacy and sub-optimal immunogenicity. Here, we combined two chemically and biologically distinct adjuvants, an oil-in-water nanoemulsion (NE) and RNA-based agonists of RIG-I to determine whether the diverse mechanisms of these adjuvants could lead to improved immunogenicity and breadth of protection against influenza virus. NE activates TLRs, stimulates immunogenic apoptosis, and enhances cellular antigen uptake, leading to a balanced TH1/TH2/TH17 response when administered intranasally. RIG-I agonists included RNAs derived from Sendai and influenza viral defective interfering RNAs (IVT DI, 3php, respectively) and RIG-I/TLR3 agonist, poly(I:C) (pIC), which induce IFN-Is and TH1-polarized responses. NE/RNA combined adjuvants potentially allow for co-stimulation of multiple innate immune receptor pathways, more closely mimicking patterns of activation occurring during natural viral infection. Mice intranasally immunized with inactivated A/Puerto Rico/8/1934 (H1N1) (PR/8) adjuvanted with NE/IVT DI or NE/3php (but not NE/pIC) showed synergistic enhancement of systemic PR/8-specific IgG with significantly greater avidity and virus neutralization activity than the individual adjuvants. Notably, NE/IVT DI induced protective neutralizing titers after a single immunization. Hemagglutinin stem-specific antibodies were also improved, allowing recognition of heterologous and heterosubtypic hemagglutinins. All NE/RNAs elicited substantial PR/8-specific sIgA. Finally, a unique cellular response with enhanced TH1/TH17 immunity was induced with the NE/RNAs. These results demonstrate that the enhanced immunogenicity of the adjuvant combinations was synergistic and not simply additive, highlighting the potential value of a combined adjuvant approach for improving the efficacy of vaccination against influenza virus.