Combined Intranasal Nanoemulsion and RIG‑I
Activating RNA Adjuvants Enhance Mucosal, Humoral, and Cellular Immunity
to Influenza Virus
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Posted on 2020-06-17 - 19:11
Current
influenza virus vaccines are focused on humoral immunity
and are limited by the short duration of protection, narrow cross-strain
efficacy, and suboptimal 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 the 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 costimulation 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 the influenza
virus.
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Wong, Pamela T.; Goff, Peter H.; Sun, Rachel J.; Ruge, Matthew J.; Ermler, Megan E.; Sebring, Alyssa; et al. (2020). Combined Intranasal Nanoemulsion and RIG‑I
Activating RNA Adjuvants Enhance Mucosal, Humoral, and Cellular Immunity
to Influenza Virus. ACS Publications. Collection. https://doi.org/10.1021/acs.molpharmaceut.0c00315