Abstract
Most licensed seasonal influenza vaccines are non-adjuvanted and rely primarily on vaccine-induced antibody titers for protection. As such, seasonal antigenic drift and suboptimal vaccine strain selection often results in reduced vaccine efficacy. Further, seasonal H3N2 influenza vaccines demonstrate poor efficacy compared to H1N1 and influenza type B vaccines. New vaccines, adjuvants, or delivery technologies that can induce broader or cross-seasonal protection against drifted influenza virus strains, likely through induction of protective T cell responses, are urgently needed. Here, we report novel lipidated TLR7/8 ligands that act as strong adjuvants to promote influenza-virus specific Th1-and Th17-polarized T cell responses and humoral responses in mice with no observable toxicity. Further, the adjuvanted influenza vaccine provided protection against a heterologous H3N2 influenza challenge in mice. These responses were further enhanced when combined with a synthetic TLR4 ligand adjuvant. Despite differences between human and mouse TLR7/8, these novel lipidated imidazoquinolines induced the production of cytokines required to polarize a Th1 and Th17 immune response in human PBMCs providing additional support for further development of these compounds as novel adjuvants for the induction of broad supra-seasonal protection from influenza virus.
Highlights
The connection between the innate andadaptive immune system is instrumental for eliciting protective, durable, vaccine-elicited protection against infectious diseases
As has been previously reported [56], mouse TLR8 is not readily activated by imidazoquinolines and other TLR8 ligands [Figure 1E; R848 plus polyDT was included as a positive control for mouse TLR8 activity as reported in [56] shown in Figure S1], despite their ability to signal through human TLR8 (Figure 1C)
We explored the ability of novel lipidated imidazoquinolines (TLR7/8 agonists) to act as adjuvants to confer protection against drifted H3N2 influenza both with and without a TLR4 agonist in mice. We found that these compounds elicited a Th1/Th17 type T cell response as well as a strongly Th1-biased humoral response
Summary
The connection between the innate andadaptive immune system is instrumental for eliciting protective, durable, vaccine-elicited protection against infectious diseases. We build upon these studies by reporting on novel lipidated imidazoquinoline TLR7/8 ligands, alone or in combination with a synthetic TLR4 ligand, and their ability to elicit strong antigen-specific humoral and Th1- or Th17-mediated T cell responses to a co-administered seasonal split H3N2 influenza vaccine in mice. The adjuvanted vaccine-induced adaptive immune responses provided durable protection from a heterosubtypic H3N2 influenza virus challenge, in the case of a combination TLR4 and TLR7/8 adjuvant. Secreted cytokines following spleen harvest and antigen restimulation (1 μg/mL whole influenza antigen, detergent split A/Victoria or whole HK68 as indicated) were measured after 72 h of stimulation by MesoScale Discovery (MSD) U-PLEX Assay Platform (MesoScale Diagnostics) to detect mouse IFNγ, IL-17, TNFα, IL-2, and IL-5
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