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BackgroundAbout half of the world’s population are living in the endemic area of dengue viruses implying that a rapid-mass vaccination may be required. In addition, a major target of dengue vaccine are children, thus, a needle-free administration is more attractive. These problems may be overcome by the alternative route of vaccination such as topical, oral and intranasal vaccination. Here, we investigated the possibility to deliver a dengue immunogen intranasally, a painless route of vaccination. The tested immunogen was the domain III of dengue serotype-3 E protein (EDIII-D3) loaded into trimethyl chitosan nanoparticles (EDIII-D3 TMC NPs). The primary human nasal epithelial cells, HNEpCs, were used as an in vitro model for nasal responses.ResultsAt tested concentrations, EDIII-D3 TMC NPs not only exerted no detectable toxicity toward HNEpC cultures but also efficiently delivered EDIII-D3 immunogens into HNEpCs. Moreover, HNEpCs quickly and strongly produced proinflammatory cytokines (IL-1β, IL-6, TNF-α), type-I IFN, the growth factors (GM-CSF, IL-7), the chemokines (MCP-1, MIP-1β, IL-8), Th1-related cytokines (IL-2, IL-12p70, IL-17, IFN-γ) and Th2-related cytokine (IL-4) in response to EDIII-D3 TMC NPs treatment.ConclusionsA potential mucosal delivery system for dengue immunogens was revealed and found to stimulate a strong local innate antiviral response which possibly leading to a systemic adaptive immunity.

Domain III of E protein of dengue virus (DENV) is a target for vaccine development. Unfortunately, this protein based platform has low general immunogenicity. To circumvent this problem, the use of an adjuvant-nanoparticle delivery system to facilitate immunogenicity of soluble DENV-EDIII protein was investigated. One of the key features of this delivery system is its ability to simultaneously deliver antigens and exert adjuvanticity on specialized immune cells. In this study, N-trimethyl chitosan (TMC) nanoparticles (NPs) were generated to be used as adjuvant and carrier for soluble E-domain III of dengue virus serotype 3 (sEDIII-D3). Using ionotropic gelation, purified sEDIII-D3 was encapsulated into TMC NPs to form EDIII-D3 TMC NPs. After optimization, EDIII-D3 TMC particles exhibited a loading efficiency of 81% and a loading capacity of 41%. The immunogenicity of EDIII-D3 TMC NPs was tested using monocyte-derived dendritic cells (MoDCs). It was found that EDIII-D3 TMC NPs were well taken up by MoDCs. In addition, EDIII-D3 TMC NP treated MoDCs significantly upregulated maturation markers (CD80, CD83, CD86 and HLA-DR) and induced secretion of various cytokines and chemokines (IFN-α, IL-1β, IL-6, IL-2, IL-12p70, IFN-γ, IL-4, IL-10, IL-8, MCP-1, macrophage inflammatory protein-1β, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor and IL-7). These results indicate that EDIII-D3 TMC NPs are potent immunogens, at least in vitro, with the ability to induce maturation of DCs and highlight the potential use of TMC NPs for enhancing immunogenicity of a non-replicating dengue vaccine.

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