Cationic DDA/TDB liposome as a mucosal vaccine adjuvant for uptake by dendritic cells in vitro induces potent humoural immunity

Abstract

The cationic dimethyldioctadecylammonium/trehalose 6,6,9-dibehenate (DDA/TDB) liposome is as a strong adjuvant system for vaccines, with remarkable immunostimulatory activity. The mucosal administration of vaccines is a potential strategy for inducing earlier and stronger mucosal immune responses to infectious diseases. In this study, we assessed whether the intranasal administration of cationic DDA/TDB liposomes combined with influenza antigen A (H3N2) can be used as a highly efficacious vaccine to induce mucosal and systemic antibody responses. Confocal laser scanning microscopy and a flow-cytometric analysis showed that the uptake of the cationic DDA/TDB liposome carrier was significantly higher than that of neutral 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (DSPC/Chol) or cationic 1,2-dioleoyl-3-trimethylammonium-propane/3β-(N-[N',N'-dimethylaminoethane]-carbamoyl (DOTAP/DC-Chol) liposomes. Our results indicate that the cationic DDA/TDB liposome is more effective in facilitating its uptake by dendritic cells (DCs) in vitro than the DSPC/Chol or DOTAP/DC-Chol liposome. DCs treated with DDA/TDB liposomes strongly expressed CD80, CD86, and MHC II molecules, whereas those treated with DSPC/Chol or DOTAP/DC-Chol liposomes did not. C57BL/6 mice intranasally immunized with H3N2-encapsulating cationic DDA/TDB liposomes had significantly higher H3N2-specific s-IgA levels in their nasal wash fluid than those treated with other formulations. The DDA/TDB liposomes also simultaneously enhanced the serum IgG IgG2a, IgG1, and IgG2b antibody responses. In summary, DDA/TDB liposomes effectively facilitated their uptake by DCs and DCs maturation in vitro, and induced significantly higher mucosal IgA, systemic IgG, IgG1, and IgG2b antibody titres than other formulations after their intranasal administration in vivo. These results indicate that DDA/TDB liposomes are a promising antigen delivery carrier for clinical antiviral applications.

Multifunctional Immunoadjuvants for Use in Minimalist Nucleic Acid Vaccines

“…The mechanism by which CAF01 stimulates INF secretion was found to be TLRs 2-, 3-, 4-, and 7-independent, as evidenced by the failure to cause a reduced immune activation effect in these specific TLR knockout mice, whereas the response is partly reduced in MyD88-deficient mice, indicating the involvement of TLR other than TLRs 2, 3, 4, and 7, or other pathways of INF secretion [ 147 ]. DDA/TDB liposomes induce higher antigen uptake and maturation of DCs more efficiently than DOTAP or DSPC liposomes [ 148 ]. TDB alone activates APCs via Syk–Card9–Bcl10–Malt1 independently from the TLR pathway [ 149 ].…”

Innovative Mucosal Vaccine Formulations Against Influenza A Virus Infections

“…heterovariant challenge (99). CAF01, another liposomal preparation containing the monocationic lipid dimethyldioctadecylammonium bromide (DDAB) and the immunostimulator α,α'-trehalose 6,6'-dibehenate was effectively uptaken by murine bone marrow-derived DCs in vitro and stimulated the maturation of the cells (100). By using the human bronchial epithelial Calu-3 cell culture model, CAF01 was shown to enhance the transport of co-administered Ag through the mucus layer and across the epithelial cells (101).…”

“…Accordingly, in mice, the i.n. administration of CAF01 with H3N2 (100) or seasonal trivalent (101) split vaccines remarkably strengthened virus-specific mucosal and systemic immune responses. Finally, polycationic liposomes composed of ceramide carbamoyl-spermine (CCS) sphingolipids complexed with cholesterol enhanced the efficacy of H1N1 monovalent or seasonal trivalent split vaccines (102, 103).…”

Cationic Nanostructures for Vaccines Design

“…In order to improve fusion of cell membranes with DODAB bilayers, which are in the rigid gel state at room temperature [ 75 ], DODAB bilayer fluidity had to be increased by using DODAB combinations with other lipids and surfactants such as the glycolipid TDB [ 15 , 76 ], the surfactant monoolein (1-monooleoyl-rac-glycerol) [ 77 ], the C24:1 β-glucosylceramide [ 78 ] or the glycolipid de-O-acylated lipooligosaccharide (dLOS) as a booster vaccine against tuberculosis [ 79 ]. In particular, intranasal immunization with DODAB/TDB combined with influenza antigen A (H3N2) induced superior humoral and cell-mediated responses; there was an effective facilitation of uptake by DC, DC maturation in vitro, increased mucosal IgA production, increased IgG, IgG1, and IgG2b antibody titers in comparison with other formulations using cationic lipids after intranasal administration in vivo [ 80 ]. Immunization of mice with a mycobacterial fusion protein in DODAB-TDB liposomes induced a strong, specific Th1-type immune response characterized by substantial production of interferon-gamma mediated by CD4 T cells and high levels of IgG2b isotype antibodies [ 15 ].…”