Alpha-galactosylceramide is an effective mucosal adjuvant for repeated intranasal or oral delivery of HIV peptide antigens

Abstract

Mucosal delivery of vaccines against sexually transmitted pathogens is important to elicit strong immune responses at biologically relevant sites. However, inclusion of appropriate adjuvants is essential to overcome the inherent mucosal tolerance. We present evidence in support of the effectiveness of co-administering alpha-Galactosylceramide (α-GalCer) as an adjuvant with a CTL-inducing HIV envelope peptide, via either oral or intranasal route, to prime antigen-specific immune responses in multiple systemic and mucosal compartments. Contrary to the known potential of repeated parenteral dosing with a-GalCer to induce NKT cell anergy that could compromise adoptive immunity development, we have observed that two and three doses delivered by the intranasal or oral route were more efficient in priming broader antigen-specific immune responses. These results demonstrate the effectiveness of α-GalCer as adjuvant for repeated intranasal or oral administration of vaccines for protection against mucosally transmitted pathogens.

Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction

“…The possibility that dietary lipids might contribute to iNKT cell activation is an exciting one. Supporting a possible role for oral lipid antigens, two studies have used orally-administered α-galactosylceramide as a vaccine adjuvant, and both studies reported a measureable result with oral administration (35,36). Studies of lipid antigens from commensal bacteria also support a role for lipids antigens in the digestive system (29,30,37,38).…”

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV + tumors when combined with an E6/E7 peptide vaccine

“…Mice were first anesthetized by i.p. injection of ketamine and xylazine hydrochloride and then administered 100 μg of each peptide with 2 μg of αGalCer intranasally as described previously (32,33). The animals were maintained with their heads in anteflexion until they regained consciousness.…”

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…Activation of iNKT cells with a-Galcer was shown to interfere with the induction of oral tolerance [32]. This sparked interest in the application of a-Galcer as a mucosal adjuvant [33,34]. Oral administration of a-Galcer increases migration of lamina propriadendritic cells (LP-DCs) to mesenteric lymph nodes, which is suggestive of increased CCR7 expression by LP-DCs [35].…”

“…The unique modulatory properties of these cells has driven increasing interest in the therapeutic potential of a-Galcer and other novel iNKT cell activators [16,38]. The immunogenicity of an oral human immunodeficiency virus (HIV) vaccine was strongly enhanced by the inclusion of a-Galcer in the formulation [33].…”

“…More recently Lee et al [46] characterized circulating MAIT cells in a large sample of 133 healthy adults and reported high variability in circulating MAIT cell numbers across subjects (0.19-21.7%). Although no significant differences in numbers between males and females were found there was a significant decrease in MAIT cell numbers in elderly subjects (n = 45, ages 61-92) versus young subjects (n = 44, ages [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”