Alpha]-GalCer analogues with branched acyl chain enhance humoral and cellular immune responses in a nasal influenza vaccine (132.11)

Abstract

Abstract α-galactosylceramide (α-GalCer) can act as a safe and effective adjuvant for a nasal vaccine that induces protective immune responses against tumors and viral infections. In this study, α-GalCer analogues were designed to have branched acyl chain by modification of their fatty acyl chain based on the CD1d/glycolipid structures. Two α-GalCer analogues with various branched chain lengths; LDH-II-28 and LDH-II-30 were prepared and evaluated for their efficacy as a nasal influenza vaccine adjuvant. These analogues displayed improved solubility over α-GalCer and effectively stained NKT cells both in mouse and human. They also potently stimulated NKT cells to exhibit different cytokine release profiles from α-GalCer in vitro and in vivo. When profiling serum cytokines in vivo, LDH-II-30 provoked both Th1/Th2 cytokines, while LDH-II-28 induced more Th2-biased cytokine release with diminished IFN-γ production. We found that single immunization of inactivated influenza virus A/PR/8/34 (PR8) together with α-GalCer analogues enhanced PR8-specific humoral and cellular immune responses in both systemic and mucosal compartments. Notably, LDH-II-30 exhibited potent adjuvant effects with significantly higher systemic IgG, mucosal sIgA Ab titers and enhanced CTL generation compared to immunization with inactivated PR8 alone, while addition of LDH-II-28 to inactivated PR8 only marginally increased PR8-specific immune responses. These results suggest that α-GalCer analogues with branched acyl chain could be used as an effective mucosal adjuvant for the induction of influenza vaccine-specific humoral and cellular immune responses.