Abstract
Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer), a synthetic glycolipid agonist of natural killer T (NKT) cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.
Highlights
Among the different strategies for delivering vaccine antigens, viral vectors merit attention because of their potency in reaching wider cell types and efficient antigen expression achieving sustained levels of antigen-specific immune responses [1]
We tested the effectiveness of α-GalCer adjuvant for improving immunity induced by antigens expressed from viral vectors employing the vesicular stomatitis viral vector encoding ovalbumin as the model antigen (VSV-OVA)
Since immune responses generated by vaccination in mice may not truly predict applicability to humans and since rhesus macaques represent a suitable nonhuman primate model close to humans, for HIV vaccine approaches, we tested the effectiveness of α-GalCer to induce natural killer T (NKT) cells responses in macaques
Summary
Among the different strategies for delivering vaccine antigens, viral vectors merit attention because of their potency in reaching wider cell types and efficient antigen expression achieving sustained levels of antigen-specific immune responses [1]. Ad serotype 5 (Ad5) based HIV vaccines tested in the past few years proven ineffective, in individuals with pre-existing Ad5 immunity [3,4,5,6,7,8]. To overcome this concern, we tested serotype-switching strategy employing other serotypes, Ad1, 2 and 6 that proved significantly more immunogenic than multiple doses of Ad5 vaccine and afforded relatively better control of viremia after pathogenic virus challenge [9,10,11]. We observed that intramuscular immunization generated stronger systemic cellular immune responses than the intra-vaginal route, but the latter yielded higher mucosal immunity, antigen-specific central memory T cells (Tcm) subset along with more animals in this group exhibiting lower viral loads [11]
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