Improving Mycobacterium bovis Bacillus Calmette-Guèrin as a Vaccine Delivery Vector for Viral Antigens by Incorporation of Glycolipid Activators of NKT Cells

Abstract

Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC) into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.

Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity

“…Our analysis also took advantage of a hCD1d KI mouse model, which more faithfully replicates many of the features of human i NKT cell responses in comparison to standard wild type mice (Venkataswamy et al, 2014; Wen et al, 2015; Wen et al, 2013). This mouse strain was generated by replacing the mouse genomic segment containing the exons encoding mCD1d with the homologous human genomic sequence (Wen et al, 2013).…”

“…However, in studies using cell culture models of human i NKT cell responses, α- C -GalCer has been found to be only weakly stimulatory, suggesting that it may not be suitable for development as a human therapeutic (Li et al, 2009a; Li et al, 2009b; Venkataswamy et al, 2014). Another strongly Th1-biasing i NKT cell agonist that was previously identified is the aminodiol (sphinganine) analogue (AH03-1 in Figure 1A) of KRN7000, which has activities similar to α- C -GalCer in mouse models (Arora et al, 2011).…”

Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response

“…When stimulated with the agonistic lipid α-galactosylceramide (αGalCer), they rapidly secrete high amounts of several cytokines, and there is growing interest in exploiting αGalCer as an immunological adjuvant (Carreno et al, 2014; Singh et al, 2014; Venkataswamy et al, 2014). iNKT cells also secrete cytokines at steady state and early after infection to influence the development and activation of surrounding immune cells (Engel and Kronenberg, 2014; Lee et al, 2013).…”

Enhancing vaccine effectiveness with delivery technology

“…Examples include Salmonella spp . [24–26]*, Mycobacterium bovis [27], Listeria monocytogenes [28–30], Vibrio cholera [31], Lactobacillus spp. [32], Staphylococcus spp.…”