Cyclic-di-GMP based immune stimulatory formulations as vaccine adjuvants

Thesis Type: Postgraduate

Institution Of The Thesis: Orta Doğu Teknik Üniversitesi, Faculty of Arts and Sciences, Department of Biology, Turkey

Approval Date: 2013


Consultant: MAYDA GÜRSEL


3́,5́-Cyclic diguanylic acid (c-di-GMP) is a bacteria-derived small cyclic di-nucleotide that functions as the universal bacterial secondary messenger. To date, studies concerning its immuno-stimulatory and immuno-modulatory effects show that cytosolic sensing of c-di-GMP by the innate immune sensor receptor STING, induces a robust type-I Interferon production in antigen presenting cells and leads to their maturation as evidenced by increased co-stimulatory molecule expression. However, the chemical structure and the anionic nature of c-di-GMP limit its efficient entry through cellular membranes, requiring its transfection to the cytosol. In this study, we explored the possibility of using three different strategies that would improve the intracellular delivery and/or boost the immunostimulatory activity of c-di-GMP. Specifically, we show that cationic peptide complexation of c-di-GMP or its encapsulation in bacteria-derived membrane vesicles (MVs) boost antigen-specific immune responses and induce a potent protective anti-tumor response in mice, relative to the free ligand. Moreover, we demonstrate that c-di-GMP shows synergistic immunostimulatory activity when used in combination with the TLR9 ligand, CpG motif containing oligodeoxynucleotide (CpG ODN). The results of this study suggest that the immune stimulatory activity of c-di-GMP can be enhanced by the use of these strategies and could contribute to the development of new vaccine adjuvants/immunotherapeutic agents for use in the clinic.