Evidence for cyclic diguanylate as a vaccine adjuvant with novel immunostimulatory activities

Cyclic diguanylate (c-di-GMP), a bacterial signaling molecule, possesses protective immunostimulatory activity in bacterial challenge models. This study explored the potential of c-di-GMP as a vaccine adjuvant comparing it with LPS, CpG oligonucleotides, and a conventional aluminum salt based adjuvant. In this evaluation, c-di-GMP was a more potent activator of both humoral and Th1-like immune responses as evidenced by the robust IgG2a antibody response it induced in mice and the strong IFN-γ, TNF-α and IP-10 responses, it elicited in mice and in vitro in non-human primate peripheral blood mononuclear cells. Further, compared to LPS or CpG, c-di-GMP demonstrated a more pronounced ability to induce germinal center formation, a hallmark of long-term memory, in immunized mice. Together, these data add to the growing body of evidence supporting the utility of c-di-GMP as an adjuvant in vaccination for sustained and robust immune responses and provide a rationale for further evaluation in appropriate models of immunization.

► We evaluated the ability of cyclic diguanylate (c-di-GMP) to act as an adjuvant. ► c-di-GMP compared favorably to other known adjuvants or their surrogates that have positive clinical experience. ► c-di-GMP yielded superior activation of humoral and Th1-like immune responses. ► c-di-GMP vigorously induced germinal center formation in immunized mice. ► c-di-GMP has a unique potential to induce sustained and robust immune responses.