Natural STING Agonist as an "Ideal" Adjuvant for Cutaneous Vaccination

A potent adjuvant that induces strong protective immunity without incurring any significant skin reactogenicity is urgently needed for cutaneous vaccination. Here, we report that a natural agonist of stimulator of interferon genes (STING), 2'3'- cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), robustly augmented and prolonged the cellular and humoral immune responses provoked by H5N1 and 2009 H1N1 pandemic influenza vaccines after a single dose of intradermal, but not intramuscular, immunization. The potency of cGAMP for cutaneous vaccination was ascribed to a large number of antigen-presenting cells resident in the skin and ready for immediate activation when cGAMP was injected. However, its potency was severely compromised in the muscle, because antigen-presenting cells could not be promptly recruited to the injection site before the injected cGAMP was diffused out. The superior adjuvant effect and safety of cGAMP were also confirmed in a more clinically relevant swine model of skin. The vigorous immune responses elicited by cGAMP with no overt skin irritation was attributable to its stay in the skin, which was brief but sufficient to activate dermal dendritic cells. This small and well-characterized self-molecule holds great promise as an ideal adjuvant for cutaneous vaccination.