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Aryl Trehalose Derivatives as Vaccine Adjuvants for Mycobacterium tuberculosis.

Despite the ever present need for an efficacious Mycobacterium tuberculosis (Mtb) vaccine, efforts for development have been largely unsuccessful. Correlates of immune protection against Mtb are not wholly defined, but Th1 and likely Th17 adaptive immune responses have been demonstrated to be necessary for vaccine-mediated protection. Unfortunately, no approved adjuvants are able to drive a Th17 response in a vaccine setting, though recent clinical trials have demonstrated proof of concept.1 Herein we present the development and characterization of a new class of potential Th17-inducing vaccine adjuvants based on the natural product Brartemicin. We synthesized and evaluated the immunostimulatory capacity of a library aryl trehalose derivatives and evaluated the structure activity relationship of the compounds in terms of the ability of compounds to engage the Mincle receptor, induce production of innate cytokines from human and murine cells, induce a pro-Th17 cytokine profile from primary human peripheral blood mononuclear cells and demonstrated efficacy in generating antibodies in combination with a tuberculosis antigen M72 in a mouse model.