Aryl Trehalose Derivatives as Vaccine Adjuvants for Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) continues to be a major health threat worldwide,
and
the development of Mtb vaccines could play a pivotal
role in the prevention and control of this devastating epidemic. Th17-mediated
immunity has been implicated in disease protection correlates of immune
protection against Mtb. Currently, there are no approved
adjuvants capable of driving a Th17 response in a vaccine setting.
Recent clinical trial results using trehalose dibehenate have demonstrated
a formulation-dependant proof of concept adjuvant system CAF01 capable
of inducing long-lived protection. We have discovered a new class
of Th17-inducing vaccine adjuvants based on the natural product Brartemicin.
We synthesized and evaluated the capacity of a library of aryl trehalose
derivatives to drive immunostimulatory reresponses and evaluated the
structure–activity relationships in terms of the ability to
engage the Mincle receptor and induce production of innate cytokines
from human and murine cells. We elaborated on the structure–activity
relationship of the new scaffold and demonstrated the ability of the
lead entity to induce a pro-Th17 cytokine profile from primary human
peripheral blood mononuclear cells and demonstrated efficacy in generating
antibodies in combination with tuberculosis antigen M72 in a mouse
model.