Development of novel C type lectin receptor agonists as Th17-inducing adjuvants for next generation TB vaccines

Abstract

Abstract Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis (TB), is one of the leading causes of death among adults. Extensively drug resistant TB is an emerging threat shown to be spreading as a result of transmission; as such it could benefit greatly from the development of a new, effective vaccine. Mtb is structurally composed of many immunostimulatory elements, including trehalose 6,6′-dimycolate (TDM). It has recently been shown that these cell wall lipids act to stimulate the immune system through engagement of the innate, C type lectin receptor Mincle. Because of their potent immune stimulating properties these compounds have come into focus as potential vaccine adjuvants but are limited due to toxicity concerns. Therefore, we created a library of synthetic trehalose-based compounds with varying structures and assessed their ability to modulate innate immunity in human and mouse immune cells. We optimized the acyl chain configuration for maximal immune stimulation in human cells and discovered divergent structure-activity-relationships between murine and human responses. We also assessed the ability of the compounds to induce a Th17-favorable cytokine profile from primary human cells. Finally, in vivo studies of the optimal in vitro determined compound demonstrated good Th17-inducing activity against a candidate Mtb recombinant antigen. Our data demonstrates the species and structure-specific activity of our novel compounds and clearly highlights the necessity of multi-species structure-activity evaluation for potential therapeutic molecules even at the earliest stages of investigation. As well this study demonstrates the clear potential for Mincle agonist compounds for use as vaccine adjuvants.