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.

结核分枝杆菌（Mycobacterium tuberculosis, Mtb）仍是全球范围内的重大公共卫生威胁，结核分枝杆菌疫苗的研发对于防控这一烈性传染病可发挥关键作用。Th17细胞介导的免疫应答已被证实与抗结核分枝杆菌的免疫保护效应密切相关。目前尚无获批的佐剂可在疫苗研发场景中诱导Th17细胞应答。近期采用二山嵛酸海藻糖酯的临床试验结果证实，佐剂系统CAF01——一种制剂依赖型的概念验证佐剂——可诱导长效免疫保护。本研究基于天然产物布拉特霉素（Brartemicin）发现了一类新型的可诱导Th17细胞应答的疫苗佐剂。本研究合成并评估了一系列芳基海藻糖衍生物文库的免疫刺激应答诱导能力，并就其结合Mincle受体、诱导人类及小鼠细胞产生先天细胞因子的能力，阐明了其构效关系。本研究进一步解析了该新型骨架的构效关系，证实先导化合物可从人原代外周血单个核细胞中诱导出促Th17细胞因子谱，并在小鼠模型中证实其与结核抗原M72联合使用时可有效诱导抗体产生。