DEVELOPMENT OF UM-1098: A NOVEL SYNTHETIC TH17 INDUCING ADJUVANT AND DELIVERY SYSTEM

开发安全有效的Th17诱导佐剂并对其进行临床评价是疫苗开发的迫切需要，以对抗包括结核分枝杆菌（Mtb）、百日咳博德氏菌、金黄色葡萄球菌、铜绿假单胞菌、肺炎链球菌、白色念珠菌、烟曲霉等细菌和真菌病原体的持续威胁。由于缺乏适当的佐剂来诱导Th17免疫，针对结核病和其他细菌和真菌病原体的疫苗接种一直受到阻碍。因此，能够诱导针对新出现的细菌和真菌病原体的广泛保护性免疫反应的下一代疫苗佐剂代表了一个关键的未满足需求。这份佐剂开发合同将推动一种这样的佐剂- UM-1098：一种诱导Th17的合成Mincle配体-进入人体临床试验。UM-1098是通过NIAID佐剂发现计划通过全面和迭代的构效关系（SAR）研究确定的，以确定一种新的合成二芳基海藻糖环受体配体与一种新的纳米颗粒递送系统配对。这种佐剂和递送系统在小鼠、猪和非人灵长类动物（NHPs）中具有良好的安全性和有效性，可以跨越多种高度相关的抗原/病原体平台，包括结核病和百日咳博德泰拉。与先前开发的Mincle佐剂相比，UM-1098的优势包括改进的配方理化性质、热稳定性、强大的安全性，最重要的是，在啮齿动物、猪和NHPs中具有优越的抗原特异性Th17、Th1和体液免疫。当与抗原共同施用时，UM-1098佐剂诱导持久的细胞介导和体液免疫，并证明对结核分枝杆菌和百日咳博德泰拉的攻击具有保护作用。

The development and clinical evaluation of safe and effective Th17 inducing adjuvants is urgently needed for the advancement of vaccines to combat the ongoing threat of bacterial and fungal pathogens including Mycobacterium tuberculosis (Mtb), Bordetella pertussis, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Aspergillus fumigatus and others. Vaccination against TB and other bacterial and fungal pathogens has been hampered by the lack of appropriate adjuvants for inducing Th17 immunity. Thus, the next generation of vaccine adjuvants capable of inducing broadly protective immune responses against emerging bacterial and fungal pathogens represents a critical unmet need. This Adjuvant Development Contract will advance one such adjuvant – UM-1098: a Th17 inducing synthetic Mincle ligand– towards human clinical trials. UM-1098 was identified through the NIAID Adjuvant Discovery Program via a comprehensive and iterative structure-activity relationship (SAR) investigations to identify a novel synthetic diaryl trehalose Mincle receptor ligand paired with a novel nanoparticle delivery system. This adjuvant and delivery system has a well-established safety and efficacy profile in mice, pigs and non-human primates (NHPs) across multiple highly relevant antigen/pathogen platforms including TB and Bordetella pertussis. The advantages of UM-1098 over previously developed Mincle adjuvants includes improved formulation physiochemical properties, thermostability, robust safety profile, and most importantly, superior antigen-specific Th17, Th1, and humoral immunity across rodents, pigs and NHPs. When co-administered with an antigen, UM-1098 adjuvant induces durable cell-mediated and humoral immunity with demonstrated protection against Mtb and Bordetella pertussis challenge.