Development of a novel adjuvanted Th1- and Th17-inducing subunit TB Vaccine

项目摘要 作为疫苗组分包括的佐剂通过调节和调节免疫原性对疫苗效力具有重大影响。 延长宿主免疫反应。虽然疫苗是预防和控制传染病的最有效方法， 尽管有许多病原体严重影响人类健康，但仍然没有有效的疫苗。为 例如，世界上四分之一的人口潜伏感染结核分枝杆菌（Mtb）， 结核病（TB）1的病原体，结核病是世界上主要的传染病杀手。目前获得许可的TB vaccine，M.牛卡介苗（BCG）在世界各地提供不同的保护效力（0-80%）2 -4。在没有 由于结核病疫苗的保护作用存在明显的相关性，我们必须探索新的有效方法 靶向广泛的T细胞反应，用于疫苗诱导的抗结核免疫。在目前的提案中，我们 假设使用驱动Th 1应答新佐剂（UM-1007，一种新的TLR 7/8激动剂）和Th 17 应答（UM-1098，一种新型Mincle激动剂）将显著增强疫苗诱导的抗TB保护。 因此，在该提案的R61阶段，我们将优化这些新的Th 1-和Th 17-诱导因子的使用。 佐剂疫苗平台，并进行原理验证研究，包括详细评估 免疫原性、抗原优化、增强肺Th 1-和Th 17-的初免-加强策略的鉴定 疫苗反应（具体目标1），并测试这些新的Th 1和Th 17诱导结核病候选疫苗是否 在小鼠结核病攻击模型中保护（具体目标2）。在R33阶段，我们将测试优化的 在气溶胶激发中用于免疫原性、安全性和保护的Th 1和Th 17诱导的TB候选疫苗 猕猴模型（具体目标3）。我们还提议，我们将实现以下里程碑。R61阶段。 里程碑1（第12个月）：产生Th 1应答的优化IM疫苗的抗原选择（UM-1007：TB） 和Th 17应答（UM-1098：TB）。里程碑2（第18个月）：确定最佳预充-加强策略， 诱导最大肺Th 1应答（UM-1007：TB）和Th 17应答（UM-1098：TB）的TB疫苗。 里程碑3（第33个月）：测试优化的UM-1007：TB和UM-1098：TB候选药物对药物的疗效 易感和耐药结核分枝杆菌和遗传多样性结核分枝杆菌感染的小鼠。里程碑4（第36个月）： 提交R33过渡包。R33阶段。里程碑5（第60个月）：免疫原性、安全性和疗效 优化的UM-1007：TB和UM-1098：TB疫苗在猕猴中的研究以及 疫苗诱导的免疫反应。里程碑6（第60个月）：最终选择新发现的结核分枝杆菌疫苗。 因此，这项资助中提出的工作将产生一种新颖的，第一种合理设计的Th 1-和/或Th 17- 诱导结核病疫苗在不久的将来用于人类。

PROJECT SUMMARY Adjuvants included as a component of a vaccine have a major impact on vaccine efficacy via modulating and prolonging host immune responses. While vaccines are the most effective way to prevent and control infectious diseases, many pathogens that significantly impact human health remain without an effective vaccine. For example, one-fourth of the world’s population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB)1, a leading infectious disease killer in the world. The currently licensed TB vaccine, M. bovis BCG (BCG) provides variable protective efficacy (0-80%) across the world2-4. In the absence of clear correlates of protection for TB vaccines, it is imperative that we explore new and effective approaches to target broad T cell responses for vaccine-induced immunity against TB. In the current proposal, we hypothesize that use of new adjuvants that drive Th1 responses (UM-1007, a novel TLR7/8 agonist) and Th17 responses (UM-1098, a novel Mincle agonist) will significantly augment vaccine-induced protection against TB. Thus, during the R61 phase of the proposal, we will optimize the use of these novel Th1- and Th17-inducing adjuvanted vaccine platforms and conduct proof-of-principle studies including detailed assessment of immunogenicity, antigen optimization, identification of prime-boost strategies that enhance lung Th1- and Th17- vaccine responses (Specific Aim 1), and test if these novel Th1- and Th17-inducing TB vaccine candidates will protect in mouse challenge models of TB (Specific Aim 2). During the R33 phase we will test the optimized Th1- and Th17-inducing TB candidate vaccines for immunogenicity, safety and protection in an aerosol challenge model in macaques (Specific Aim 3). We also propose that we will meet the following milestones. R61 phase. Milestone 1 (Month 12): Antigen selection for an optimized IM vaccine producing a Th1 response (UM-1007:TB) and a Th17 response (UM-1098:TB). Milestone 2 (Month 18): Identification of the best prime-boost strategy for a TB vaccine inducing maximal lung Th1 responses (UM-1007:TB) and Th17 responses (UM-1098:TB). Milestone 3 (Month 33): Testing efficacy of optimized UM-1007:TB and UM-1098:TB candidates against drug susceptible and drug resistant Mtb and in genetically diverse Mtb-infected mice. Milestone 4 (Month 36): Submission of R33 transition package. R33 phase. Milestone 5 (Month 60): Immunogenicity, safety and efficacy studies of optimized UM-1007:TB and UM-1098:TB vaccines in macaques and in-depth characterization of vaccine-induced immune responses. Milestone 6 (Month 60): Final selection of newly discovered Mtb vaccine. Thus, the work proposed in this grant will result in a novel, first-of-kind rationally designed Th1- and/or Th17- inducing TB vaccine for use in humans in the near future.