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

项目总结 佐剂作为疫苗的一个组成部分，通过调节和调节免疫系统对疫苗效力产生重大影响。 延长宿主免疫反应。而疫苗是预防和控制传染病的最有效方法 在疾病方面，许多严重影响人类健康的病原体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)的病原体1，世界主要的传染病杀手。当前许可的TB 卡介苗(BCG)在全球范围内提供不同的保护效力(0-80%)2-4。在缺席时 有了明确的结核病疫苗保护相关性，我们必须探索新的有效方法 以广泛的T细胞反应为靶点进行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Th1应答的新佐剂(新型TLR7/8激动剂UM-1007)和Th17 反应(一种新的Mincle激动剂UM-1098)将显著增强疫苗诱导的对结核病的保护。 因此，在建议的R61阶段，我们将优化这些新的Th1和Th17诱导的使用 并进行原则验证研究，包括详细评估 免疫原性，抗原优化，增强肺Th1-和Th17-的主要增强策略的鉴定- 疫苗反应(特定目标1)，并测试这些新的Th1和Th17诱导结核病候选疫苗是否将 在小鼠激发结核病模型中保护(特定目标2)。在R33阶段，我们将测试优化后的 诱导Th1和Th17的结核候选疫苗在气雾剂挑战中的免疫原性、安全性和保护性 猕猴模型(特定目标3)。我们还建议，我们将实现以下里程碑。R61相。 里程碑1(12个月)：为产生Th1反应的优化IM疫苗选择抗原(UM-1007：TB) 和Th17响应(UM-1098：TB)。里程碑2(第18个月)：确定最佳优质助推战略 一种诱导最大肺Th1应答(UM-1007：TB)和Th17应答(UM-1098：TB)的结核疫苗。 里程碑3(第33个月)：测试优化的UM-1007：TB和UM-1098：候选结核病对药物的疗效 敏感和耐药的结核分枝杆菌和遗传多样性的结核分枝杆菌感染小鼠。里程碑4(36个月)： 提交R33过渡方案。R33期。里程碑5(第60个月)：免疫原性、安全性和有效性 优化的UM-1007：TB和UM-1098：TB疫苗在猕猴体内的研究和深入特性 疫苗诱导的免疫反应。里程碑6(第60个月)：新发现的结核分枝杆菌疫苗的最终选择。 因此，这项拨款中提议的工作将导致一种新颖的、第一种合理设计的Th1和/或Th17- 在不久的将来诱导用于人类的结核病疫苗。

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.