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

开发新型佐剂 Th1 和 Th17 诱导亚基结核疫苗

• 批准号: 10576407
• 负责人: Jay T. Evans
• 金额: $ 48.02万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576407
• 关键词: Adjuvant; Adult; Aerosols; Agonist; Antigens; Bacille Calmette-Guerin vaccination; Cells; Clinical Trials; Communicable Diseases; Data; Development; Disease; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Evaluation; Funding; Future; Genetic; Grant; Health; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; Inbred Mouse; Inbreeding; Interferon Type II; Interferons; Lead; Licensing; Lung; Macaca; Macaca mulatta; Mediating; Modeling; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Predisposition; Prevention; Production; Pulmonary Tuberculosis; Recombinants; Resistance; Route; Safety; T cell response; T-Lymphocyte; TLR7 gene; Testing; Th1 Cells; Tuberculosis; Tuberculosis Vaccines; Vaccine Production; Vaccines; Work; cytokine; efficacy evaluation; efficacy study; efficacy testing; efficacy validation; high throughput technology; immunogenicity; lead candidate; lead optimization; mouse model; mucosal vaccine; nonhuman primate; novel; pathogen; pre-clinical; prevent; protective efficacy; rational design; resistant strain; response; safety study; safety testing; single cell sequencing; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine immunogenicity; vaccine platform; vaccine response; vaccine safety; vaccine strategy; vaccine-induced immunity

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.

项目概要 作为疫苗成分的佐剂通过调节和作用对疫苗功效产生重大影响 延长宿主的免疫反应，而疫苗是预防和控制感染的最有效方法。 疾病，许多严重影响人类健康的病原体仍然没有有效的疫苗。 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，是世界上主要的传染病杀手。目前获得许可的结核病。 在没有疫苗的情况下，牛分枝杆菌卡介苗 (BCG) 在全球范围内提供不同的保护功效 (0-80%)2-4。 由于结核病疫苗的保护具有明显的相关性，因此我们必须探索新的有效方法 针对疫苗诱导的结核病免疫的广泛 T 细胞反应。 特别是使用驱动 Th1 反应的新佐剂（UM-1007，一种新型 TLR7/8 激动剂）和 Th17 反应（UM-1098，一种新型 Mincle 激动剂）将显着增强疫苗诱导的结核病保护作用。 因此，在提案的 R61 阶段，我们将优化这些新型 Th1 和 Th17 诱导药物的使用 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 Th1- 和 Th17- 的初免-加强策略的识别 疫苗反应（具体目标 1），并测试这些新型 Th1 和 Th17 诱导结核病候选疫苗是否会 在 TB 小鼠挑战模型中提供保护（具体目标 2）。在 R33 阶段，我们将测试优化后的模型。 Th1 和 Th17 诱导结核病候选疫苗在气溶胶挑战中具有免疫原性、安全性和保护作用 我们还建议我们将达到以下里程碑。 里程碑 1（第 12 个月）：针对产生 Th1 反应的优化 IM 疫苗的抗原选择 (UM-1007:TB) 和 Th17 反应 (UM-1098:TB) 里程碑 2（第 18 个月）：确定最佳初免-加强策略。 诱导最大肺 Th1 反应 (UM-1007:TB) 和 Th17 反应 (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:TB 候选药物的功效 易感和耐药 Mtb 以及遗传多样性 Mtb 感染小鼠的里程碑 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、安全性和有效性。 在猕猴中优化 UM-1007:TB 和 UM-1098:TB 疫苗的研究及其深入表征 里程碑 6（第 60 个月）：新发现的 Mtb 疫苗的最终选择。 因此，本次资助中提出的工作将产生一种新颖的、首创的合理设计的 Th1- 和/或 Th17- 在不久的将来诱导结核疫苗用于人类。