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.

项目摘要 作为疫苗组成部分的调节器对疫苗效率通过调节和 延长宿主免疫反应。疫苗是预防和控制感染性的最有效方法 疾病，许多显着影响人类健康的病原体仍然没有有效的疫苗。为了 例如，世界四分之一的人口受到结核分枝杆菌（MTB）的感染 结核病（TB）1的病因，世界上主要的传染病杀手。目前有执照的结核病 疫苗M. Bovis BCG（BCG）在世界2-4上提供了可变的保护有效性（0-80％）。在缺席的情况下 与结核病疫苗保护的明确相关性，我们必须探索新的有效方法 针对疫苗诱导的对结核病的免疫力靶向广泛的T细胞反应。在当前的提议中，我们 假设使用驱动Th1响应的新调节器（UM-1007，新型TLR7/8激动剂）和TH17 反应（UM-1098，一种新颖的大小激动剂）将显着增加疫苗诱导的对结核病的保护。 在提案的R61阶段，我们将优化这些新颖的Th1和Th17诱导的使用 调整后的疫苗平台并进行原本研究证明，包括详细评估 免疫原性，抗原优化，增强肺Th1和Th17-的质量增强策略的鉴定 疫苗反应（特定AIM 1），并测试这些新型TH1和TH17诱导的TB疫苗候选者是否会 在TB的小鼠挑战模型中保护（特定目标2）。在R33阶段，我们将测试优化 Th1和Th17诱导的TB候选疫苗在气溶胶挑战中具有免疫原性，安全性和保护性 猕猴中的模型（特定目标3）。我们还建议我们将达到以下里程碑。 R61相。 里程碑1（第12个月）：针对产生Th1响应的优化IM疫苗的抗原选择（UM-1007：TB） 和Th17响应（UM-1098：TB）。里程碑2（第18个月）：标识最佳的促进策略 TB疫苗诱导最大肺TH1反应（UM-1007：TB）和TH17响应（UM-1098：TB）。 里程碑3（33个月）：优化UM-1007的测试效率：TB和UM-1098：针对药物的结核病候选者 易感和耐药的MTB以及遗传多样的MTB感染小鼠。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，安全性和效率 优化UM-1007的研究：TB和UM-1098：猕猴中的结核病疫苗和深入的表征 疫苗诱导的免疫反应。里程碑6（第60个月）：最终选择了新发现的MTB疫苗。 这是这笔赠款中提出的工作将导致一个新颖的，最初的理性设计的Th1-和/或Th17-- 在不久的将来诱导结核病疫苗用于人类。