Advancing Innovative Next_generation Heterologous Vaccines Against Tuberculosis

推进创新的下一代抗结核异源疫苗

• 批准号: 10620357
• 负责人: GILLIAN L BEAMER
• 金额: $ 52.62万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620357
• 关键词: Address; Adjuvant; Aliquot; Animal Model; Animals; Antigens; BCG Live; Bacille Calmette-Guerin vaccination; Binding; Biological Assay; Biological Response Modifiers; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cavia; Cells; Cellular Assay; Cellular Immunity; Clinical Trials; Communicable Diseases; Databases; Development; Disease; Emulsions; Ensure; Epidemiology; Equilibrium; Euthanasia; Experimental Animal Model; Failure; Formulation; Future; Genes; Genetic Variation; Genotype; Goals; Human; Humoral Immunities; IL17 gene; Immune; Immunity; Immunize; Immunoglobulin A; Immunoglobulin G; Inbred Mouse; Inbred Strain; Infection; Inflammatory Response; Interferon Type II; Intramuscular; Ligands; Liposomes; Lung; Measurable; Measures; Mediating; Mind; Modality; Modeling; Modern 1601-history; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Newly Diagnosed; Outcome; Patients; Persons; Phase; Phenotype; Population; Pre-Clinical Model; Predisposition; Proteins; Pulmonary Tuberculosis; RNA; RNA amplification; RNA vaccine; Reproducibility; Reproduction; Rodent Model; Route; Sampling Studies; Serum; Spleen; Squalene; T cell response; T-Lymphocyte; Testing; Tissue Sample; Tissues; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Work; World Health Organization; aluminum sulfate; burden of illness; candidate identification; candidate selection; clinical candidate; combat; design; disease transmission; efficacy testing; immunogenic; immunogenicity; innovation; insight; lead candidate; nano; next generation; novel; novel vaccines; pathogen; pre-clinical; pre-clinical assessment; response; screening; statistics; success; thermostability; transmission process; tuberculosis immunity; vaccine candidate; vaccine development; vaccine discovery; vaccine platform; vaccine trial

PROJECT SUMMARY/ABSTRACT Throughout modern history, tuberculosis (TB) has killed more people than any other infectious disease to date (estimated > 2 billion people over the past 350 years) and TB continues to kill 4,000 patients each day. In 2019 alone, the World Health Organization estimated that ~1.4 million people died of TB and 8-9 million patients were newly diagnosed. The only approved vaccine, M. bovis Bacille Calmette-Guerin (BCG) has had many successes but its protection is variable and BCG-vaccinated TB patients still transmit M.tb. Across the globe, an equilibrium of transmission and disease exists such that one new case of pulmonary TB arises from each existing TB patient; thus, efforts must be reinvigorated to drive TB rates lower. New strategies are needed to combat TB including discovery and advancement of new vaccines to control the pathogen Mycobacterium tuberculosis (M.tb). With that end goal in mind, we answer the call for RFA AI-21-007: Innovation for Tuberculosis Vaccine Discovery (ITVD), forming partnerships between PIs with vaccine development expertise, and expertise using animal models of TB. We propose three novel means to advance TB vaccines. In the R61 phase, we develop and identify the best performing new vaccine candidates. Specifically, we (i) combine the ID93 protein antigen with new adjuvants designed to maximize mucosal immune responses and durability; (ii) capitalize on novel RNA platform to create vaccines expressing ID93 and related M.tb antigens to induce rapid and durable immunity; (iii) optimize heterologous protein/RNA prime-boost candidates for strong and durable mucosal, humoral, and cellular anti-M.tb immunity, and select the final candidates to move into challenge studies. To maximize early-stage development, rigor, and reproducibility, we perform immunogenicity studies in a selected panel of Collaborative Cross (CC) inbred strains, representing known differential susceptibility to M.tb infection. In the R33 phase, i.e., M.tb challenge studies, we exploit the Diversity Outbred (DO) mouse population for its outstanding representation of genotypic and phenotypic diversity equivalent to humans, a major hurdle in TB vaccine development efforts to date. We will also test the final vaccine candidates in guinea pigs, the classic preclinical model for TB vaccines to ensure success in 2 animal models.

项目摘要/摘要 在整个现代历史上，结核病（TB）杀死的人数比任何其他感染力都多 迄今为止的疾病（过去350年中估计> 20亿人）和结核病继续杀死 每天4,000名患者。仅在2019年，世界卫生组织估计约有140万 人们死于结核病和8-9万患者。唯一批准的疫苗。 Bovis Bacille Calmette-Guerin（BCG）取得了许多成功，但其保护是可变的，并且 BCG接种疫苗的结核病患者仍在发送M.TB。在全球范围内，传播的平衡 并且存在疾病，因此每位现有的结核病患者引起了一个新的肺结核病病例。 因此，必须重新启动努力以降低结核病率。需要新的策略来对抗 结核病包括发现和发展新疫苗以控制病原体分枝杆菌 结核病（M.TB）。考虑到最终目标，我们回答RFA AI-21-007的呼吁：创新 对于结核病疫苗发现（ITVD），与疫苗之间建立了PIS之间的伙伴关系 开发专业知识和使用TB动物模型的专业知识。我们提出了三种新颖的手段 推进结核病疫苗。在R61阶段，我们开发并确定最佳性能的新 候选疫苗。具体而言，我们（i）将ID93蛋白抗原与新佐剂相结合 旨在最大化粘膜免疫反应和耐用性； （ii）利用新颖的RNA 平台创建表达ID93和相关M.TB抗原以诱导快速耐用的疫苗 免疫; （iii）优化耐用和耐用的异源蛋白/RNA Prime-Brim-trom候选者 粘膜，体液和细胞抗M.TB免疫，并选择最终候选者进入 挑战研究。为了最大化早期发展，严格和可重复性，我们执行 在选定的协作交叉（CC）近交菌株中的免疫原性研究， 代表已知的M.TB感染差异敏感性。在R33阶段，即M.TB 挑战研究，我们利用了多样性杂种（DO）小鼠人口的出色 基因型和表型多样性相当于人类的代表，这是结核病的主要障碍 迄今为止，疫苗开发工作。我们还将测试豚鼠中的最终疫苗候选物， 结核病疫苗的经典临床前模型，以确保在两种动物模型中取得成功。