Advancing Innovative Next_generation Heterologous Vaccines Against Tuberculosis

推进创新的下一代抗结核异源疫苗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要纵观现代历史，结核病 (TB) 造成的死亡人数比任何其他传染病都多迄今为止的疾病（过去 350 年估计超过 20 亿人）和结核病继续导致死亡每天有 4,000 名患者。仅 2019 年，世界卫生组织估计就有约 140 万多人死于结核病，新诊断出 8-900 万患者。唯一批准的疫苗，M. 牛卡介苗 (BCG) 已取得许多成功，但其保护作用各不相同，并且接种卡介苗的结核病患者仍然传播结核分枝杆菌。在全球范围内，传输平衡疾病的存在使得每一位现有结核病患者都会出现一例新的肺结核病例；因此，必须重新努力降低结核病发病率。需要新的策略来应对结核病，包括发现和开发新疫苗来控制病原体分枝杆菌结核病（M.tb）。考虑到这一最终目标，我们响应 RFA AI-21-007 的号召：创新结核病疫苗研发 (ITVD)，在 PI 与疫苗之间建立合作伙伴关系开发专业知识以及使用结核病动物模型的专业知识。我们提出了三种新颖的方法推进结核病疫苗的研发。在 R61 阶段，我们开发并确定性能最佳的新产品候选疫苗。具体来说，我们 (i) 将 ID93 蛋白抗原与新佐剂结合旨在最大限度地提高粘膜免疫反应和持久性； (ii) 利用新型 RNA 平台创建表达 ID93 和相关 M.tb 抗原的疫苗，以快速、持久地诱导免疫; (iii) 优化异源蛋白/RNA初免-加强候选物以获得强效且持久的效果粘膜、体液和细胞抗 M.tb 免疫，并选择最终候选者进入挑战研究。为了最大限度地提高早期开发、严谨性和可重复性，我们执行在选定的协作杂交（CC）近交株组中进行免疫原性研究，代表已知的结核分枝杆菌感染易感性差异。在R33相，即M.tb 挑战研究中，我们利用多样性远交 (DO) 小鼠群体的出色表现与人类相当的基因型和表型多样性的表征，这是结核病的主要障碍迄今为止的疫苗开发工作。我们还将在豚鼠身上测试最终的候选疫苗，结核病疫苗的经典临床前模型，确保在 2 种动物模型中取得成功。