Development of Novel mRNA Vaccines Against Mycobacterium tuberculosis

新型结核分枝杆菌 mRNA 疫苗的开发

• 批准号: 10625373
• 负责人: KENT E. KESTER
• 金额: $ 42.23万
• 依托单位: INTERNATIONAL AIDS VACCINE INITIATIVE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625373
• 关键词: Adjuvant; Adolescent; Adult; Algorithms; Animal Model; Animals; Antigenic Diversity; Antigens; COVID-19; COVID-19 pandemic; Cause of Death; Cavia; Cessation of life; Clinical; Clinical Trials; Codon Nucleotides; Communicable Diseases; Data; Data Set; Development; Diabetes Mellitus; Disease; Dose; Drug resistance in tuberculosis; Epidemic; Evaluation; Generations; Goals; HIV; Head; Human; Incidence; Individual; Infectious Agent; Lead; Learning; Mammalian Cell; Messenger RNA; Modeling; Modification; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Persons; Phase; Phase I Clinical Trials; Positioning Attribute; Proteins; Public Health; RNA vaccine; Recombinant Proteins; Regimen; Reporting; Research; Subunit Vaccines; Sustainable Development; Technology; Time; Tuberculosis; Tuberculosis Vaccines; United Nations; Vaccination; Vaccines; Viral Vector; clinical development; cost effective; design; glycosylation; immunogenicity; immunological diversity; innovation; lead candidate; mycobacterial; non-Native; nonhuman primate; novel; novel strategies; novel vaccines; pandemic disease; phase 1 study; pre-clinical; prevent; product development; programs; research and development; tool; transmission process; vaccine candidate; vaccine development; vector vaccine

Project Summary/Abstract Tuberculosis remains one of the top ten leading causes of death worldwide (1). Based on the most current information from WHO 2020 report, in 2019 an estimated 1.4 million people died from TB and approximately 10,000,000 fell ill (2). The COVID-19 pandemic has led to massive decreases in TB case identification and Stop TB estimates an additional 1.4 million TB deaths will be registered over the next 4 years (3, 4). This, together with the growing threat of drug-resistant TB and the co-epidemics of TB with HIV and diabetes makes ending the TB epidemic more crucial than ever before. A vaccine that prevents adolescents and adults from acquiring, developing, and transmitting TB would be the single most cost-effective tool in ending the TB epidemic (5). The TuBerculosis Vaccine Initiative (TBVI) and Treatment Action Group (TAG) TB Vaccine Pipelines report twelve subunit vaccines including recombinant protein/adjuvant and viral vector vaccines spanning from preclinical through Phase 3 development (6, 7). Of these, nine include Ag85 (Ag85A or B) and six include ESAT6. The highly limited antigenic and immunological diversity present in the pipeline is a significant gap in efforts to develop a novel, effective vaccine. The proposed research is intended to bring needed antigenic and platform diversity to the pre-clinical TB vaccine pipeline using Moderna’s cutting-edge mRNA vaccine technology and expertise. Within the R61 phase of this program, we will first optimize mycobacterial antigen sequences for expression in mammalian cells using Moderna’s proprietary learnings and algorithms. These principles will be applied to the development of three candidate mRNA vaccines, including 1) an antigen cassette previously shown to induce protection in animal models when delivered as a protein plus adjuvant, 2) a new antigen cassette including novel antigens, and 3) the M72 antigen shown to induce protection in humans when delivered as recombinant protein with the AS01E adjuvant. We will then use data from murine immunogenicity and protection studies to select the two best candidates for advancement into the R33 phase. Within the R33 phase, we will use the guinea pig challenge model to downselect to a final lead candidate for further advancement. Once a final lead candidate is selected, additional studies will be conducted to further characterize the candidate, including protection in genetically diverse mice and an immunogenicity study in nonhuman primates to optimize the vaccination regimen for clinical use. By the end of this program, we will have a novel lead vaccine candidate ready for advancement into IND- enabling studies and early development as a vaccine to prevent TB disease in adults and adolescents.

项目概要/摘要 结核病仍然是全球十大死亡原因之一 (1)。基于最新的 根据世界卫生组织 2020 年报告的信息，2019 年估计有 140 万人死于结核病，约 10,000,000 人患病 (2)。 COVID-19 大流行导致结核病病例确诊和停止数量大幅减少 TB 估计未来 4 年将有 140 万人因结核病死亡 (3, 4)。这个，一起 随着耐药结核病的威胁日益增加，以及结核病与艾滋病毒和糖尿病的共同流行，使得结核病的终结 结核病流行比以往任何时候都更加重要。一种疫苗可以防止青少年和成人感染， 发展和传播结核病将是结束结核病流行的最具成本效益的单一工具(5)。 结核病疫苗倡议 (TBVI) 和治疗行动小组 (TAG) 结核病疫苗管道报告 十二种亚单位疫苗，包括重组蛋白/佐剂和病毒载体疫苗 临床前至第 3 阶段开发 (6, 7)。其中，九个包括 Ag85（Ag85A 或 B），六个包括 ESAT6。管道中存在的高度有限的抗原和免疫多样性是一个巨大的差距 努力开发一种新型、有效的疫苗。拟议的研究旨在带来所需的抗原和 使用 Moderna 的尖端 mRNA 疫苗为临床前结核病疫苗管道提供平台多样性 技术和专业知识。 在该计划的 R61 阶段，我们将首先优化分枝杆菌抗原序列以在 使用 Moderna 专有的学习和算法来研究哺乳动物细胞。这些原则将适用于 开发三种候选 mRNA 疫苗，包括 1) 先前显示可诱导的抗原盒 以蛋白质加佐剂的形式提供时对动物模型的保护作用，2) 新的抗原盒 包括新抗原，以及 3) M72 抗原被证明可以在人体中产生保护作用 重组蛋白与 AS01E 佐剂。然后我们将使用来自小鼠免疫原性和保护的数据 研究选择两名最佳候选人进入 R33 阶段。在R33阶段，我们将 使用豚鼠挑战模型来向下选择最终的主要候选者以进一步推进。一次决赛 选择主要候选人后，将进行额外的研究以进一步表征候选人，包括 对遗传多样性小鼠的保护以及对非人灵长类动物的免疫原性研究，以优化 临床使用的疫苗接种方案。 到该计划结束时，我们将拥有一种新的先导候选疫苗，准备进入 IND- 促进研究和早期开发疫苗以预防成人和青少年结核病。