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.

项目摘要/摘要 结核病仍然是全球十大死亡原因之一（1）。基于最新的 世界卫生组织报告的信息，2019年，估计有140万人死于结核病 10,000,000研究员（2）。 COVID-19大流行导致结核病病例识别并停止大幅下降 TB估计将在未来4年内登记140万TB死亡（3，4）。这，在一起 随着耐药性结核病的威胁日益严格，与艾滋病毒和糖尿病的结核病的共同体使结局结束 结核病的流行比以往任何时候都更为重要。一种防止青少年和成年人获取的疫苗， 开发和传输结核病将是结束结核病流行的最具成本效益的工具（5）。 结核病疫苗倡议（TBVI）和治疗行动组（TAG）TB疫苗管道报告 十二种亚基疫苗，包括重组蛋白/辅助和病毒载体疫苗的疫苗 临床前3阶段的发展（6，7）。其中九个包括AG85（AG85A或B），其中六个包括 esat6。管道中存在的高度有限的抗原和免疫学多样性是一个显着的差距 开发一种新颖，有效的疫苗的努力。拟议的研究旨在带来所需的抗原和 使用Moderna的尖端mRNA疫苗到临床前结核病疫苗管道的平台多样性 技术和专业知识。 在此程序的R61阶段中，我们将首先优化分枝杆菌抗原序列以表达 使用Moderna的专有学习和算法的哺乳动物细胞。这些原则将应用于 开发三种候选mRNA疫苗，包括1）先前显示的抗原盒 动物模型的保护当作为蛋白质加调整时，2）新的抗原盒 包括新型抗原，3）显示的M72抗原在交付时诱导人类保护 AS01E调整的重组蛋白。然后，我们将使用鼠免疫原性和保护的数据 研究选择了两个最佳候选者，以促进R33阶段。在R33阶段，我们将 使用几内亚猪挑战模型将最终的主要候选者降低，以进一步发展。一次决赛 选择铅候选人，将进行其他研究，以进一步表征候选人，包括 一般多种小鼠的保护和非人类隐私的免疫原性研究，以优化 临床用途的疫苗接种方案。 到该计划结束时，我们将有一个新颖的铅疫苗候选者，准备进步 使研究和早期发展作为疫苗，以预防成人和青少年的结核病疾病。