Development of Novel mRNA Vaccines Against Mycobacterium tuberculosis

项目总结/摘要 结核病仍然是全球十大主要死亡原因之一（1）。依据最新 根据世卫组织2020年报告的信息，2019年估计有140万人死于结核病， 10，000，000人患病（2）。COVID-19大流行导致结核病病例识别和停止的大规模减少 结核病估计，在未来4年内，将有140万人死于结核病（3，4）。连同 随着耐药结核病的威胁日益严重，结核病与艾滋病毒和糖尿病的共同流行， 结核病的流行比以往任何时候都更加严重。一种预防青少年和成年人获得， 发展和传播结核病将是结束结核病流行的唯一最具成本效益的工具（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 12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III期开发（6，7）。其中，9个包括Ag 85（Ag 85 A或B），6个包括 ESAT 6.管道中存在的高度有限的抗原和免疫学多样性是一个显著的差距， 努力开发一种新的有效疫苗。这项研究的目的是将所需的抗原和 使用Moderna尖端mRNA疫苗的临床前结核病疫苗管道的平台多样性 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，以便在 使用Moderna的专有知识和算法来研究哺乳动物细胞。这些原则将适用于 开发了三种候选mRNA疫苗，包括1）先前显示诱导 当作为蛋白质加佐剂递送时在动物模型中的保护，2）新的抗原盒 包括新的抗原，和3）M72抗原显示当作为新的抗原递送时在人中诱导保护作用， 重组蛋白与AS 01 E佐剂的融合。然后，我们将使用来自小鼠免疫原性和保护的数据， 研究选择两个最佳候选人进入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潜在客户候选人以进一步提升。一次决赛 选定主要候选人后，将进行其他研究以进一步描述候选人的特征，包括 在遗传多样性小鼠中的免疫保护和在非人灵长类动物中的免疫原性研究，以优化 临床使用的疫苗接种方案。 在这个项目结束时，我们将有一个新的先导候选疫苗准备进入IND- 使研究和早期开发成为预防成人和青少年结核病的疫苗。

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.