Novel multivalent viral vectored tuberculosis vaccines targeting lung immunity

摘要 标题：针对肺免疫的新型多价病毒载体结核病疫苗 结核病仍然是最致命的细菌感染，有1000多万新的活动性结核病病例。 全世界每年确诊和150万人死于结核病，因为没有非常有效的 预防性疫苗。结核分枝杆菌(Mtb)在约25%的人中也会导致无症状的潜伏感染 全世界的人口。潜伏感染的人一生中患活动性结核病的风险为10%。 预防肺部结核分枝杆菌感染、限制潜伏期重新激活和/或治疗有效的疫苗 结核病是当务之急。这项R21提案的目的是探索独特的免疫学 基于PICV的新型疫苗平台与新型结核分枝杆菌抗原结合的特性 开发下一代结核病疫苗。PICV是一种具有双节段RNA基因组的非致病性阿雷诺病毒。 该方案利用了由三个RNA片段rP18tri组成的重组PICV，rP18tri可以编码两个 表达抗原的附加开放阅读框架(ORF)。RP18tri平台安全、多功能、诱导性强 平衡抗体和T细胞反应。此外，rP18tri平台易于修改以产生多种 这使得对候选抗原的快速分析能够识别那些导致 最大的保护。这项拟议的研究将检验这样一种假设，即优化后的多价抗原 通过rP18tri病毒载体平台滴鼻将诱导对肺部结核分枝杆菌的强大保护性免疫 感染。概念验证研究的初步数据表明，基于rP18tri的结核病疫苗可以 高效产生，诱导强大的抗原特异性T细胞免疫，保护肺部结核分枝杆菌感染 在老鼠的气溶胶挑战模型中。在此R21提案中，我们将生成额外的基于rP18tri的矢量 具有新免疫原的多价结核疫苗候选疫苗(目标1)，评估抗体以及系统和 这些疫苗诱导的小鼠肺组织驻留T细胞反应(目标2)，并评估这些疫苗的疗效 预防小鼠模型中结核分枝杆菌感染的疫苗(目标3)。这项研究意义重大，因为它 预计将生产至少一种病毒载体多价结核病疫苗候选疫苗，并证明其安全性和 对小鼠的疗效将进入下一阶段的临床前和临床评估。这项研究也是 有望产生关于新的结核分枝杆菌抗原诱导的保护性免疫的新知识，这将指导 下一代结核病疫苗的设计，并推进PICV载体平台的开发，该平台将 拓展抗击传染病的工具箱。

Abstract Title: Novel multivalent viral vectored tuberculosis vaccines targeting lung immunity Tuberculosis (TB) persists as the deadliest bacterial infection, with more than 10 million new cases of active TB diagnosed and 1.5 million deaths attributed to TB worldwide each year, because there is no highly effective preventative vaccine. Mycobacterium tuberculosis (Mtb) also causes asymptomatic latent infections in ~25% of the world’s population. Latently infected individuals have a 10% lifetime risk of developing active TB disease. Vaccines that prevent pulmonary Mtb infection, limit reactivation from latency and/or therapeutically treat active TB disease are urgently needed. The objective of this R21 proposal is to explore the unique immunological features of an innovative Pichinde virus (PICV)-based vaccine platform combined with novel Mtb antigens to develop next generation TB vaccines. PICV is a non-pathogenic arenavirus with a bi-segmented RNA genome. The proposal exploits a recombinant PICV engineered with three RNA segments, rP18tri, which can encode two additional open-reading frames (ORFs) to express antigens. The rP18tri platform is safe, versatile and induces balanced antibody and T cell responses. Moreover, the rP18tri platform is simple to modify to produce a variety of multivalent antigens, which enables rapid analysis of candidates to identify those antigens that induce the greatest protection. The proposed research will test the hypothesis that optimized multivalent antigens delivered intranasally via the rP18tri viral vector platform will induce robust protective immunity against pulmonary Mtb infection. Preliminary data from proof-of-concept studies establish that rP18tri-based TB vaccines can be efficiently generated, induce strong antigen-specific T cell immunity and protect against pulmonary Mtb infection in a mouse aerosol challenge model. In this R21 proposal, we will generate additional rP18tri vector-based multivalent TB vaccine candidates with novel immunogens (Aim 1), evaluate antibody as well as systemic and lung tissue-resident T cell responses induced by these vaccines in mice (Aim 2), and assess the efficacy of these vaccines for prevention of Mtb infection in a mouse model (Aim 3). The study is significant because it is expected to produce at least one viral vectored multivalent TB vaccine candidate with demonstrated safety and efficacy in mice to be advanced to the next phases of preclinical and clinical evaluations. The study is also expected to generate new knowledge on protective immunity induced by novel Mtb antigens, which will guide the design of next generation TB vaccines, and to advance development of the PICV vector platform, which will expand the toolbox for fighting infectious diseases.