Novel multivalent viral vectored tuberculosis vaccines targeting lung immunity

针对肺部免疫的新型多价病毒载体结核疫苗

• 批准号: 10738913
• 负责人: YUYING LIANG
• 金额: $ 18.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738913
• 关键词: Adult; Advanced Development; Aerosols; Antibodies; Antibody Response; Antigens; Arenavirus; Attenuated; Bacterial Infections; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell surface; Cellular Immunity; Cessation of life; Childhood; Communicable Diseases; Complex; Data; Development; Diagnosis; Disease; Engineering; Exhibits; Genome; Goals; Immune response; Immunity; Immunologics; Individual; Infection; Knowledge; Licensing; Lung; Memory; Modeling; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Open Reading Frames; Phase; Pichinde virus; Population; Prevention; Preventive vaccine; Proteins; Pulmonary Tuberculosis; RNA; Recombinants; Research; Route; Safety; Structure of parenchyma of lung; T cell response; T-Lymphocyte; Testing; Therapeutic; Tuberculosis; Tuberculosis Vaccines; Tuberculosis diagnosis; Vaccination; Vaccine Research; Vaccines; Viral Vector; Virulent; adaptive immune response; antigen test; antigen-specific T cells; design; efficacy evaluation; fighting; immunogenicity; improved; innovation; latent infection; lifetime risk; long term memory; mouse model; next generation; novel; pathogen; preclinical evaluation; prevent; protective efficacy; reactivation from latency; recruit; research clinical testing; tuberculosis immunity; vaccine candidate; vaccine development; vaccine efficacy; vaccine platform; vaccine response; vector

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.

抽象的 标题：针对肺部免疫的新型多价病毒载体结核疫苗 结核病 (TB) 仍然是最致命的细菌感染，新增活动性结核病例超过 1000 万例 由于没有高效的治疗方法，全世界每年有 150 万人被确诊为结核病并因此死亡 预防性疫苗结核分枝杆菌 (Mtb) 也会导致约 25% 的人出现无症状潜伏感染。 世界人口中潜伏感染者一生中罹患活动性结核病的风险为 10%。 预防肺部结核分枝杆菌感染、限制潜伏期再激活和/或治疗活性结核分枝杆菌的疫苗 结核病急需R21提案的目的是探索独特的免疫学。 基于 Pichinde 病毒 (PICV) 的创新疫苗平台的特点与新型 Mtb 抗原相结合， 开发下一代结核病疫苗 PICV 是一种具有双节段 RNA 基因组的非致病性沙粒病毒。 该提案利用了由三个 RNA 片段 rP18tri 设计的重组 PICV，它可以编码两个 rP18tri 平台安全、通用且可诱导，具有额外的开放阅读框 (ORF)。 此外，rP18tri 平台易于修改以产生多种抗体和 T 细胞反应。 多价抗原，这使得能够快速分析候选物以识别那些诱导 拟议的研究将检验优化多价抗原提供的假设。 通过 rP18tri 病毒载体平台鼻内注射将诱导针对肺 Mtb 的强大保护性免疫 概念验证研究的初步数据表明，基于 rP18tri 的结核疫苗可以用于预防感染。 高效生成，诱导强抗原特异性 T 细胞免疫并预防肺部 Mtb 感染 在小鼠气溶胶挑战模型中，在这个 R21 提案中，我们将生成额外的基于 rP18tri 向量的模型。 具有新型免疫原的多价结核候选疫苗（目标 1），评估抗体以及全身和 这些疫苗在小鼠体内诱导肺组织驻留 T 细胞反应（目标 2），并评估这些疫苗的功效 在小鼠模型中预防 Mtb 感染的疫苗（目标 3）。 预计将生产至少一种已证明安全性的病毒载体多价结核候选疫苗 该研究还在小鼠中进行的疗效将进入下一阶段的临床前和临床评估。 预计将产生关于新型 Mtb 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，这将 扩大抗击传染病的工具箱。