Vaccination Strategies for Primary and Latent Pulmonary TB

原发性和潜伏性肺结核的疫苗接种策略

• 批准号: 6781599
• 负责人: ALISTAIR John RAMSAY
• 金额: $ 37.52万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781599
• 关键词: Poxviridae; bacterial genetics; clinical research; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; immune response; immunomagnetic separation; immunoprecipitation; inhalation drug administration; interleukin 15; laboratory mouse; latent bacterial disease; mucosal immunity; nucleic acid sequence; respiratory infections; tuberculosis; vaccine development; vector vaccine

Tuberculosis (TB) is the most frequent cause of death from a single infectious agent. While active disease results from about 5% of exposures, most develop a 'latent' infection without symptoms. Most cases of recurrent TB result from 'reactivation' of such infections, although exogenous re-infection is a significant factor in endemic regions, calling into question the efficacy of 'naturally-acquired' immunity. Live Mycobacterium bovis bacillus Calmette-Guerin (BCG) is the only vaccine currently available. While protective in children, it has had negligible impact on the global Tb epidemic and is unsafe in immunodeficient individuals. We have recently shown that consecutive immunization with DNA vaccines and attenuated fowlpoxvirus (FPV) vectors encoding similar model vaccine antigens generates high levels of antigen-specific, interferon-gamma-secreting CD4+ and CD8+ T cells that persist in vivo for at least 6 months and, importantly, exhibit markedly increased sensitivity for the immunizing antigen. In terms of T cell memory, antigen challenge leads to rapid expansion of systemic and mucosal T cell effectors in DNA/FPV prime-boosted animals, reaching levels as high as 30% of total T cell numbers. The latter may be particularly important in pulmonary TB, where little attention has been paid to local immune responses. The primary aim of this proposal is test the hypothesis that prime-boost vaccination-induced T cell responses will control primary infection and reactivation of latent TB infection. Our goal is to generate protective T cell responses in both systemic and mucosal (pulmonary) tissues against key mycobacterial antigens expressed in acute and latent stages of infection. Specifically, we will determine protective efficacy of systemic (IM) prime-boosting against (i) acute infection following low-close aerosol challenge of vaccinated mice with M. tuberculosis and (ii) reactivation in a murine model of latent TB disease. We will also (iii) study the protective capacity of our prime-boost vaccines when given mucosally (IN) and will characterize systemic and mucosal (pulmonary) CD4+ and CD8+ T cell responses in each of these models. Codon optimization of mycobacterial genes expressed in our vaccines and co-delivery of IL-15 genes will be used in attempts to further enhance the magnitude and memory of T cell responses. The capacity of this approach to generate strong, sustained Th1-type CD4+ and CD8+ T cell responses is particularly attractive in the context of TB and HIV infection, where maintenance of Th1 responses is critical for protective immunity.

结核病（TB）是单个感染剂最常见的死亡原因。虽然大约5％的暴露导致活性疾病导致，但大多数人会出现“潜在”感染而没有症状。大多数复发性结核病病例是由于这种感染的“重新激活”导致的，尽管外源性重新感染是地方性区域的重要因素，却质疑“自然获得”免疫的功效。实时分枝杆菌牛芽孢杆菌Calmette-Goerin（BCG）是目前唯一可用的疫苗。尽管儿童保护性，但对全球结核病流行的影响却忽略不计，并且在免疫缺陷的个体中不安全。我们最近表明，用DNA疫苗和减弱的Fowlpoxvirus（FPV）载体连续免疫，编码相似的模型疫苗抗原会产生高水平的抗原特异性，干扰素分泌CD4+和CD8+ T细胞，至少在6个月和6个月内持续6个月，以及在体内持续6个月，以及活体内。 重要的是，对免疫抗原的敏感性显着提高。在T细胞记忆方面，抗原挑战会导致DNA/FPV促进动物的全身和粘膜T细胞效应子快速扩张，达到总T细胞数量的30％。后者在肺结核中可能尤其重要，在肺结核中，很少关注局部免疫反应。该提案的主要目的是检验以下假设：促进疫苗接种诱导的T细胞反应将控制主要感染和潜在TB感染的重新激活。我们的目标是针对在急性和潜在感染阶段表达的关键分枝杆菌抗原，在全身和粘膜（肺）组织中产生保护性T细胞反应。具体而言，我们将确定全身性（IM）促进的保护性疗效 反对（i）在潜伏性结核病的鼠模型中对疫苗接种小鼠的低关闭气溶胶挑战和（ii）重新激活的急性感染。我们还将（iii）研究粘液（IN）时素促进疫苗的保护能力，并将表征每个模型中的系统性和粘膜（肺）CD4+和CD8+ T细胞反应。在我们的疫苗中表达的分枝杆菌基因和IL-15基因共递送的密码子优化将用于进一步增强T细胞反应的大小和记忆。这种方法产生强大，持续的能力 在TB和HIV感染的背景下，Th1型CD4+和CD8+ T细胞反应特别有吸引力，在TB和HIV感染的情况下，TH1反应的维持对于保护性免疫至关重要。