Vaccination strategies against pulmonary tuberculosis

肺结核疫苗接种策略

• 批准号: 6746555
• 负责人: ALISTAIR John RAMSAY
• 金额: $ 21.3万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746555
• 关键词: Mycobacterium tuberculosis; Poxviridae; T lymphocyte; active immunization; biotechnology; disease /disorder model; immunologic memory; interleukin 15; laboratory mouse; latent bacterial disease; leukocyte activation /transformation; tuberculosis; tuberculosis vaccines; vaccine development; vector vaccine

DESCRIPTION (provided by applicant): Tuberculosis (TB) is the most frequent cause of death from a single infectious agent. Active disease follows about 5% of exposures, but most develop a 'latent' infection without symptoms that may reactivate later, particularly during immune deficiency. Live M. bovis bacillus Calmette-Guerin (BCG) is the only currently available vaccine but has had negligible impact on the global epidemic. Indeed, the rise of HIV infection has raised serious safety concerns, with disseminated infection reported in HIV-seropositives following BCG vaccination. Clearly there is an urgent need for safer, more effective vaccination for protective responses that, ideally, will prevent or contain latent TB infection. We have recently shown that consecutive immunization with DNA vaccines and attenuated fowlpoxvirus vectors encoding similar vaccine antigens generates high levels of antigen-specific, interferon-gamma-secreting CD4+ and CD8+ T cells that, importantly, exhibit markedly increased sensitivity (avidity) for the immunizing antigen. In terms of memory, antigen challenge led to rapid expansion of systemic and mucosal T cell effectors in vaccinated animals, reaching levels as high as 30% of total T cell numbers. Mucosal T cells may be particularly important in pulmonary TB, where little attention has been paid to local immune responses. Here, our primary aim is to test the hypothesis that T cell responses induced by prime-boost vaccination will control primary TB infection and the establishment or reactivation of latent infection. Our goal is to generate protective T cell responses against key antigens of M. tuberculosis (MTb) normally expressed (i) in acute infection and (ii) during progression to a nonreplicating persistent state. The latter are poorly studied but are of central importance to our proposal, since they represent novel and highly selective targets for vaccine strategies that may forestall or contain latent infection. Specifically, we will test the protective efficacy of systemic prime-boosting against (i) low-dose aerosol challenge with MTb and (ii) reactivation in murine models of latent TB disease. We will also study (iii) the protective capacity of prime-boost vaccines given mucosally and characterize systemic and mucosal (pulmonary) CD4+ and CD8+ T cell responses in these models. Co-delivery of IL-15 genes will be tested for their ability to enhance magnitude and memory of T cell immunity. The capacity of our approach to generate strong, sustained Th1-type CD4+ and CD8+ T cell responses is highly attractive in the context of TB and HIV infection, where maintenance of such responses against key proteins of MTb may be critical for protection.

描述（由申请人提供）：结核病（TB）是单个传染病药物最常见的死亡原因。活性疾病遵循约5％的暴露，但大多数会出现“潜在”感染，而没有症状可能会在以后重新激活的症状，尤其是在免疫缺陷期间。 Live M. Bovis Bacillus Calmette-Guerin（BCG）是目前唯一可用的疫苗，但对全球流行病的影响微不足道。实际上，艾滋病毒感染的兴起引起了严重的安全问题，在BCG疫苗接种后，艾滋病毒 - 呼吸诱导中报道了传播感染。显然，迫切需要采取更安全，更有效的疫苗接种，以防止或包含潜在的结核病感染。我们最近表明，用DNA疫苗连续免疫并减弱编码相似疫苗抗原的禽毒病毒载体会产生高水平的抗原特异性，干扰素分泌CD4+和CD8+ T细胞，这些细胞表现出了显着提高敏感性（actavity）的免疫化抗原，这些抗原表现出了显着提高的。在记忆方面，抗原挑战导致疫苗接种动物中系统性和粘膜T细胞效应子的快速扩张，达到了总T细胞数量的30％。粘膜T细胞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。在这里，我们的主要目的是检验以下假设：促进疫苗接种引起的T细胞反应将控制原发性结核病感染以及潜在感染的建立或重新激活。我们的目标是针对急性感染中通常表达的（i）的结核分枝杆菌（MTB）的关键抗原产生保护性T细胞反应，并且在进展为非复制持续状态的过程中（II）。后者的研究很少，但对我们的提议至关重要，因为它们代表了可能阻止或含有潜在感染的疫苗策略的新颖且高度选择性的目标。具体而言，我们将测试针对（i）对（i）对（i）对MTB低剂量气溶胶挑战和（ii）在潜在结核病模型中重新激活（ii）重新激活（ii）的保护性功效。我们还将研究（iii）在这些模型中，给定粘膜和粘膜（肺）CD4+和CD8+ T细胞反应的质量增强疫苗的保护能力。 IL-15基因的共传递将测试其增强T细胞免疫的大小和记忆的能力。在结核病和艾滋病毒感染的背景下，我们产生强，持续的Th1型CD4+和CD8+ T细胞反应的能力非常有吸引力，在这种情况下，对MTB关键蛋白的这种反应维持可能对保护至关重要。