MECHANISMS OF RESPONSE TO PULMONARY VACCINATION

肺部疫苗接种的反应机制

• 批准号: 6473253
• 负责人: Anthony James Hickey
• 金额: $ 28.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473253
• 关键词: active immunization; aerosols; guinea pigs; immunomodulators; inhalation drug administration; nonhuman therapy evaluation; tuberculosis vaccines; vaccine development

DESCRIPTION: (Provided by Applicant) Given the notorious variability in the protective efficacy of the current tuberculosis (TB) vaccine, BCG, in diverse populations around the world, there is a clear need for an improved TB vaccine. Although a major scientific effort over the past several years has produced literally hundreds of potential TB vaccine candidates, very little research has gone into alternative delivery systems and new adjuvants which will be required for purified protein or peptide vaccines. More importantly, given the pulmonary route of exposure by which most TB patients acquire their primary infection, it is surprising that little data derived regarding aerosol vaccination can be found in the recent biomedical literature. There are many reasons, a priori, to expect that direct immunization of the lung would have intrinsic advantages over parenteral routes of vaccination. Delivery of immunogens and adjuvant to the alveolar spaces using a microparticle aerosols should elicit local immune responses, which are effective at controlling the early replication of virulent Mycobacterium tuberculosis (MTB). Expertise in microparticle formulation, pulmonary aerosol delivery, a guinea pig model of low-dose pulmonary MTB and guinea pig immunology will be employed to elucidate the mechanisms by which aerosol vaccination leads to protection against virulent challenge. It is proposed that: (1) Lung delivery of immunostimulatory adjuvants (Muramyl dipeptide and trehalose dimycolate) in microparticle formulations will upregulate proinflammatory and co-stimulatory functions in resident alveolar macrophages; (2) The combination of immunogenic mycobacterial proteins with the adjuvant in microparticles will induce a strong expression of local antigen-specific T and B lymphocyte responses in the lung; (3) Aerosol vaccination with the optimal combination of protein antigen (Ag 85 complex)/adjuvant/micro-particles will protect guinea pigs against low-dose pulmonary challenge with virulent MTB. The significance of this work lies in the novelty of pulmonary vaccination for the treatment of tuberculosis and the knowledge of the immune response gained from targeted antigen delivery to the lungs.

描述：(由申请人提供)鉴于 当前结核病(TB)疫苗卡介苗在不同地区的保护效果 在世界各地的人口中，显然需要一种改进的结核病疫苗。 尽管过去几年的一项重大科学努力产生了 从字面上看，数以百计的潜在结核病疫苗候选者几乎没有研究 进入替代给药系统和需要的新佐剂 用于纯化蛋白或多肽疫苗。更重要的是，考虑到肺部 大多数结核病患者获得初次感染的接触途径， 令人惊讶的是，几乎没有关于气雾剂疫苗接种的数据可以 在最近的生物医学文献中发现。先验地说，有很多原因 预计对肺部的直接免疫将具有固有的优势 通过非肠道接种疫苗的途径。将免疫原和佐剂交付给 使用微粒气雾剂的肺泡腔应能引起局部免疫。 反应，有效地控制毒力的早期复制 结核分枝杆菌(MTB)肺微粒制剂方面的专业知识 雾化吸入低剂量肺结核杆菌豚鼠模型及豚鼠 免疫学将被用来阐明气溶胶的作用机制。 接种疫苗可以预防致命的挑战。有建议说 这是：(1)免疫刺激佐剂的肺部递送(Muramyl二肽和 微粒制剂中的海藻糖二聚氰酸酯)将上调 常驻肺泡巨噬细胞的促炎和共刺激功能； (2)免疫原性分枝杆菌蛋白与佐剂的结合 微粒会诱导局部抗原特异性T细胞和 B淋巴细胞在肺中的反应；(3)最佳气雾剂接种 蛋白质抗原(Ag85复合体)/佐剂/微粒的组合将 用强毒力结核杆菌保护豚鼠免受低剂量肺攻击。这个 这项工作的意义在于肺部疫苗接种的新颖性。 结核病的治疗和对免疫反应的了解 将抗原定向输送到肺部。