MECHANISMS OF RESPONSE TO PULMONARY VACCINATION

描述：（由申请人提供）考虑到已知的 目前的结核病（TB）疫苗BCG在不同人群中的保护效果 在世界各地的人口中，显然需要改进的结核病疫苗。 尽管在过去几年里，一项重大的科学努力已经产生了 几乎有数百种潜在的结核病疫苗候选者，很少有研究 进入替代输送系统和新的佐剂， 用于纯化的蛋白质或肽疫苗。更重要的是，考虑到肺部 大多数结核病患者获得原发感染的暴露途径， 令人惊讶的是，很少有关于气雾剂接种的数据可以被 在最近的生物医学文献中发现。有许多原因，先验， 预期肺部的直接免疫具有内在优势 而不是通过肠胃外途径接种疫苗。将免疫原和佐剂递送至 使用微粒气雾剂的肺泡空间应该引起局部免疫 反应，这是有效地控制早期复制的毒力 结核分枝杆菌（MTB）。微粒制剂、肺部 气雾剂给药、低剂量肺结核豚鼠模型和豚鼠 免疫学将被用来阐明气溶胶 疫苗接种导致对毒性攻击的保护。拟 （1）免疫刺激佐剂（胞壁酰二肽和胞壁酰肽）的肺递送 海藻糖二霉菌酸酯）将上调 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质与佐剂的组合， 微粒将诱导局部抗原特异性T细胞的强烈表达， 肺内B淋巴细胞反应;（3）用最佳剂量的 蛋白抗原（Ag 85复合物）/佐剂/微粒的组合将 保护豚鼠免受毒性MTB的低剂量肺攻击。的 这项工作的意义在于肺疫苗接种的新奇， 结核病的治疗和从结核病中获得的免疫反应知识 将抗原靶向递送至肺部。

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.