Immuno-Prophylaxis-Therapy & Diagnosis of Tularemia

描述(由申请人提供)： 这一合作研究计划的主要目标是：(1)开发一种候选疫苗(S)，以预防吸入性图拉热(由土拉氏方济氏菌引起)；(2)开发用于被动免疫的多锥体抗体库，以缓解或预防通过吸入途径获得的图拉氏丝虫病的急性疾病；(3)开发诊断系统，利用免疫化学和/或基因扩增方法在临床标本和环境中检测图拉氏丝虫病。 在项目1中，我们将制备并用于实验系统中的候选疫苗--图拉氏狸殖吸虫脂多糖衍生的O-多糖和荚膜多糖。我们将使用结合物和临床相关的佐剂和递送系统来招募T细胞，以帮助增强免疫反应。我们还将创建这两种糖原型的多肽替代品(称为模拟物)，并将其用于免疫。将对小鼠进行免疫，以评估疫苗对抗图拉氏丝虫气雾剂攻击的效果。 在项目2中，我们将设计针对图拉氏丝虫的多克隆抗体表达文库，并检验被动给药在预防和治疗实验诱导的吸入性图拉热症方面的效果。我们将使用广泛定向的多克隆抗体来确定总体疗效，使用去除了假定的颠覆性(封闭)抗体的文库，并产生针对O-多糖的单特异性多克隆来被动免疫小鼠，并评估对图拉氏丝虫气溶胶攻击的保护作用。 在项目3中，我们将开发三种诊断系统，使用基因扩增和免疫化学检测来检测临床和环境样本中的图拉氏丝虫。将开发一种转录介导扩增(TMA)试验来检测呼吸道分泌物中的图拉氏杆菌，并开发一种免疫化学试验来检测呼吸道分泌物和尿液中的弗朗西斯氏菌抗原，并监测环境空气样本。

DESCRIPTION (provided by applicant): The major objectives of this Co-operative Research Program will be to: (1) develop a vaccine candidate(s) to protect against inhalational tularemia (caused by Francisella tularensis); (2) to develop a polyconal antibody library to be used for passive immunization to ameliorate or prevent acute illness from F. tularensis acquired by the inhalational route and (3) to develop diagnostic systems to detect F. tularensis in clinical specimens and in the environment using immunochemical and/or gene amplification methods. In Project 1, we will prepare and use as vaccine candidates in experimental systems, F. tularensis lipopolysaccharide derived O-polysaccharide and capsular polysaccharides. We will use conjugates and clinically relevant adjuvant and delivery systems to recruit T cell help to enhance immune responses. We will also create peptide surrogates (called mimics) of the two saccharide prototypes and use these for immunization. Mice will be immunized to assess vaccine efficacy against aerosol challenge with F. tularensis. In Project 2, we will design polyclonal antibody expression libraries against F. tularensis and examine the efficacy of passive administration in preventing and treating experimentally induced inhalational tularemia. We will use widely directed polyclonal antibodies to determine overall efficacy, use libraries depleted of putative subversive (blocking) antibodies and generate monospecific polyclonals directed against O-polysaccharides to passively immunize mice and assess protection from aerosol challenge with F. tularensis. In Project 3, we will develop three diagnostic systems, using gene amplification and immunochemical detection, to detect F. tularensis in clinical and environmental specimens. A transcription mediated amplification (TMA) assay will be developed to detect F. tularensis in respiratory secretions and an immunochemical test to detect Francisella antigens in respiratory secretions and urine and for monitoring environmental air samples.