Immuno-Prophylaxis-Therapy & Diagnosis of Tularemia

描述（由申请人提供）： 该合作研究计划的主要目标是：（1）开发一种候选疫苗，以预防吸入性土拉菌病（由土拉弗朗西斯菌引起）;（2）开发一种用于被动免疫的多克隆抗体库，以改善或预防由土拉弗朗西斯菌引起的急性疾病。通过吸入途径获得的土拉菌;（3）开发诊断系统以检测F.使用免疫化学和/或基因扩增方法检测临床样品和环境中的土拉菌。 在项目1中，我们将制备并在实验系统中使用F.土拉菌脂多糖衍生的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募集T细胞，以帮助增强免疫应答。我们还将创建两种糖原型的肽替代物（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F.土拉热。 在项目2中，我们将设计抗F.土拉菌病，并检查被动给药在预防和治疗实验诱导的吸入性土拉菌病中的功效。 我们将使用广泛定向的多克隆抗体来确定总体功效，使用耗尽推定的破坏性（阻断）抗体的文库，并产生针对O-多糖的单特异性多克隆抗体来被动免疫小鼠，并评估对F.土拉热。 在项目3中，我们将开发三种诊断系统，利用基因扩增和免疫化学检测，检测F。临床和环境标本中的土拉菌。转录介导的扩增（TMA）检测将被开发来检测F。用于检测呼吸道分泌物中的土拉菌，以及用于检测呼吸道分泌物和尿液中的弗朗西斯菌抗原以及用于监测环境空气样品的免疫化学测试。

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.