Glanders Vaccine Developement

描述(由申请人提供)： 我们广泛而长期的目标是开发预防由马来伯克霍尔德氏菌引起的扁桃体和由假鼻疽引起的类鼻疽病的人类疫苗。在目前拟议的研究中，我们将检查小动物和马对马雷氏杆菌和伪鼻疽杆菌候选疫苗的免疫反应，并将在挑战研究中确定免疫治疗干预的有效性，目的是制定计划，将结果推广到人类疫苗。正在评估的主要假设是，免疫治疗干预是预防由马来杆菌引起的腺体和预防由密切相关的假鼻疽引起的类鼻疽病的可行方法。在过去的几年里，我们在确定马利氏杆菌和假鼻疽杆菌的毒力决定因素方面取得了重大进展，我们假设它们将是结合疫苗的优秀候选成分。特别值得注意的是，这两种生物的表面都存在两种多糖结构，这两种结构对这两种生物的毒力都是至关重要的。它们是细胞外多糖胶囊(CPS)和脂多糖O抗原(OPS)。我们建议将CPS和OPS多糖偶联到六种载体蛋白上，这些载体蛋白被证明或预测在假鼻疽杆菌和马来杆菌的致病过程中发挥重要作用。CPS和OPS还将与重组外毒素A结合，重组外毒素A是一种已被证明有效的多糖基疫苗载体蛋白。我们相信，这一策略将确定一种疫苗，该疫苗将在小鼠感染模型中保护马来杆菌的攻击，并在作为该有机体的自然宿主的马中保护马来杆菌的攻击。如果被证明在预防扁桃体方面是成功的，这种疫苗将随后用于人体试验，以调查澳大利亚和泰国对类鼻疽病的保护作用。我们的具体目标是：1.评价CPS和OPS对载体蛋白偶联的小鼠和马的免疫应答。2.在BALB/c小鼠感染模型中，检测结合载体蛋白的CPS和OPS对马来芽胞杆菌攻击的保护作用。3.验证CPS和OPS结合物对BALB/c小鼠有保护作用的假说也能保护马免受马来芽胞杆菌攻击。我们认为，免疫治疗干预是预防由马来杆菌引起的扁桃体和预防由密切相关的假鼻疽引起的类鼻疽病的一种可行的方法。由于马利氏杆菌和假鼻疽杆菌作为生物恐怖主义的代理人具有重要意义(B类，美国疾病控制中心)和生物战，有效疫苗的开发尤其令人关注。疫苗还将具有相当大的多用途潜力，因为这些微生物引起的疾病在世界各地区被公认为新出现的传染病。

DESCRIPTION (provided by applicant): Our broad, long-term objectives are to develop human vaccines for the prevention of glanders caused by Burkholderia mallei, and for melioidosis caused by B. pseudomallei. In the currently proposed studies, we will examine the immune response to B. mallei and B. pseudomallei vaccine candidates in small animals and in the horse, and we will determine the efficacy of immunotherapeutic interventions in challenge studies with an aim toward developing plans for extending the results to a human vaccine. The major hypothesis being evaluated is that immunotherapeutic intervention is a viable approach for the prevention of glanders caused by B. mallei and for the prevention of melioidosis caused by the closely related organism, B. pseudomallei. We have made significant progress in the last number of years in the identification of the virulence determinants of B. mallei and B. pseudomallei which we hypothesize will be excellent candidates as components of conjugate vaccines. Of particular note are two polysaccharide structures present on the surface of both of these organisms which are critical for the virulence of both of these. These are an extracellular polysaccharide capsule (CPS) and lipopolysaccharide O-antigen (OPS). We propose to conjugate the CPS and OPS polysaccharides to six carrier proteins shown or predicted to play important roles in pathogenesis by B. pseudomallei and B. mallei. CPS and OPS will also be conjugated to recombinant exotoxin A, a proven efficacious carrier protein of polysaccharide-based vaccines. We believe that this strategy will identify a vaccine that will protect against B. mallei challenge in a mouse model of infection as well as against B. mallei challenge in the horse which is the natural host for the organism. If shown to be successful in preventing glanders, this vaccine will be subsequently used in human trials to investigate protection against melioidosis in Australia and Thailand. Our specific aims are: 1. To evaluate the immune response to CPS and OPS conjugated to the carrier proteins in mice and in the horse. 2. To determine the ability of CPS and OPS conjugated to the carrier proteins to protect against B. mallei challenge in a BALB/c mouse model of infection. 3. To test the hypothesis that CPS and OPS conjugates which are protective in BALB/c mice will also protect the horse against B. mallei challenge. We believe that immunotherapeutic intervention is a viable approach for the prevention of glanders caused by B. mallei and for the prevention of melioidosis caused by the closely related organism, B. pseudomallei. Since B. mallei and B. pseudomallei are of significance as agents of bioterrorism (Category B, Centers for Disease Control, U.S.) and biological warfare, the development of effective vaccines are of particular concern. Vaccines will also have considerable multi-use potential since the diseases caused by these organisms are recognized as emerging infectious diseases in various areas of the world.