Glanders Vaccine Developement

鼻疽疫苗开发

• 批准号: 8103209
• 负责人: Donald E. WOODS
• 金额: $ 6.17万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103209
• 关键词: 3-Dimensional; Animals; Antibody Formation; Area; Australia; Bacterial Adhesins; Biological Warfare; Bioterrorism; Burkholderia mallei; Burkholderia pseudomallei; Carrier Proteins; Categories; Centers for Disease Control and Prevention (U.S.); Conjugate Vaccines; DCNU; Development; Disaccharides; Disease; Emerging Communicable Diseases; Epithelial Cells; Equus caballus; Exotoxins; Family; Glanders; Human; Immune response; Immunotherapeutic agent; Inbred BALB C Mice; Infection; Intervention; Lipopolysaccharides; Malleus; Melioidosis; Modeling; Mus; Needles; O Antigens; Organism; Pathogenesis; Play; Polysaccharides; Positioning Attribute; Prevention; Prevention approach; Proteins; Recombinants; Role; Serum; Structure; Surface; Surface Antigens; System; Testing; Thailand; Vaccines; Virulence; base; capsule; extracellular; member; mouse model; prevent; vaccine candidate

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.

描述（由申请人提供）： 我们广泛的长期目标是开发人类疫苗，以预防由Burkholderia Mallei引起的腺体，以及由B. pseudomallei引起的Melioidosis。在目前提出的研究中，我们将检查对小动物和马中候选疫苗疫苗的免疫反应，我们将确定挑战研究中免疫治疗干预措施的功效，目的是为了开发将结果扩展到人类疫苗的计划。评估的主要假设是，免疫治疗干预是预防由麦芽芽孢杆菌引起的腺体和预防由密切相关的有机体引起的梅尔细胞胞病症的可行方法。我们在最后几年中取得了重大进展，以鉴定马利芽孢杆菌和假单胞菌的毒力决定因素，我们认为这将是出色的候选者作为结合疫苗的组成部分。特别值得注意的是，这两个生物的表面上存在两个多糖结构，这对于这两种生物的毒力至关重要。这些是细胞外多糖胶囊（CPS）和脂多糖O-抗原（OPS）。我们建议将CPS和OPS多糖与六种或预测的六种载体蛋白结合在一起，从而通过B. pseudomallei和B. mallei在发病机理中起重要作用。 CPS和OPS也将被缀合与重组外毒素A，这是一种基于多糖的疫苗的有效载体蛋白。我们认为，该策略将确定一种疫苗，该疫苗将在小鼠感染模型中预防马利芽孢杆菌挑战，并在马匹中反对马利芽孢杆菌挑战，这是生物体的天然宿主。如果证明在预防腺体方面取得了成功，该疫苗将随后在人体试验中用于研究澳大利亚和泰国的黑胶病的保护。我们的具体目的是：1。评估对CPS的免疫反应和对小鼠和马中载体蛋白结合的OPS的免疫反应。 2。确定在BALB/C小鼠感染模型中，与载体蛋白相结合的CP和OPS防止B. mallei挑战的能力。 3。为了测试以下假设：在BALB/C小鼠中具有保护性的CP和OPS共轭物也将保护马匹攻击Mallei B. Mallei挑战。我们认为，免疫治疗干预是预防由麦芽芽孢杆菌引起的腺体和预防由密切相关的有机体B. pseudomallei引起的粉刺的可行方法。由于B. Mallei和B. pseudomallei是生物恐怖主义的药物（B类，疾病控制中心，美国）和生物战的重要性，因此特别关注有效疫苗的开发。疫苗也将具有巨大的多用途潜力，因为这些生物引起的疾病被认为是世界各地的新兴传染病。

项目成果

Capsule influences the deposition of critical complement C3 levels required for the killing of Burkholderia pseudomallei via NADPH-oxidase induction by human neutrophils.

• DOI: 10.1371/journal.pone.0052276
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Woodman ME;Worth RG;Wooten RM
• 通讯作者: Wooten RM