Shigella dysenteriae vaccine construction

痢疾志贺氏菌疫苗的构建

• 批准号: 7628444
• 负责人: Eileen M. Barry
• 金额: $ 35.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628444
• 关键词: Animal Model; Animals; Antibiotic Resistance; Antibody Formation; Antigens; Attenuated; Automobile Driving; Bacillus anthracis; Biological Assay; Categories; Cavia; Cessation of life; Clinical; Clinical Research; Clinical Trials; Collection; Data; Development; Disease; Dose; Epidemic; Epidemiologic Studies; Epitopes; Food; Generations; Genes; Genetic Techniques; Human Volunteers; Immune response; Immunity; Immunization; Lead; Life; Modeling; Modification; Molecular Genetics; Mutation; Operon; Organism; Outcome; Performance; Plasmids; Population; Predictive Value; Production; Prophylactic treatment; Research; Research Personnel; Role; Safety; Series; Serotyping; Shiga Toxin; Shigella; Shigella Vaccines; Shigella dysenteriae; Shigella flexneri; System; Testing; Therapeutic; Toxin; Vaccines; Virulence; Virulent; Water; anthrax toxin; attenuation; base; biodefense; design; disorder prevention; expression vector; genome sequencing; immunogenic; in vitro Assay; in vitro testing; neutralizing antibody; oral vaccine; pathogen; pre-clinical; programs; promoter; prophylactic; protective efficacy; response; technique development; tool; vaccine candidate; vector

DESCRIPTION (provided by applicant): Shigella dysenteriae Type 1 is one of the most fearsome of the Category B Priority agents owing to its high infectivity at low doses, severe disease sequelae, and ability to cause explosive epidemics in naive populations. No prophylactic vaccine or specific therapy exists for prevention of disease caused by this pathogen and therapeutic options are limited against the majority of clinical isolates which are increasingly multiply antibiotic resistant. S. dysenteriae Type 1 is easily spread by tainted food or water and an intentional act of contamination could lead to widespread serious disease and death in a population with no immunity to this organism. Recent clinical trials with attenuated strains of Shigella flexneri have reinforced the safety and efficacy, of live Shigella vaccine candidates and confirmed the attenuating capacity of mutations in the guaBA, set, and sen genes. These data provide a strategy for the rational design of a series of live, attenuated S. dysenteriae vaccine strains based on a combination of these mutations in addition to elimination of shiga toxin activity. In addition, by inserting a constitutive promoter driving expression of the shiga toxin B subunit in these attenuated strains, shiga toxin neutralizing immune responses could be elicited and provide protection not only against S. dysenterae but also against other shiga toxin-producing pathogens. Using our collection of S. flexneri vaccine strains with known clinical outcomes we propose to modify animal and in vitro assays to increase the sensitivity for distinguishing differences between strains at the preclinical level. Refined assays will allow greater predictive power of subsequent clinical performance resulting in accelerated advancement of the most promising candidate strain or strains to clinical trials and production. The live attenuated strains can then be used to express protective antigens or epitopes from other priority pathogens. We will design systems for expression of PA from B. anthracis from stabilized plasmid constructs, chromosomally integrated and in secreted form by fusion to ClyA. Relevance: These studies will result in a series of live attenuated Shigella dysenteriae vaccine candidates for advancement to clinical trials and for use in the development of a multivalent, oral vaccine to protect against multiple priority agent diseases which will help protect citizens from potential biothreats.

描述（由申请方提供）：由于其在低剂量下的高感染性、严重的疾病后遗症以及在未感染人群中引起爆发性流行病的能力，1型志贺菌是B类优先病原体中最可怕的病原体之一。没有预防性疫苗或特异性疗法可用于预防由该病原体引起的疾病，并且针对大多数临床分离株的治疗选择有限，这些临床分离株越来越具有多重抗生素耐药性。S. 1型沙门氏菌很容易通过受污染的食物或水传播，故意的污染行为可能导致对该生物体没有免疫力的人群广泛传播严重疾病和死亡。最近用福氏志贺菌减毒株进行的临床试验加强了活志贺菌候选疫苗的安全性和有效性，并证实了guaBA、set和sen基因突变的减毒能力。这些数据为一系列减毒活S.除了消除滋贺毒素活性之外，还基于这些突变的组合的霍乱弧菌疫苗株。此外，通过在这些减毒菌株中插入驱动滋贺毒素B亚基表达的组成型启动子，可以引发滋贺毒素中和免疫应答，并且不仅提供针对S.志贺毒素不仅对大肠杆菌，而且对其他产生滋贺毒素的病原体也有效。使用我们的S.具有已知临床结果的弗氏疫苗株我们建议修改动物和体外测定以增加在临床前水平区分菌株之间差异的灵敏度。经过改进的检测试剂盒将提高后续临床性能的预测能力，从而加速最有希望的候选菌株进入临床试验和生产。然后，减毒活菌株可用于表达来自其他优先病原体的保护性抗原或表位。我们将设计从B表达PA的系统。炭疽杆菌，其来自稳定的质粒构建体，染色体整合并通过融合到ClyA而呈分泌形式。相关性：这些研究将产生一系列减毒志贺氏菌活疫苗候选物，用于临床试验，并用于开发多价口服疫苗，以预防多种优先病原体疾病，这将有助于保护公民免受潜在的生物威胁。