Shigella dysenteriae vaccine construction

痢疾志贺氏菌疫苗的构建

• 批准号: 7241472
• 负责人: Eileen M. Barry
• 金额: $ 36.05万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241472
• 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; Facility Construction Funding Category; Food; Generations; Genes; Genetic Techniques; Human Volunteers; Immune response; Immunity; Immunization; In Vitro; Lead; Life; Modeling; Modification; Molecular Genetics; Mutation; Operon; Organism; Outcome; Performance; Plasmids; Population; Predictive Value; Production; Prophylactic treatment; Range; 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; neutralizing antibody; oral vaccine; pathogen; pre-clinical; programs; promoter; prophylactic; response; technique development; tool; 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（由申请人提供）：1型志贺氏痢疾菌是最可怕的B类优先制剂之一，因为它在低剂量下具有高传染性，严重的疾病后遗症，并且能够在幼稚人群中引起爆炸性流行。目前还没有预防性疫苗或特异性治疗方法来预防这种病原体引起的疾病，而且针对大多数临床分离株的治疗选择有限，这些分离株越来越具有多重抗生素耐药性。1型痢疾链球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这种有机体没有免疫力的人群广泛的严重疾病和死亡。最近对福氏志贺氏菌减毒株的临床试验加强了志贺氏菌活疫苗候选株的安全性和有效性，并证实了guaBA、set和sen基因突变的减毒能力。这些数据为在消除志贺毒素活性的基础上，结合这些突变，合理设计一系列减毒痢疾链球菌活疫苗株提供了一种策略。此外，通过在这些减毒菌株中插入一个驱动志贺毒素B亚基表达的组成启动子，可以激发志贺毒素中和免疫反应，并提供保护，不仅可以抵抗痢疾杆菌，还可以抵抗其他产生志贺毒素的病原体。利用我们收集的已知临床结果的弗氏沙门氏菌疫苗菌株，我们建议修改动物和体外试验，以提高在临床前水平区分菌株差异的敏感性。精细化的分析将允许对后续临床表现有更大的预测能力，从而加速最有希望的候选菌株进入临床试验和生产。然后，这些减毒活株可用于表达来自其他优先病原体的保护性抗原或表位。我们将设计系统，从稳定的质粒结构中表达炭疽杆菌的PA，染色体整合，并通过与ClyA融合以分泌形式表达。相关性：这些研究将产生一系列志贺菌痢疾减毒活疫苗候选物，以推进临床试验，并用于开发多价口服疫苗，以预防多种重点病原体疾病，这将有助于保护公民免受潜在的生物威胁。