Bacteriophage-based approach for managing Shigella infections

基于噬菌体的志贺氏菌感染管理方法

• 批准号: 10624218
• 负责人: Wilbur H. Chen
• 金额: $ 117.26万
• 依托单位: INTRALYTIX, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624218
• 关键词: Age; Antibiotic Resistance; Antibiotics; Bacterial Infections; Bacteriophages; Bioinformatics; Biological Products; Blood; Cessation of life; Child; Cholera; Clinical; Clinical Trials; Communicable Diseases; Control Groups; Cyclic GMP; Data; Developing Countries; Development; Development Plans; Diarrhea; Diarrheagenic E. coli; Digestive System Disorders; Disease; Disease Outbreaks; Dose; Double-Blind Method; Ensure; Etiology; Evaluation; FDA approved; Feces; Fever; Food; Food Contamination; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal tract structure; Goals; Good Clinical Practice; Guidelines; Human; Incidence; Infection; Inpatients; Institutional Review Boards; Lactoferrin; Legal; Lytic; Maryland; Measures; Medical; Medical center; Modeling; Modernization; Monitor; Morbidity - disease rate; Mucosal Immune Responses; Nausea; New York; Oral Administration; Outpatients; Phase; Placebo Control; Placebos; Preparation; Prevalence; Process; Protocols documentation; Public Health; Randomized; Regulation; Research; Resources; Risk Reduction; Safety; Series; Serious Adverse Event; Severities; Sexual Transmission; Shigella; Shigella Infections; Shigella flexneri; Signs and Symptoms; Techniques; Treatment Protocols; Universities; Vaccines; Vibrio cholerae; beneficial microorganism; clinical application; contaminated water; data management; disorder risk; efficacy evaluation; efficacy trial; enteric pathogen; epidemic potential; fecal microbiome; follow-up; food consumption; gut microbiota; human morbidity; human mortality; innovation; manufacture; medical schools; microbiome; microbiota; mortality; next generation sequencing; novel; pathogenic bacteria; phase I trial; pre-Investigational New Drug meeting; prevent; resistant Shigella; resistant strain; safety assessment; success; technology platform; tool; vaccine development

ABSTRACT Bacterial diseases of the gastrointestinal (GI) tract continue to be a major worldwide cause of human morbidity and mortality. Among various enteric pathogens, Shigella spp. are some of the most common and deadly bacterial pathogens. They are responsible for ~125 million worldwide cases of shigellosis and ~14,000 deaths annually, the majority in children under the age of 5 and occurring in developing countries [1-3]. Preventing and treating shigellosis with conventional tools (e.g., vaccines and antibiotics) has proven to be very difficult, and the increasing prevalence of multi-antibiotic-resistant Shigella strains [4-7] creates the alarming possibility that these already staggering morbidity and mortality rates may further increase. The CDC [6] and WHO [7] have recently emphasized the threat of antibiotic resistant Shigella, and is underscored further by the increasing prevalence of antibiotic resistant Shigella in food [4], occurrence through sexual transmission [5] and unusually large outbreaks [8]. Therefore, alternative approaches for reducing the incidence and severity of Shigella infections are urgently needed. Ideally, these approaches will be affordable, so that they can be widely distributed in developing countries where resources are scarce and Shigella infections are a significant public health concern. They also should be non-antibiotic-based, so their continued use will not promote the emergence of antibiotic-resistant strains of Shigella or other enteric pathogens. We believe that bacteriophages offer one such approach. Lytic bacteriophages present a platform technology which can be used to develop a series of products for the treatment of various infectious diseases of bacterial etiology. In developing this platform technology for human clinical applications and integrating it into modern medical practices, we focus here on evaluating the safety and efficacy of our Shigella phage preparation (ShigActive™) in Phase 1/2a human clinical trials. The aims of this proposal are to: 1) manufacture the ShigActive™ clinical trial material; 2) set the regulatory framework for concurrence and approval by regulatory entities; and 3) perform an FDA-approved proof-of-concept Phase 1 safety and Phase 2a efficacy trial using a controlled human infection model of shigellosis. This study will also generate novel, preliminary microbiome data of bacteriophage interaction with normal gut microbiota. This will be the first clinical trial of a bacteriophage preparation for managing Shigella infections conducted under FDA guidelines. If successful, our studies here will provide an innovative, safe, and effective approach for managing Shigella infections. Moreover, they also will provide critical groundwork for developing additional phage preparations against other bacterial pathogens of concern, including Vibrio cholerae, diarrheagenic Escherichia coli, and other important bacterial agents of GI tract disease.

摘要 胃肠道细菌疾病仍然是全球人类发病的主要原因。 和死亡率。在各种肠道病原体中，志贺氏菌属(Shigella spp.)是一些最常见和最致命的 细菌病原体。它们导致全世界约1.25亿例志贺氏菌病病例和约1.4万人死亡 每年，大多数发生在发展中国家的5岁以下儿童[1-3]。预防和 用常规工具(如疫苗和抗生素)治疗志贺氏菌病已被证明是非常困难的， 多重耐药志贺氏菌菌株的日益流行[4-7]造成了令人担忧的可能性 这些已经令人震惊的发病率和死亡率可能会进一步上升。疾控中心[6]和世卫组织[7]已经 最近强调了耐药志贺氏菌的威胁，并进一步强调了越来越多的 具有抗生素耐药性的志贺氏菌在食物中的流行率[4]，通过性传播发生[5]和异常情况 大规模暴发[8]。因此，减少志贺氏菌发病率和严重程度的替代方法 感染是迫切需要的。理想情况下，这些方法将是负担得起的，因此它们可以广泛应用 分布在发展中国家，那里资源稀缺，志贺氏菌感染是一个重要的公众 健康问题。它们也不应该是以抗生素为基础的，所以继续使用它们不会促进 出现具有抗药性的志贺氏菌或其他肠道病原体。我们相信 噬菌体提供了一种这样的方法。裂解噬菌体提供了一种平台技术，可以 用于开发系列产品，用于治疗各种感染性疾病的细菌病原学。在……里面 为人类临床应用开发这一平台技术并将其融入现代医学 在实践中，我们重点评估我们的志贺氏菌噬菌体制剂(志贺氏菌活性™)的安全性和有效性。 在1/2a期人体临床试验中。本方案的目的是：1)研制高活性™临床 试验材料；2)为监管实体的同意和批准设定监管框架；以及3) 执行FDA批准的概念验证1期安全性和2a期疗效试验 志贺氏菌病人感染模型。这项研究还将产生新的、初步的微生物组数据 噬菌体与正常肠道微生物群的相互作用。这将是噬菌体的第一次临床试验。 根据FDA指南进行的志贺氏菌感染管理准备工作。如果成功，我们在这里的研究 将为控制志贺氏菌感染提供一种创新、安全和有效的方法。此外，他们还 将为开发更多针对其他细菌病原体的噬菌体制剂提供关键基础 令人关注的，包括霍乱弧菌、致泻性大肠杆菌和其他重要的胃肠道细菌 肠道疾病。