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: 10158437
• 负责人: Wilbur H. Chen
• 金额: $ 143.97万
• 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/10158437
• 关键词: Age; Antibiotic Resistance; Antibiotics; Bacterial Infections; Bacteriophages; Bioinformatics; Biological; Blood; Centers for Disease Control and Prevention (U.S.); 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; Epidemic; Etiology; Evaluation Research; FDA approved; Feces; Fever; Food; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal tract structure; Goals; Good Clinical Practice; Guidelines; Human; Incidence; Infection; Inpatients; Institutional Review Boards; Lactoferrin; Lead; Legal; Lytic; Maryland; Measures; Medical; Medical center; Modeling; Modernization; Monitor; Morbidity - disease rate; Mucosal Immune Responses; Nausea; New York; Oral; Oral Administration; Outpatients; Phase; Placebo Control; Placebos; Preparation; Prevalence; Process; Protocols documentation; Public Health; Randomized; Regulation; Resources; Safety; Series; Serious Adverse Event; Severities; Sexual Transmission; Shigella; Shigella Infections; Shigella flexneri; Signs and Symptoms; Techniques; Technology; Time; Treatment Protocols; Universities; Vaccines; Vibrio cholerae; base; beneficial microorganism; clinical application; contaminated water; data management; disorder risk; efficacy trial; enteric pathogen; fecal microbiome; follow-up; food consumption; gut microbiota; human morbidity; human mortality; innovation; medical schools; meetings; microbiome; microbiota; mortality; next generation sequencing; novel; pathogenic bacteria; phase I trial; prevent; resistant Shigella; resistant strain; safety assessment; success; 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.

抽象的 胃肠道 (GI) 细菌性疾病仍然是全球人类发病的主要原因 在各种肠道病原体中，志贺氏菌是最常见和致命的。 它们导致全球约 1.25 亿志贺氏菌病病例和约 14,000 人死亡。 每年，大多数发生在发展中国家的 5 岁以下儿童中 [1-3]。 事实证明，用传统工具（例如疫苗和抗生素）治疗志贺氏菌病非常困难，并且 多重抗生素耐药志贺氏菌菌株的日益流行 [4-7] 造成了令人震惊的可能性： CDC [6] 和 WHO [7] 已经令人震惊的发病率和死亡率可能会进一步增加。 最近强调了抗生素耐药性志贺氏菌的威胁，并通过日益增加的情况进一步强调了这一点 食品中抗生素耐药志贺氏菌的流行 [4]，通过性传播 [5] 发生且异常 因此，需要采取替代方法来降低志贺氏菌的发病率和严重程度。 理想情况下，这些方法是负担得起的，以便能够广泛推广。 分布于资源匮乏的发展中国家，志贺氏菌感染是一个重要的公共卫生问题 它们还应该不含抗生素，因此继续使用不会促进健康问题。 我们认为志贺氏菌或其他肠道病原体的抗生素耐药菌株的出现。 噬菌体提供了一种这样的方法，裂解性噬菌体提供了一种平台技术。 用于开发治疗细菌性病因的各种感染性疾病的系列产品。 开发该平台技术用于人类临床应用并将其融入现代医学 实践中，我们重点评估志贺氏菌噬菌体制剂 (ShigActive™) 的安全性和有效性 该提案的目的是： 1) 生产 ShigActive™ 临床试验。 试验材料；2) 制定监管框架以供监管机构同意和批准；以及 使用受控的方法进行 FDA 批准的概念验证 1 期安全性和 2a 期疗效试验 这项研究还将产生志贺氏菌病的新的初步微生物组数据。 噬菌体与正常肠道微生物群的相互作用这将是噬菌体的首次临床试验。 如果成功的话，我们的研究将按照 FDA 的指导方针进行。 将为管理志贺氏菌感染提供一种创新、安全、有效的方法。 将为开发针对其他细菌病原体的额外噬菌体制剂提供关键基础 值得关注的细菌，包括霍乱弧菌、致腹泻性大肠杆菌和其他重要的胃肠道细菌 道疾病。