Bacteriophage-based approach for managing Shigella infections

摘要 胃肠道的细菌性疾病仍然是世界范围内人类发病的主要原因 and mortality.在各种肠道病原体中，志贺氏菌属（Shigella spp.）是最常见和最致命的 细菌病原体它们造成了全世界约1.25亿志贺氏菌病病例和约14，000人死亡 每年，大多数是5岁以下的儿童，发生在发展中国家[1-3]。预防和 用常规工具治疗志贺氏菌病（例如，疫苗和抗生素）已被证明是非常困难的， 多重抗生素耐药志贺菌菌株的日益流行[4-7]产生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进一步增加。[6][7][8][9][10] 最近强调了抗生素耐药性志贺氏菌的威胁，并进一步强调了日益增加的 食物中耐抗生素志贺氏菌的流行率[4]，通过性传播的发生率[5]和异常 大爆发[8]。因此，降低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于 分布在资源稀缺的发展中国家，志贺氏菌感染是一个重要的公共问题。 健康问题。它们也应该是非抗生素基础的，所以它们的继续使用不会促进 志贺氏菌或其他肠道病原体的耐药性菌株的出现。我们认为 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， 用于开发治疗各种细菌性病原感染性疾病的系列产品。在 开发用于人类临床应用的平台技术，并将其整合到现代医学中。 实践中，我们在这里重点评估我们的志贺氏菌噬菌体制剂（ShigActive™）的安全性和有效性 1/2a期人体临床试验。本提案的目的是：1）生产ShigActive™临床 试验材料; 2）制定监管机构同意和批准的监管框架;以及3） 进行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。这将是第一个噬菌体的临床试验 根据FDA指南进行的志贺氏菌感染管理的准备工作。如果成功，我们在这里的研究 将为志贺氏菌感染的管理提供一种创新、安全和有效的方法。而且他们还 将为开发针对其他细菌病原体的其他噬菌体制剂提供关键基础 包括霍乱弧菌、大肠杆菌和其他重要的胃肠道细菌因子。 道疾病。

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.