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.

Public Health Relevance

We anticipate that our novel phage-based preparation (ShigActive?) will reduce the risk of diseases due to consuming foods or water contaminated with Shigella spp. This approach is expected to have a significant positive public health impact in reducing worldwide morbidity and mortality due to Shigella infections of which there are ~125 million worldwide cases of shigellosis and ~14,000 deaths annually, the majority in children under the age of 5. Moreover, success of our studies is likely to lead to the development of other phage-based products for many other gastrointestinal diseases of bacterial etiology, including those having epidemic potential (e.g., cholera).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1)
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Mills, Melody
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Intralytix, Inc.
United States
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