Product optimization to commercialize an oral bacteriophage cocktail that prevents cholera in real-world settings

产品优化，以将可在现实环境中预防霍乱的口服噬菌体混合物商业化

• 批准号: 10349544
• 负责人: Andrew Camilli
• 金额: $ 97.52万
• 依托单位: PHAGEPRO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349544
• 关键词: Acute; Adult; Advisory Committees; Africa; Animals; Antibiotic Resistance; Antibiotics; Asia; Bacteria; Bacteriophages; Biological Assay; Chemoprophylaxis; Cholera; Cholera Vaccine; Climate; Clinical; Clinical Trials; Cold Chains; Collection; Communities; Contracts; Country; Dependence; Disease; Disease Outbreaks; Dose; Drug resistance; Emergency treatment; Ensure; Environment; Epidemic; Excipients; Family; Formulation; Funding; Future; Geographic Distribution; Health; Household; Hygiene; In Vitro; Individual; Infant; Infrastructure; Intervention; Interview; Investments; Logistics; Measures; Methods; Modeling; Mus; Oral; Oryctolagus cuniculus; Particle Size; Patients; Persons; Pharmaceutical Preparations; Phase; Play; Prevention; Preventive; Process; Production; Prophylactic treatment; Quality Control; Refrigeration; Resistance; Resources; Risk; Role; Sanitation; Scheme; Services; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Small Intestines; Solid; Source; Symptoms; Target Populations; Testing; Time; Vibrio cholerae; Water; World Health Organization; base; clinical efficacy; community transmission; contaminated water; cost; diarrheal disease; dosage; dysbiosis; first-in-human; high risk; holistic approach; improved; in vivo; indexing; infection risk; manufacturing process; prevent; protective efficacy; response; success; surveillance study; transmission process

Project Summary Cholera is an acute and severe disease caused by the bacterium Vibrio cholerae that is spread primarily through contaminated water sources due to a lack of adequate sanitation infrastructure. The World Health Organization estimates that there are at least 3 million cases globally per year, 40 percent of which are spread through household transmission. Current prevention methods, such as the oral cholera vaccine (OCV) and water, sanitation, and hygiene (WASH) campaigns, require significant investment of resources and time for efficacy, but household contacts of cholera patients often present with cholera symptoms two to three days after the initial patient becomes sick. In addition, the preventive use of antibiotics is not recommended due to widespread resistance and the known negative consequences of dysbiosis. There is a pressing need to develop a targeted clinical intervention to prevent the community spread of cholera using a rapid prophylactic treatment. PhagePro aims to fill this gap with its first product ProphaLytic-VcTM (PVC). PVC is an orally administered bacteriophage (phage) cocktail comprised of Vibriophages ICP1, ICP2, and ICP3. In this Phase II SBIR proposal, we aim to further develop PVC for deployment in real-world settings as part of a cholera toolkit that includes WASH and OCV campaigns. First, we aim to test co-administration of PVC with the OCV, particularly as the WHO Global Task Force on Cholera Control (GTFCC) recommends that National Cholera Control Plans (NCCP) move towards integration of services to reduce logistical burden and costs. In addition, the majority of interviewed stakeholders stated that a holistic approach is critical to cholera control. Second, we have identified that cold chain dependence is a major contributor to OCV campaign costs. Therefore, we aim to build upon our Phase I STTR success to develop PVC in a solid dosage formulation. This will increase the stability of PVC in hot and humid environments, enabling Ministries of Health to stockpile PVC in-country and distribute to identified cholera hotspots without the use of the cold chain. This mechanism will increase timeliness of the cholera outbreak response, which has been identified as the key factor in controlling an outbreak in both endemic and non-endemic settings. Third, we aim to optimize phage ratios in PVC to most effectively kill circulating strains of V. cholerae. We will collect 96 clinical isolates from recent epidemics in South Asia and Africa in the past 3 years to determine host range coverage. Additionally, we will optimize the ratio of phages on 2 representative clinical isolates to best reduce V. cholerae colonization in mice. Lastly, we will establish a post- exposure, pre-symptomatic rabbit model to better simulate clinical settings for the HCs during the high-risk period and demonstrate that PVC can effectively prevent the onset of symptoms. At the successful conclusion of Phase II, we will have a solid dosage formulation of PVC that is effective in preventing the onset of cholera symptoms in an established household transmission model for cholera. Future investments and non-dilutive funding will fund clinical surveillance studies, GMP manufacturing for clinical trials, and a first-in-human trial to demonstrate proof-of-clinical-efficacy.

项目总结