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.

项目概要 霍乱是一种由霍乱弧菌引起的急性严重疾病，主要传播 由于缺乏足够的卫生基础设施，水源受到污染。世界卫生 该组织估计全球每年至少有 300 万例病例，其中 40% 是传播病例 通过家庭传播。目前的预防方法，例如口服霍乱疫苗（OCV）和水， 环境卫生和个人卫生 (WASH) 运动需要投入大量资源和时间才能取得成效， 但霍乱患者的家庭接触者通常在初次发病两到三天后出现霍乱症状 病人生病了。此外，由于抗生素的广泛使用，不建议预防性使用抗生素。 抵抗力和生态失调的已知负面后果。迫切需要制定有针对性的 使用快速预防性治疗来预防霍乱社区传播的临床干预。噬菌体Pro 旨在通过其首款产品 ProphaLytic-VcTM (PVC) 来填补这一空白。 PVC是一种口服噬菌体 （噬菌体）混合物由噬菌体 ICP1、ICP2 和 ICP3 组成。 在此第二阶段 SBIR 提案中，我们的目标是进一步开发 PVC 以在现实环境中部署，作为一部分 包括 WASH 和 OCV 活动的霍乱工具包。首先，我们的目标是测试 PVC 与 OCV，特别是世界卫生组织全球霍乱控制工作组 (GTFCC) 建议国家 霍乱控制计划 (NCCP) 致力于整合服务，以减少后勤负担和成本。在 此外，大多数受访利益攸关方表示，整体方法对于控制霍乱至关重要。 其次，我们发现冷链依赖是 OCV 活动成本的一个主要因素。所以， 我们的目标是在第一阶段 STTR 成功的基础上开发固体制剂中的 PVC。这会增加 PVC 在炎热和潮湿环境中的稳定性，使卫生部能够在国内和国外储存 PVC 在不使用冷链的情况下分发到已确定的霍乱热点地区。该机制将提高时效性 霍乱疫情应对措施已被确定为控制霍乱疫情的关键因素 流行和非流行环境。第三，我们的目标是优化 PVC 中的噬菌体比例，以最有效地杀死噬菌体 霍乱弧菌的流行菌株。我们将从南亚和南亚地区近期流行病中收集96株临床分离株 非洲过去3年确定的寄主范围覆盖范围。此外，我们将优化噬菌体的比例 2 种代表性临床分离株可最大程度地减少霍乱弧菌在小鼠体内的定植。最后，我们将建立一个后 暴露、症状前兔子模型，以更好地模拟高危期 HC 的临床环境 并证明PVC可以有效预防症状的发生。 在第二阶段成功结束时，我们将拥有一种 PVC 固体制剂，可有效 在已建立的霍乱家庭传播模型中预防霍乱症状的出现。未来 投资和非稀释资金将资助临床监测研究、临床试验的 GMP 生产、 以及首次人体试验以证明临床功效。