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.

项目摘要 霍乱是由细菌弧菌霍乱引起的一种急性和严重疾病，主要是散布的 由于缺乏适当的卫生基础设施，通过受污染的水源。世界健康 组织估计，全球至少有300万例案件，其中40％被传播 通过家庭传播。当前的预防方法，例如口服霍乱疫苗（OCV）和水， 卫生和卫生（WASH）活动需要大量资源和效力时间投资， 但是霍乱患者的家庭接触经常出现霍乱症状 病人生病。此外，由于广泛的范围，不建议使用预防性抗生素 抗性和营养不良的已知负面后果。迫切需要开发目标 临床干预以防止使用快速预防治疗的霍乱社区传播。 phagepro 旨在通过其第一个预言VCTM（PVC）来填补这一空白。 PVC是一种口服的噬菌体 （噬菌体）由颤音iCP1，ICP2和ICP3组成的鸡尾酒。 在此阶段II SBIR提案中，我们旨在进一步开发PVC作为现实世界中部署的一部分 包括WASH和OCV活动在内的霍乱工具包。首先，我们旨在测试PVC的共同管理 OCV，特别是因为世卫组织全球霍乱控制工作队（GTFCC）建议国家 霍乱控制计划（NCCP）朝着整合服务以减少后勤负担和成本。在 此外，大多数接受采访的利益相关者表示，整体方法对于霍乱控制至关重要。 其次，我们已经确定冷链依赖是OCV运动成本的主要贡献者。所以， 我们的目标是建立我们的I阶段STTR成功，以在固体剂量配方中开发PVC。这将增加 PVC在热和潮湿环境中的稳定性，使健康部以库存PVC内部和 在不使用冷链的情况下将其分发到已鉴定的霍乱热点。这种机制将增加及时性 霍乱爆发反应，该反应已被确定为控制两者的爆发的关键因素 地方性和非流行环境。第三，我们旨在优化PVC中的噬菌体比率，以最有效地杀死 V.霍乱的循环菌株。我们将从南亚最近的流行病中收集96种临床分离株和 在过去的三年中，非洲以确定宿主范围的覆盖范围。此外，我们将优化噬菌体的比率 2代表性的临床分离株可最大程度地减少小鼠中的霍乱弧菌定植。最后，我们将建立一个职位 - 暴露，症状前兔模型，以更好地模拟高风险时期HCS的临床环境 并证明PVC可以有效防止症状发作。 在第二阶段的成功结论中，我们将拥有PVC的固体剂量配方，这是有效的 在霍乱的既定家庭传播模型中防止霍乱症状的发作。未来 投资和非债券资金将资助临床监视研究，GMP制造进行临床试验， 以及人类的第一个试验，以证明临床效果证明。