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

项目摘要 霍乱是一种急性和严重的疾病，由霍乱弧菌引起，主要传播 由于缺乏适当的卫生基础设施，受污染的水源。《世界卫生》 该组织估计，全球每年至少有300万个病例，其中40%是传播的 通过家庭传播。目前的预防方法，如口服霍乱疫苗(OCV)和水， 卫生和个人卫生(洗涤)运动需要投入大量资源和时间才能见效， 但与霍乱患者有家庭接触的人通常在最初感染霍乱后2至3天出现霍乱症状。 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。 抗药性和已知的生物失调的负面后果。迫切需要制定一种有针对性的 采用快速预防性治疗预防霍乱社区传播的临床干预措施。PhagePro 旨在通过其第一款产品ProphaLytic-VcTM(PVC)填补这一空白。聚氯乙烯是一种口服的噬菌体 (噬菌体)由噬菌体ICP1、ICP2和ICP3组成的鸡尾酒。 在此第二阶段SBIR提案中，我们的目标是进一步开发用于在现实世界环境中部署的PVC，作为 一个霍乱工具包，其中包括WASH和OCV运动。首先，我们的目标是测试聚氯乙烯与 OCV，特别是世卫组织霍乱控制全球工作组(GTFCC)建议国家 霍乱控制计划(NCCP)朝着整合服务的方向发展，以减少后勤负担和成本。在……里面 此外，大多数受访的利益攸关方表示，整体办法对霍乱控制至关重要。 其次，我们已经发现，冷链依赖是OCV活动成本的主要贡献者。因此， 我们的目标是在第一阶段STTR成功的基础上，开发固体剂量配方的聚氯乙烯。这将增加 聚氯乙烯在湿热环境中的稳定性，使卫生部能够在国内和 在不使用冷链的情况下分发到确定的霍乱热点。这一机制将增加及时性。 霍乱暴发反应，这已被确定为控制两地暴发的关键因素 地方性和非地方性环境。第三，我们的目标是优化聚氯乙烯中的噬菌体比例，以最有效地杀灭 霍乱弧菌的循环菌株。我们将从南亚和亚洲最近的疫情中收集96个临床分离株 非洲近3年来确定东道主范围的覆盖面。此外，我们还将优化噬菌体的比例 2个具有代表性的临床分离株，以最大限度地减少霍乱弧菌在小鼠体内的定植。最后，我们将设立一个职位- 暴露，症状前兔模型，更好地模拟高危期HCS的临床环境 并证明聚氯乙烯能有效地预防症状的发生。 在第二阶段的成功结束后，我们将拥有有效的聚氯乙烯固体剂量配方 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 投资和非稀释性资金将为临床监测研究、临床试验的GMP制造、 以及第一次人体试验，以证明临床疗效。

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.