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

项目摘要 霍乱是由霍乱弧菌引起的一种急性和严重的疾病， 由于缺乏足够的卫生基础设施，这些人通过受污染的水源生活。世界卫生 该组织估计，全球每年至少有300万例病例，其中40%是传播性的。 通过家庭传播。目前的预防方法，如口服霍乱疫苗（OCV）和水， 讲卫生运动需要投入大量资源和时间才能取得成效， 但与霍乱病人有家居接触的人士，通常会在首次感染霍乱后两至三天出现霍乱征状。 病人生病了。此外，不建议预防性使用抗生素，因为 抵抗和已知的生态失调的负面后果。迫切需要制定有针对性的 采用快速预防性治疗的临床干预措施，防止霍乱在社区传播。噬菌体蛋白 旨在通过其首款产品ProphaLytic-VcTM（PVC）填补这一空白。PVC是一种口服噬菌体 （噬菌体）混合物，其包含弧菌噬菌体ICP 1、ICP 2和ICP 3。 在第二阶段SBIR提案中，我们的目标是进一步开发PVC，以便在现实环境中部署， 包括讲卫生运动和儿童接触控制运动在内的霍乱工具包。首先，我们的目标是测试PVC与 OCV，特别是世卫组织全球霍乱控制工作组（GTFCC）建议， 霍乱控制计划（NCCP）正朝着服务一体化的方向发展，以减少后勤负担和成本。在 此外，大多数受访的利益攸关方表示，采取综合办法对霍乱控制至关重要。 其次，我们已经确定，冷链依赖是OCV活动成本的主要贡献者。因此，我们认为， 我们的目标是在第一阶段STTR成功的基础上开发固体剂型的PVC。这将增加 PVC在湿热环境中的稳定性，使卫生部能够在国内储存PVC， 在不使用冷链的情况下向已确定的霍乱热点地区分发。这一机制将提高及时性 霍乱疫情应对措施，这已被确定为控制两地疫情的关键因素， 地方性和非地方性环境。第三，我们的目标是优化PVC中的噬菌体比例，以最有效地杀死 霍乱弧菌的循环菌株我们将从南亚最近的流行病中收集96株临床分离株， 非洲在过去3年中，以确定主机范围覆盖。此外，我们将优化的比例， 2种代表性临床分离株，以最好地减少小鼠中的霍乱弧菌定殖。最后，我们将设立一个职位- 暴露，症状前兔模型，以更好地模拟高风险期HC的临床环境 并证明PVC可以有效预防症状的发生。 在第二阶段的成功结束时，我们将拥有一种有效的PVC固体剂型， 在已建立的霍乱家庭传播模式中预防霍乱症状的出现。未来 投资和非稀释性资金将资助临床监测研究，用于临床试验的GMP制造， 并进行首次人体试验以证明其临床疗效。

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.