Developing a Scalable Manufacturing Process for an Oral Bacteriophage Product that Prevents Cholera

开发预防霍乱的口服噬菌体产品的可扩展制造工艺

• 批准号: 10086723
• 负责人: Andrew Camilli
• 金额: $ 5.5万
• 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 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10086723
• 关键词: Acute; Adult; Animal Model; Animals; Antibiotics; Antigens; Bacteria; Bacteriophages; Businesses; Cholera; Cholera Toxin; Cholera Vaccine; Clinical; Communities; Contracts; Country; Cyclic GMP; Data; Disease; Dose; Ensure; Epidemic; Frequencies; Funding; Genes; Genome; Genomics; Goals; Growth; Household; Infant; Infection; Infrastructure; Intervention; Investments; Lipopolysaccharides; Measures; Membrane Proteins; Methods; Mus; Mutate; Names; Nature; Oral; Oral Administration; Oryctolagus cuniculus; Pathogenesis; Patients; Phase; Phase I Clinical Trials; Phenotype; Poverty; Prevention; Preventive; Production; Prophylactic treatment; Protocols documentation; Refrigeration; Reproducibility; Resistance; Resources; Safety; Sampling; Sanitation; Scheme; Seeds; Small Business Technology Transfer Research; Small Intestines; Source; Symptoms; Temperature; Testing; Time; Universities; Vaccination; Variant; Vibrio cholerae; Virulence; Virulent; World Health Organization; base; cGMP production; clinical development; contaminated water; diarrheal disease; dysbiosis; experience; infection risk; innovation; large scale production; manufacturing process; medical schools; member; milliliter; novel; preclinical study; prevent; receptor; side effect; success; systemic toxicity; 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 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. The goal of the proposed studies is to demonstrate feasibility of developing our phage-based clinical intervention, ProphaLytic-VC, to prevent the community spread of cholera. ProphaLytic-VC is an orally administered cocktail of three different phages known as ICP1, ICP2, and ICP3. To date, these are the only three virulent phages found in association with epidemic strains of cholera. Detailed genomic and phenotypic characterization each of the phages has been conducted by the academic partner, resulting in genome sequences, annotation, and identification of the host receptors. The combination of the three has been evaluated to demonstrate potency in reducing colonization of V. cholerae and prevention of cholera symptoms in two animal models of V. cholerae colonization and pathogenesis. Here, we propose studies to optimize a robust and scalable manufacturing process for ProphaLytic-VC, as there is currently little manufacturing experience in the USA due to the novel nature of the product. We will construct two phage production strains, develop a scalable phage production and purification scheme, and evaluate any potential local of systemic toxicity. At the successful conclusion of Phase I, we will have a resultant Master Phage Stock (MPS) of ProphaLytic-VC from an optimized large-scale production scheme that is potent against V. cholerae and safe with repeated oral administration. STTR Phase II funding will be used to fund further activities to generate a working phage seed stock from the MPS to proceed with a Phase I clinical trial.

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。目前的预防方法需要大量的资源投资， 不过，与霍乱病人有家居接触的人士，往往会出现两至三个霍乱病征， 在第一个病人生病后的几天。此外，不建议预防性使用抗生素 由于广泛的耐药性和已知的生态失调的负面后果。迫切需要 制定有针对性的临床干预措施，使用快速预防剂预防霍乱的社区传播 治疗所提出的研究的目标是证明开发我们的基于噬菌体的临床治疗的可行性。 预防性干预，即预防性VC，以防止霍乱的社区传播。ProphaLytic-VC是一种口服 三种不同的药物的混合物，称为ICP 1，ICP 2和ICP 3。到目前为止，这些是唯一的 发现的与霍乱流行株有关的三种有毒的细菌。详细的基因组和表型 每一个基因组的特征都是由学术合作伙伴进行的， 序列、注释和宿主受体的鉴定。这三者的结合， 评价以证明减少霍乱弧菌定殖和预防霍乱症状的效力 在两种动物模型的霍乱弧菌定植和发病机制。在这里，我们提出了研究，以优化一个 ProphaLytic-VC的稳健和可扩展的生产工艺，因为目前几乎没有生产 由于产品的新颖性，在美国的经验。我们将构建两个噬菌体生产菌株， 开发可扩展的噬菌体生产和纯化方案，并评估任何潜在的局部或系统性 毒性在第一阶段成功结束时，我们将得到的主噬菌体储备（MPS）为 ProphaLytic-VC来自优化的大规模生产方案，对霍乱弧菌有效且安全 反复口服给药。STTR第二阶段的资金将用于资助进一步的活动， 来自MPS的工作噬菌体种子储备以进行I期临床试验。