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.

项目总结 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。目前的预防方法需要投入大量的资源和 见效时间，但与霍乱患者有家庭接触的人通常出现两到三种霍乱症状 最初的病人生病后的几天内。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物失调的负面后果。有迫切的需要 制定有针对性的临床干预措施，使用快速预防措施防止霍乱的社区传播 治疗。建议研究的目的是证明我们以噬菌体为基础的临床应用的可行性。 干预，ProphaLytic-VC，以防止霍乱的社区传播。ProphaLytic-VC是一种口服 注射三种不同噬菌体的鸡尾酒，分别为ICP1、ICP2和ICP3。到目前为止，这些是唯一 与霍乱流行株有关的三个致命噬菌体。详细的基因组和表型 每一个噬菌体的特征都是由学术伙伴进行的，结果是基因组 宿主受体的序列、注释和鉴定。这三者的结合一直是 评估在减少霍乱弧菌定植和预防霍乱症状方面的效力 在霍乱弧菌定植和致病的两种动物模型中。在这里，我们建议进行研究，以优化 ProphaLytic-VC强大且可扩展的制造流程，因为目前几乎没有制造 由于该产品的新颖性，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，并评估任何可能的局部或系统性 毒性。在第一阶段成功结束时，我们将拥有一个主噬菌体库存(MPS) 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，以产生 正在从MPS中提取噬菌体种子库，以进行I期临床试验。