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

基本信息

批准号：
10097213
负责人：
Andrew Camilli
金额：
$ 8.3万
依托单位：
PHAGEPRO, INC.
依托单位国家：
美国
项目类别：
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/10097213
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

项目摘要

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.

项目概要霍乱是一种由霍乱弧菌引起的急性严重疾病，主要传播由于缺乏足够的卫生基础设施，水源受到污染。世界卫生该组织估计全球每年至少有 300 万例病例，其中 40% 是传播病例通过家庭传播。目前的预防方法需要大量的资源投入和起效时间尚需时日，但霍乱患者的家庭接触者通常会出现两到三种霍乱症状最初的病人生病后几天。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，使用快速预防措施来防止霍乱的社区传播治疗。拟议研究的目标是证明开发基于噬菌体的临床药物的可行性干预措施 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混合物，称为 ICP1、ICP2 和 ICP3。迄今为止，这些是唯一发现与霍乱流行株有关的三种剧毒噬菌体。详细的基因组和表型学术合作伙伴对每个噬菌体进行了表征，从而产生了基因组宿主受体的序列、注释和鉴定。三者的结合已经是经评估显示其在减少霍乱弧菌定植和预防霍乱症状方面的功效在两种霍乱弧菌定植和发病机制的动物模型中。在这里，我们提出研究以优化 ProphaLytic-VC 的稳健且可扩展的制造工艺，因为目前的制造量很少由于产品的新颖性，我们在美国积累了丰富的经验。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。第一阶段成功结束后，我们将获得以下的噬菌体母液 (MPS)： ProphaLytic-VC 采用优化的大规模生产方案，对霍乱弧菌有效且安全并反复口服给药。 STTR 第二阶段资金将用于资助进一步的活动，以产生来自 MPS 的工作噬菌体种子库存，以进行 I 期临床试验。