Good Manufacturing Practices Master Cell and Working Cell Banks and GMP Pilot Lot of Prototype Shigella flexneri 2a live vector expressing enterotoxigenic E. coli antigens, CVD 1208S 122

良好生产规范主细胞和工作细胞库以及表达产肠毒素大肠杆菌抗原的福氏志贺氏菌 2a 活载体原型 GMP 中试批次，CVD 1208S 122

• 批准号: 9363198
• 负责人: Eileen M. Barry
• 金额: $ 96.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-08 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9363198
• 关键词: Address; Animal Model; Antigens; Attenuated; Categories; Cells; Chemistry; Child; Chromosomes; Cities; Clinical; Clinical Trials; Colony-forming units; Combined Vaccines; Contracts; Data; Developing Countries; Development; Disease; Engineering; Enterotoxins; Excretory function; Fermentation; Formulation; Freezing; Funding; Future; Genes; Goals; Grant; Guidelines; Human; I-antigen; Immune response; In Vitro; Industrialization; Investigational Drugs; Investigational New Drug Application; Laboratory Research; Lead; Licensure; Manufacturer Name; Methods; Mission; Organism; Pattern; Performance; Phase; Phase I Clinical Trials; Preparation; Process; Production; Redwood; Running; Safety; Series; Services; Shigella; Shigella flexneri; Technology Transfer; Testing; Translating; Translations; Traveler' s diarrhea; United States Food and Drug Administration; Vaccines; Vial device; Vibrio cholerae O1; Visit; Vulnerable Populations; Work; Writing; cell bank; colonization factor antigens; enterotoxigenic Escherichia coli; immunogenicity; in vivo; liquid formulation; oral vaccine; paragon; pathogen; pilot lot production; portion control; pre-clinical; preclinical study; prevent; prototype; research clinical testing; scale up; vaccine candidate; vaccine development; vector

Project Summary /Abstract Shigella and enterotoxigenic Escherichia coli (ETEC) are two of the most important diarrheal pathogens worldwide, causing moderate-to-severe diarrheal disease in young children in developing countries and travelers' diarrhea among U.S. travelers who visit developing countries. We have developed a lead candidate prototype Shigella-enterotoxigenic Escherichia coli (ETEC) vaccine candidate strain, CVD 1208S-122, which consists of an attenuated ∆guaBA,∆set,∆sen Shigella flexneri 2a strain engineered to express ETEC colonization factor antigen I (CFA/I) and the B and A2 subunits of heat-labile enterotoxin (LThA2B) from genes integrated into the chromosome. In animal models this prototype has elicited protective immune responses against these two important human diarrheal pathogens. The overall goal of this proposal is to translate this prototype Shigella-ETEC vaccine construct from an academic research laboratory vaccine candidate to a potential human vaccine ready to enter Phase 1 clinical trials (under other funding) to evaluate its safety, clinical tolerability, excretion pattern, transmissibility to close contacts, and immunogenicity. We have engaged an industrial partner, PaxVax, Inc. of Redwood City, CA. PaxVax is committed to becoming a future manufacturer of our multivalent combination vaccine and will provide overall strategic guidance for this translation, including regulatory support (in preparation of the chemistry/manufacture/control (CMC) portion of the IND, advice on interaction with contract manufacturing organizations (CMOs), and other industrial know- how. To accomplish this transition from promising research laboratory candidate to potential human trial, we propose the following activities. Aim 1. Technology transfer, Cell Bank production, process development and pilot scale-up of Shigella-ETEC vaccine candidate CVD 1208S-122. Aim 2: Comprehensive cGMP pilot production lot to provide 3000 vials of CVD 1208S-122. Aim 3: Comprehensive pre-clinical studies on the cGMP pilot lot formulation of CVD 1208S-122 to underpin submission of an IND to the FDA to prepare for Phase 1 and 2 clinical trials.

项目概要/摘要 志贺氏菌和产肠毒素大肠杆菌 (ETEC) 是两种最重要的腹泻病原体 在世界范围内，引起发展中国家幼儿中度至重度腹泻病 我们已经开发了一个主要候选方案。 原型志贺氏菌产肠毒素大肠杆菌 (ETEC) 疫苗候选菌株 CVD 1208S-122， 由减毒的 ΔguaBA、Δset、Δsen 福氏志贺氏菌 2a 菌株组成，经改造可表达 ETEC 来自基因的定植因子抗原 I (CFA/I) 以及不耐热肠毒素 (LThA2B) 的 B 和 A2 亚基 在动物模型中，该原型引发了保护性免疫反应。 对抗这两种重要的人类腹泻病原体 该提案的总体目标是转化这一点。 志贺氏菌-ETEC 疫苗原型构建体从学术研究实验室候选疫苗到 潜在的人类疫苗已准备好进入第一阶段临床试验（在其他资助下）以评估其安全性， 我们已经研究了临床耐受性、排泄模式、密切接触者的传播性和免疫原性。 位于加利福尼亚州雷德伍德城的 PaxVax, Inc. 是工业合作伙伴，致力于成为未来。 我们的多价组合疫苗的制造商并将为此提供总体战略指导 翻译，包括监管支持（准备化学/制造/控制（CMC）部分） IND、与合同制造组织 (CMO) 互动的建议以及其他工业知识 为了实现从有前途的研究实验室候选人到潜在的人体试验的转变，我们如何。 提出以下活动。 目标1.志贺氏菌-ETEC的技术转让、细胞库生产、工艺开发和中试放大 候选疫苗 CVD 1208S-122。 目标 2：综合 cGMP 中试生产批次，提供 3000 瓶 CVD 1208S-122。 目标 3：对 CVD 1208S-122 的 cGMP 中试批次配方进行全面的临床前研究以支撑 向FDA提交IND，为1期和2期临床试验做准备。