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.

项目总结/摘要 志贺菌和产肠毒素大肠杆菌是两种重要的肠道致病菌 在世界范围内，在发展中国家的幼儿中造成中度至重度的疟疾， 在访问发展中国家的美国游客中，我们已经找到了一个主要候选人 原型志贺氏菌-产肠毒素大肠杆菌（ETEC）疫苗候选菌株CVD 1208 S-122，其 由经工程改造表达ETEC的减毒福氏志贺菌2a菌株组成 定植因子抗原I（CFA/I）和不耐热肠毒素（LThA 2 B）的B和A2亚单位 整合到染色体中。在动物模型中，这种原型引发了保护性免疫反应 对抗这两种重要的人类肠道病原体本提案的总体目标是将 从学术研究实验室候选疫苗到 潜在的人类疫苗准备进入1期临床试验（在其他资金下），以评估其安全性， 临床耐受性、排泄模式、对密切接触者的传播性和免疫原性。我们已聘请 工业合作伙伴PaxVax公司位于加利福尼亚州红杉城。PaxVax致力于成为未来 我们的多价组合疫苗的生产商，并将为此提供全面的战略指导 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，以及其他行业知识， 怎么做为了完成从有前途的研究实验室候选人到潜在的人体试验的过渡，我们 建议开展以下活动。 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 1208 S-122。 目的2：全面cGMP中试生产批次，以提供3000瓶CVD 1208 S-122。 目的3：对CVD 1208 S-122的cGMP中试批次制剂进行全面的临床前研究，以支持 向FDA提交IND，为1期和2期临床试验做准备。