Advanced Development of a Combined Shigella-ETEC Vaccine

志贺氏菌-ETEC 联合疫苗的先进开发

• 批准号: 10704845
• 负责人: Eileen M. Barry
• 金额: $ 105.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704845
• 关键词: Advanced Development; Animal Model; Antigens; Antimicrobial Resistance; Attenuated; Attenuated Vaccines; Biological Products; Child; Chromosomes; Clinical; Clinical Trials; Combined Vaccines; Consultations; Data; Dedications; Developing Countries; Development; Diarrhea; Disease; Documentation; Engineering; Ensure; Enterotoxins; Escherichia coli Vaccines; Excretory function; Fermentation; Formulation; Funding; Funding Mechanisms; Genes; Goals; Good Manufacturing Process; Human; Immune response; In Vitro; Industrialization; Intervention; Investigational Drugs; Laboratory Research; Lead; Military Personnel; Mission; Modification; National Institute of Allergy and Infectious Disease; Organism; Pattern; Performance; Phase I Clinical Trials; Phase II Clinical Trials; Plasmids; Population; Populations at Risk; Principal Investigator; Procedures; Process; Production; Research Institute; Safety; Series; Shigella; Shigella Vaccines; Shigella flexneri; Shigella sonnei; Target Populations; Testing; Toxin; Translating; Vaccine Production; Vaccines; Vial device; Virulence; Visit; Vulnerable Populations; Work; burden of illness; cell bank; colonization factor antigens; diarrheal disease; enteric pathogen; enterotoxigenic Escherichia coli; experience; immunogenic; immunogenicity; in vivo; lot production; manufacture; novel; pathogen; pre-clinical; preclinical study; prevent; programs; protective efficacy; prototype; research clinical testing; scale up; success; vaccine candidate; vaccine development; vaccine distribution; vaccine immunogenicity

Program Director/Principal Investigator (Last, First, Middle): Barry, Eileen M. Project Summary Shigella and enterotoxigenic Escherichia coli (ETEC) are two of the most important diarrheal pathogens worldwide, causing significant disease in young children in developing countries and in U.S. travelers, including military personnel, who visit developing countries. Both pathogens have been designated by WHO, CDC and NIAID as priorities for the development of new interventions due to the significant disease burden of these increasingly antimicrobial resistant organisms. A combined vaccine provides additive value by targeting two important enteropathogens with a single formulation. We have developed 2 lead prototype Shigella-ETEC vaccine candidates that include the most important components of a broadly protective vaccine. CVD 1208S- 321 consists of an attenuated Shigella flexneri 2a strain engineered to express ETEC colonization factor CFA/I and the LTA2 and B subunits of heat-labile enterotoxin from genes integrated into the Shigella chromosome. CVD 1233-SP::CS2-CS-V2 consists of attenuated S. sonnei engineered with a novel stabilized virulence plasmid modification that provides a transformative advantage for stable and consistent vaccine production and immunogenicity. This strain is engineered for optimal expression of ETEC antigens CS2 and CS3 from the chromosome. Animal models confirmed the induction of protective immune responses by both vaccine strains against these two important human diarrheal pathogens. The overall goal of this proposal is to translate these prototype Shigella-ETEC vaccine constructs from academic research laboratory vaccine candidates to potential human vaccines ready to enter Phase 1 clinical trials (under other funding). Several industrial partners have been engaged to supply the required expertise to assure success of this process. The Walter Reed Army institute of Research Pilot Bioproduction Facility (WRAIR PBF), a world expert in Shigella vaccine production, will produce cGMP cell banks and pilot vaccine lots with documentation required for IND submission. CVD will perform pre- clinical IND-enabling studies with supporting documentation sufficient for vaccine advancement. Experts from Biologics Consulting will oversee all steps in the development and documentation process to assure compliance with requirements for FDA INDs. Vaccine Company Inc., a newly formed company that is committed to the rapid development and deployment of vaccines for global use, will provide consultation and overall strategic guidance for the ultimate expedient deployment of these vaccines. The collective expertise of the assembled team will ensure expeditious development of Shigella-ETEC vaccine candidates with requisite FDA conformity for rapid advancement to clinical trials and deployment to target populations. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目主任/首席调查员(最后、第一、中间)：巴里、艾琳·M。 项目摘要 志贺氏菌和产肠毒素大肠杆菌(ETEC)是引起腹泻的两种重要病原菌 在世界范围内，在发展中国家的幼儿和美国旅行者中造成重大疾病，包括 军事人员，他们访问发展中国家。这两种病原体都已被世卫组织、疾控中心和 NIAID作为开发新干预措施的优先事项，因为这些疾病造成了重大的疾病负担 抗菌素抗药性日益增强的生物。一种联合疫苗通过针对两种疫苗提供附加价值 重要的肠道病原体只有一种配方。我们已经开发了双铅原型志贺氏菌-ETEC 包括具有广泛保护性的疫苗的最重要成分的候选疫苗。CVD 1208S- 321由表达ETEC定植因子CFA/I的减毒福氏志贺氏菌2a菌株组成 不耐热肠毒素基因的LTA2和B亚基整合到志贺氏菌的染色体上。 CVD1233-SP：：CS2-CS-V2由一种新型稳定毒力质粒构建的宋内氏弱毒杆菌组成 为稳定和一致的疫苗生产提供变革性优势的修改 免疫原性。该菌株是为优化表达ETEC抗原CS2和CS3而设计的。 染色体。动物模型证实两种疫苗株均可诱导保护性免疫反应 对这两种重要的人类腹泻病原体。这项提案的总体目标是将这些 志贺氏菌ETEC疫苗原型构建从学术研究实验室候选疫苗到潜在疫苗 人类疫苗准备进入第一阶段临床试验(在其他资助下)。几个行业合作伙伴已经 一直致力于提供必要的专业知识，以确保这一进程的成功。沃尔特里德陆军学院 世界志贺氏菌疫苗生产专家研究试点生物生产设施(WRAIR PBF)将生产 CGMP细胞库和试点疫苗批次，以及IND提交所需的文件。CVD将执行预 具有足以支持疫苗进展的支持文件的临床IND使能研究。来自中国的专家 生物制品咨询公司将监督开发和文档流程中的所有步骤，以确保合规性 符合FDA INDS的要求。疫苗公司，一家新成立的公司，致力于快速 开发和部署全球使用的疫苗，将提供咨询和总体战略指导 才能最终方便地部署这些疫苗。集合的团队的集体专业知识将 确保快速开发符合FDA要求的志贺氏菌ETEC候选疫苗 推进到临床试验并部署到目标人群。 OMB编号0925-0001/0002(批准的第03/2020版至2023年2月28日)续页格式页