Advanced Development of a Combined Shigella-ETEC Vaccine

项目负责人/主要研究者（最后一名、第一名、中间名）：巴里、艾琳M. 项目摘要 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，在发展中国家和美国旅行者的幼儿中造成严重疾病，包括 访问发展中国家的军事人员。这两种病原体都已被世卫组织、疾病预防控制中心和 NIAID作为开发新干预措施的优先事项，因为这些疾病的重大疾病负担 越来越多的抗微生物生物。联合疫苗通过靶向两个 重要的肠道病原体与单一配方。我们已经开发了2个主要的原型志贺氏菌-ETEC 候选疫苗包括广泛保护性疫苗的最重要成分。CVD 1208S- 321由经工程化以表达ETEC定植因子CFA/I的减毒福氏志贺菌2a菌株组成 以及来自整合到志贺氏菌染色体中的基因的不耐热肠毒素的LTA 2和B亚单位。 CVD 1233-SP：：CS2-CS-V2由减毒的S.用新的稳定毒力质粒改造Sonnei 为稳定和一致的疫苗生产提供变革性优势的修饰， 免疫原性该菌株经过工程改造，可最佳表达来自大肠杆菌的ETEC抗原CS2和CS3。 染色体动物模型证实了两种疫苗株诱导的保护性免疫应答 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这些 从学术研究实验室候选疫苗到潜在的志贺氏菌-ETEC疫苗原型构建 人类疫苗准备进入第一阶段临床试验（在其他资金下）。一些工业合作伙伴已经 一直在提供所需的专门知识，以确保这一进程的成功。沃尔特里德陆军学院 研究试点生物生产设施（WRAIR PBF），在志贺氏菌疫苗生产的世界专家，将产生 cGMP细胞库和中试疫苗批次，以及IND提交所需的文件。CVD将执行预- 临床IND使能研究，支持性文件足以促进疫苗的发展。专家 生物制品咨询公司将监督开发和文件编制过程中的所有步骤，以确保合规性 符合FDA IND的要求。疫苗公司，一家新成立的公司，致力于快速 开发和部署供全球使用的疫苗，将提供咨询和总体战略指导 为这些疫苗的最终快速部署。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ETEC候选疫苗， 推进临床试验并部署到目标人群。 OMB编号0925-0001/0002（修订版03/2020批准至02/28/2023）页码继续格式页码

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