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

项目总监/首席研究员（最后，第一，中间）：Barry，Eileen M. 项目摘要 志贺氏菌和肠毒素大肠杆菌（ETEC）是最重要的腹泻病原体 在全球范围 军事人员，访问发展中国家。两种病原体都被WHO，CDC和 NIAID是由于这些重大疾病负担而成为新干预措施的优先事项 越来越多的抗菌抗性生物。组合疫苗通过针对两个 重要的肠病原体具有单个公式。我们已经开发了2个铅原型志贺氏菌 - 元素 候选疫苗包括广泛保护疫苗的最重要组成部分。 CVD 1208s- 321由一个衰减的志贺氏菌2a菌株组成，该菌株设计为表达ETEC定植因子CFA/I 以及来自整合到志贺氏染色体中的基因的热能肠毒素的LTA2和B亚基。 CVD 1233-SP :: CS2-CS-V2由衰减的S. Sonnei组成，该S. Sonnei用新颖的稳定毒力质粒设计 修改为稳定且一致的疫苗生产提供了变革性优势和 免疫原性。该菌株经过设计，可用于最佳表达ETEC抗原CS2和CS3 染色体。动物模型证实了两种疫苗菌株诱导保护性免疫反应 针对这两种重要的人腹泻病原体。该提议的总体目标是翻译这些 原型Shigella-Etec疫苗从学术研究实验室疫苗到潜在的疫苗结构 人类疫苗准备进入1期临床试验（根据其他资金）。几个工业伙伴有 订婚以提供所需的专业知识，以确保此过程的成功。沃尔特·里德陆军学院 研究试验生物生产设施（WRAIR PBF）是志贺氏菌疫苗生产的世界专家，将产生 CGMP细胞库和试验疫苗批次，其中需要提交文档。 CVD将执行前 临床辅助研究和支持文件足以进行疫苗进展。专家 生物制剂咨询将监督开发和文档过程中的所有步骤，以确保合规性 对FDA IND的要求。疫苗公司Inc.，一家新成立的公司，致力于快速 开发和部署疫苗以供全球使用，将提供咨询和整体战略指导 这些疫苗的最终方便部署。集会团队的集体专业知识将 确保迅速开发具有必要的FDA候选候选疫苗候选者 临床试验的进步和针对目标人群的部署。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面