Advanced Development of a Combined Shigella-ETEC Vaccine

志贺氏菌-ETEC 联合疫苗的先进开发

基本信息

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
项目类别：
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

项目摘要

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. 项目概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，对发展中国家的幼儿和美国旅行者造成严重疾病，包括访问发展中国家的军事人员。这两种病原体均已被 WHO、CDC 和由于这些疾病造成的严重疾病负担，NIAID 成为开发新干预措施的优先事项越来越多的微生物对抗菌药物产生耐药性。联合疫苗通过针对两种药物提供附加价值单一制剂可抑制重要的肠道病原体。我们开发了 2 个主要原型 Shigella-ETEC 候选疫苗包括广泛保护性疫苗的最重要成分。 CVD 1208S- 321 由减毒福氏志贺氏菌 2a 菌株组成，经过改造可表达 ETEC 定植因子 CFA/I 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 LTA2 和 B 亚基。 CVD 1233-SP::CS2-CS-V2 由采用新型稳定毒力质粒改造的减毒 Sonnei 组成为稳定一致的疫苗生产提供变革性优势的修改免疫原性。该菌株经过工程改造，可最佳表达 ETEC 抗原 CS2 和 CS3 染色体。动物模型证实两种疫苗株都能诱导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）。多家产业合作伙伴已致力于提供所需的专业知识，以确保这一过程的成功。沃尔特里德陆军研究所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 细胞库和试验疫苗批次以及 IND 提交所需的文件。 CVD将执行预支持临床 IND 的研究，并提供足以促进疫苗进展的支持文件。专家来自生物制剂咨询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 IND 的要求。 Vaccine Company Inc.是一家新成立的公司，致力于快速开发疫苗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以最终方便地部署这些疫苗。组装团队的集体专业知识将确保快速开发志贺氏菌-ETEC 候选疫苗，并符合 FDA 的要求，以实现快速开发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 已批准至 02/28/2023）页面延续格式页面