Initial clinical evaluation of attenuated Shigella flexneri 2a live vector expressing enterotoxigenic Escherichia coli antigens, strain CVD 1208S-122.

项目摘要 志贺氏菌和产肠毒素大肠杆菌（ETEC）是两种重要的肠道病原体。没有 预防志贺氏菌和ETEC的疫苗。疫苗开发中心（CVD）的使命是开发 在最脆弱的人群中预防疟疾的疫苗已经导致建立了一个 原型志贺氏菌-ETEC疫苗候选菌株，命名为CVD 1208 S-122。菌株CVD 1208 S-122由以下组成 一株经基因工程改造表达ETEC的减毒ΔguaBA、Δset、Δsen福氏志贺菌2a菌株 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 整合到志贺氏菌染色体中。本提案的总体目标是进行概念验证， 一项随机、双盲、安慰剂对照、剂量递增的试验性cGMP I期临床评价 菌株CVD 1208 S-122批次。每剂减毒活疫苗将在住院患者中接种。 将在96小时（4天）内对环境（研究隔离病房）和反应原性进行直接评估 观察.将进行粪便培养，从粪便、血液和粪便中分离疫苗株 将分析标本对疫苗接种的免疫应答。这项临床试验旨在 狭义地侧重于提供安全性的初步评估，回答菌株是否稳定，以及 评价志贺氏菌-ETEC联合疫苗方法的免疫原性。 目标1.评估CVD 1208 S-122的安全性和耐受性。 目标二。测量CVD 1208 S-122的排泄模式、遗传稳定性和可传递性。 目标3：检查对CVD 1208 S-122的免疫应答。 这些研究目的将根据当地法律的在临床试验的背景下进行评估 和法规要求、适用的美国联邦法规、ICH指南和药物临床试验质量管理规范 (GCP)标准我们有一个计划，以确保临床监测，持续的质量管理与质量 保证和质量控制活动、外部独立安全监督和数据管理。

Project Summary Shigella and enterotoxigenic Escherichia coli (ETEC) represent two important enteric pathogens. There are no vaccines to prevent both Shigella and ETEC. The Center for Vaccine Development's (CVD) mission to develop vaccines that prevent diarrheal disease in the most vulnerable populations has resulted in construction of a prototype Shigella-ETEC vaccine candidate strain, named CVD 1208S-122. Strain CVD 1208S-122 consists of an attenuated ΔguaBA, Δset, Δsen Shigella flexneri 2a strain that has been 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 Shigella chromosome. The overall goal of this proposal is to conduct a proof-of-concept, randomized, double-blinded, placebo-controlled, dose-escalation Phase 1 clinical evaluation on a pilot cGMP lot of strain CVD 1208S-122. Each dose of the live, attenuated vaccine will be administered in the inpatient setting (Research Isolation Ward) and reactogenicity will be assessed over 96 hours (4 days) of direct observation. Stool cultures will be performed, vaccine strains will be isolated from stool, and blood and stool specimens will be analyzed for the immunologic responses to vaccination. This clinical trial is designed to be narrowly focused to provide the preliminary assessment of safety, answer whether the strain is stable, and evaluate the immunogenicity to our Shigella-ETEC combination vaccine approach. Aim1. Assess the safety and tolerability of CVD 1208S-122. Aim 2. Measure the excretion pattern, genetic stability, and transmissibility of CVD 1208S-122. Aim 3. Examine the immune response to CVD 1208S-122. These research aims will assessed within the context of a clinical trial to be conducted according to local legal and regulatory requirements, applicable US federal regulations, ICH guidelines, and Good Clinical Practice (GCP) standards. We have a plan for ensuring clinical monitoring, ongoing quality management with quality assurance and quality control activities, external independent safety oversight, and data management.