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菌。没有 预防志贺氏菌和ETEC的疫苗。疫苗开发中心(CVD)的研发使命 在最脆弱的人群中预防腹泻疾病的疫苗导致了 志贺氏菌-ETEC疫苗候选原型株，命名为CVD 1208S-122。CVD1208S-122菌株由 一株减毒的Δguaba，ΔSet，ΔSen福氏志贺氏菌2a，已经被设计成表达ETEC 克隆因子抗原I(CFA/I)和不耐热肠毒素B、A2亚基(LThA2B)基因 整合到志贺氏菌染色体中。这项提案的总体目标是进行概念验证， 一种试点cGMP的随机、双盲、安慰剂对照、剂量递增的1期临床评价 大量菌株CVD1208S-122。每一剂减毒活疫苗都将在住院患者身上接种。 环境(研究隔离病房)和反应性将在96小时(4天)内直接进行评估 观察。将进行粪便培养，从粪便、血液和粪便中分离出疫苗菌株 将分析样本对疫苗接种的免疫学反应。这项临床试验旨在 狭隘地提供安全性的初步评估，回答菌株是否稳定，以及 评价我们的志贺氏菌-ETEC联合疫苗方法的免疫原性。 目的：1.评估CVD1208S-122的安全性和耐受性。 目的2.测定CVD1208S-122的排泄规律、遗传稳定性和传播性。 目的3.检测对CVD1208S-122的免疫应答。 这些研究目标将在将根据当地法律进行的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、非物质文化遗产指南和良好临床实践 (GCP)标准。我们有一个计划来确保临床监测，持续的质量管理和质量 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.