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

对表达产肠毒素大肠杆菌抗原（CVD 1208S-122 菌株）的福氏志贺氏菌 2a 活载体进行初步临床评估。

• 批准号: 10212188
• 负责人: Eileen M. Barry
• 金额: $ 152.92万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212188
• 关键词: Abdomen; Adverse reactions; Antibodies; Antigen Targeting; Antigens; Attenuated; Attenuated Vaccines; Blood specimen; Child; Chromosomal Stability; Chromosomes; Clinical; Clinical Trials; Colony-forming units; Combined Vaccines; Detection; Developing Countries; Development; Diarrhea; Dose; Double-Blind Method; Dysentery; Engineering; Ensure; Enterotoxins; Escherichia coli Vaccines; Evaluation; Excretory function; Feces; Fever; Funding; GMP lots; Gastrointestinal tract structure; Genes; Genetic; Goals; Good Clinical Practice; Guidelines; Hemagglutination; Homing; Hour; Human; I-antigen; Immune response; Immunoglobulin A; Immunoglobulin-Secreting Cells; Ingestion; Inpatients; Investigational New Drug Application; Legal; Lymphocyte; Measures; Mission; Monitor; Mucosal Immune Responses; Mutation; Names; Organism; Pattern; Persons; Phase; Placebos; Plasmablast; Principal Investigator; Proteins; Quality Control; Randomized; Regulation; Research; Safety; Sample Size; Serum; Shigella; Shigella flexneri; System; Testing; Traveler' s diarrhea; United States National Institutes of Health; Vaccination; Vaccines; Vulnerable Populations; bactericide; cell bank; colonization factor antigens; data management; design; diarrheal disease; enteric pathogen; enterotoxigenic Escherichia coli; first-in-human; human study; immunogenicity; integrin alpha4beta7; neutralizing antibody; pathogen; preclinical study; prevent; prototype; quality assurance; research clinical testing; safety assessment; stool sample; vaccine candidate; vaccine development; vector; volunteer; ward

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.

项目概要 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。 疫苗开发中心 (CVD) 的使命是开发预防志贺氏菌和 ETEC 的疫苗。 预防最脆弱人群腹泻疾病的疫苗已导致建立一个 志贺氏菌-ETEC疫苗候选株原型，命名为CVD 1208S-122，菌株CVD 1208S-122由以下成分组成。 一种减毒的 ΔguaBA、Δset、Δsen 福氏志贺氏菌 2a 菌株，经过改造可表达 ETEC 来自基因的定植因子抗原 I (CFA/I) 以及不耐热肠毒素 (LThA2B) 的 B 和 A2 亚基 该提案的总体目标是进行概念验证， 对试点 cGMP 进行随机、双盲、安慰剂对照、剂量递增的 1 期临床评估 每剂 CVD 1208S-122 株减毒活疫苗将在住院患者体内注射。 将在 96 小时（4 天）的直接时间内评估环境（研究隔离病房）和反应原性 进行粪便培养，从粪便、血液和粪便中分离疫苗株。 该临床试验将分析样本对疫苗接种的免疫反应。 专注于提供安全性的初步评估，回答菌株是否稳定，以及 评估我们的志贺氏菌-ETEC 联合疫苗方法的免疫原性。 目标 1. 评估 CVD 1208S-122 的安全性和耐受性。 目标 2. 测量 CVD 1208S-122 的排泄模式、遗传稳定性和传播性。 目标 3. 检查对 CVD 1208S-122 的免疫反应。 这些研究目标将在根据当地法律进行的临床试验的背景下进行评估 和监管要求、适用的美国联邦法规、ICH 指南和良好临床实践 我们制定了确保临床监测、持续质量管理的计划。 保证和质量控制活动、外部独立安全监督以及数据管理。