An Expanded Multivalent Vaccine to Prevent MDR Shigella and ETEC Disease

预防 MDR 志贺氏菌和 ETEC 疾病的扩展多价疫苗

• 批准号: 10584477
• 负责人: Eileen M. Barry
• 金额: $ 97.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584477
• 关键词: 5 year old; Acceleration; Adhesions; Adult; Animals; Antigens; Antimicrobial Resistance; Attenuated; Biological Models; Centers for Disease Control and Prevention (U.S.); Child; Clinical Trials; Collaborations; Combined Vaccines; Data; Developing Countries; Disease; Disease Outbreaks; Engineering; Enterotoxins; Epidemiology; Escherichia coli Vaccines; Evaluation; Funding; Future; Genes; Goals; Heterophile Antigens; Human; Immune response; Immunity; Immunization; Infection; Licensure; Maintenance; Mass Immunization; Methods; Minor; Modeling; Mucous Membrane; Multi-Drug Resistance; Mutation; Oral; Pathogenesis; Plasmids; Population; Production; Public Health; Research Personnel; Route; Safety; Scientist; Serotyping; Shigella; Shigella Vaccines; Shigella flexneri; Shigella sonnei; Surface; Therapeutic Intervention; Toxin; Toxoids; Translating; Vaccination; Vaccine Design; Vaccines; Virulence; Virulence Factors; Visit; colonization factor antigens; efficacy evaluation; enteric pathogen; enterotoxigenic Escherichia coli; epidemiologic data; experience; guinea pig model; high risk population; immunogenicity; improved; manufacture; mouse model; neutralizing antibody; new technology; oral vaccine; passive antibodies; pathogen; pathogenic bacteria; pre-clinical; preclinical evaluation; prevent; programs; protective efficacy; research clinical testing; resistance mechanism; resistant Shigella; response; vaccine candidate; vaccine development; vaccine formulation; vector; volunteer

The goal of this proposal is to construct a vaccine that is broadly protective against the epidemiologically most important Shigella serotypes and toxin and colonization factor types of enterotoxigenic E. coli (ETEC), two enteropathogens of substantial public health importance to the U.S. and global populations. Both pathogens are designated serious threats by the Centers for Disease Control (CDC) in the U.S. due to increasing multidrug resistance leading to fewer options for therapeutic intervention. Shigella and ETEC readily acquire antimicrobial resistance mechanisms and additional virulence factors, making these pathogens important emerging threats. An oral vaccine with broad coverage against the most prevalent circulating isolates would be beneficial to multiple populations, including: 1) adult and child travelers who visit less developed countries where these infections are hyperendemic; 2) children and adults in certain high risk populations in the US; 3) children < age 5 years in developing countries, and 4) for mass immunization to control natural or deliberate outbreaks. The vaccine will consist of a mixed inoculum of 6 live attenuated strains of Shigella expressing ETEC colonization factor antigens and antigens to induce toxin neutralizing antibodies against heat labile (LT) and heat stable (ST) toxins. Oral immunization is an effective method for inducing mucosal as well as systemic immune responses believed to be important in protection against these enteropathogens and oral delivery is a practical route for product deployment and for enhancing compliance. We are taking advantage of the successful completion of five attenuated Shigella vaccine strains expressing heterologous antigens during the previous CETR funding period, and using current epidemiological data, as well as novel technological advances, to improve and broaden the vaccine formulation in order to maximize the protective efficacy of this Shigella-ETEC vaccine product and optimize features for production. Our specific objective is to complete vaccine candidate optimization and pre- clinical evaluation to enable IND submission for advancement to clinical trials. This project relates directly to the overarching goal of this Program to develop active vaccination and passive antibody strategies to prevent disease caused by multidrug-resistant bacterial pathogens. The collective expertise provided by CETR project investigators and collaborating scientists along with the Center for Vaccine Development's experience in translating products through manufacture and clinical evaluation, will accelerate efforts to advance vaccine development.

该提案的目标是构建一种能够广泛预防流行病学上最严重的疾病的疫苗。 重要的志贺氏菌血清型以及产肠毒素大肠杆菌 (ETEC) 的毒素和定植因子类型，两种 对美国和全球人口具有重大公共卫生重要性的肠道病原体。两种病原体都是 由于多种药物的增加，被美国疾病控制中心 (CDC) 指定为严重威胁 耐药性导致治疗干预的选择更少。志贺氏菌和 ETEC 很容易获得抗菌剂 耐药机制和其他毒力因素，使这些病原体成为重要的新兴威胁。 一种针对最流行的循环分离株具有广泛覆盖范围的口服疫苗将有益于多种疾病 人群，包括： 1) 前往这些感染所在的欠发达国家的成人和儿童旅行者 高流行性； 2）美国某些高危人群中的儿童和成人； 3) 年龄<5岁的儿童 发展中国家，4) 进行大规模免疫以控制自然或故意爆发。该疫苗将 由 6 种表达 ETEC 定植因子抗原的减毒活志贺氏菌菌株的混合接种物组成 和抗原诱导针对热不稳定（LT）和热稳定（ST）毒素的毒素中和抗体。口服 免疫接种是诱导粘膜和全身免疫反应的有效方法，被认为是 对于预防这些肠道病原体很重要，口服给药是产品的实用途径 部署和增强合规性。我们正在利用五项工作的顺利完成 在上一个 CETR 资助期间表达异源抗原的减毒志贺氏菌疫苗株， 并利用当前的流行病学数据以及新技术进步来改进和扩大 疫苗配方，以最大限度地发挥志贺氏菌-ETEC 疫苗产品的保护功效，并且 优化生产功能。我们的具体目标是完成候选疫苗的优化和预 临床评估，以便提交 IND 以便进入临床试验。该项目直接关系到 该计划的总体目标是制定主动疫苗接种和被动抗体策略，以预防 由多重耐药细菌病原体引起的疾病。 CETR 项目提供的集体专业知识 研究人员和合作科学家以及疫苗开发中心的经验 通过制造和临床评估转化产品，将加速推进疫苗的努力 发展。