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.

该提案的目的是建造一种广泛保护在流行病学上的疫苗 重要的志菌血清型和毒素和定植因子类型的肠毒素大肠杆菌（ETEC），两个 对美国和全球人口的重要公共卫生重要性的肠道病原体。两种病原体都是 由于多药的增加，美国疾病控制中心（CDC）指定严重威胁 阻力导致治疗干预的选择较少。志贺氏菌和ETEC很容易获得抗菌剂 抗性机制和其他毒力因素，使这些病原体的重要威胁变得重要。 针对最普遍的循环分离株具有广泛覆盖范围的口服疫苗对多种有益 人口，包括：1）访问这些感染较不发达国家的成人和儿童旅行者 高流行； 2）美国某些高风险人群的儿童和成人； 3）儿童<5岁 发展中国家和4）大规模免疫以控制自然或故意爆发。疫苗将 由表达ETEC定植因子抗原的6种活衰减菌株的混合接种物组成 和抗原可诱导毒素中和抗体抗体抗体（LT）和热稳定（ST）毒素。口服 免疫是诱导粘膜以及被认为是的系统性免疫反应的有效方法 保护这些肠道病和口服交付很重要是产品的实用途径 部署和增强合规性。我们正在利用成功完成五个 衰减的志贺氏菌疫苗菌株在上一个CORT的资金期间表达异源抗原的菌株， 并使用当前的流行病学数据以及新的技术进步，以改善和扩大 疫苗制剂以最大程度地提高该志贺氏菌疫苗产品的保护作用和 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先 临床评估以使IND提交临床试验的进步。该项目直接与 该计划的总体目标是开发主动疫苗接种和被动抗体策略以防止 由多药耐药细菌病原体引起的疾病。 CERT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来翻译产品，将加速促进疫苗的努力 发展。