An Expanded Multivalent Vaccine to Prevent MDR Shigella and ETEC Disease

这项提议的目标是构建一种疫苗，对流行病学上最流行的疾病具有广泛的保护作用。 志贺菌重要血清型及产肠毒素E.大肠杆菌（ETEC），2 肠道病原体对美国和全球人群具有重要的公共卫生意义。这两种病原体都是 美国疾病控制中心（CDC）指定的严重威胁， 耐药性导致治疗干预的选择较少。志贺氏菌和ETEC容易获得抗菌剂 耐药性机制和其他毒力因子，使这些病原体成为重要的新兴威胁。 一种针对最流行的流行分离株的广泛覆盖的口服疫苗将有益于多种 人群，包括：1）访问这些感染的欠发达国家的成人和儿童旅行者 高流行性; 2）美国某些高风险人群中的儿童和成人; 3） 发展中国家，以及4）大规模免疫，以控制自然或故意爆发。该疫苗将 由6株表达ETEC定植因子抗原的志贺氏菌减毒活菌株的混合接种物组成 以及诱导针对热不稳定（LT）和热稳定（ST）毒素的毒素中和抗体的抗原。口服 免疫是诱导粘膜以及全身免疫应答的有效方法 在预防这些肠道病原体和口服递送方面重要是， 部署和加强合规性。我们正在利用成功完成五个 在先前CETR资助期间表达异源抗原的减毒志贺氏菌疫苗株， 并利用目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，以最大限度地提高该志贺氏菌-ETEC疫苗产品的保护效力， 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- 临床评价，以使IND提交进入临床试验。该项目直接关系到 该计划的总体目标是开发主动疫苗接种和被动抗体策略， 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沿着与疫苗开发中心的经验， 通过生产和临床评估转化产品，将加快推进疫苗的努力， 发展

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.