An Expanded Multivalent Vaccine to Prevent MDR Shigella and ETEC Disease

这项提议的目标是构建一种广泛预防大多数流行病的疫苗。 产肠毒素大肠杆菌(ETEC)的重要志贺氏菌血清型和毒素及定植因子型，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 由于越来越多的多种药物，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减少。志贺氏菌和ETEC容易获得抗菌剂 抗性机制和额外的毒力因子，使这些病原体成为重要的新兴威胁。 针对最流行的流通分离株的广泛覆盖的口服疫苗将有益于 人口，包括：1)访问感染这些疾病的欠发达国家的成人和儿童旅行者 高度流行；2)美国某些高危人群中的儿童和成人；3)5岁的儿童 发展中国家，以及4)大规模免疫以控制自然或故意暴发。疫苗将会 由6株表达ETEC定植因子抗原的减毒志贺氏菌混合接种组成 和抗原，以诱导针对热不稳定(LT)和热稳定(ST)毒素的毒素中和抗体。口头的 免疫是诱导粘膜和全身免疫反应的有效方法，据信是 对这些肠道病原体的保护很重要，口服是一种实用的产品途径 部署和加强合规性。我们正在利用成功完成的五个 减毒志贺氏菌疫苗株在前一次CETR资助期间表达异源抗原， 并利用当前的流行病学数据以及新的技术进步来改善和扩大 疫苗配方，以最大限度地发挥志贺氏菌-ETEC疫苗产品的保护效果 为生产优化功能。我们的具体目标是完成候选疫苗的优化和预 临床评估，以支持IND提交以推进临床试验。该项目直接与 该方案的总体目标是发展主动疫苗接种和被动抗体战略，以预防 由耐多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在 通过制造和临床评估来翻译产品，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.