Effect of Oral Immunization with the Ty21a Typhoid Vaccine on Local and Systemic

研制中预防耐药伤寒的改良伤寒疫苗 国家是全球公共卫生的一个高度优先事项。伤寒沙门氏菌作为生物恐怖因子的潜在用途增加了 研究这种重要的全球病原体的另一个原因。这个项目的目标是在 粘膜和全身水平，包括短期和长期体液免疫和细胞介导免疫(CMI) 口服伤寒沙门氏菌减毒活疫苗及其相互作用的研究 在Ty21a免疫和肠道微生物区系之间。改良活体口腔伤寒疫苗的研制 由于缺乏保护性的具体决定因素的详细信息，疫苗一直受到阻碍。 对伤寒沙门氏菌感染免疫。此外，伤寒沙门氏菌的效应器和记忆免疫反应 血液循环和肠道微环境的特征尚未确定。因为胃肠道是 伤寒沙门氏菌的进入部位，在当地是否存在有效和持续的免疫反应 微环境很可能在防止感染方面起着关键作用。伤寒患者的研究结果 在成人中对减毒伤寒沙门氏菌进行的疫苗试验表明，针对常见伤寒沙门氏菌的抗体(Ab) 抗原似乎对伤寒沙门氏菌的感染起到了保护作用，然而，目前还不清楚这种抗体是否 中介保护或作为更具优势的保护性细胞介导性免疫的替代品 (CMI)导致这种无细胞伤寒沙门氏菌的消除。尽管孩子们站在 从改进的伤寒疫苗中受益最大，只有关于血清抗体的粗略信息 水平，据我们所知，没有关于诱导抗体分泌细胞(ASC)的报道， 这组个体中的记忆B细胞(BM)或CMI。老年人是另一个人口群体， 在对这种口服疫苗产生免疫反应方面研究不足，因为没有任何信息。 可用于诱导抗体或CMI反应。人们日益意识到 肠道微生物区系在健康和疾病中的作用也提出了关于复合体的影响的问题 口服免疫中生活在胃肠道中的微生物群落，反之亦然。 因此，这个应用程序除了检查免疫反应外，还将检查相互作用 儿童、成人和儿童对Ty21a免疫的免疫应答与肠道微生物区系之间的关系 老年人。总体而言，本申请涉及发展对伤寒沙门氏菌免疫的两个重要方面。

The development of improved typhoid vaccines to prevent antibiotic-resistant typhoid fever in developing countries is a high global public health priority. The potential use of S. Typhi as a bioterror agent has added an additional reason to study this important global pathogen. The goal of this project is to characterize, at the mucosal and systemic levels, both short and long-term humoral and cell-mediated immunity (CMI) induced by oral immunization with the licensed attenuated S. Typhi Ty21a vaccine and to explore the interactions between Ty21a immunization and the gut microbiota. The development of improved live oral typhoid vaccines has been hampered by a lack of detailed information of the specific determinants of protective immunity to S. Typhi infection. Moreover, the effector and memory immune responses to S. Typhi in circulation and in the gut microenvironment have not been characterized. Since the gastrointestinal tract is the site of entry of S. Typhi, the presence of effective and sustained immune responses in the local microenvironment are likely to be pivotal in protection from infection. Results from studies in typhoid patients and vaccine trials with attenuated S. Typhi strains in adults suggest that antibodies (Ab) to common S. Typhi antigens appear to play a protective role against S. Typhi infection, however, it is not known if such Abs mediate protection or serve as a surrogate for the more dominant protective cellular mediated immunity (CMI) resulting in the elimination of this iritracellular S. Typhi. In spite of the fact that children stand to benefit the most from improved typhoid vaccines, only cursory information is available concerning serum Ab levels and, to our knowledge, there are no reports on the induction of antibody secreting cells (ASC), memory B cells (BM) or CMI in this group of individuals. The elderly represent another population group that is understudied in terms of the generation of immune responses to this oral vaccine, as no information is available concerning the induction of either Ab or CMI responses. The growing awareness of the importance of the gut microbiota in health and disease has also raised the question as to the influence of the complex community of microorganisms that inhabit the gastrointestinal tract in oral immunization and vice versa. Therefore, this application in addition to examining the immune response, will also examine the interactions between immune responses to Ty21a immunization and the gut microbiota in children, adults and the elderly. Overall this application addresses two important aspects of the development of immunity to S. Typhi.