Protective immune mechanisms to S. dysenteriae 1 vaccines in cynomolgus macaques

志贺氏菌是一种全球性感染，在某些环境中传播迅速。一种血清型， 志贺菌1型（S.病原体1），可导致毁灭性的流行病，病死率高 因此，它已被归类为B类优先病原体，具有很高的潜力，可用作 生化武器目前还没有针对志贺氏菌的疫苗。志贺氏菌有效疫苗的研制 由于缺乏关于保护性免疫的具体决定因素的信息， 志贺氏菌感染由于与执行挑战相关的风险所施加的限制， 野生型S.在临床试验中促进疫苗开发，一种非人类 灵长类动物模型是迫切需要的。我们已经建立了野生型S. 迄今为止，该菌株表现出100%的攻击率（6/6只食蟹猴 用10 e11 cfu灌胃攻击）。此外，我们进一步了解了 激发后引发的免疫应答。在本申请中，我们建议通过以下方式继续这些研究： （1）评价用新的胃内免疫的假设， 减毒鼠伤寒沙门沙门氏菌1突变株对野生型沙门氏菌的胃内攻击具有保护作用。 （2）评估以下假设，即在循环中观察到一组定义的免疫应答， 用S. 1和/或用野生型S. A1与保护相关并且代表存在于效应位点的那些（即，粘膜 组织）和次级淋巴器官。这些转化研究是进一步我们的核心， 了解介导对S. 1和长寿 （3）评价猴免疫后的免疫效果， 减毒鼠伤寒沙门大肠杆菌1菌株对猴子粪便中结肠微生物群的影响以及 现有微生物群对观察到的免疫应答和保护免受攻击的影响。最后，我们将 即将进行的减毒S.细菌1菌株CVD 1256，以评价 假设在人体全身和局部观察到的免疫应答与 与食蟹猴中的保护作用相关（目的1和2）。这些研究将提供宝贵的 这些见解可能会加速减毒疫苗的发展。紫茎泽兰1.

Shigella is a global infection that is notorious for disseminating rapidly in certain settings. One serotype, Shigella dysenteriae type 1 (S. dysenteriae 1), can cause devastating pandemics with high case fatality rates and thus it has been classified as a Category B priority pathogen with high potential to be used as a biological weapon. There is no available vaccine for Shigella. The development of effective Shigella vaccines has been hampered by a considerable lack of information of the specific determinants of protective immunity to Shigella infection. Because of the limitations imposed by the risks associated with performing challenge studies with wild type S. dysenteriae 1 in clinical trials to advance vaccine development, a non-human primate model is urgently needed. We have already established a challenge model with wild-type S. dysenteriae 1 strain 1617 which, to date, exhibited an attack rate of 100% (6 of 6 cynomolgus macaques challenged with 10e11 cfu intragastrically). Furthermore, we have advanced our understanding of the immune responses elicited following challenge. In this application we propose to continue these studies by addressing the following Specific Aims: (1) evaluate the hypothesis that intragastric immunization with novel attenuated S. dysenteriae 1 mutant strains elicits protection from intragastric challenge with wild type S. dysenteriae 1; (2) evaluate the hypotheses that a defined set of immune responses observed in circulation in cynomolgus immunized with attenuated strains of S. dysenteriae 1 and/or challenged with wild type S. dysenteriae 1 correlate with protection and are representative of those present at effector sites (i.e., mucosal tissues) and secondary lymphoid organs. These translational studies are central to further our understanding of the immunological mechanisms that mediate protection to S. dysenteriae 1 and longevity of the responses to vaccination in humans, (3) To evaluate the effects of immunization of monkeys with attenuated S. dysenteriae 1 strains on the colonic microbiota in stools of monkeys and the impact of the existing microbiota on the observed immune responses and protection from challenge. Finally, we will take advantage of an upcoming trial with the attenuated S. dysenteriae 1 strain CVD 1256 to evaluate the hypothesis that the immune responses observed systemically and locally in humans are similar to those that correlate with protection in cynomolgus macaques (Aims 1 and 2). These studies will provide valuable insights that might accelerate the development of attenuated vaccines for S. dysenteriae 1.