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

志贺氏菌是一种全球性感染，以在某些环境中迅速传播而臭名昭著。一种血清型， 志贺氏菌1型(志贺氏菌1型)可导致高病死率的毁灭性大流行。 因此，它被归类为B类优先病原菌，具有很高的利用潜力 生物武器。目前还没有针对志贺氏菌的疫苗。高效志贺氏菌疫苗的研究进展 由于对保护性免疫的具体决定因素缺乏信息而受到阻碍 志贺氏菌感染。由于与执行质询相关的风险所带来的限制 研究野生型痢疾链球菌1的临床试验，以推进疫苗开发，一个非人类 迫切需要灵长类动物模型。我们已经用野生型S建立了挑战模型。 到目前为止，1617株痢疾杆菌的发病率为100%(6只食蟹猴中有6只 胃内挑战10e11 CFU)。此外，我们还提高了对 在接下来的挑战中引起免疫反应。在本申请中，我们建议通过以下方式继续这些研究 解决以下具体目标：(1)评估新的胃内免疫假说 减毒志贺氏菌1突变株对野生型志贺氏菌胃内攻击的保护作用 痢疾1；(2)评估假设，在循环中观察到的一组确定的免疫反应 用痢疾链霉菌1型减毒株免疫食蟹和/或用野生型S。 痢疾1与保护性有关，并且代表那些出现在效应部位(即粘膜)的痢疾 组织)和次级淋巴器官。这些翻译研究是进一步发展我们的 了解介导对痢疾链球菌1的保护和长寿的免疫学机制 对人类接种疫苗的反应，(3)评估猴的免疫效果 减毒沙门氏菌1型对猕猴大便中结肠微生物区系的影响 现有微生物群对观察到的免疫反应和抵御挑战的保护。最后，我们将带着 即将进行的用减毒沙门氏菌1株CVD1256进行试验的优势 假设在人类系统和局部观察到的免疫反应类似于 与食蟹猴的保护相关(目标1和2)。这些研究将提供有价值的 可能加速开发痢疾链球菌减毒疫苗的见解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.