Oral vaccine interactions in human intestinal enteroids

项目摘要 世界卫生组织（WHO）推荐的两种用于儿童免疫接种的口服活疫苗 口服轮状病毒疫苗（ORV）和口服脊髓灰质炎病毒疫苗（OPV）。这两种疫苗都是在 许多中等收入和低收入国家的免疫规划，并共同管理的方案 原因几项研究已经证明了免疫反应和疫苗接种的显着减弱， 当OPV联合给药时，ORV，尽管ORV对OPV疫苗应答的干扰有限。 关于这两种疫苗在体外的相互作用以及OPV 干扰ORV的情况仍然未知。在这项新的拨款申请中，我们的目的是确定：（i）ORV和OPV如何 共同感染和共同复制在小儿胃肠上皮，（ii）先天免疫效应是什么 （iii）这些先天性免疫缺陷是如何产生的， 应答影响ORV和OPV的复制。我们假设先天性肠上皮细胞 小儿胃肠上皮对OPV和两种肠溶疫苗共感染的反应将 减少ORV的复制，并且该因子有助于减少对ORV的免疫应答。我们将 使用称为人胃肠上皮的生物学和生理学相关模型 肠类肠炎（HIE），用于评估对OPV和ORV的相互作用和先天免疫应答。HIE 从小儿小肠活检中培养的培养物将用于ORV和OPV菌株的感染 目前正在全世界的儿童中使用。因此，这些研究产生的数据将 与正在研究的疫苗和使用疫苗的年龄组直接相关。随着调查人员 在流行病学和肠道感染和疫苗的实地研究，分子病毒学和病毒 脊髓灰质炎病毒和轮状病毒的发病机制，并在HIE培养，我们将利用新的HIE技术来解决 这是一个对公共卫生至关重要的问题。这项研究旨在解决共同的问题， 当疫苗共同施用时发生的感染效应，以及OPV的前剂量效应。后者 在许多高风险国家中模拟出生剂量的OPV给药，导致OPV脱落延长， 可能直到ORV和OPV共给药时。混合感染模型的建立 在儿科人类HIE中OPV和ORV相互作用的研究对于（i）获得关于疫苗的机制见解至关重要 病毒相互作用和先天免疫的活，减毒疫苗在胃肠道上皮，（ii）发展 用于评价干预措施以改善疫苗反应的生理学相关临床前系统 开展大型、昂贵的临床研究，以及（iii）建立一个可以申请的平台 评估疫苗和/或其他具有临床意义的肠溶制剂之间的相互作用。

PROJECT SUMMARY Two live, oral vaccines recommended by the World Health Organization (WHO) for childhood immunizations are oral rotavirus vaccines (ORV) and oral poliovirus vaccines (OPV). Both vaccines are implemented in the immunization programs of many middle and low income countries and are co-administered for programmatic reasons. Several studies have documented a significantly diminished immune response and vaccine take to ORV when OPV is co-administered, although there is limited interference of ORV on OPV vaccine response. There is limited data on interactions between the 2 vaccines in vitro and the mechanisms by which OPV interferes with ORV remain unknown. In this new grant application, we aim to identify: (i) how ORV and OPV co-infect and co-replicate in pediatric gastrointestinal epithelium, (ii) what innate immune effectors are produced in response to infections with both vaccines individually and together, and (iii) how these innate responses affect the replication of ORV and OPV. We hypothesize that innate intestinal epithelia cell responses to OPV and co-infection of two enteric vaccines in the pediatric gastrointestinal epithelium will reduce the replication of ORV and this factor contributes to the diminished immune response to ORV. We will use a biologically and physiologically relevant model of the human gastrointestinal epithelium called human intestinal enteroids (HIEs) for assessment of interactions and innate immune responses to OPV and ORV. HIE cultures developed from pediatric small intestinal biopsies will be used for infection with ORV and OPV strains that are currently being administered to children worldwide. Data generated from these studies will therefore be of direct relevance to the vaccines being studied and in age-groups where they are utilized. As investigators with expertise in epidemiology and field studies of enteric infections and vaccines, molecular virology and viral pathogenesis of poliovirus and rotavirus and in HIE culture, we will utilize the novel HIE technology to address a question of fundamental public health importance. The proposed study is designed to address both a co- infection effect that occurs when the vaccines are co-administered, and a prior-dose effect of OPV. The latter mimics the administration of a birth dose of OPV in many at-risk countries resulting in extended OPV shedding, possibly up to when a dose of ORV and OPV are co-administered. The establishment of a co-infection model for OPV and ORV interaction in pediatric human HIEs is critical to (i) gain mechanistic insights into vaccine virus interactions and innate immunity to live, attenuated vaccines in the gastrointestinal epithelium, (ii) develop physiologically relevant pre-clinical systems for evaluation of interventions to improve vaccine response before large, expensive clinical studies are carried out, and (iii) establish a platform that can be applied for assessment of interactions between vaccines and/or other enteric agents of clinical relevance.