Oral vaccine interactions in human intestinal enteroids

项目总结 世界卫生组织(WHO)推荐用于儿童免疫的两种口服活疫苗 口服轮状病毒疫苗(ORV)和口服脊髓灰质炎病毒疫苗(OPV)。这两种疫苗都在 许多中低收入国家的免疫方案，并共同管理方案 理由。几项研究已经证明，免疫反应和疫苗接种显著减弱 口服脊髓灰质炎疫苗联合接种时的口服脊髓灰质炎疫苗，尽管口服脊髓灰质炎病毒对口服脊髓灰质炎疫苗的干预有限。 关于这两种疫苗之间的体外相互作用和OPV感染机制的数据有限 干扰ORV的因素仍不清楚。在这项新的赠款申请中，我们的目标是确定：(I)ORV和OPV如何 儿科胃肠上皮共感染和共复制：(Ii)什么是先天免疫效应 为应对单独和共同接种疫苗的感染而产生的，以及(Iii)这些先天的 应答影响ORV和OPV的复制。我们假设先天肠道上皮细胞 小儿胃肠上皮对口服脊髓灰质炎疫苗和两种肠道疫苗混合感染的反应 减少ORV的复制，这一因素导致对ORV的免疫反应减弱。我们会 使用生物学和生理学上相关的人类胃肠上皮模型 用于评估OPV和ORV的相互作用和先天免疫反应的肠类(HIE)。HIE 从儿科小肠活检组织培养出来的培养物将用于感染ORV和OPV菌株 目前正在对世界各地的儿童进行管理。因此，这些研究产生的数据将是 与正在研究的疫苗和使用疫苗的年龄组直接相关。作为调查人员 在肠道感染和疫苗、分子病毒学和病毒的流行病学和实地研究方面具有专业知识 脊髓灰质炎病毒和轮状病毒的发病机制以及在HIE培养中，我们将利用新的HIE技术来解决 这是一个关系到基本公共卫生的问题。这项拟议的研究旨在解决共同-- 联合接种疫苗时发生的感染效应，以及口服脊髓灰质炎疫苗的先前剂量效应。后者 在许多高危国家模拟出生剂量的口服脊髓灰质炎疫苗的管理，导致口服脊髓灰质炎疫苗的延长脱落， 可能直到同时服用一剂ORV和口服脊髓灰质炎疫苗时。一种混合感染模型的建立 对于OPV和ORV来说，儿科HIE中的相互作用对于(I)获得对疫苗的机械性见解至关重要 胃肠道上皮中的病毒相互作用和对减毒活疫苗的先天免疫：(Ii)开发 生理上相关的临床前系统，用于评估改善疫苗反应的干预措施 开展大型、昂贵的临床研究，以及(Iii)建立可申请的平台 评估疫苗和/或其他具有临床意义的肠道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.