Functional profiling of OSP-specific and other antibodies during shigella infection

项目摘要/摘要 志贺氏菌感染是资源有限环境中幼儿腹泻疾病的主要原因， 每年导致数万人死亡。对志贺氏菌病的保护与 用针对O-特异性多糖(OSP)的抗体，但对其他 人们还注意到，抗原与保护相关。抗志贺氏菌的功能特性 抗体也被认为与保护相关，包括补体激活和 诱导宿主细胞吞噬活性的能力。尽管如此，志贺氏菌OSP结合疫苗未能 在实地试验中保护幼儿，尽管为年龄较大的儿童和成年人提供保护。我们 提出这样的问题可能不仅反映在以下抗体强度(滴度)上的差异 疫苗接种，但抗体功能效应器属性的差异，包括Fc相互作用 与先天免疫系统有关。人们注意到，这种差异与保护有关 对抗一系列传染性病原体。为了解决这个问题，我们建议定义抗体功能 以及与预防志贺氏菌感染有关的生物物理属性，包括年轻的 儿童，在达卡的一个非正式住区使用家庭接触研究设计方法， 孟加拉。我们建议用北美疫苗和 受控人类感染模型(CHIM)及相关研究我们预计我们将确定一个 与预防志贺氏菌病相关的抗体属性的概况，即这一知识 将关键地指导疫苗的开发和评估工作，这一知识将集中于 未来的机械学研究。

PROJECT SUMMARY/ABSTRACT Shigella infection is a leading cause of diarrheal illness in young children in resource-limited settings, and results in tens of thousands of deaths each year. Protection against shigellosis is associated with antibodies targeting O-specific polysaccharide (OSP), but immune responses against other antigens have also been noted to correlate with protection. Functional attributes of anti-shigella antibodies have also been noted to correlate with protection, including complement activation and ability to induce host cell phagocytic activity. Despite this, a shigella OSP-conjugate vaccine failed to protect young children in a field trial, despite providing protection in older children and adults. We propose that such issues may reflect differences not only in antibody magnitude (titer) following vaccination, but also differences in antibody functional effector attributes, including Fc interactions with the innate immune system. Such differences have been noted to correlate with protection against a range of infectious pathogens. To address this, we propose to define antibody functional and biophysical attributes associated with protection against shigella infection, including in young children, using a household contact study design approach in an informal settlement area in Dhaka, Bangladesh. We propose to complement this analysis with data from North American vaccine and Controlled Human Infection Models (CHIMs) and related studies. We anticipate that we will identify a profile of antibody attributes that correlates with protection against shigellosis, that this knowledge will critically guide vaccine development and evaluation efforts, and that this knowledge will focus future mechanistic studies.