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

项目总结/摘要 志贺氏菌感染是资源有限环境中幼儿腹泻病的主要原因， 每年导致成千上万人死亡预防志贺氏菌病与 与针对O-特异性多糖（OSP）的抗体，但针对其他 还注意到抗原与保护相关。抗志贺菌的功能属性 还注意到抗体与保护作用相关，包括补体激活， 诱导宿主细胞吞噬活性的能力。尽管如此，志贺菌OSP结合疫苗未能 在田间试验中保护幼儿，尽管在年龄较大的儿童和成人中提供保护。我们 我认为这些问题可能不仅反映了以下抗体大小（滴度）的差异， 疫苗接种，而且抗体功能效应子属性的差异，包括Fc相互作用 与先天免疫系统有关。这种差异已被注意到与保护 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 和生物物理属性与保护免受志贺氏菌感染，包括在年轻 在达卡的一个非正式居住区， 孟加拉国.我们建议用北美疫苗的数据来补充这一分析， 受控人类感染模型（CHIM）和相关研究。我们预计，我们将确定一个 与志贺氏菌病保护相关的抗体属性谱， 将严格指导疫苗开发和评估工作，这些知识将集中在 未来的机械研究。

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.