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

志贺氏菌感染期间 OSP 特异性抗体和其他抗体的功能分析

• 批准号: 10468290
• 负责人: Edward T. Ryan
• 金额: $ 76.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468290
• 关键词: Acute; Address; Adult; American; Antibodies; Antibody Affinity; Antibody Response; Antibody titer measurement; Antigens; Area; Attenuated; Bangladesh; Binding; Biological Assay; Biophysics; Cessation of life; Child; Complement; Complement Activation; Conjugate Vaccines; Data; Enzyme-Linked Immunosorbent Assay; Evaluation; Fc Receptor; Future; General Hospitals; Goals; Household; Human; Immune response; Immune system; Immunity; Immunoglobulin Constant Region; Immunologics; Infection; Innate Immune System; Institutes; Knowledge; Massachusetts; Mediating; Modeling; Morbidity - disease rate; Mucins; NK Cell Activation; O Antigens; Organism; Pattern; Phagocytes; Phagocytosis; Plasmids; Play; Process; Public Health; Research; Research Design; Research Institute; Research Personnel; Resource-limited setting; Resources; Role; Sampling; Sampling Studies; Shigella; Shigella Infections; Shigella Vaccines; Shigella sonnei; Specificity; System; Universities; Ursidae Family; Vaccinated; Vaccination; Vaccines; Validation; Virulence Factors; Work; arm; bactericide; base; diarrheal disease; glycosylation; international center; monocyte; mortality; neutrophil; pathogen; response; vaccine candidate; vaccine development; vaccine evaluation; vaccine trial; volunteer

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.

项目摘要/摘要 志贺氏菌感染是在资源有限的环境下幼儿腹泻病的主要原因， 并每年导致成千上万的死亡。保护志核病是相关的 用靶向O特异性多糖（OSP）的抗体，但针对其他的免疫反应 还注意到抗原与保护相关。抗辣椒的功能属性 还注意到抗体与保护相关，包括补体激活和 诱导宿主细胞吞噬活性的能力。尽管如此，一种志贺氏菌OSP结合疫苗未能 尽管为年龄较大的儿童和成人提供保护，但在现场试验中保护幼儿。我们 提出此类问题可能不仅反映了抗体大小（滴度）的差异 疫苗接种，但在抗体功能效应子属性方面的差异，包括FC相互作用 与先天免疫系统。已经注意到这种差异与保护相关 针对一系列感染性病原体。为了解决这个问题，我们建议定义抗体功能 和与志贺氏菌感染有关的生物物理属性，包括在年轻人中 儿童，使用达卡非正式定居区的家庭联系研究设计方法， 孟加拉国。我们建议通过北美疫苗和 受控的人类感染模型（CHIM）和相关研究。我们预计我们将确定 与保护志菌相关的抗体属性的概况，该知识是 将批判性地指导疫苗的开发和评估工作，并且这些知识将集中 未来的机械研究。