Characteristics and protective efficacy of human antibodies against M. tuberculosis

人类结核分枝杆菌抗体的特点和保护功效

基本信息

批准号：
10525039
负责人：
Jacqueline Michele Achkar
金额：
$ 8.8万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10525039
关键词：
Active Immunization Affinity Antibodies Antibody Response Antibody Therapy Antibody-mediated protection Antigens BCG Vaccine Bacille Calmette-Guerin vaccination Belief Binding COVID-19 Carbohydrates Cause of Death Cellular Immunity Characteristics Communicable Diseases Complex Conjugate Vaccines Data Development Disease Epitopes Exposure to Funding Glycoconjugates Goals Health Human Immune Immune response Immunoglobulin G Immunologics Immunotherapy In Vitro Individual Knowledge Lighting Location Mediating Monoclonal Antibodies Mus Mycobacterium tuberculosis Oligosaccharides Passive Immunization Patients Phagocytosis Polysaccharides Preparation Public Health Publishing Research Respiratory Tract Infections Role Sampling Serum South African Specificity Surface Testing Tuberculosis Tuberculosis Vaccines Underrepresented Minority Vaccination Vaccines base experimental study extracellular glycosylation human monoclonal antibodies in vivo macrophage novel pathogen pathogenic microbe polyclonal human antibody prevent protective efficacy tuberculin purified protein derivative vaccination strategy vaccine development

项目摘要

Abstract Active tuberculosis (TB), a transmissible uncontrolled respiratory infection caused by Mycobacterium tuberculosis (Mtb), is a global public health problem and one of the top 10 causes of death worldwide. More effective vaccines for the protection against TB are urgently needed. The currently available Bacillus Calmette- Guerin (BCG) vaccine has been in use for almost a century but provides insufficient protection against TB. A major obstacle in the TB vaccine field is the limited understanding of the full breadth of the immune components involved in the protection against TB. Currently, TB vaccine development is focused on eliciting or boosting cell- mediated immunity, but increasing evidence suggests that antibodies also have a role in the protection against TB. To gain a better understanding of specific protective antibody responses that could be induced in humans by vaccination, detailed characterization and functional studies of human polyclonal and monoclonal Abs (mAbs) to potentially protective epitopes are required. Antibodies to capsular and other surface polysaccharides are protective against a several microbial pathogens, including those with intracellular location such as Mtb. Human antibody levels to Mtb capsular polysaccharides are not only greatly variable, they are also tremendously heterogeneous in their binding specificity to oligosaccharide motifs within the polysaccharide. Our published and preliminary data suggest that protection is due to IgG reactivity to specific oligosaccharide motifs. Based on these novel data, our overarching hypotheses are: 1) Human antibodies to specific capsular polysaccharides are protective against Mtb; and 2) protection by these antibodies arises from reactivity to specific oligosaccharide motifs within the polysaccharide. Our specific aims are: 1. To generate and characterize human polyclonal and mAbs to Mtb surface glycans; 2. To determine the effects of Mtb surface-specific human Abs on macrophage functions; and 3. To establish the protective efficacy of Mtb surface-specific human Abs in vivo. Our overarching goal is to determine the oligosaccharide epitopes of Mtb surface carbohydrates that are most relevant for protection Although some of our most successful vaccines are based on inducing antibodies to capsular polysaccharides, the field has started to move to oligosaccharide-conjugate vaccines, which, in addition to targeting the most relevant epitopes, have the advantage of greater product consistency compared to the heterogeneous preparations of purified polysaccharides of most marketed glycoconjugate vaccines. The knowledge gained could inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.

抽象的活动性结核病 (TB)，一种由分枝杆菌引起的不受控制的传染性呼吸道感染结核病（Mtb）是一个全球性的公共卫生问题，也是全球十大死因之一。更多的迫切需要有效的疫苗来预防结核病。目前可用的卡介苗- 盖林 (BCG) 疫苗已使用近一个世纪，但对结核病的保护作用不足。一个结核病疫苗领域的主要障碍是对免疫成分的全面了解有限参与结核病的预防。目前，结核病疫苗的开发重点是引发或增强细胞- 介导的免疫，但越来越多的证据表明抗体也能起到保护作用结核病。更好地了解可能在人类中诱导的特定保护性抗体反应通过疫苗接种、人类多克隆和单克隆抗体 (mAb) 的详细表征和功能研究需要潜在的保护性表位。针对荚膜和其他表面多糖的抗体是对多种微生物病原体具有保护作用，包括那些位于细胞内的病原体，例如结核分枝杆菌。人类 Mtb 荚膜多糖的抗体水平不仅变化很大，而且变化很大它们与多糖内寡糖基序的结合特异性不同。我们出版的和初步数据表明，这种保护作用是由于 IgG 对特定寡糖基序的反应性。基于根据这些新数据，我们的首要假设是：1）针对特定荚膜多糖的人类抗体对 Mtb 具有保护作用； 2) 这些抗体的保护作用来自于对特定寡糖的反应性多糖内的基序。我们的具体目标是： 1. 产生并表征人类多克隆和针对 Mtb 表面聚糖的单克隆抗体； 2. 确定 Mtb 表面特异性人抗体对巨噬细胞的影响功能； 3. 确定 Mtb 表面特异性人抗体的体内保护功效。我们的首要目标是确定 Mtb 表面碳水化合物中最重要的寡糖表位。与保护相关尽管我们一些最成功的疫苗是基于诱导抗体除了荚膜多糖，该领域已开始转向寡糖结合疫苗，此外与针对最相关表位的产品相比，具有更高的产品一致性优势大多数市售糖复合物疫苗的纯化多糖的异质制剂。这获得的知识可以为开发疫苗和基于抗体的免疫疗法的新策略提供信息对抗结核病。