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

• 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
• 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

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.

摘要 活动性结核病（TB），一种由分枝杆菌引起的可传播的不受控制的呼吸道感染 结核病（Mtb）是一个全球性的公共卫生问题，也是全世界10大死亡原因之一。更 迫切需要预防结核病的有效疫苗。目前可用的卡介苗- 卡介苗（BCG）已使用了近世纪，但对结核病的保护不足。一 结核病疫苗领域的一个主要障碍是对免疫成分的全面了解有限 参与预防结核病。目前，结核病疫苗开发的重点是诱导或促进细胞增殖， 介导的免疫，但越来越多的证据表明，抗体也有保护作用， TB.为了更好地了解可能在人类中诱导的特异性保护性抗体反应， 通过疫苗接种，对人多克隆和单克隆抗体（mAb）进行详细的表征和功能研究， 需要潜在的保护性表位。抗荚膜和其他表面多糖的抗体是 保护免受几种微生物病原体，包括具有细胞内位置的那些，如Mtb。人类 针对Mtb荚膜多糖的抗体水平不仅变化很大， 在一些实施方案中，多糖在其与多糖内的寡糖基序的结合特异性方面是异质的。我们的出版和 初步数据表明，保护作用是由于IgG对特定寡糖基序的反应性。基于 根据这些新的数据，我们的总体假设是：1）针对特异性荚膜多糖的人抗体 具有针对Mtb的保护作用;和2）这些抗体的保护作用源于对特定低聚糖的反应性 多糖中的基序。我们的具体目标是：1.为了生成和表征人多克隆和 针对Mtb表面聚糖的mAb; 2.为了确定Mtb表面特异性人Abs对巨噬细胞的作用， 功能; 3。建立结核分枝杆菌表面特异性人抗体的体内保护效力。 我们的首要目标是确定结核分枝杆菌表面碳水化合物的寡糖表位， 尽管我们最成功的一些疫苗是基于诱导抗体， 除了荚膜多糖外，该领域已开始转向寡糖缀合物疫苗， 靶向最相关的表位，具有更大的产品一致性的优势， 大多数市售的糖缀合物疫苗的纯化多糖的异质制剂。的 获得的知识可以为开发疫苗和基于Ab的免疫疗法提供新的策略 对抗结核病。