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: 10649613
• 负责人: Jacqueline Michele Achkar
• 金额: $ 71.61万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649613
• 关键词: Active Immunization; Affinity; Alternative Therapies; Antibodies; Antibody Therapy; Antibody-mediated protection; BCG Vaccine; Bacille Calmette-Guerin vaccination; Bacteria; Belief; Binding; Cause of Death; Cell Wall; Cells; Cellular Immunity; Characteristics; Communicable Diseases; Complex; Conjugate Vaccines; Data; Development; Disease; Epitopes; Foundations; Goals; Heterogeneity; Human; Humoral Immunities; Immune; Immune response; Immunoglobulin G; Immunotherapy; In Vitro; Knowledge; Lighting; Location; Macrophage; Mediating; Monoclonal Antibodies; Mus; Mycobacterium tuberculosis; Natural Immunity; Oligosaccharides; Passive Immunization; Phagocytosis; Polysaccharides; Proteins; Public Health; Publishing; Respiratory Tract Infections; Role; Sampling; South African; Specificity; Surface; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Virulence Factors; arm; capsule; experimental study; extracellular; glycosylation; human monoclonal antibodies; immunogenic; improved; in vivo; insight; lipoarabinomannan; novel; pathogen; pathogenic microbe; polyclonal human antibody; prevent; protective efficacy; response; tool; translational study; tuberculosis immunity; vaccination strategy; vaccine development

Abstract Active tuberculosis (TB), a transmissible respiratory infection caused by uncontrolled Mycobacterium tuberculosis (Mtb) infection, is worldwide one of the top 10 causes of death. To control this major global public health problem alternative therapies and a more effective vaccine 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 the epitopes involved in human protection and inducible 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 several microbial pathogens, including those with intracellular location. Using novel glycan arrays our published and preliminary data show that human Abs to Mtb surface glycans are highly heterogeneous in their binding specificity and differ in both their reactivity to oligosaccharide motifs and their functions between BCG vaccination and/or controlled (latent) versus uncontrolled (TB) Mtb infection. Our overarching hypotheses are: 1) Human Abs to AM are protective against Mtb, and 2) protection by these Abs arises from reactivity to specific OS motifs within AM. 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 identify key immunogenic Mtb glycotopes that render Ab-mediated protection in humans. The information gained could fill a critical gap in the current knowledge of TB immunity and inform new strategies for developing both vaccines and Ab-based immunotherapies against TB.

抽象的 活动性结核病 (TB)，一种由不受控制的分枝杆菌引起的传染性呼吸道感染 结核病（Mtb）感染，是全球十大死亡原因之一。为了控制这个全球主要公众 迫切需要健康问题的替代疗法和更有效的疫苗。目前可用的 卡介苗 (BCG) 疫苗已使用近一个世纪，但提供的疫苗不足 预防结核病。结核病疫苗领域的一个主要障碍是对全面了解的有限 参与预防结核病的免疫成分。目前，结核病疫苗的研发重点是 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具有 在预防结核病方面发挥作用。更好地了解参与人类保护的表位 并可通过疫苗接种、人类多克隆和功能研究的详细表征和功能研究来诱导 需要针对潜在保护性表位的单克隆抗体 (mAb)。包膜抗体和其他抗体 表面多糖对多种微生物病原体具有保护作用，包括细胞内病原体 地点。使用新型聚糖阵列，我们已发表的初步数据表明，人类对 Mtb 表面的抗体 聚糖的结合特异性高度异质，并且对寡糖的反应性也不同 BCG 疫苗接种和/或受控（潜伏）与不受控（TB）结核分枝杆菌之间的基序及其功能 感染。我们的首要假设是：1) 人类 AM 抗体对 Mtb 具有保护作用，2) 具有保护作用 这些 Abs 的产生源于对 AM 内特定 OS 基序的反应。我们的具体目标是： 1. 产生并 表征人类多克隆抗体和 Mtb 表面聚糖的单克隆抗体； 2. 确定 Mtb 表面的影响 - 对巨噬细胞功能的特定人类抗体； 3. 确定 Mtb 表面的保护功效 体内特定的人类抗体。我们的首要目标是鉴定关键的免疫原性 Mtb 糖表位，从而使 Ab 介导的人类保护。所获得的信息可以填补当前知识的一个关键空白 结核病免疫并为开发针对结核病的疫苗和基于抗体的免疫疗法提供新策略 结核病。