HUMAN ANTIBODY RESPONSE TO HAEMOPHILUS INFLUENZAE B

B 型流感嗜血杆菌的人类抗体反应

• 批准号: 3146480
• 负责人: Moon H. Nahm
• 金额: $ 13.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3146480
• 关键词: Haemophilus influenzae; Haemophilus influenzae vaccines; Native Americans; SDS polyacrylamide gel electrophoresis; active immunization; adult human (21+); antiantibody; antibody formation; antibody specificity; antigen antibody reaction; bacterial capsules; enzyme linked immunosorbent assay; gene expression; human population genetics; human therapy evaluation; immunoglobulin G; immunoglobulin genes; immunoglobulin structure; infant human (0-1 year); laboratory mouse; laboratory rat; molecular cloning; monoclonal antibody; newborn animals; preschool child (1-5)

Haemophilus influenzae type b (Hib) is a significant pathogen for young children. Several types of vaccines (conjugate and CHO) have been produced to induce protective antibodies (Abs), Abs to the CHO capsule of Hib (Hib- PS). However, the magnitude of these human anti-Hib-PS Ab responses vary greatly (among individuals and vaccines) and anti-Hib-PS Ab may differ in affinity and protective potency. These quantitative and qualitative variabilities complicate assessment of vaccine efficacy in different populations of young children. We have demonstrated heterogeneity in the V region repertoire of anti-Hib-PS Abs by identifying their VL genes (e.g., A2, O18 VK genes). A2 gene is most commonly used. Having established the heterogeneity in the structure of individual Ab clones, we now propose to investigate how variations in function and regulation of individual Ab clones can affect host protection. To study variation in function of anti-Hib-PS clonal Abs, we will: 1) determine the variability in Ab affinity among clonal Abs, 2) compare affinity of IgG1 Ab clones induced with a conjugate vaccine in young children and adults, 3) determine variability in protective potency among clonal Abs in newborn rats, and 4) associate protective potency with Ab affinity and with VL primary structure in newborn rats. To study the regulation of the expression of individual Ab clones, we will: 1) complete the development of serological assays specific for all the different VL types of anti-Hib-PS Abs by making a monoclonal Ab specific for the anti- Hib-PS Ab using the O18 gene. Using these assays, we will then 2) determine if the three available conjugate vaccines induce different Ab repertoires in adults, 3) determine if young children express Ab V region repertoires different from adults, 4) determine the prevalence of A2 gene deletion, 5) determine if any genetic factor including the kappa chain haplotype affects Ab V region repertoire by studying a genetically well characterized population, and 6) determine if a select population expresses Ab repertoire different from others by studying Navajo Indians who are poorly responsive to Hib-PS. Our study will provide detailed knowledge of expression and function of individual clones of Abs to a CHO antigen (Ag) and an analogous protein Ag directly in human. That knowledge will be highly useful to our long term goal of studying Ag-driven human B cell maturation. Our studies should be also relevant to developing conjugate vaccines to other medically important bacteria such as S. pneumonia.

流感嗜血杆菌B型（HIB）是年轻人的重要病原体 孩子们。 已经生产了几种类型的疫苗（结合和CHO） 为了诱导保护性抗体（ABS），对Hib的Cho胶囊的ABS（hib-- PS）。 但是，这些人类抗HIB-PS AB反应的大小各不相同 （在个人和疫苗中）和抗HIB-PS AB的AB上可能有所不同 亲和力和保护效力。 这些定量和定性 变异性使评估疫苗功效的评估复杂 幼儿的人口。 我们已经证明了V中的异质性 抗Hib-PS ABS的区域曲目通过识别其VL基因（例如 A2，O18 VK基因）。 A2基因是最常用的。 建立了 单个AB克隆结构的异质性，我们现在建议 调查如何功能和调节单个AB的变化 克隆会影响宿主保护。 为了研究抗Hib-PS克隆ABS功能的变化，我们将：1） 确定克隆ABS中AB亲和力的变异性，2）比较 IgG1 AB克隆的亲和力在Young中诱导的结合疫苗诱导 儿童和成人，3）确定保护效力的变异性 新生大鼠的克隆腹肌，4）将保护效力与AB相关 新生大鼠的亲和力和VL主要结构。 研究 调节单个AB克隆的表达，我们将：1）完成 针对所有不同VL的血清学测定的开发 抗HIB-PS ABS的类型通过制造针对抗抗的单克隆AB 使用O18基因的HIB-PS AB。 使用这些测定，我们将2） 确定三种可用的共轭疫苗是否诱导不同的AB 成人的曲目，3）确定幼儿是否表达AB v区域 与成年人不同的曲目，4）确定A2基因的流行率 缺失，5）确定是否包括Kappa链在内的任何遗传因素是否包括 单倍型通过研究遗传学良好地影响AB V区域库 人口的特征，6）确定某些人口是否表达 通过研究纳瓦霍印第安人，与他人不同 对HIB-PS的反应不佳。 我们的研究将提供有关表达和功能的详细知识 ABS的单个克隆到CHO抗原（Ag）和类似蛋白Ag 直接在人类中。 这些知识将对我们的长期有用 研究由Ag驱动的人类B细胞成熟的目标。 我们的研究应该是 也与将共轭疫苗开发到其他重要的医学重要 细菌，例如肺炎链球菌。