HUMAN ANTIBODY RESPONSE TO HAEMOPHILUS INFLUENZAE B

流感嗜血杆菌B型（Haemophilus influenzae type，HiB）是一种重要的青少年致病菌 孩子 已经生产了几种类型的疫苗（结合物和CHO） 为了诱导保护性抗体（Abs），针对Hib的CHO囊的Abs（Hib- PS）。 然而，这些人抗Hib-PS Ab应答的幅度不同， （在个体和疫苗之间）和抗Hib-PS抗体可能存在差异， 亲和力和保护效力。 这些定量和定性的 变异性使评估疫苗在不同地区的效力复杂化 年轻的儿童人口。 我们已经证明了V 通过鉴定抗Hib-PS Ab的VL基因（例如， A2、O 18 VK基因）。 A2基因是最常用的。 在建立了 单个Ab克隆结构的异质性，我们现在提出 研究单个抗体的功能和调节的变化 克隆会影响主机保护。 为了研究抗Hib-PS克隆抗体的功能变化，我们将：1） 确定克隆Ab之间Ab亲和力的可变性，2）比较 结合疫苗诱导的IgG 1 Ab克隆在幼龄动物中的亲和力 儿童和成人，3）确定保护效力的变化， 新生大鼠中的克隆Abs，以及4）将保护效力与Ab 亲和力和VL一级结构。 研究 为了调节单个Ab克隆的表达，我们将：1）完成 开发对所有不同VL具有特异性的血清学测定 通过制备对抗Hib-PS抗体特异的单克隆抗体， 使用O 18基因的Hib-PS Ab。 使用这些分析，我们将2） 确定三种可用的结合疫苗是否诱导不同的Ab 3）确定幼儿是否表达Ab V区 与成人不同的基因库，4）决定A2基因的流行 5）确定是否有任何遗传因子，包括κ链， 单倍型通过研究一个基因井影响Ab V区库 特征化的群体，以及6）确定选择的群体是否表达 通过研究纳瓦霍印第安人， 对Hib-PS反应不佳。 我们的研究将提供详细的表达和功能的知识， 抗CHO抗原（Ag）和类似蛋白Ag的Ab的单个克隆 直接在人体内。 这些知识将对我们的长期发展非常有用。 目的是研究Ag驱动的人B细胞成熟。 我们的学习应该是 还与开发针对其他医学上重要的 细菌如S.肺炎

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.