HUMAN ANTIBODY RESPONSE TO HAEMOPHILUS INFLUENZAE B

B型流感嗜血杆菌(Hib)是一种重要的青少年致病菌。 孩子们。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)，抗Hib的CHO胶囊的抗体(Hib- PS)。然而，这些人类抗Hib-PS抗体反应的大小各不相同 抗Hib-PS抗体(在个体和疫苗之间)可能有很大差异 亲和力和保护力。这些数量和质量 不同的变异性使疫苗效力评估复杂化 年幼的儿童人口。我们已经证明了V中的异质性 通过鉴定抗Hib-PS抗体的VL基因(例如， A2、O18 VK基因)。A2基因是最常用的基因。在建立了 单个抗体克隆结构的异质性，我们现在建议 研究单个抗体的功能和调节的变化 克隆可能会影响主机保护。 为了研究抗Hib-PS克隆抗体的功能变异，我们将：1) 确定克隆抗体之间抗体亲和力的变异性，2)比较 结合疫苗诱导的免疫球蛋白1抗体在幼鼠体内的亲和力 儿童和成人，3)确定保护效力的变异性 新生大鼠的克隆性抗体，以及4)保护力与抗体的相关性 与新生大鼠的VL一级结构有亲和力。为了研究 调节单个抗体克隆的表达，我们将：1)完成 不同类型VL特异性血清学检测方法的研究进展 制备特异性抗Hib-PS单抗的研究 使用O18基因的Hib-PS抗体。使用这些化验方法，我们将2) 确定三种可用的结合疫苗是否诱导不同的抗体 成人的谱系，3)确定幼儿是否表达抗体V区 不同于成人的谱系，4)决定A2基因的患病率 缺失，5)确定是否有任何包括kappa链的遗传因素 单倍型通过研究一个遗传良好的基因影响抗体V区谱 特征化的群体，以及6)确定选择的群体是否表达 AB曲目与其他曲目不同，通过研究纳瓦霍印第安人 对Hib-PS反应不佳。 我们的研究将提供关于表达和功能的详细知识 抗CHO抗原和类似蛋白Ag的单抗克隆 直接在人类身上。这些知识将对我们的长期发展大有裨益 研究抗原驱动的人B细胞成熟的目标。我们的学习应该是 也与开发与其他医学上重要的结合疫苗有关 肺炎链球菌等细菌。

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.