VARIABLE GENE DEFECTS AND PNEUMOCOCCAL SUSCEPTIBILITY

说明(摘自申请者摘要)：接种疫苗的基本原理 肺炎球菌衣壳多糖(PPS)疫苗是诱导调理的 针对PPS的抗体，这是预防链球菌所必需的 肺炎。然而，现有的PPS疫苗在以下方面的免疫原性较差 许多患者是肺炎球菌感染的最高风险人群。基于 根据证据，我们假设免疫球蛋白的表达减少 来自VH3亚组的基因翻译成受损的抗PPS反应：i) PPS抗体是寡克隆的，使用VH3亚群的基因；ii) 据报道，肺炎球菌风险患者的VH3表达减少。 对PPS疫苗反应差的感染。此应用程序 建议确定人类抗体的结构-功能关系 引起成人侵袭性肺炎球菌感染的血清3型肺炎链球菌 还有孩子。具体的目的是：1)确定化合物的分子结构 人重组转基因小鼠产生的抗PPS-3单抗 免疫球蛋白基因座；2)确定小鼠感染的特征，并作为光学或 体外非调理；3)使用AIM中定义的分子结构的单抗 1和目的2中定义的功能功效，以选择PPS 3的多肽模拟物 表位，并使用这些多肽来确定PPS是否在 患者识别保护性、非保护性或增强疾病的表位。 我们的研究将提供证据来支持或驳斥这样的假设 肺炎球菌疫苗失败的原因是不能产生抗体 PPS表位具有一定的分子结构。这项工作将提供一种新的 关于结构-功能关系的科学知识库 可用于临床评价疫苗效果的PPS 3抗体 并为肺炎球菌高危患者开发更多免疫原性疫苗 感染。

DESCRIPTION (Adapted from Applicant's Abstract): The rationale for vaccination with pneumococcal capsular polysaccharide (PPS) vaccines is to induce opsonic antibodies to PPS, which are required for protection against Streptococcus pneumoniae. However, available PPS-based vaccines are poorly immunogenic in many patients at the highest risk for pneumococcal infection. Based on the following evidence we hypothesize that reduced expression of immunoglobulin genes from the VH3 subgroup translates into an impaired anti-PPS response: i) antibodies to PPS are oligoclonal and use genes from the VH3 subgroup; ii) reduced VH3 expression has been reported in patients at risk for pneumococcal infection that generate poor responses to PPS vaccines. This application proposes to determine structure-function relationships for human antibodies to serotype 3 S. pneumoniae, a cause of invasive pneumococcal infection in adults and children. The specific aims are: 1) To determine the molecular structure of human mAbs to PPS 3 generated in transgenic mice reconstituted with human immunoglobulin loci; 2) To characterize the infection in mice and as opsonic or non-opsonic in vitro; 3) To use mAbs with molecular structure as defined in Aim 1 and functional efficacy as defined in Aim 2 to select peptide mimics of PPS 3 epitopes, and to use the peptides to determine if PPS-elicited antibodies in patients recognize protective, non-protective or disease-enhancing epitopes. Our studies will provide evidence to support or refute the hypothesis that pneumococcal vaccine failure results from an inability to produce antibodies to PPS epitopes with a certain molecular structure. This work will provide a new scientific knowledge base regarding structure-function relationships for antibodies to PPS 3 that can be used clinically to evaluate vaccine efficacy and to develop more immunogenic vaccines for patients at risk for pneumococcal infection.