Antibody immunity to serotype 3 Streptococcus pneumoniae

描述（由申请方提供）：2000年引入一种蛋白结合疫苗后，侵袭性肺炎球菌病（IPD）的发病率发生了显著变化，该疫苗含有肺炎链球菌（肺炎球菌）（PCV 7）的7种最常见致病血清型（ST）的荚膜多糖（PPS）。最显著的变化是由于畜群保护，含PCV的ST的IPD大幅减少，但这伴随着非疫苗ST的出现和血清型3（ST 3）的显著增加。ST 3是美国和全球成人和儿童肺炎和脓胸的主要原因，预示着比其他ST更高的独立死亡风险。尽管在成人使用的23价PPS疫苗（PV 23）中存在ST 3部分，即肺炎球菌荚膜多糖3（PPS 3），但关于PV 23是否预防肺炎的数据存在冲突，并且与PPS 3，PCV 13的新缀合物预防ST 3的能力也不确定。因此，迫切需要更好地了解对ST 3的抗体免疫，并找到更好的新方法来治疗ST 3疾病。本申请的目的是鉴定和表征针对ST 3的人抗体。为了实现这一点，我们将通过创新的单细胞表达克隆方法从PPS疫苗接受者中分离针对PPS 3的人单克隆抗体（huMAb），并确定它们在ST 3定殖、肺炎和脓毒症的小鼠模型中的功效，作为它们的基因使用和多样性、PPS 3表位特异性和针对PPS 3的功能活性的函数。 体外ST 3，在鉴定ST 3的治疗性huMAb方面迈出了第一步。此外，我们将使用保护性huMAb的表位和功能方面作为探针来询问PPS疫苗接受者的PPS 3应答。该项目中开发的huMAbs将作为ST 3的候选治疗药物，它提供的关于ST 3抗体免疫的新科学信息将使我们能够以一种以前不可能的方式剖析PPS 3对疫苗的反应，并为ST 3疫苗鉴定新的保护性PPS 3抗原。因此，该项目将对临床医学产生重大影响，通过消除通过新型治疗剂预防ST 3的巨大障碍，并通过对抗体免疫，ST 3发病机制和宿主-ST 3相互作用的新见解对基础科学产生重大影响。

DESCRIPTION (provided by applicant): The incidence of invasive pneumococcal disease (IPD) changed markedly after the introduction in 2000 of a protein conjugate vaccine with capsular polysaccharides (PPS) of seven of the most common disease-causing serotypes (ST) of Streptococcus pneumoniae (pneumococcus) (PCV7). The most dramatic change was a major reduction in IPD with PCV-included STs due to herd protection, but this was accompanied by the emergence of non-vaccine STs and a marked rise in serotype 3 (ST3). ST3 is a leading cause of pneumonia and empyema in adults and children in the U.S. and globally and portends an independent, higher risk of death than other STs. Though there is a ST3 moiety, pneumococcal capsular polysaccharide 3 (PPS3) in the 23- valent PPS vaccine (PV23) used in adults, data on whether PV23 prevents pneumonia are conflicting and the ability of a new conjugate with PPS3, PCV13 to prevent ST3 is uncertain. Thus, there is an urgent need for a better understanding of antibody immunity to ST3 and to find better new ways to treat ST3 disease. The goal of this application is to identify and characterize human antibodies that protect against ST3. To accomplish this we will isolate human monoclonal antibodies (huMAbs) to PPS3 from PPS vaccine recipients by an innovative, single cell expression cloning approach and determine their efficacy in mouse models of ST3 colonization, pneumonia and sepsis as a function of their gene use and diversity, PPS3 epitope specificity, and functional activity against ST3 in vitro, taking the first steps in identifying therapeutic huMAbs for ST3. In addition, we wil use the epitopes and functional aspects of protective huMAbs as probes to interrogate PPS3 responses of PPS vaccine recipients. The huMAbs developed in this project will serve as candidate therapeutics for ST3 and the new scientific information it provides on antibody immunity to ST3 will make it possible to dissect PPS3 responses to vaccines in a way that has not been possible before and to identify novel, protective PPS3 antigens for ST3 vaccines. Thus, the project will have a major impact on clinical medicine by removing what have been formidable roadblocks in prevention of ST3 via novel therapeutic agents and on basic science via new insights into antibody immunity, ST3 pathogenesis and host-ST3 interaction.