Antibody immunity to serotype 3 Streptococcus pneumoniae

描述(申请人提供)：侵袭性肺炎球菌病(IPD)的发病率在2000年引入一种含有七种最常见的致病血清型肺炎链球菌(肺炎球菌)(PCV7)的衣壳多糖(PPS)的蛋白质结合疫苗后发生了显著变化。最戏剧性的变化是由于群体保护，包括PCV的STS导致IPD大幅减少，但伴随而来的是非疫苗STS的出现和3型血清(ST3)的显著上升。ST3是美国和全球成人和儿童肺炎和脓胸的主要原因，并预示着独立的、比其他STS更高的死亡风险。尽管在成人使用的23价PPS疫苗(PV23)中存在ST3部分，肺炎球菌荚膜多糖3(PPS3)，但关于PV23是否预防肺炎的数据相互矛盾，而且与PPS3的新结合物PCV13预防ST3的能力尚不确定。因此，迫切需要更好地了解ST3抗体免疫，寻找更好的治疗ST3疾病的新方法。这项应用的目标是识别和表征人类抗体对ST3的保护作用。为了实现这一目标，我们将通过一种创新的单细胞表达克隆方法从PPS疫苗接受者中分离出抗PPS3的人类单抗(HuMAbs)，并在ST3定植、肺炎和脓毒症小鼠模型中测定它们的有效性，作为它们的基因使用和多样性、PPS3表位特异性和抗PPS3功能活性的函数。 ST3的体外实验，为鉴定ST3的治疗性HuMAb迈出了第一步。此外，我们将利用保护性HuMAb的表位和功能方面作为探针来询问PPS疫苗接受者的PPS3反应。该项目开发的HuMAb将作为ST3的候选疗法，它提供的关于ST3抗体免疫的新科学信息将使我们能够以以前不可能的方式剖析PPS3对疫苗的反应，并为ST3疫苗识别新的保护性PPS3抗原。因此，该项目将对临床医学产生重大影响，消除通过新型治疗药物预防ST3的巨大障碍，并通过对抗体免疫、ST3发病机制和宿主-ST3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.