Antibody immunity to serotype 3 Streptococcus pneumoniae

描述（由申请人提供）：在2000年引入含有七种最常见致病血清型（ST）肺炎链球菌（PCV7）的荚膜多糖（PPS）的蛋白质结合疫苗后，侵袭性肺炎球菌病（IPD）的发病率发生了显着变化。最显著的变化是，由于群体保护，包括pcv的STs的IPD大幅减少，但这伴随着非疫苗STs的出现和血清3型（ST3）的显著增加。ST3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STs更高的独立死亡风险。尽管在成人使用的23价PPS疫苗（PV23）中有一个ST3片段，肺炎球菌荚膜多糖3 (PPS3)，但关于PV23是否预防肺炎的数据是相互矛盾的，并且与PPS3的新结合物PCV13预防ST3的能力是不确定的。因此，迫切需要更好地了解ST3的抗体免疫，寻找更好的治疗ST3疾病的新方法。本应用程序的目的是鉴定和表征人抗ST3的抗体。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疫苗受体中分离出抗PPS3的人单克隆抗体（huMAbs），并通过其基因使用和多样性、PPS3表位特异性和抗PPS3的功能活性，确定其在ST3定植、肺炎和败血症小鼠模型中的功效

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.