Antibody immunity to serotype 3 Streptococcus pneumoniae

对血清型 3 肺炎链球菌的抗体免疫

• 批准号: 9198809
• 负责人: Liise-anne Pirofski
• 金额: $ 9.01万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198809
• 关键词: Antibody; immunity; serotype; Streptococcus; pneumoniae

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.

描述（由申请人提供）：2000年引入蛋白质结合疫苗的侵袭性肺炎球菌疾病（IPD）的发生率发生了明显变化，该蛋白质结合疫苗含有链球菌链球菌（ST）的七种最常见的引起疾病的血清型（pps）的蛋白质共轭疫苗（PPS）发生了变化。最引人注目的变化是，由于牛群的保护，IPD的重大减少，包括PCV的STS，但这伴随着非疫苗STS的出现以及血清型3（ST3）的显着增加。 ST3是美国和全球儿童肺炎和脓肿的主要原因，比其他STS预示着独立，更高的死亡风险。尽管有ST3部分，但在成年人中使用的23个Valent PPS疫苗（PV23）中的肺炎球菌囊膜多糖3（PPS3），但有关PV23的数据，有关PV23是否可以防止肺炎与PPS3，PPSV13，PCV13，PCV13，PCV13的能力相互矛盾。因此，迫切需要更好地理解对ST3的抗体免疫，并找到更好的治疗ST3疾病的方法。该应用的目的是识别和表征保护ST3的人类抗体。为此，我们将通过一种创新的，单细胞表达的克隆方法将人类单克隆抗体（Humabs）从PPS疫苗接受者中隔离到PPS3，并确定其在ST3殖民的鼠标模型中的功效，肺炎，肺炎和seppsis作为其基因使用和多样性的功能，PPS3 Eptipoper特异性和功能性活动，并确定其功能 ST3在体外，迈出了识别ST3治疗性Humab的第一步。此外，我们将使用保护性Humabs的表位和功能方面作为探针来询问PPS疫苗受体的PPS3反应。该项目中开发的HUMAB将作为ST3的候选治疗剂，其对ST3的抗体免疫提供的新科学信息将使以前和识别ST3疫苗的新颖，保护性PPS3抗原的新颖，保护性PPS3抗原的方式将PPS3反应剖分为疫苗。因此，通过新的治疗剂预防ST3和基础科学，通过对抗体免疫，ST3发病机理和HOSTS-ST3相互作用的新见解，该项目将对临床医学产生重大影响。