Effects of aging and HIV infection on the response to pneumococcal vaccine

描述：HIV感染者(HIV)和老年人是推荐接种肺炎球菌疫苗的主要成人人群，因为他们对肺炎链球菌(肺炎球菌)高度敏感，肺炎链球菌是美国和全球社区获得性肺炎和医院内肺炎的主要原因。2012年秋季晚些时候，自2010年以来推荐给婴儿/儿童并自2011年批准用于成人的13价肺炎球菌荚膜多糖(PPS)结合疫苗(PCV13)被推荐给HIV成人。本项目是根据PAR 12-175“艾滋病毒/艾滋病和老龄化的多学科研究”提交的，目的是确定老龄化和艾滋病毒感染PCV13反应的影响。在之前的工作中，我们的团队发现了B细胞和抗体库缺陷与HIV个体受损的PPS抗体反应之间的联系，并确定了PPS抗体的新功能活性，以保护小鼠免受肺炎球菌败血症和肺炎的侵袭。受这些研究的启发，我们将深入分析中年(50-65岁)和老年(65岁)HIV和HIV-个体对PCV13的血清学、B细胞、功能和分子反应，并将数据收集到PCV13反应的血清学和分子特征中。我们将使用标准的血清学和功能分析，以及针对PCV13被开发来预防的临床重要肺炎球菌血清型的PPS抗体功能活性的新分析。然后，我们将使用系统生物学来确定PCV13应答的分子机制，并将B细胞、血清学和转录图谱组装成应答的生物标志物。本项目的具体目标是：1)确定年龄和HIV感染对PCV13抗体和B细胞应答的影响；2)确定年龄和HIV感染对PCV13诱导的抗体功能活性的影响；3)确定年龄和HIV感染对PCV13分子应答的影响。由于成人肺炎球菌疫苗反应的生物标志物尚不可用，本研究中确定的生物标志物将填补一个重大空白，并提供一个破译PCV13疗效的平台，一个指导未来在老年艾滋病毒和艾滋病毒感染者中使用疫苗的路线图，改善疫苗免疫原性的线索，以及开发新方法预防最高风险人群肺炎球菌疾病的途径。

DESCRIPTION: HIV-infected (HIV+) and elderly individuals are the main adult populations for whom pneumococcal vaccine is recommended as they are highly susceptible to Streptococcus pneumoniae (pneumococcus), the leading cause of community acquired and in-hospital pneumonia in the U.S. and globally. In late fall 2012, a 13 valent pneumococcal capsular polysaccharide (PPS) conjugate vaccine (PCV13) recommended for infants/children since 2010 and approved for adults since 2011, was recommended for HIV+ adults. The goal of this project, submitted in response to PAR 12-175 "Multidisciplinary studies of HIV/AIDS and Aging", is to determine the effects of aging and HIV infection PCV13 response. In prior work, our group discovered links between B cell and antibody repertoire deficiencies and impaired PPS antibody responses in HIV+ individuals and identified novel functional activities of PPS antibodies that protect against pneumococcal sepsis and pneumonia in mice. Informed by these studies, we will perform in depth analyses of the serological, B cell, functional and molecular responses to PCV13 of middle aged (50-65 yrs) and elderly (>65 yrs) HIV+ and HIV- individuals and assemble the data into serological and molecular signatures of PCV13 response. We will use standard serological and functional assays along with novel assays of PPS antibody functional activity against clinically important pneumococcal serotypes that PCV13 was developed to prevent. Then, we will use systems biology to identify molecular mechanisms of PCV13 response and assemble B cell, serological and transcriptional profiles into biomarkers of response. The specific aims of this project are: 1) To determine the effects of age and HIV infection on the antibody and B cell response to PCV13; 2) To determine the effects of age and HIV infection on PCV13-elicited antibody functional activity; 3) To determine the effects of age and HIV infection on the molecular response to PCV13. As biomarkers of adult pneumococcal vaccine response are not available, those identified in this study will fill a major gap and provid a platform to decipher PCV13 efficacy, a roadmap to guide future vaccine use in elderly HIV+ and HIV- individuals, clues to improve vaccine immunogenicity, and pathways to develop new approaches to prevent pneumococcal disease in those who are most at risk.