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

描述：艾滋病毒感染者 (HIV ) 和老年人是建议接种肺炎球菌疫苗的主要成年人群，因为他们对肺炎链球菌（肺炎球菌）高度敏感，而肺炎链球菌是美国和全球社区获得性肺炎和院内肺炎的主要原因。 2012 年秋末，一种 13 价肺炎球菌荚膜多糖 (PPS) 结合疫苗 (PCV13) 被推荐用于艾滋病毒成人，该疫苗自 2010 年起推荐用于婴儿/儿童，自 2011 年起批准用于成人。该项目是根据 PAR 12-175“HIV/AIDS 和老龄化的多学科研究”提交的，其目标是确定老龄化和 HIV 感染 PCV13 反应的影响。在之前的工作中，我们的小组发现了 HIV 个体中 B 细胞和抗体库缺陷与 PPS 抗体反应受损之间的联系，并确定了 PPS 抗体可预防小鼠肺炎球菌败血症和肺炎的新功能活性。根据这些研究，我们将对中年（50-65岁）和老年（>65岁）HIV和HIV个体对PCV13的血清学、B细胞、功能和分子反应进行深入分析，并将数据汇总成PCV13反应的血清学和分子特征。我们将使用标准血清学和功能测定以及针对 PCV13 旨在预防的临床重要肺炎球菌血清型的 PPS 抗体功能活性的新型测定。然后，我们将利用系统生物学来识别 PCV13 反应的分子机制，并将 B 细胞、血清学和转录谱组装成反应的生物标志物。该项目的具体目标是： 1）确定年龄和HIV感染对PCV13抗体和B细胞反应的影响； 2) 确定年龄和HIV感染对PCV13引发的抗体功能活性的影响； 3) 确定年龄和HIV感染对PCV13分子反应的影响。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 功效的平台、指导未来老年 HIV 和 HIV 个体使用疫苗的路线图、提高疫苗免疫原性的线索，以及开发新方法来预防高危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.