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

产品说明：HIV感染者（HIV+）和老年人是推荐使用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）高度易感，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，自2010年以来推荐用于婴儿/儿童并自2011年以来批准用于成人的13价肺炎球菌荚膜多糖（PPS）结合疫苗（PCV 13）被推荐用于HIV+成人。该项目的目标是响应PAR 12-175“艾滋病毒/艾滋病和老龄化的多学科研究”，以确定老龄化和艾滋病毒感染PCV 13反应的影响。在之前的工作中，我们的团队发现了HIV+个体中B细胞和抗体库缺陷与PPS抗体应答受损之间的联系，并确定了PPS抗体的新功能活性，这些抗体可以保护小鼠免受肺炎球菌败血症和肺炎的侵害。根据这些研究，我们将深入分析中年（50-65岁）和老年（>65岁）HIV+和HIV-个体对PCV 13的血清学、B细胞、功能和分子应答，并将数据汇集成PCV 13应答的血清学和分子特征。我们将使用标准血清学和功能测定沿着PPS抗体功能活性的新型测定，以对抗临床上重要的肺炎球菌血清型，而PCV 13正是为了预防这些血清型而开发的。然后，我们将使用系统生物学来确定PCV 13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。本项目的具体目的是：1）确定年龄和HIV感染对PCV 13抗体和B细胞应答的影响; 2）确定年龄和HIV感染对PCV 13诱导的抗体功能活性的影响; 3）确定年龄和HIV感染对PCV 13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不可用，本研究中确定的生物标志物将填补一个主要空白，并提供一个解释PCV 13疗效的平台，一个指导未来在老年HIV+和HIV-个体中使用疫苗的路线图，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.