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年人群，因为他们对肺炎链球菌（肺炎球菌）非常敏感，肺炎球菌是美国和全球社区获得性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）自2010年以来被推荐用于婴儿/儿童，自2011年以来被批准用于成人，被推荐用于艾滋病毒阳性成人。该项目的目标是根据PAR 12-175“HIV/AIDS和衰老的多学科研究”提交的，目的是确定衰老和HIV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+个体中PPS抗体反应受损之间的联系，并发现了PPS抗体的新功能活性，可以保护小鼠免受肺炎球菌败血症和肺炎。根据这些研究，我们将深入分析中年（50-65岁）和老年（50-65岁）HIV+和HIV-个体对PCV13的血清学、B细胞、功能和分子反应，并将这些数据整合到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，以及针对临床重要的肺炎球菌血清型的PPS抗体功能活性的新分析，PCV13是为了预防而开发的。然后，我们将利用系统生物学来确定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。该项目的具体目的是：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，本研究发现的这些生物标志物将填补这一重大空白，为解读PCV13的有效性提供平台，为指导未来在老年HIV+和HIV-个体中使用疫苗提供路线图，为提高疫苗免疫原性提供线索，并为开发预防肺炎球菌疾病的新方法提供途径。

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.