Immune response to pneumococcal vaccination in aging HIV positive adults.

老年艾滋病毒阳性成年人对肺炎球菌疫苗接种的免疫反应。

• 批准号: 8593394
• 负责人: M.A. Julia WESTERINK
• 金额: $ 30.22万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593394
• 关键词: Adjuvant; Adult; Affect; Age-Years; Aging; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; BLR1 gene; Bacterial Pneumonia; Binding; Biological Assay; Blood specimen; CD19 gene; CD4 Positive T Lymphocytes; CXCL13 gene; Carrier Proteins; Cell Proliferation; Childhood; Chronic; Clinical; Conjugate Vaccines; Data; Development; Diphtheria; Disease; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Future; Goals; HIV; HIV Seropositivity; Helper-Inducer T-Lymphocyte; Highly Active Antiretroviral Therapy; IL2 gene; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Immunoglobulin M; Incidence; Individual; Inflammation; Interferon Type II; Interleukin-10; Ionomycin; Knowledge; Label; Life Expectancy; MS4A1 gene; Manuscripts; Measures; Memory B-Lymphocyte; Methods; Multivariate Analysis; Nature; Participant; Patients; Persons; Phenotype; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Pneumonia; Polysaccharides; Polyvalent pneumococcal vaccine; Population; Preparation; Production; Recommendation; Regimen; Research; Secondary to; Staining method; Stains; Streptococcus pneumoniae; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TI 2 Antigens; Testing; Vaccination; Vaccines; Vulnerable Populations; Work; base; cross reacting material 197; cytokine; efficacy trial; high risk; humoral immunity deficiency; immunosenescence; improved; inflammatory marker; interleukin-21; novel; older patient; peripheral blood; public health relevance; response; young adult

DESCRIPTION: Streptococcus pneumonia is the most common cause of bacterial pneumonia in HIV+ individuals. Despite routine pneumococcal polysaccharide vaccination (PPV23) and the widespread use of HAART, antibody levels and the functional activity of antibodies are lower than in HIV-negative persons and disease incidence therefore remains 35-50 fold higher than in HIV negative individuals. Similarly, PPV23 is less effective in the elderly. The introduction of HAART has led to a significant increase in life-expectancy of HIV+ persons and soon more than 50% of HIV positive individuals will be older than 50. This population will likely be at very high risk for IPD based on their immune deficiencies secondary to HIV AND immunosenescence as suggested using multivariate analysis. Although there is considerable overlap in B cell alterations caused by HIV and by aging we have recently found that aging and HIV result in distinct B cell deficiencies. The recommendations for pneumococcal vaccination in HIV+ persons have recently changed to include the 13-valent conjugate vaccine (PCV13). Although several studies show short-term efficacy or increased antibody response in HIV+ persons with PCV13, others do not, in either HIV+ population or in elderly. Large efficacy trials necessary to establish clinical superiority of PCV13 compared to PPV23 will likely not be conducted, particularly in the aging HIV+ population. It is therefore essential that we define immune responses to conjugated and free- polysaccharide preparations by examining traditional antibody and functional levels and at B and T cell levels, critically affected by aging and HIV, both characterized by chronic inflammation. The fundamental question posed in this proposal is: will PCV followed by PPV23 elicit an immune response compatible with improved protection or is it identical to the immune response following PPV23, known to be associated with suboptimal protection? Aim 1 test the hypothesis that vaccination with either PPV23 alone or a PCV13 containing regimen results in comparable antibody levels/functional activity, determined by levels of chronic inflammation. In aim 2, we test the hypothesis that the levels and phenotype of PPS-specific B cells will be comparable between the PPV23 and PCV13/PPV23 recipients. Phenotype analysis using a variety of B cell markers will be used to characterize PPS-labeled B cells. Specific phenotypes will be correlated with antibody levels, OPA and inflammatory markers and compared to historic populations immunized with PPV23. In aim 3 we will test the hypothesis that functional T cell helper responses to the conjugate vaccine will predict levels of switched B cells and IgG produced after vaccination. This work is important and novel because it examines antigen-specific responses post immunization to the number one cause of pneumonia in HIV and elderly patients. It is high impact as it will determine if either of the present vaccines is acceptable methods of inducing protective immunity or new methods with different adjuvants are required.

描述：肺炎链球菌是 HIV + 个体细菌性肺炎的最常见原因。尽管常规肺炎球菌多糖疫苗（PPV23）和HAART的广泛使用，抗体水平和抗体的功能活性仍低于HIV阴性个体，因此疾病发病率仍然比HIV阴性个体高35-50倍。同样，PPV23 对老年人的效果较差。 HAART 的引入使 HIV 阳性者的预期寿命显着增加，很快超过 50% 的 HIV 阳性者将超过 50 岁。由于继发性免疫缺陷，该人群可能面临极高的 IPD 风险根据多变量分析的建议，HIV 和免疫衰老。尽管 HIV 和衰老引起的 B 细胞改变有相当大的重叠，但我们最近发现衰老和 HIV 会导致明显的 B 细胞缺陷。 HIV+ 人群的肺炎球菌疫苗接种建议最近发生变化，包括 13 价结合疫苗 (PCV13)。尽管一些研究表明，对于感染 PCV13 的 HIV 阳性者有短期疗效或抗体反应增强，但其他研究则表明，无论是 HIV 阳性人群还是老年人，都没有这种效果。确定 PCV13 相对于 PPV23 的临床优势所需的大型疗效试验可能不会进行，特别是在老龄化的 HIV+ 人群中。因此，我们有必要通过检查传统抗体和功能水平以及 B 和 T 细胞水平来定义对缀合和游离多糖制剂的免疫反应，而 B 和 T 细胞水平受到衰老和 HIV 的严重影响，两者都以慢性炎症为特征。该提案提出的基本问题是：PCV 之后的 PPV23 是否会引发与改善的保护相容的免疫反应，或者它是否与已知与次优保护相关的 PPV23 之后的免疫反应相同？目标 1 检验以下假设：单独接种 PPV23 或含 PCV13 的疫苗接种方案可产生可比较的抗体水平/功能活性，具体取决于慢性炎症水平。 在目标 2 中，我们测试了以下假设：PPS 特异性 B 细胞的水平和表型在 PPV23 和 PCV13/PPV23 受体之间具有可比性。使用多种 B 细胞标记物的表型分析将用于表征 PPS 标记的 B 细胞。特定表型将与抗体水平、OPA 和炎症标志物相关，并与历史上接受 PPV23 免疫的人群进行比较。在目标 3 中，我们将检验以下假设：功能性 T 细胞辅助细胞对结合疫苗的反应将预测疫苗接种后产生的转换 B 细胞和 IgG 的水平。这项工作非常重要且新颖，因为它检查了免疫后对艾滋病毒和老年患者肺炎的首要原因的抗原特异性反应。它具有很高的影响力，因为它将确定现有疫苗是否是可接受的诱导保护性免疫的方法，或者是否需要使用不同佐剂的新方法。