Cellular Immune Responses Induced by SIVdelta-vif plus IL-15 DNA Vaccine

SIVdelta-vif 加 IL-15 DNA 疫苗诱导的细胞免疫反应

基本信息

批准号：
7494904
负责人：
Ellen Elizabeth Sparger
金额：
$ 7.6万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-17 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7494904
关键词：
Acquired Immunodeficiency Syndrome Adjuvant Animal Model Antibodies Antigens Attenuated Biological Assay CD8B1 gene Cell Degranulation Cell surface Cessation of life Color Cytotoxic T-Lymphocytes DNA DNA Vaccines Development Epidemic Funding Future Growth Factor HIV HIV-1 Highly Active Antiretroviral Therapy IL7R gene Immune Immune response Immunization Immunotherapeutic agent Infection Interferons Interleukin 7 Receptor Interleukin-15 Interleukin-2 Interleukins Investigation Lymphocyte Macaca Macaca mulatta Monkeys Patients Peripheral Blood Mononuclear Cell Plasmids Proteins Proviruses Public Health Reporting SIV Sampling Standards of Weights and Measures Surface T memory cell T-Cell Proliferation T-Lymphocyte Testing Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States National Institutes of Health Vaccinated Vaccination Vaccine Design Vaccines Vagina Viral load measurement Virus cytokine design expression vector human TNF protein immunogenicity improved new technology novel plasmid DNA programs response therapeutic vaccine tool vaccine effectiveness vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): The need is pressing to develop an effective and safe vaccine against the human immunodeficiency virus (HIV) with the primary objective of arresting the spread of the AIDS epidemic. Design of such efficacious vaccines will be facilitated by the elucidation of immune correlates of vaccine-induced protection. We have conducted vaccination studies in rhesus macaques to evaluate a plasmid DNA containing a vif-deleted SIVmac239 provirus (SIVvif provirus) as a proviral DNA vaccine. Furthermore we investigated the adjuvant activity of a rhesus macaque interleukin (IL)-15 expression plasmid when co-inoculated with the SIV?vif proviral DNA. Findings from these studies indicated that co-immunization with an IL-15 plasmid expression vector affords a significant adjuvant effect to the SIV vif-deleted proviral DNA vaccine and enhanced protection against vaginal challenge with pathogenic SIVmac251. Furthermore, examination of SIV-specific cellular immune responses by interferon-? ELISpot and T cell proliferation assays revealed a significant enhancement of interferon-? ELISpot responses by inclusion of IL-15 as an adjuvant for the proviral DNA vaccine. These NIH-funded vaccine studies have now been concluded. We propose to further examine virus-specific cellular immune responses from cryopreserved PBMC samples banked from these same vaccine studies, using a 10 color multi-parameter flow cytometric assay. This assay will evaluate SIV-induced T cell intracellular expression of cytokines including interferon-?, tumor necrosis factor (TNF)-a, and interleukin-2 and also test for expression of specific cell surface markers for cytotoxic T cell degranulation (CD107a), CD8 T cell memory development (CD127 or IL-7 receptor a) and a negative immunoregulatory protein (program death 1/PD-1). This type of immune response assessment was not described in the original NIH proposal that funded these SIV?vif DNA vaccine studies. However, this investigation is now well justified by observations from these studies and by recent reports showing the utility of these functional profiles to elucidate immune correlates that are critical for vaccine design. The hypothesis is that implementation of novel tools for comprehensive immune response analysis in macaques vaccinated with SIV?vif proviral DNA with or without IL-15 expression plasmid, will elucidate an immune correlate(s) for IL-15 adjuvant activity and vaccine-induced control of virus load. Furthermore, Il-15 has been considered as a potential immunotherapeutic for patients on HAART. Accordingly, careful elucidation of cellular immune responses associated with a potentially effective cytokine adjuvant such as IL-15 may impact design of future HIV-1 vaccines and therapeutics. PUBLIC HEALTH RELEVANCE: Findings from recent studies in monkey animal models, suggested that including a lymphocyte growth factor designated interleukin (IL)-15, as part of the highly attenuated SIV?vif DNA vaccine, improved the effectiveness of this vaccine. However standard tests for vaccine-induced immune responses did not identify a specific cause or mechanism by which IL-15 improved the vaccine. We propose to further examine virus-specific cellular immune responses using new technologies developed over the past decade, to identify mechanisms by which IL-15 improved this DNA vaccine. Findings from these studies may then be used for future design for more effective HIV-1 vaccines, as well as design for immunotherapeutics for HIV-1 infection.

描述（由申请人提供）：迫切需要开发一种有效且安全的针对人类免疫缺陷病毒（HIV）的疫苗，其主要目标是阻止艾滋病流行的传播。阐明疫苗诱导保护的免疫相关性将有助于设计这种有效的疫苗。我们在恒河猴中进行了疫苗接种研究，以评估含有 vif 删除的 SIVmac239 原病毒（SIVvif 原病毒）的质粒 DNA 作为原病毒 DNA 疫苗。此外，我们研究了恒河猴白细胞介素 (IL)-15 表达质粒与 SIV?vif 前病毒 DNA 共接种时的佐剂活性。这些研究结果表明，与 IL-15 质粒表达载体共同免疫可为 SIV vif 缺失的原病毒 DNA 疫苗提供显着的佐剂作用，并增强对致病性 SIVmac251 阴道攻击的保护。此外，通过干扰素-α检查SIV特异性细胞免疫反应。 ELISpot 和 T 细胞增殖测定显示干扰素-β 显着增强。通过添加 IL-15 作为原病毒 DNA 疫苗的佐剂进行 ELISpot 反应。这些由美国国立卫生研究院资助的疫苗研究现已结束。我们建议使用 10 色多参数流式细胞术进一步检查来自这些相同疫苗研究的冷冻保存的 PBMC 样本的病毒特异性细胞免疫反应。该测定将评估 SIV 诱导的 T 细胞胞内细胞因子表达，包括干扰素-α、肿瘤坏死因子 (TNF)-a 和白细胞介素-2，并测试细胞毒性 T 细胞脱粒的特定细胞表面标志物 (CD107a) 的表达。 CD8 T 细胞记忆发育（CD127 或 IL-7 受体 a）和负免疫调节蛋白（程序死亡 1/PD-1）。资助这些 SIV?vif DNA 疫苗研究的最初 NIH 提案中并未描述这种类型的免疫反应评估。然而，这些研究的观察结果和最近的报告显示，这些功能图谱可用于阐明对疫苗设计至关重要的免疫相关性，现在这项研究已得到充分证明。假设在接种了 SIV?vif 前病毒 DNA（有或没有 IL-15 表达质粒）的猕猴中使用新工具进行综合免疫反应分析，将阐明 IL-15 佐剂活性和疫苗诱导控制的免疫相关性病毒载量。此外，IL-15已被认为是HAART患者的潜在免疫治疗药物。因此，仔细阐明与潜在有效的细胞因子佐剂（例如 IL-15）相关的细胞免疫反应可能会影响未来 HIV-1 疫苗和治疗方法的设计。公共健康相关性：最近对猴子动物模型的研究结果表明，将一种称为白细胞介素 (IL)-15 的淋巴细胞生长因子作为高度减毒 SIV?vif DNA 疫苗的一部分，可提高该疫苗的有效性。然而，疫苗诱导免疫反应的标准测试并未确定 IL-15 改善疫苗的具体原因或机制。我们建议使用过去十年开发的新技术进一步检查病毒特异性细胞免疫反应，以确定 IL-15 改进这种 DNA 疫苗的机制。这些研究的结果可用于未来设计更有效的 HIV-1 疫苗，以及设计针对 HIV-1 感染的免疫疗法。