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）：需要对人类免疫缺陷病毒（HIV）开发有效且安全的疫苗，其主要目的是阻止艾滋病流行的传播。通过阐明疫苗诱导的保护的免疫相关性，将促进这种有效疫苗的设计。我们已经在恒河猕猴中进行了疫苗接种研究，以评估含有VIF缺失的SIVMAC239病毒（Sivvif Provirus）的质粒DNA作为前病毒DNA疫苗。此外，我们研究了与SIV？VIF前病毒DNA共接种时，恒河猕猴白介素（IL）-15表达质粒的佐剂活性。这些研究的发现表明，与IL-15质粒表达载体共免疫具有对SIV杀性的前病毒DNA疫苗的显着佐剂作用，并通过致病性SIVMAC251增强了针对阴道挑战的保护。此外，通过干扰素检查SIV特异性细胞免疫反应？ ELISPOT和T细胞增殖分析显示干扰素 - 显着增强？通过将IL-15作为前病毒DNA疫苗的佐剂纳入ELISPOT反应。这些NIH资助的疫苗研究现已得出结论。我们建议使用10种颜色的多参数流式细胞术测定法，进一步研究来自这些相同疫苗研究的冷冻保存PBMC样品的病毒特异性细胞免疫反应。该测定法将评估SIV诱导的细胞因子的T细胞内表达，包括干扰素 - 肿瘤坏死因子（TNF）-A和白介素2，并测试特异性细胞表面标记的表达细胞毒性T细胞脱粒化（10107a），CD8 T细胞造成的死亡（CD127或cd127或cd127或IL-l-7）（CD127A）和A（CD8 1/pd-1）。这种类型的免疫反应评估未在原始的NIH提案中描述，该提案资助了这些SIV？VIF DNA疫苗研究。但是，这些研究的观察结果和最近的报告表明，这些功能特征阐明了对疫苗设计至关重要的免疫相关性的效用。假设是，实施新的工具，用于在带有或不具有IL-15表达质粒的SIV疫苗接种的猕猴中进行全面的免疫反应分析，是否会阐明用于IL-15辅助活性的免疫相关性（S），并诱导了对病毒负载的疫苗控制。此外，IL-15被认为是HAART患者的潜在免疫治疗。因此，仔细阐明与潜在有效的细胞因子辅助（例如IL-15）相关的细胞免疫反应可能会影响未来的HIV-1疫苗和治疗剂的设计。公共卫生相关性：猴子动物模型最近研究的结果表明，包括指定白介素（IL）-15的淋巴细胞生长因子，作为高度减弱的SIV？VIF DNA疫苗的一部分，提高了该疫苗的有效性。但是，对疫苗诱导的免疫反应的标准测试并未确定IL-15改善疫苗的特定原因或机制。我们建议使用过去十年中开发的新技术进一步检查病毒特异性的细胞免疫反应，以确定IL-15改善该DNA疫苗的机制。然后，这些研究的发现可用于将来设计，以进行更有效的HIV-1疫苗，以及用于HIV-1感染的免疫治疗剂的设计。