Alpha-galactosycleramide as a mucosal adjuvant for HIV antigens

α-半乳糖酰胺作为 HIV 抗原的粘膜佐剂

• 批准号: 7849955
• 负责人: Jagannadha K Sastry
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849955
• 关键词: Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adjuvant; Adopted; Animal Model; Antigen-Presenting Cells; Antigens; Area; Biological Response Modifiers; CD8B1 gene; Cancer Vaccines; Clinical; Data; Dendritic Cells; Dendritic cell activation; Development; Future; Glycolipids; Goals; HIV; HIV-1; Human; Human immunodeficiency virus test; Immune; Immune response; Immunity; Kinetics; Macaca mulatta; Mediating; Modeling; Mucous Membrane; Mus; Oral; Outcome; Peptides; Preparation; Proteins; Regimen; Route; SIV Vaccines; Sexually Transmitted Diseases; Site; Surface; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tumor Antigens; Vaccination; Vaccines; Viral; Viral Antigens; Virus Diseases; alpha-galactosylceramide; base; cell type; cytokine; design; efficacy testing; env Gene Products; immunogenicity; killer T cell; nonhuman primate; pathogen; public health relevance; response; tumor immunology; uptake; vaccine candidate; vaccine delivery

DESCRIPTION (provided by applicant): Vaccination for protection against sexually transmitted diseases such as acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection should concentrate on inducing strong antigen-specific humoral and cellular immune responses as a mucosal barrier for viral entry. However, delivery of vaccines, specifically those based on proteins, to the mucosal surfaces is generally inefficient and requires the use of suitable adjuvants that could directly potentiate the effector T cells and the antigen-presenting cells (APC), such as the dendritic cells (DC), and/or mobilize the innate immune responses. The synthetic glycolipid alpha-glactosylceramide (aGalCer), a potent activator of natural killer T (NKT) cells, a major innate immune mediator cell type, has been shown to be safe and effective when administered by the parenteral routes for enhancing specific immune responses to tumor vaccines in several animal model studies. We obtained pilot data showing induction of systemic and mucosal cellular immune responses to HIV as well as non-HIV peptide antigens after intranasal and oral delivery in mice only when aGalCer was co-administered. Based on these results we hypothesize that mucosal delivery of HIV antigens using aGalCer as adjuvant will be a safe and effective approach for inducing strong mucosal and systemic immunity. Furthermore, we hypothesize that DC at mucosal compartments can be activated by aGalCer-mediated NKT cell responses to enable the DC to present HIV antigenic peptides to CD4+ and CD8+ T cells. We propose to harness the adjuvant potential of aGalCer employing the HIV-1 envelope protein, as a test antigen, specifically delivered by the mucosal routes to prime efficient mucosal and systemic immune responses. Our proposed studies will also analyze the underlying mechanisms for the adjuvant activity of aGalCer. To achieve these goals we propose to: Evaluate mucosal adjuvant activity of aGalCer for priming humoral and cellular immune responses to HIV-1 delivered, as protein or expressed from adenoviral vector, by the intranasal and oral routes. Determine potential associations between the kinetics of NKT cell and DC activation and priming of antigen-specific T cells in the mucosal and systemic compartments when aGalCer is used for delivery of antigens by the intranasal and oral routes to mice. Successful outcome (i.e. potent induction of mucosal and systemic antigen-specific immune responses using aGalCer as mucosal adjuvant) will enable us to extend the immunogenicity studies in future proposals for testing HIV/SIV vaccine candidates in the nonhuman primate model comprised of Indian-origin rhesus macaques followed by efficacy testing against mucosal challenge with pathogenic SIV/SHIV strains. PUBLIC HEALTH RELEVANCE: Successful outcome (i.e. potent induction of mucosal and systemic antigen-specific immune responses) will enable us to extend the immunogenicity studies in future proposals for testing HIV/SIV vaccine candidates in the nonhuman primate model comprised of Indian-origin rhesus macaques followed by efficacy testing against mucosal challenge with pathogenic SIV/SHIV strains.

描述（由申请人提供）：预防性传播疾病（如由人类免疫缺陷病毒（HIV）感染引起的获得性免疫缺陷综合征（AIDS））的疫苗接种应集中于诱导强烈的抗原特异性体液和细胞免疫应答，作为病毒进入的粘膜屏障。然而，将疫苗，特别是基于蛋白质的疫苗递送至粘膜表面通常是低效的，并且需要使用合适的佐剂，所述佐剂可以直接增强效应T细胞和抗原呈递细胞（APC），如树突状细胞（DC），和/或动员先天免疫应答。合成糖脂α-半乳糖神经酰胺（aGalCer）是一种天然杀伤T（NKT）细胞（一种主要的先天性免疫介导细胞类型）的强效激活剂，在几项动物模型研究中，通过胃肠外途径给药可安全有效地增强对肿瘤疫苗的特异性免疫应答。我们获得的试验数据显示，仅当共施用aGalCer时，在小鼠中鼻内和口服递送后诱导对HIV以及非HIV肽抗原的全身和粘膜细胞免疫应答。基于这些结果，我们假设使用aGalCer作为佐剂的HIV抗原的粘膜递送将是诱导强粘膜和全身免疫的安全有效的方法。此外，我们假设粘膜区室的DC可以被aGalCer介导的NKT细胞应答激活，以使DC能够将HIV抗原肽呈递给CD 4+和CD 8 + T细胞。我们建议利用aGalCer的佐剂潜力，采用HIV-1包膜蛋白作为测试抗原，通过粘膜途径特异性递送以引发有效的粘膜和全身免疫应答。我们提出的研究还将分析aGalCer佐剂活性的潜在机制。为实现这些目标，我们建议： 评价aGalCer的粘膜佐剂活性，用于引发对通过鼻内和口服途径作为蛋白质递送或从腺病毒载体表达的HIV-1的体液和细胞免疫应答。 确定当aGalCer用于通过鼻内和口服途径向小鼠递送抗原时，粘膜和全身隔室中NKT细胞动力学和DC活化与抗原特异性T细胞引发之间的潜在关联。 成功的结果（即使用aGalCer作为粘膜佐剂有效诱导粘膜和全身抗原特异性免疫应答）将使我们能够在未来的提案中扩展免疫原性研究，用于在由印度恒河猴组成的非人灵长类动物模型中测试HIV/SIV候选疫苗，然后进行针对致病性SIV/SHIV毒株粘膜攻击的效力测试。公共卫生相关性：成功的结果（即粘膜和全身抗原特异性免疫应答的强效诱导）将使我们能够在未来的提案中扩展免疫原性研究，用于在由印度恒河猴组成的非人灵长类动物模型中检测HIV/SIV候选疫苗，然后进行针对致病性SIV/SHIV毒株粘膜攻击的有效性检测。