Alpha-galactosycleramide as a mucosal adjuvant for HIV antigens

描述（由申请人提供）：预防由人类免疫缺陷病毒（HIV）感染引起的性传播疾病（如获得性免疫缺陷综合征（艾滋病））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反应，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到粘膜表面通常效率低下，并且需要使用合适的佐剂，这些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/或调动先天免疫反应。合成糖脂α -冰原神经酰胺（aGalCer）是一种天然杀伤T细胞（NKT）的有效激活剂，是一种主要的先天免疫介质细胞类型，在一些动物模型研究中，经肠外给药增强肿瘤疫苗的特异性免疫反应已被证明是安全有效的。我们获得的初步数据显示，仅当aGalCer联合给药时，经鼻和口服给药后，小鼠对HIV和非HIV肽抗原的全身和粘膜细胞免疫反应才会被诱导。基于这些结果，我们假设使用aGalCer作为佐剂的HIV抗原粘膜递送将是一种安全有效的诱导强粘膜和全身免疫的方法。此外，我们假设粘膜区室的DC可以被agalcer介导的NKT细胞反应激活，使DC能够向CD4+和CD8+ T细胞呈递HIV抗原肽。我们建议利用aGalCer的佐剂潜力，利用HIV-1包膜蛋白作为测试抗原，通过粘膜途径特异性递送，以获得有效的粘膜和全身免疫反应。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：

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.