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

基本信息

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
项目类别：
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

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

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项目摘要

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）：防止性传播疾病的疫苗接种，例如由人类免疫缺陷病毒（HIV）感染引起的可获得的免疫缺陷综合征（AIDS），应集中于诱导强大的抗原特异性体液和细胞免疫反应作为病毒进入的粘膜障碍。但是，将疫苗（特别是基于蛋白质的疫苗）输送到粘膜表面通常效率低下，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）（例如树突状细胞（DC）），并且或动员了先天免疫反应。合成糖脂α-乳乳糖基酰胺（Agalcer）是一种有效的天然杀伤剂T（NKT）细胞的有效活化剂，一种主体免疫介质细胞类型，当通过肠胃外路线增强对几种动物动物模型研究中肿瘤疫苗的特定免疫反应时，已证明是安全有效的。我们获得了启发性数据，显示仅当Agalcer共同给药时，鼻内和口服递送后，全身和粘膜细胞免疫反应以及小鼠的非HIV肽抗原的诱导。基于这些结果，我们假设使用Agalcer作为辅助的粘膜递送HIV抗原将是一种安全有效的方法，可诱导强粘膜和全身免疫力。此外，我们假设粘膜室的DC可以通过agalcer介导的NKT细胞反应激活，以使DC能够对CD4+和CD8+ T细胞呈现HIV抗原肽。我们建议利用使用HIV-1包膜蛋白作为测试抗原的agalcer的辅助潜力，该抗原是由粘膜途径专门提供的，以促进有效的粘膜和全身免疫反应。我们提出的研究还将分析Agalcer辅助活性的潜在机制。为了实现这些目标，我们建议：评估agalcer的粘膜辅助活性，用于通过鼻内和口服路线从腺病毒载体或从腺病毒载体表达的蛋白质或从腺病毒载体表达的HIV-1的粘膜辅助活性。确定NKT细胞的动力学与DC激活的动力学与粘膜特异性T细胞的启动与抗原特异性T细胞的启动和全身隔室时，当使用Agalcer通过鼻内和口服途径向小鼠递送抗原。成功的结果（即使用agalcer作为粘膜佐剂对粘膜和全身性抗原特异性免疫反应的有效诱导将使我们能够在未来的建议中扩展免疫原性研究，以测试HIV/SIV疫苗候选者在非人类的灵长类动物中，由印度摩纳哥蛋白麦芽麦粉促进了梅加蛋白含量，伴随着印度摩西蛋白麦芽麦粉的挑战，伴随着印度摩西蛋白麦粒子的测试。菌株。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反应的有效诱导）将使我们能够在未来测试HIV/SIV疫苗候选者的未来提案中扩展免疫原性研究，该疗程由印度 - 疏远麦克雷克斯（Rhesus Macaques）进行了反对攻击的效果攻击，在非人类的Primate模型中进行了反对的攻击。