FcRn-targeted mucosal HIV vaccine

FcRn 靶向粘膜 HIV 疫苗

基本信息

批准号：
8409840
负责人：
C. David Pauza
金额：
$ 77.56万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-20 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8409840
关键词：
AIDS prevention Acetylmuramyl-Alanyl-Isoglutamine Adjuvant Antibodies Antigen-Presenting Cells Antigens B-Lymphocytes Bacteria Binding Biology Carbohydrate Chemistry Carbohydrates Cells Chimeric Proteins Complex Dendritic Cells Dose Drug Formulations Engineering Ensure Epidemic Epithelial Epithelial Cells Epithelium Fc Receptor Future Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Human Human Herpesvirus 2 IgG Receptors IgG2 Immune Immune response Immunity Immunization Immunology In Vitro Individual Interleukin-12 Intramuscular Knowledge Life Link Macaca Macaca mulatta Methods Modeling Modification Mucosal Immunity Mus Nose Oligosaccharides Polysaccharides Preparation Protein Glycosylation Proteins Recombinants Regimen Route Sexual Transmission Sialic Acids Simplexvirus Site Subunit Vaccines Surface T cell response T-Lymphocyte Testing Vaccines Virus Virus Diseases base design experience improved in vitro testing innovation interdisciplinary collaboration mouse model mucosal site mucosal vaccine multidisciplinary neonatal Fc receptor new technology nonhuman primate novel plasmid DNA prevent protective efficacy receptor rectal response sensor transcytosis uptake vector

项目摘要

DESCRIPTION (provided by applicant): Sexual transmission is the dominant mode for HIV spread worldwide. Our goal is to develop a subunit vaccine based on the HIV gp120 envelope glycoprotein, which can be delivered via atraumatic mucosal inoculation to elicit durable protective immunity. In order to immunize at mucosal sites, we need an efficient method for delivering gp120 and adjuvant to mucosal immune cells. We constructed fusion proteins consisting of gp120 linked to the Fc portion of IgG2 antibodies. The fusion protein Fc segment binds Fc receptor neonatal (FcRn) on mucosal epithelium, and crosses the epithelial barrier by non-degradative transcytosis to access underlying antigen presenting cells. Adjuvant, in our case muramyl dipeptide (MDP), is conjugated directly to the gp120-Fc fusion protein through modification of terminal sialic acid residues (Env-Fc-MDP). Thus, conjugated adjuvant and antigen are co-delivered to presenting cells. MDP was selected because it increases co-stimulatory molecule and IL-12 expression by dendritic cells, and should enhance T and B cell responses to HIV Env. The potency and durability of gp120 immune responses is increased with a prime/boost strategy where mucosal priming with fusion protein is followed by intramuscular boosting with gp120 plus soluble MDP. Our studies utilize in vitro or mouse models to optimize immunization strategies with fusion protein and adjuvant. Nonhuman primate studies optimize dose and route for immunization using an unrelated fusion protein (HSV-2 glycoprotein D-Fc), then test whether mucosal Env-Fc-MDP followed by intramuscular Env + soluble MDP elicits protection against repetitive, low-dose intrarectal inoculation with SHIV162p3. This project is an interdisciplinary collaboration between Dr. Zhu, expert in mouse models and Fc receptor biology, Dr. Wang, who is a glycobiologist and organic chemist expert in protein glycosylation, and Dr. Pauza who has extensive experience in nonhuman primate models, mucosal immunology and mucosal virus infections. The innovative route for mucosal antigen delivery, use of chemically-conjugated adjuvant to improve T cell responses, and our prime/boost strategy is a safe and potentially effective method for eliciting durable protective immunity against sexual transmission of HIV-1. PUBLIC HEALTH RELEVANCE: We are developing a safe and effective vaccine to prevent sexual transmission of HIV. Using new technology, we can deliver individual HIV proteins across mucosal surfaces to elicit protective immune responses at the body sites where virus is first encountered. Our strategy is distinct from approaches using plasmid DNA, recombinant bacteria or engineered virus to deliver HIV proteins, and affords us complete control over the vaccine composition, including formulation, conjugated adjuvant needed to improve the immune response, and dose.

描述（由申请人提供）：性传播是全球艾滋病毒传播的主要模式。我们的目标是基于HIV GP120包膜糖蛋白开发亚基疫苗，该疫苗可以通过促进的粘膜接种来传递，以引起耐用的保护性免疫。为了在粘膜部位进行免疫，我们需要一种有效的方法将GP120和辅助剂递送至粘膜免疫细胞。我们构建了由与IgG2抗体FC部分相关的GP120组成的融合蛋白。融合蛋白FC节段结合粘膜上皮上的FC受体新生儿（FCRN），并通过非降解的转介症跨越上皮屏障，以访问潜在的抗原呈现细胞。在我们的情况下，佐剂穆拉米尔二肽（MDP）通过修饰末端唾液酸残基（ENV-FC-MDP）直接连接到GP120-FC融合蛋白。因此，共轭佐剂和抗原被共同延伸至呈现细胞。之所以选择MDP，是因为它通过树突状细胞增加了共刺激分子和IL-12的表达，并且应增强对HIV Env的T和B细胞反应。 GP120免疫反应的效力和耐用性通过素数/增强策略提高，其中融合蛋白的粘膜启动随后用GP120加上可溶性MDP加强肌肉内增强。我们的研究利用体外或小鼠模型来优化融合蛋白和佐剂的免疫策略。非人类灵长类动物研究使用无关的融合蛋白（HSV-2糖蛋白D-FC）优化剂量和途径，然后测试是否粘膜INV-FC-MDP，然后是肌内ENV +可溶性MDP在SHIV162PUP SHIV162PUP的肌内uScull uscull +可溶性MDP保护剂。该项目是Zhu博士，鼠标模型专家和FC受体生物学专家，王博士之间的跨学科合作，他是蛋白质糖基化的糖基因医生和有机化学专家，Pauza博士在非人类灵长类动物模型，粘膜免疫学和粘膜病毒学上拥有丰富的经验。粘膜抗原递送的创新途径，使用化学偶联的佐剂来改善T细胞反应，以及我们的主要/增强策略是一种安全且潜在的有效方法，可为您提供耐用的保护性免疫，以防止HIV-1的性传播。公共卫生相关性：我们正在开发一种安全有效的疫苗，以防止艾滋病毒的性传播。使用新技术，我们可以在首次遇到病毒的身体部位上传递跨粘膜表面的单个HIV蛋白，以引起保护性免疫反应。我们的策略与使用质粒DNA，重组细菌或工程病毒的方法不同，以提供HIV蛋白，并为我们完全控制疫苗成分，包括配方，共轭辅助剂，以改善免疫反应和剂量。