FcRn-targeted mucosal HIV vaccine

FcRn 靶向粘膜 HIV 疫苗

• 批准号: 8513912
• 负责人: C. David Pauza
• 金额: $ 71.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/8513912
• 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; public health relevance; receptor; rectal; response; sensor; transcytosis; uptake; vector

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.

描述(申请人提供)：性传播是艾滋病毒在全球传播的主要方式。我们的目标是开发一种基于HIV gp120包膜糖蛋白的亚单位疫苗，它可以通过无创粘膜接种来诱导持久的保护性免疫。为了在黏膜部位进行免疫，需要一种有效的方法将gp120和佐剂输送到黏膜免疫细胞。我们构建了由连接到IgG2抗体Fc部分的gp120组成的融合蛋白。融合蛋白Fc片段与黏膜上皮细胞上的Fc受体结合，通过非降解性的细胞转运跨越上皮屏障，获得潜在的抗原提呈细胞。佐剂，在我们的案例中是胞壁二肽(MDP)，通过末端唾液酸残基的修饰(Env-Fc-MDP)直接连接到gp120-Fc融合蛋白上。因此，偶联佐剂和抗原被共同递送到呈递细胞。MDP之所以被选中，是因为它能增加树突状细胞表达共刺激分子和IL-12，并能增强T细胞和B细胞对HIV Env的应答。Gp120免疫反应的效力和持久性通过初始/增强策略得到提高，在该策略中，先用融合蛋白启动黏膜，然后再用gp120和可溶性MDP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。非人灵长类动物研究优化了使用无关融合蛋白(HSV-2糖蛋白D-Fc)进行免疫的剂量和路线，然后测试粘膜Env-Fc-MDP和肌肉内Env+可溶性MDP是否对SHIV162p3重复、低剂量直肠接种产生保护作用。这个项目是由小鼠模型和Fc受体生物学专家朱博士，蛋白质糖基化方面的糖生物学家和有机化学家专家王博士，以及在非人类灵长类动物模型、粘膜免疫学和粘膜病毒感染方面拥有丰富经验的Pauza博士共同开展的跨学科合作。粘膜抗原传递的创新途径，使用化学偶联佐剂来提高T细胞反应，以及我们的PRIME/BOOST策略是一种安全且潜在有效的方法，可以诱导持久的保护性免疫，以防性传播HIV-1。