FcRn-targeted mucosal HIV vaccine

FcRn 靶向粘膜 HIV 疫苗

• 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
• 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

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，该疫苗可以通过无创伤性粘膜接种来引起持久的保护性免疫。为了在粘膜部位进行免疫，我们需要一种有效的方法将gp120和佐剂递送到粘膜免疫细胞。我们构建了gp120与IgG2抗体Fc部分连接的融合蛋白。融合蛋白Fc片段结合粘膜上皮上的Fc新生受体（FcRn），并通过非降解胞吞作用穿过上皮屏障，进入下层抗原提呈细胞。在我们的研究中，佐剂是muramyl二肽（MDP），通过末端唾液酸残基（Env-Fc-MDP）的修饰直接与gp120-Fc融合蛋白结合。因此，结合佐剂和抗原被共同递送到呈递细胞。之所以选择MDP，是因为它可以增加树突状细胞的共刺激分子和IL-12的表达，并且可以增强T细胞和B细胞对HIV Env的反应。gp120免疫反应的效力和持久性可以通过启动/增强策略来提高，即融合蛋白的粘膜启动后，gp120加可溶性MDP的肌内增强。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使用不相关的融合蛋白（HSV-2糖蛋白D-Fc）优化免疫剂量和途径，然后测试粘膜Env- fc -MDP之后肌肉内Env +可溶性MDP是否能引起对重复低剂量SHIV162p3直肠内接种的保护。该项目是由小鼠模型和Fc受体生物学专家朱博士、蛋白质糖基化的糖生物学家和有机化学家王博士以及在非人灵长类动物模型、粘膜免疫学和粘膜病毒感染方面具有丰富经验的Pauza博士跨学科合作完成的。粘膜抗原递送的创新途径，使用化学偶联佐剂来改善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，可引发针对HIV-1性传播的持久保护性免疫。