Nanoemulsion-based vaccine for chronic hepatitis B virus

慢性乙型肝炎病毒纳米乳疫苗

• 批准号: 7806254
• 负责人: JAMES R. BAKER
• 金额: $ 29.73万
• 依托单位: BLUEWILLOW BIOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806254
• 关键词: Acute; Acute Hepatitis; Adjuvant; Adult; Africa; Age; Aging; Aluminum Hydroxide; Animal Model; Antibodies; Antibody Formation; Antigens; Asia; B-Lymphocytes; Biological Sciences; CD8B1 gene; Caucasians; Caucasoid Race; Cells; Cellular Immunity; Cessation of life; Characteristics; Chronic; Chronic Hepatitis B; Chronic Kidney Failure; Cirrhosis; Clinical; Combined Modality Therapy; Data; Developing Countries; Development; Disease; Dose; Drug Formulations; Emulsions; End stage renal failure; Evaluation; Exposure to; Foundations; Frequencies; Goals; Grant; HLA-A2 Antigen; Health; Helper-Inducer T-Lymphocyte; Hemodialysis; Hepatitis; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B Virus; Histocompatibility Antigens Class II; Homing; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunization Schedule; Immunosuppression; Incidence; Individual; Infection; Inflammation; Inflammatory; Institute of Medicine (U.S.); Interferon-alpha; Interferons; Intramuscular; Kidney Diseases; Kidney Failure; Kidney Transplantation; Laboratories; Licensing; Life; Liver; Liver Failure; Liver diseases; Major Histocompatibility Complex; Mediating; Michigan; Modeling; Mucous Membrane; Mus; Nanotechnology; National Institute of Allergy and Infectious Disease; Needles; Nose; Oils; Organ Donor; Oryctolagus cuniculus; Pathway interactions; Patient Monitoring; Patients; Pharmacotherapy; Phase; Phase I Clinical Trials; Pilot Projects; Poloxamer; Poloxamers; Polymerase; Population; Preparation; Prevent viral transmission; Prevention; Primary carcinoma of the liver cells; Production; Recovery; Refrigeration; Regimen; Risk; Risk Factors; Safety; Schedule; Simian B disease; Site; Skin; Small Business Technology Transfer Research; Solutions; Solvents; Span 80; Specificity; Speed; Staging; Surface; T cell response; T-Lymphocyte; Temperature; Therapeutic Agents; Toxic effect; Transgenic Model; Transgenic Organisms; Tween 80; United States; United States Food and Drug Administration; Universities; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; Water; aluminum sulfate; base; blood product; cell mediated immune response; clinical toxicology; cost; cytokine; disease transmission; drug resistant virus; high risk; immune function; immunogenicity; inhibitor/antagonist; insight; nanoemulsion; neutralizing antibody; novel; novel vaccines; patient population; pre-clinical; prevent; programs; prophylactic; prototype; public health relevance; research clinical testing; research study; response; safety study; stability testing; surfactant; therapeutic vaccine; transmission process; vaccine development; viral liver disease

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is the most common cause of chronic viral liver disease worldwide. More than 370 million people are chronically infected with HBV leading to nearly one million deaths annually as a result of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Currently available therapies against chronic HBV are expensive, require long-term administration over many years, and often fail to control viral persistence, replication and the progression of necro-inflammatory liver disease. These patients also have the potential for life-long spread of infection. A prophylactic vaccine would provide the best solution for prevention of hepatitis B virus infection. However, the current vaccines while generally effective are less useful in high-risk populations with renal disease or other immunological abnormalities. In addition, the current alum-based vaccine does not induce the type of cell-mediated immunity necessary to treat patients who cannot clear HBV. Therefore, current immunization strategies for hepatitis B cannot be employed as therapeutic vaccines. NanoBio Corporation (Ann Arbor, MI) and the University of Michigan, Michigan Nanotechnology Institute for Medicine and Biological Sciences are developing a nanoemulsion (NE) based adjuvant to enhance the immunogenicity and intranasal delivery of vaccine antigens. Nanoemulsion adjuvants are oil-in-water emulsions prepared by high speed homogenization using innocuous surfactants and solvents as stabilizers with an average droplet size of 200-600 nm. These adjuvants have been shown in animal models to augment targeting of vaccine antigens to the immune system while safely eliciting potent humoral and Th1-type cellular immune responses without inducing inflammation. In addition, the NE vaccine formulations for needle-free delivery are highly stable at room temperature enabling wide spread storage without refrigeration. The overall goal of the Phase I STTR program is to demonstrate that a nanoemulsion-based HBV vaccine can induce immune responses in the presence of confounding factors such as renal failure. This group is at high risk for complications of HBV infection when compared to normal individuals. Therefore, the studies will evaluate and optimize a novel NE-based intranasal vaccine for maximum HBV-specific CD4+ and CD8+ T-cell and humoral immune responses against hepatitis B surface antigen (HBsAg) in normal mice and in mice with chronic renal failure as a model for immune-impaired humans. A pre-clinical safety and tolerability study will be conducted in rabbits as a requirement for progression to human trials. After successful completion of the phase I program, a phase II STTR application will be prepared culminating in an FDA- approved phase I clinical trial to evaluate safety, dose range, immunogenicity and preliminary efficacy against chronic hepatitis B virus in humans with renal failure. In addition, these studies will provide the foundation for the use of this formulation as a therapeutic vaccine for chronically infected individuals. This new vaccine would have great value as a commercialized product to reduce the risk and associated financial burden of HBV- associated liver diseases and deaths both in the United States and globally. PUBLIC HEALTH RELEVANCE: Hepatitis B virus (HBV) is the most common cause of chronic viral liver disease. The proposed studies will develop a novel nanoemulsion-based intranasal vaccine to prevent viral transmission and development of severe complications such as cirrhosis, liver failure and hepatocellular carcinoma (HCC) in immune compromised and chronically infected patients. Development of a safe, needle-free, easy-to-administer and highly effective nanoemulsion-based vaccine would have great value for use as a therapeutic agent against chronic HBV infection in the United States and globally.

描述（由申请人提供）：乙型肝炎病毒（HBV）是全世界慢性病毒性肝病的最常见原因。超过 3.7 亿人慢性感染 HBV，每年导致近百万人因肝硬化、肝功能衰竭和肝细胞癌 (HCC) 死亡。目前针对慢性乙型肝炎的可用疗法价格昂贵，需要多年长期给药，并且常常无法控制病毒的持续存在、复制和坏死性炎症性肝病的进展。这些患者也有可能终身传播感染。预防性疫苗将为预防乙型肝炎病毒感染提供最佳解决方案。然而，目前的疫苗虽然普遍有效，但对于患有肾病或其他免疫异常的高危人群却不太有用。此外，目前的明矾疫苗不能诱导治疗无法清除乙型肝炎病毒的患者所需的细胞介导免疫类型。因此，目前的乙型肝炎免疫策略不能用作治疗性疫苗。 NanoBio 公司（密歇根州安娜堡）和密歇根大学纳米技术医学与生物科学研究所正在开发一种基于纳米乳剂 (NE) 的佐剂，以增强疫苗抗原的免疫原性和鼻内递送。纳米乳佐剂是采用无毒的表面活性剂和溶剂作为稳定剂，通过高速均质制备的水包油乳剂，平均液滴尺寸为200-600 nm。这些佐剂已在动物模型中被证明可以增强疫苗抗原对免疫系统的靶向性，同时安全地引发有效的体液和 Th1 型细胞免疫反应，而不诱发炎症。此外，用于无针注射的 NE 疫苗配方在室温下高度稳定，无需冷藏即可广泛储存。 第一阶段 STTR 计划的总体目标是证明基于纳米乳剂的 HBV 疫苗可以在存在肾衰竭等混杂因素的情况下诱导免疫反应。与正常人相比，这一群体发生乙型肝炎病毒感染并发症的风险较高。因此，这些研究将评估和优化一种新型的基于 NE 的鼻内疫苗，以最大程度地提高正常小鼠和慢性肾功能衰竭小鼠的 HBV 特异性 CD4+ 和 CD8+ T 细胞以及针对乙型肝炎表面抗原 (HBsAg) 的体液免疫反应。免疫受损的人类模型。作为进入人体试验的必要条件，将在兔子身上进行临床前安全性和耐受性研究。成功完成第一阶段计划后，将准备第二阶段 STTR 申请，最终进行 FDA 批准的第一阶段临床试验，以评估肾衰竭患者对慢性乙型肝炎病毒的安全性、剂量范围、免疫原性和初步疗效。此外，这些研究将为使用该制剂作为慢性感染个体的治疗性疫苗奠定基础。这种新疫苗作为商业化产品具有巨大的价值，可降低美国和全球乙型肝炎相关肝病和死亡的风险和相关经济负担。 公共卫生相关性：乙型肝炎病毒 (HBV) 是慢性病毒性肝病的最常见原因。拟议的研究将开发一种新型的基于纳米乳剂的鼻内疫苗，以防止免疫受损和慢性感染患者的病毒传播和严重并发症的发生，例如肝硬化、肝衰竭和肝细胞癌（HCC）。开发一种安全、无针、易于给药且高效的纳米乳剂疫苗对于在美国和全球作为慢性乙型肝炎病毒感染的治疗剂具有巨大的价值。