Nanoemulsion-based vaccine for chronic hepatitis B virus

慢性乙型肝炎病毒纳米乳疫苗

基本信息

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
项目类别：
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

项目摘要

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）是全球慢性病毒肝病的最常见原因。由于肝硬化，肝脏衰竭和肝细胞癌（HCC），每年长期感染了3.7亿多人的HBV感染HBV。目前针对慢性HBV的可用疗法价格昂贵，需要长期给药多年，并且通常无法控制病毒持久性，复制和死灵炎性肝病的进展。这些患者还具有终生传播感染的潜力。预防性疫苗将为预防丙型肝炎病毒感染提供最佳解决方案。但是，当前的疫苗通常在肾脏疾病或其他免疫异常的高风险种群中有效。此外，当前基于明矾的疫苗不会诱导无法清除HBV的患者所需的细胞介导的免疫力。因此，当前针对丙型肝炎的免疫策略不能用作治疗疫苗。 Nanobio Corporation（密歇根州Ann Arbor）和密歇根大学纳米技术研究所医学与生物科学研究所正在开发基于纳米乳液（NE）辅助物，以增强疫苗抗原的免疫原性和鼻内递送。纳米乳剂佐剂是通过使用无害的表面活性剂和溶剂作为平均液滴尺寸为200-600 nm的稳定剂来制备的水中乳液。这些佐剂已在动物模型中显示，以增强疫苗抗原对免疫系统的靶向，同时安全引起有效的体液和Th1型细胞免疫反应而不会诱发炎症。另外，在室温下，用于无针递送的NE疫苗配方高度稳定，可以在不制冷的情况下进行广泛的扩散存储。 I期STTR计划的总体目标是证明基于纳米乳剂的HBV疫苗可以在存在诸如肾衰竭等混杂因素的情况下诱导免疫反应。与正常个体相比，该组患有HBV感染并发症的风险很高。因此，研究将评估和优化一种新型的基于NE的基于NE的鼻内疫苗，以针对正常小鼠中针对丙型肝炎表面抗原（HBSAG）的最大HBV特异性CD4+和CD8+ T细胞以及体液免疫反应，以及在具有慢性肾衰竭的小鼠中，作为免疫影响人类的慢性肾衰竭。将在兔子中进行临床前的安全性和耐受性研究，以作为对人类试验的发展的要求。成功完成I期计划后，将准备II期STTR应用，最终在FDA批准的I期临床试验中进行最终评估，以评估针对肾衰竭人类的慢性肝炎病毒的安全性，剂量范围，免疫原性和初步疗效。此外，这些研究将为长期感染的个体使用该配方作为治疗疫苗的基础。这种新疫苗作为商业化产品具有巨大的价值，可以减少美国和全球HBV相关肝病和死亡的风险和相关财务负担。公共卫生相关性：丙型肝炎病毒（HBV）是慢性病毒肝病的最常见原因。拟议的研究将开发一种新型的基于纳米乳液的鼻内疫苗，以防止在免疫受损和慢性感染的患者中，例如肝硬化，肝衰竭和肝细胞癌癌（HCC）等严重并发症的发展。开发安全，无针头，易于加工和高效的基于纳米乳液的疫苗将具有巨大的价值，可以用作美国和全球及全球慢性HBV感染的治疗剂。