Nanoemulsion-based vaccine for chronic hepatitis B virus

描述（由申请人提供）：B肝炎病毒（HBV）是全球慢性病毒性肝病最常见的原因。超过3.7亿人慢性感染HBV，每年导致近100万人死于肝硬化、肝衰竭和肝细胞癌（HCC）。目前可用的针对慢性HBV的疗法是昂贵的，需要多年的长期施用，并且通常不能控制病毒持续存在、复制和坏死性炎症性肝病的进展。这些患者也有可能终身感染。预防性疫苗将为预防B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，但在患有肾脏疾病或其他免疫异常的高危人群中用处不大。此外，目前基于明矾的疫苗不能诱导治疗不能清除HBV的患者所需的细胞介导的免疫类型。因此，目前针对B型肝炎的免疫策略不能用作治疗性疫苗。 NanoBio公司（安阿伯，密歇根州）和密歇根大学医学和生物科学纳米技术研究所正在开发一种基于纳米乳液（NE）的佐剂，以增强疫苗抗原的免疫原性和鼻内递送。纳米乳液佐剂是通过使用无害的表面活性剂和溶剂作为稳定剂的高速均质化制备的水包油乳液，平均液滴尺寸为200-600 nm。这些佐剂已在动物模型中显示出增强疫苗抗原对免疫系统的靶向，同时安全地引发有效的体液和Th 1型细胞免疫应答而不诱导炎症。此外，用于无针递送的NE疫苗制剂在室温下高度稳定，能够在不冷藏的情况下广泛储存。 I期STTR计划的总体目标是证明基于纳米乳剂的HBV疫苗可以在存在混杂因素（如肾衰竭）的情况下诱导免疫应答。与正常人相比，这一组是HBV感染并发症的高危人群。因此，本研究将评估和优化一种新型的基于NE的鼻内疫苗，用于在正常小鼠和慢性肾衰竭小鼠中最大化HBV特异性CD 4+和CD 8 + T细胞和体液免疫应答，以对抗B表面抗原（HBsAg），作为免疫受损人类的模型。将在家兔中进行临床前安全性和耐受性研究，作为进入人体试验的要求。在I期项目成功完成后，将准备II期STTR申请，最终将进行FDA批准的I期临床试验，以评估安全性、剂量范围、免疫原性和对肾衰竭人类慢性B型肝炎病毒的初步疗效。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提供基础。这种新疫苗作为商业化产品将具有巨大的价值，以降低美国和全球HBV相关肝病和死亡的风险和相关经济负担。 公共卫生相关性：B型肝炎病毒（HBV）是慢性病毒性肝病最常见的原因。拟议的研究将开发一种新型的基于纳米乳液的鼻内疫苗，以预防免疫功能低下和慢性感染患者的病毒传播和严重并发症，如肝硬化，肝功能衰竭和肝细胞癌（HCC）的发展。开发一种安全、无针、易于给药和高效的基于纳米乳剂的疫苗将在美国和全球范围内作为抗慢性HBV感染的治疗剂具有巨大价值。

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.