Nanoemulsion-based vaccine for chronic hepatitis B virus

描述(申请人提供)：乙肝病毒(乙肝)是全球慢性病毒性肝病最常见的原因。每年有超过3.7亿人慢性感染乙肝病毒，导致近100万人死于肝硬变、肝功能衰竭和肝细胞癌。目前可用的治疗慢性乙肝的方法昂贵，需要多年的长期给药，而且往往无法控制病毒的持久性、复制和坏死性炎症性肝病的进展。这些患者还有可能终身传播感染。预防性疫苗将为预防乙肝病毒感染提供最佳解决方案。然而，目前的疫苗虽然总体上有效，但在患有肾脏疾病或其他免疫异常的高危人群中用处较小。此外，目前以明矾为基础的疫苗不能诱导治疗无法清除乙肝病毒的患者所需的细胞介导免疫类型。因此，目前的乙肝免疫策略不能用作治疗性疫苗。NanoBio公司(密歇根安娜堡)和密歇根大学密歇根大学纳米技术医学和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腔递送。纳米乳液助剂是以无毒的表面活性剂和溶剂为稳定剂，采用高速均质法制备的水包油型乳状液，平均液滴尺寸为200-600 nm。这些佐剂已经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，同时安全地激发有效的体液和Th1型细胞免疫反应，而不会引发炎症。此外，无针注射的乙脑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乙肝疫苗可以在存在肾功能衰竭等混杂因素的情况下诱导免疫反应。与正常人群相比，这一群体感染乙肝病毒并发症的风险很高。因此，该研究将评估和优化一种基于NE的新型鼻腔疫苗，该疫苗可在正常小鼠和慢性肾衰小鼠中最大限度地产生针对乙肝病毒表面抗原(HBs)的CD4+和CD8+T细胞和体液免疫反应，作为免疫受损人类的模型。将在兔身上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。在第一阶段计划成功完成后，将准备第二阶段STTR应用，最终将进行FDA批准的第一阶段临床试验，以评估安全性、剂量范围、免疫原性和对患有肾功能衰竭的人类慢性乙肝病毒的初步疗效。此外，这些研究将为将该配方用作慢性感染者的治疗性疫苗奠定基础。这种新疫苗作为一种商业化产品将具有巨大的价值，可以在美国和全球范围内降低与乙肝病毒相关的肝病和死亡的风险和相关的经济负担。 公共卫生相关性：乙肝病毒(乙肝)是慢性病毒性肝病最常见的原因。拟议的研究将开发一种基于纳米乳剂的新型鼻腔疫苗，以防止病毒传播和免疫低下和慢性感染患者的严重并发症，如肝硬变、肝功能衰竭和肝细胞癌(HCC)的发展。开发一种安全、无针、易于管理和高效的纳米乳剂疫苗，在美国和全球范围内作为慢性乙肝病毒感染的治疗剂具有很大的价值。

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.