Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma

描述(由申请人提供)：感染乙肝病毒可导致慢性肝炎和肝细胞癌。目前治疗慢性乙肝病毒感染的方法只是中等有效，而且受到严重副作用和病毒耐药性的限制。因此，仍然需要新的治疗方法来治疗这种严重的疾病。在清除病毒的急性感染者中，宿主T细胞对乙肝病毒的反应是强烈的和多特异性的，但在那些成为慢性感染者的人中，这种反应很弱，而且集中在狭隘的范围内。治疗性疫苗接种诱导足以控制病毒的免疫反应是治疗慢性乙型肝炎的一种可能的新方法。遗憾的是，目前的乙肝疫苗对治疗性疫苗并不有效。虽然它能产生强烈的中和抗体反应来预防感染，但它不能诱导在感染后消除病毒所需的强大的CD8T细胞反应。目前的疫苗对于在世界流行的欠发达地区广泛进行预防性疫苗接种也不是最理想的，因为它不能对所有人产生保护，保护性抗体反应随着时间的推移而下降，而且需要多次接种才能获得长期免疫。重组水泡性口炎病毒(VSV)疫苗载体可诱导CD8T细胞和抗体对多种病原体产生较强的保护性应答，并有望成为治疗性疫苗。我们将验证这样一种假设，即表达乙肝病毒结构蛋白的重组VSV将制成有效的疫苗，用于预防和治疗性免疫。我们将构建表达乙肝病毒蛋白的重组VSV疫苗载体，鉴定免疫动物对VSV/乙肝病毒的免疫应答，并确定VSV/乙肝疫苗载体能否在慢性乙肝小鼠模型中诱导有效的免疫应答。一种单剂提供长期免疫的改进预防性疫苗或一种有效的治疗性疫苗将有可能预防数百万例与乙肝病毒相关的肝细胞癌。 公共卫生相关性：慢性乙肝病毒感染每年导致全球数百万人死于肝硬变和肝细胞癌。目前治疗乙肝病毒感染的方法只能起到一定的效果，而且常常伴随着严重的副作用和病毒耐药性。一种改进的预防性疫苗和/或一种有效的治疗性疫苗将有可能预防数百万与乙肝相关的肝癌病例。

DESCRIPTION (provided by applicant): Infection with the hepatitis B virus (HBV) can lead to chronic hepatitis and hepatocellular carcinoma. Current therapies for chronic HBV infection are only moderately effective, and are limited by severe side effects and viral resistance. Thus, there remains a need for new therapies for this serious disease. The host T cell response to HBV is vigorous and multi-specific in acutely infected people who clear the virus, but it is weak and narrowly focused in those who become chronically infected. Therapeutic vaccination to induce an immune response sufficient to control the virus is a possible new approach for the treatment of chronic hepatitis B. Unfortunately; the current HBV vaccine is not effective for therapeutic vaccination. Although it produces a strong neutralizing antibody response that prevents infection, it does not induce the potent CD8 T cell response needed to eliminate the virus after infection. The current vaccine is also not optimal for widespread prophylactic vaccination in endemic underdeveloped regions of the world, as it does not induce protection in all individuals, the protective antibody response decreases over time, and multiple doses are required for long-lasting immunity. Recombinant vesicular stomatitis virus (VSV) vaccine vectors induce strong protective CD8 T cell and antibody responses to a variety of pathogens, and are also showing promise as therapeutic vaccines. We will test the hypothesis that recombinant VSV expressing the HBV structural proteins will make effective vaccines for prophylactic and therapeutic immunization against HBV. We will generate recombinant VSV vaccine vectors that express HBV proteins, characterize the immune response to VSV/HBV in vaccinated animals, and determine if VSV/HBV vaccine vectors induce an effective immune response in mouse models of chronic HBV. An improved prophylactic vaccine that provides long-term immunity in a single dose or an effective therapeutic vaccine would have the potential to prevent millions of cases of HBV-associated hepatocellular carcinoma. Public Health Relevance: Chronic hepatitis B virus (HBV) infection leads to millions of deaths each year worldwide from liver cirrhosis and hepatocellular carcinoma. Current therapies for HBV infection are only moderately effective, and are often accompanied by severe side effects and viral resistance. An improved prophylactic vaccine and/or an effective therapeutic vaccine would have the potential to prevent millions of cases of HBV-associated liver cancer.