Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma

描述（由申请人提供）：B肝炎病毒（HBV）感染可导致慢性肝炎和肝细胞癌。目前慢性HBV感染的治疗方法仅中度有效，并且受到严重副作用和病毒耐药性的限制。因此，仍然需要针对这种严重疾病的新疗法。在清除病毒的急性感染者中，宿主T细胞对HBV的反应是强烈和多特异性的，但在慢性感染者中，这种反应很弱，而且集中在狭窄的范围内。治疗性疫苗接种以诱导足以控制病毒的免疫反应，是治疗慢性乙型肝炎B的一种可能的新方法。不幸的是，目前的HBV疫苗对治疗性疫苗接种无效。虽然它产生了强烈的中和抗体反应，防止感染，但它不会诱导感染后消除病毒所需的有效CD 8 T细胞反应。目前的疫苗对于世界上地方性不发达地区的广泛预防性疫苗接种也不是最佳的，因为它不能在所有个体中诱导保护，保护性抗体应答随着时间的推移而降低，并且需要多次剂量才能持久免疫。重组水泡性口炎病毒（VSV）疫苗载体诱导针对多种病原体的强保护性CD 8 T细胞和抗体应答，并且还显示出作为治疗性疫苗的前景。我们将测试的假设，表达HBV结构蛋白的重组VSV将成为有效的疫苗，用于预防和治疗免疫对HBV。我们将产生表达HBV蛋白的重组VSV疫苗载体，表征接种动物对VSV/HBV的免疫应答，并确定VSV/HBV疫苗载体是否在慢性HBV小鼠模型中诱导有效的免疫应答。一种改进的预防性疫苗，提供长期的免疫力，在一个单一的剂量或有效的治疗性疫苗将有可能防止数百万例HBV相关的肝细胞癌。 公共卫生相关性：慢性B型肝炎病毒（HBV）感染每年导致全世界数百万人死于肝硬化和肝细胞癌。目前治疗HBV感染的方法只有中度有效，并且经常伴随严重的副作用和病毒耐药性。改进的预防性疫苗和/或有效的治疗性疫苗将有可能预防数百万例HBV相关肝癌。

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.