Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma

描述（由申请人提供）：乙型肝炎病毒（HBV）感染可导致慢性肝炎和肝细胞癌。目前治疗慢性HBV感染的方法只有中等效果，并且受到严重副作用和病毒耐药性的限制。因此，对这种严重疾病仍然需要新的治疗方法。在清除病毒的急性感染者中，宿主T细胞对HBV的反应是强烈的和多特异性的，但在慢性感染者中，它是微弱的和狭窄的。治疗性疫苗接种可诱导足以控制病毒的免疫反应，这可能是治疗慢性乙型肝炎的一种新方法。目前的乙肝疫苗对治疗性接种无效。虽然它能产生强烈的中和抗体反应来防止感染，但它不能诱导感染后消除病毒所需的有效CD8 T细胞反应。目前的疫苗也不是在世界上流行的不发达地区广泛进行预防性接种的最佳疫苗，因为它不能在所有个体中产生保护作用，保护性抗体反应随着时间的推移而减少，并且需要多次剂量才能获得长期免疫。重组水疱性口炎病毒（VSV）疫苗载体诱导对多种病原体的强保护性CD8 T细胞和抗体反应，并且也显示出作为治疗性疫苗的希望。我们将检验表达HBV结构蛋白的重组VSV能否制作有效的HBV预防和治疗免疫疫苗的假设。我们将生成表达HBV蛋白的重组VSV疫苗载体，表征接种动物对VSV/HBV的免疫反应，并确定VSV/HBV疫苗载体是否在小鼠慢性HBV模型中诱导有效的免疫反应。一种改进的预防性疫苗或一种有效的治疗性疫苗可以单剂提供长期免疫，有可能预防数百万例hbv相关的肝细胞癌。

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.