Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma

预防肝细胞癌的病毒疫苗载体

基本信息

批准号：
7900191
负责人：
MICHAEL ROBEK
金额：
$ 2.2万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900191
关键词：
Adverse effects Animals Antibody Formation Apoptosis Attenuated Avidity CD8B1 gene Cessation of life Chronic Hepatitis Chronic Hepatitis B Core Protein Data Disease Dose Glycoproteins Hepatitis B Hepatitis B Vaccines Hepatitis B Virus Hepatocyte Histology Immune response Immunity Immunization Individual Infection Infection prevention Inflammation Interleukin-2 Lead Ligands Liver Liver Cirrhosis Malignant neoplasm of liver Measures Modeling Mus Plasmids Primary carcinoma of the liver cells Production Recombinants Serum Simian B disease Southern Blotting Specificity Spleen Staining method Stains Structural Protein Surface T memory cell T-Lymphocyte Testing Therapeutic Time Transfection Transgenic Mice Vaccinated Vaccination Vaccines Vaccinia virus Vesicular stomatitis Indiana virus Viral Proteins Viral Vaccines Virus Virus Replication cytokine enzyme linked immunospot assay immunogenicity improved killings mouse model neutralizing antibody novel strategies pathogen prevent prophylactic public health relevance response therapeutic vaccine vector vector vaccine vector-induced viral resistance virus core

项目摘要

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.

描述（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。目前针对慢性乙型肝炎病毒感染的治疗方法仅具有中等效果，并且受到严重副作用和病毒耐药性的限制。因此，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 的反应是强烈且多特异性的，但在慢性感染者中则较弱且集中。通过治疗性疫苗接种来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。目前的乙型肝炎疫苗对于治疗性疫苗接种无效。虽然它产生强烈的中和抗体反应来预防感染，但它不会诱导感染后消除病毒所需的有效 CD8 T 细胞反应。目前的疫苗也不是世界上流行的欠发达地区广泛预防性疫苗接种的最佳选择，因为它不能对所有个体产生保护，保护性抗体反应会随着时间的推移而减弱，并且需要多次剂量才能获得持久的免疫力。重组水泡性口炎病毒 (VSV) 疫苗载体可诱导针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前景。我们将检验以下假设：表达 HBV 结构蛋白的重组 VSV 将成为针对 HBV 的预防性和治疗性免疫的有效疫苗。我们将生成表达 HBV 蛋白的重组 VSV 疫苗载体，表征接种动物中对 VSV/HBV 的免疫反应，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反应。一种改进的单剂量提供长期免疫力的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与乙型肝炎病毒相关的肝细胞癌病例。公共卫生相关性：慢性乙型肝炎病毒 (HBV) 感染每年导致全世界数百万人死于肝硬化和肝细胞癌。目前针对乙型肝炎病毒感染的治疗方法效果有限，并且常常伴有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与乙型肝炎病毒相关的肝癌病例。