Viral Vaccine Vectors to Prevent Hepatocellular Carcinoma

预防肝细胞癌的病毒疫苗载体

• 批准号: 8092019
• 负责人: MICHAEL ROBEK
• 金额: $ 4.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/8092019
• 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; Memory; 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 cell response; 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; 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; Memory; 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 cell response; 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

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（由申请人提供）：丙型肝炎病毒（HBV）感染可导致慢性肝炎和肝细胞癌。慢性HBV感染的当前疗法仅适度有效，并且受到严重的副作用和病毒抗性的限制。因此，仍然需要解决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的反应是剧烈且多特异性的，但它弱且狭窄地集中在被长期感染的人中。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的一种新方法。不幸的是。当前的HBV疫苗对治疗疫苗无效。尽管它产生了防止感染的强中和抗体反应，但它不会诱导感染后消除病毒所需的有效的CD8 T细胞反应。当前的疫苗也不是世界各地欠发达地区广泛预防性疫苗接种的最佳选择，因为它并不引起所有个体的保护，随着时间的推移，保护性抗体反应会降低，并且需要多种剂量才能进行长期免疫力。重组囊泡口腔炎病毒（VSV）疫苗载体诱导强烈的保护性CD8 T细胞和对多种病原体的抗体反应，并且也表现为治疗性疫苗的希望。我们将测试以下假设：表达HBV结构蛋白的重组VSV将对针对HBV进行预防性和治疗性免疫有效疫苗。我们将生成表达HBV蛋白的重组VSV疫苗向量，表征对接种疫苗的动物对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。改进的预防性疫苗可在单剂量或有效的治疗疫苗中提供长期免疫力，将有可能预防数百万例HBV相关的肝细胞癌。 公共卫生相关性：慢性肝炎病毒（HBV）感染每年因肝肝硬化和肝细胞癌而导致全世界数百万死亡。 HBV感染的当前疗法仅适度有效，并且通常伴有严重的副作用和病毒抗性。改善的预防性疫苗和/或有效的治疗疫苗有可能预防数百万例HBV相关的肝癌。