Development of a DNA Vaccine for Chronic HBV Infection

慢性乙型肝炎病毒感染 DNA 疫苗的开发

• 批准号: 7197356
• 负责人: CLAIRE Frances EVANS
• 金额: $ 19.59万
• 依托单位: ICHOR MEDICAL SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197356
• 关键词: Acute Hepatitis; Address; Adverse event; Animal Model; Animals; Antigens; Antiviral Agents; Antiviral Therapy; Benefits and Risks; Carcinoma; Characteristics; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Chronic viral hepatitis; Clinical; Clinical Research; Condition; Consensus; DNA; DNA Vaccines; DNA delivery; Data; Development; Disease; Disease model; Disease remission; Dose; Electroporation; End Point; Evaluation; Gene Transfer Techniques; Genomics; Goals; Health Care Costs; Hepatitis B Virus; Hepatitis Viruses; Human; Immune Tolerance; Immune response; Immunization; Individual; Infection; Injection of therapeutic agent; Investigation; Liver Cirrhosis; Mediating; Methods; Minority; Modality; Modeling; Morbidity - disease rate; Mus; Oryctolagus cuniculus; Patients; Personal Satisfaction; Pharmacotherapy; Phase; Population; Positioning Attribute; Procedures; Protocols documentation; Public Health; Research; Research Personnel; Risk; Safety; Simian B disease; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Standards of Weights and Measures; Surface Antigens; T-Lymphocyte; Technology; Therapeutic; Treatment Protocols; United States Food and Drug Administration; Vaccination; Vaccine Therapy; Vaccines; Viral; Viral Antigens; Viral Load result; Virus; Virus Diseases; Woodchuck; Woodchuck Hepatitis B Virus; anti-hepatitis B; base; design; efficacy evaluation; immunogenicity; improved; mortality; neonate; plasmid DNA; protocol development; research clinical testing; response; restoration; scale up; size; vaccine efficacy; vector; viral DNA; virus core

DESCRIPTION (provided by applicant): Acute hepatitis B virus (HBV) infection is generally self-limited. However, patients who remain chronically infected are at increased risk for chronic hepatitis, cirrhosis and liver carcinoma. Only a minority of these patients can be cured by antiviral therapy. Establishing strong immune responses to HBV with a vaccine alone, or in the context of the low viral loads achievable with current antiviral drug therapy, could help induce remission or even cure the disease. Based on the ability to induce strong cellular immune responses, plasmid DNA (pDNA) vaccines are a promising modality for chronic hepatitis B. However, successful development of pDNA immunization for this indication has been hampered by the low magnitude and inconsistent responses characteristic of current pDNA delivery modalities. Using its TriGridTM electroporation (EP) DNA delivery technology, Ichor has demonstrated a dramatic increase in potency and immunogenicity of pDNA vectors encoding HBV antigens in animal models. Based on these results, it is our hypothesis that Ichor EP-based pDNA vaccination against HBV subunits can form the basis for an effective therapeutic vaccination against chronic HBV infection. In order to assess the validity of this hypothesis and demonstrate the basic feasibility of the proposed approach, we will conduct an evaluation of efficacy in an accepted disease model: Ichor has established relationships with clinicians and researchers to enable evaluation of its DNA vaccine approach in the woodchuck model of chronic viral hepatitis. Feasibility of a therapeutic HBV DNA vaccine will be assessed by characterizing immunological, virological, and safety endpoints in the woodchuck model. Additional evaluation of key safety endpoints identified by the FDA will be conducted in rabbits. The data collected in SBIR Phase I will form the basis for the submission of an IND enabling initiation of a Phase I clinical study to be conducted under SBIR Phase II. Relevance of the research to public health - Chronic infection with hepatitis B virus is associated with serious morbidity, significant health care costs, and the risk of contamination to others, which is a huge public health problem. Current antiviral therapies decrease viral loads without completely eliminating the virus. The treatment of this condition would be much improved by a safe and effective vaccine therapy that could durably eradicate the virus.

描述（由申请人提供）： 急性乙型肝炎病毒（HBV）感染通常具有自限性。 然而，长期感染的患者患慢性肝炎、肝硬化和肝癌的风险增加。 这些患者中只有少数可以通过抗病毒治疗治愈。 单独使用疫苗或在当前抗病毒药物治疗可实现低病毒载量的情况下建立针对乙型肝炎病毒的强烈免疫反应，可能有助于缓解甚至治愈该疾病。 基于诱导强烈细胞免疫反应的能力，质粒 DNA (pDNA) 疫苗是治疗慢性乙型肝炎的一种有前途的方式。然而，目前 pDNA 的低强度和不一致的反应特征阻碍了针对该适应症的 pDNA 免疫的成功开发。交付方式。 Ichor 利用其 TriGridTM 电穿孔 (EP) DNA 递送技术，在动物模型中证明编码 HBV 抗原的 pDNA 载体的效力和免疫原性显着增加。 基于这些结果，我们假设针对 HBV 亚单位的基于 Ichor EP 的 pDNA 疫苗接种可以构成针对慢性 HBV 感染的有效治疗性疫苗接种的基础。 为了评估这一假设的有效性并证明所提出方法的基本可行性，我们将在公认的疾病模型中进行功效评估：Ichor 已与临床医生和研究人员建立了关系，以便能够在该模型中评估其 DNA 疫苗方法。慢性病毒性肝炎的土拨鼠模型。 将通过表征土拨鼠模型中的免疫学、病毒学和安全性终点来评估治疗性 HBV DNA 疫苗的可行性。 FDA 确定的关键安全终点的额外评估将在兔子身上进行。 SBIR 第一阶段收集的数据将构成提交 IND 的基础，以便启动在 SBIR 第二阶段进行的第一阶段临床研究。 该研究与公共卫生的相关性——乙型肝炎病毒的慢性感染与严重的发病率、巨大的医疗保健费用以及感染他人的风险有关，这是一个巨大的公共卫生问题。 目前的抗病毒疗法只能降低病毒载量，但不能完全消除病毒。 如果能够持久消灭这种病毒，安全有效的疫苗疗法将大大改善这种疾病的治疗。