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）：急性肝炎病毒（HBV）感染通常是自限的。 但是，持续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来治愈。 单独使用疫苗或使用当前抗病毒药物治疗可实现的低病毒负荷来建立对HBV的强烈免疫反应，可以帮助诱导缓解甚至治愈该疾病。 基于诱导强细胞免疫反应的能力，质粒DNA（PDNA）疫苗是慢性肝炎的一种有希望的方式。但是，成功开发了这种迹象的PDNA免疫的发展受到当前PDNA递送方式的低大小和不一致的反应的阻碍。 使用其Trigridtm电穿孔（EP）DNA递送技术，Ichor证明了在动物模型中编码HBV抗原的PDNA载体的效力和免疫原性的急剧增加。 基于这些结果，我们的假设是，基于Ichor EP基于HBV亚基的PDNA疫苗接种可以为抗慢性HBV感染的有效治疗疫苗接种构成基础。 为了评估该假设的有效性并证明了所提出的方法的基本可行性，我们将在公认的疾病模型中评估疗效：Ichor与临床医生和研究人员建立了关系，以促进其在慢性病毒肝炎木制模型中评估其DNA疫苗方法。 治疗性HBV DNA疫苗的可行性将通过在Woodchuck模型中表征免疫，病毒学和安全终点来评估。 FDA确定的关键安全终点的其他评估将在兔子中进行。 SBIR I期收集的数据将构成提交IDS启动I期临床研究的基础，以SBIR II期进行。 这项研究与公共卫生的相关性 - 肝炎病毒的慢性感染与严重的发病率，严重的医疗保健成本以及对他人污染的风险有关，这是一个巨大的公共卫生问题。 当前的抗病毒疗法可降低病毒载量，而无需完全消除病毒。 通过安全有效的疫苗疗法可以持久地消除病毒的治疗将大大改善这种情况。