Development of a DNA Vaccine for Chronic HBV Infection

描述（由申请人提供）：急性B型肝炎病毒（HBV）感染通常是自限性的。 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的低病毒载量的背景下建立对HBV的强烈免疫应答，可能有助于诱导缓解甚至治愈疾病。 质粒DNA（pDNA）疫苗能够诱导强烈的细胞免疫应答，是治疗慢性B型肝炎的一种有前景的方式。 然而，用于该适应症的pDNA免疫的成功开发受到当前pDNA递送模式的低幅度和不一致应答特征的阻碍。 使用其TriGridTM电穿孔（EP）DNA递送技术，Ichor已证明在动物模型中编码HBV抗原的pDNA载体的效力和免疫原性显著增加。 基于这些结果，我们假设针对HBV亚基的基于Ichor EP的pDNA疫苗接种可以形成针对慢性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，并证明所提出的方法的基本可行性，我们将在一个公认的疾病模型中进行疗效评估：Ichor已经与临床医生和研究人员建立了关系，以便在慢性病毒性肝炎的土拨鼠模型中评估其DNA疫苗方法。 治疗性HBV DNA疫苗的可行性将通过土拨鼠模型中的免疫学、病毒学和安全性终点来评估。 将在家兔中对FDA确定的关键安全性终点进行额外评价。 在SBIR I期收集的数据将构成IND提交的基础，从而启动将在SBIR II期下进行的I期临床研究。 研究与公共卫生的相关性-慢性B型肝炎病毒感染与严重的发病率、显著的医疗保健成本和污染他人的风险相关，这是一个巨大的公共卫生问题。 目前的抗病毒疗法减少病毒载量，但没有完全消除病毒。 通过安全有效的疫苗疗法，可以持久地根除病毒，这种情况的治疗将得到很大改善。

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.