Development of a DNA Vaccine for Chronic HBV Infection

描述(申请人提供)：急性乙肝病毒(乙肝)感染通常是自限性的。然而，长期感染的患者患慢性肝炎、肝硬变和肝癌的风险增加。这些患者中只有一小部分可以通过抗病毒治疗治愈。单独使用疫苗或在目前抗病毒药物治疗可实现的低病毒载量的背景下，建立对乙肝病毒的强大免疫反应，可能有助于缓解甚至治愈疾病。基于诱导强大的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景的方法。然而，由于目前PDNA传递方式的低量和反应不一致的特点，这一适应症的PDNA免疫的成功发展一直受到阻碍。利用其TriGridTM电穿孔(EP)DNA递送技术，Ichor在动物模型中证明了编码乙肝病毒抗原的PDNA载体的效力和免疫原性显著提高。基于这些结果，我们的假设是，基于Ichor EP的针对HBV亚单位的PDNA疫苗可以形成针对慢性乙肝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建议方法的基本可行性，我们将在一个公认的疾病模型中进行疗效评估：Ichor已与临床医生和研究人员建立了关系，以使其DNA疫苗方法能够在土拨鼠慢性病毒性肝炎模型中进行评估。治疗性HBVDNA疫苗的可行性将通过土拨鼠模型中免疫学、病毒学和安全终点的特征来评估。FDA确定的关键安全终点的额外评估将在兔子身上进行。在SBIR第一阶段收集的数据将成为提交IND的基础，以便启动将在SBIR第二阶段进行的第一阶段临床研究。这项研究与公共卫生的相关性--慢性乙肝病毒感染与严重的发病率、巨大的医疗保健成本以及对他人的污染风险相关，这是一个巨大的公共卫生问题。目前的抗病毒疗法减少了病毒载量，但并没有完全消除病毒。通过一种安全有效的疫苗疗法可以持久地根除病毒，这种疾病的治疗将得到极大的改善。

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.