Development of a DNA Vaccine for Chronic HBV Infection

描述（由申请人提供）：急性乙型肝炎病毒（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达到的低病毒载量的背景下建立对HBV的强免疫应答，可能有助于诱导缓解甚至治愈疾病。基于诱导强细胞免疫应答的能力，质粒DNA （pDNA）疫苗是治疗慢性乙型肝炎的一种很有前途的方式。然而，目前pDNA递送方式的低强度和不一致的应答特征阻碍了pDNA免疫的成功发展。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HBV抗原的pDNA载体的效力和免疫原性的显著提高。基于这些结果，我们假设基于Ichor ep的针对HBV亚基的pDNA疫苗可以为有效的治疗性慢性HBV感染疫苗奠定基础。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，我们将在一种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的免疫学、病毒学和安全性终点进行评估。FDA确定的关键安全终点的额外评估将在家兔中进行。SBIR I期收集的数据将构成提交IND的基础，从而启动SBIR II期进行的I期临床研究。研究与公共卫生的相关性——慢性乙型肝炎病毒感染与严重的发病率、巨大的卫生保健费用和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，但没有完全消除病毒。如果有一种安全有效的疫苗疗法，可以持久地根除这种病毒，对这种疾病的治疗将大大改善。

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.