A RECOMBINANT HEPETITIS C VACCINE

该项目的目标是开发一种预防丙型肝炎病毒感染的疫苗。丙型肝炎病毒是肠道外传播的非甲非乙型肝炎的主要病原体，也是世界范围内肝炎、肝硬化和肝细胞癌的主要原因。由于丙型肝炎病毒包膜蛋白的突变，丙型肝炎病毒具有很高的变异性。这些突变导致病毒的“准物种”，这些病毒不会被针对其他准物种而形成的抗体中和。突变主要发生在病毒包膜蛋白E2氨基末端的高变区1(Hvr1)内。因此，为了使任何疫苗有效，它必须诱导能够中和任何这些准物种的抗体，从而防止建立初始感染。这个第一阶段项目的具体目标是(1)构建一个多决定簇抗原，包括已知的和潜在的HVR1序列的文库；(2)将该文库呈现在一个高度免疫原性的载体部分(高级抗原呈递平台)上；(3)证明该构建物能结合抗丙型肝炎病毒抗体；以及(4)证明该免疫原能诱导高滴度的抗丙型肝炎病毒包膜抗体。第二阶段的研究将包括评估这种免疫原在易感宿主中的保护效果。拟议的商业应用：超过3亿人感染丙型肝炎病毒。消除这种疾病需要一种疫苗。根据乙肝病毒，这相当于每年约5亿美元的产品。

The goal of this project is the development of a vaccine for the prevention of hepatitis C viral infection. The hepatitis C virus (HCV) is the primary etiologic agent of parenterally transmitted non-A, non-B hepatitis and is a major cause of hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. HCV is highly variable due to mutations within the HCV envelope proteins. These mutations lead to viral "quasi-species" that are not neutralized by the antibodies formed in response to other quasi-species. The mutations occur predominantly within the hypervariable region 1 (HVR1), found at the amino terminus of the viral envelope protein, E2. Therefore, in order for any vaccine to be effective, it must elicit antibodies capable of neutralizing any of these quasi species, and thereby prevent establishment of the initial infection. The specific aims of this phase I project are to (1) construct a multideterminant antigen, consisting of a library of known as well as potential sequences of the HVR1; (2) present this library on a highly immunogenic on carrier moiety (Advanced Antigen Presentation Platform); (3) demonstrate that this construct binds anti-HCV antibodies; and (4) demonstrate that this immunogen induces high titre anti-HCV envelope antibodies. Phase II studies would involve assessing the protective efficacy of such an immunogen in susceptible hosts. PROPOSED COMMERCIAL APPLICATIONS: Over 300 million people are infected with HCV. Elimination of this disease will require a vaccine. Based on the hepatitis B virus this would represent about a $500 million dollar per year product.