Department of Immunology and Microbial Science and International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6205-10. doi: 10.1073/pnas.1114927109. Epub 2012 Apr 4.
Hepatitis C virus (HCV) infects ∼2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human mAbs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies to HCV.
丙型肝炎病毒 (HCV) 感染了全球约 2%的人口。据估计，埃及每年有超过 50 万例新感染病例，是 HCV 感染率最高的国家。有效的疫苗将有助于控制这一不断扩大的全球健康负担。HCV 高度变异，有效的疫苗应针对病毒的保守 T 细胞和 B 细胞表位。先前已经报道了与 E2 病毒包膜糖蛋白上的 CD81 受体结合位点 (CD81bs) 重叠的保守 B 细胞表位，这些表位为疫苗提供了有希望的靶点。在这项研究中，我们通过使用 exhaustive-panning 策略，从 HCV 免疫噬菌体展示抗体文库中分离出 73 种识别病毒包膜糖蛋白复合物 E1E2 上五个不同抗原区域的人源单克隆抗体。这些 mAbs 中有许多具有广谱中和活性。特别是，mAb AR4A 识别 E1E2 复合物上 CD81bs 外部的不连续表位，对多种 HCV 基因型具有异常广泛的中和活性，并在小动物模型中防止异源 HCV 攻击。该 mAb 面板将有助于设计和开发疫苗候选物，以诱导针对 HCV 的广谱中和抗体。
