rojjer 发表于 2016-1-5 17:11:35

最新综述:丙肝疫苗研发的机遇与挑战

丙型肝炎病毒(Hepatitic C virus, HCV)属黄病毒科(Flaviviridae)、肝炎病毒属(hepacivirus),为单股正链RNA病毒。目前全球约1.85亿人感染HCV,其中1.3-1.7亿为慢性感染,每年有35万人死于丙型肝炎导致的肝硬化和肝癌。我国是丙型肝炎感染人数最多的国家,有近3千万HCV感染者,尤其近年来我国丙肝病例不断增加,对公共卫生构成了沉重的负担。


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

      New cases of viral hepatitis in China from 2003 to 2014. Data source: Chinese Center for Disease Control and Prevention


近年来,随着多种针对HCV的抗病毒药物(direct-acting antiviral agents, DAA)的上市,丙型肝炎治疗发生了革命性的进步,新上市的抗病毒药将丙型肝炎的SVR提高到95%以上,让人们看到了根除HCV的希望。尽管如此,昂贵的药物价格($70,000-110,000/疗程)使大部分病人无法承担,很难被纳入医疗保险的范围。预防性疫苗的广泛接种在天花、脊髓灰质炎的根除过程中扮演了至关重要的角色,但是目前没有针对HCV的疫苗;因此开发有效的预防性疫苗从而阻断新发感染,成为丙肝研究的重中之重。

NSR发表的由中国科学院上海巴斯德研究所李大鹏、黄忠教授和钟劲教授联合撰写的综述文章“Hepatitis C virus vaccine development: old challenges and new opportunities”(http://nsr.oxfordjournals.org/content/2/3/285.full)主要从丙肝病毒的病毒学和免疫学角度介绍了在丙肝病毒疫苗研发中的难题与研究进展,包括抗体反应和细胞免疫反应的诱导、细胞模型与动物模型的开发等,并归纳了目前处于临床实验阶段的疫苗及其前景,最后对理想的丙肝疫苗提出了展望。

该文总结了HCV感染在人体中引起的免疫反应。由于HCV通过各种机制逃避天然免疫反应,大部分病人未能在感染初期产生有效的免疫反应而转为慢性感染,随后由于HCV基因组的高变性,新产生的病毒能够逃逸获得性免疫反应,尤其是中和抗体;然而仍有20-25%的病人可以通过在早期产生中和抗体和T细胞免疫反应自发清除HCV感染,说明了在感染早期中和抗体对于抵抗感染的重要性,这也是预防性疫苗研究的目标主要方向。

从发现HCV开始,研究人员就在试图开发疫苗。然而由于各种细胞模型和动物模型的缺乏,疫苗研究举步维艰。2005年,HCV细胞培养模型的建立带了这一领域革命性的突破,使得研究人员能够在体外细胞培养中对疫苗诱导的中和抗体进行中和实验评价。动物模型方面,黑猩猩是最接近人类的感染模型,能建立HCV急性感染和慢性感染。但随着动物伦理的发展,黑猩猩体内的疫苗保护实验已经被全面禁止。人肝脏细胞移植小鼠由于缺乏完整的免疫系统,只能进行被动免疫实验。2013年起建立的HCV受体人源化转基因小鼠,能够允许HCV病毒的进入,并通过活体成像对感染进行定量,是第一个能够进行主动免疫实验的小动物模型,极大地便利了基于中和抗体的HCV疫苗评价。



目前临床实验阶段的预防性疫苗有三种。第一是基于包膜蛋白E1/E2的重组亚单位疫苗,能够诱导中和抗体;另外两种是基于重组腺病毒以及痘病毒载体疫苗,表达非结构蛋白,在人体内诱导细胞免疫反应。尽管如此,产量、成本以及中和抗体的广度仍是目前预防性疫苗领域存在的问题,也可能对疫苗上市产生影响。
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Vaccine candidates against HCV in clinical trials.

本文还对理想的丙肝疫苗提出了展望。由于治疗药物DAA的广泛应用,治疗性疫苗尽管可以作为备选与其他药物联合使用。但其重要性受到很大冲击。但预防性疫苗仍然应是未来丙肝病毒全球防控的重要工具。因此,最理想的丙肝疫苗应该组成简单,成本低廉,易于大规模生产,能同时诱导广谱中和抗体和细胞免疫反应,并能诱导长期甚至终生免疫记忆。这也是在HCV疫苗研发过程中需要设法实现的目标。(来源:科学网)
全文链接:http://nsr.oxfordjournals.org/content/2/3/285.full
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