Li Ka Shing Applied Virology Institute, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Dept of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.
J Hepatol. 2024 Dec;81(6):941-948. doi: 10.1016/j.jhep.2024.06.029. Epub 2024 Jul 8.
BACKGROUND & AIMS: An optimal HCV vaccine requires the induction of antibodies that neutralise the infectivity of many heterogenous viral isolates. In this study, we have focused on determining the optimal recombinant envelope glycoprotein component to elicit cross-neutralising antibodies against global HCV genotypes. We compared the immunoreactivity and antigenicity of the HCV genotype 1a strain H77C-derived envelope glycoprotein heterodimer gpE1/gpE2 with that of recombinant gpE2 alone.
Characterisation of the envelope glycoproteins was accomplished by determining their ability to bind to a panel of broadly cross-neutralising monoclonal antibodies. Immunogenicity was determined by testing the ability of vaccine antisera to neutralise the infectivity in vitro of a panel of pseudotyped HCV particles in which gpE1/gpE2 derived from representative isolates of the major global HCV genotypes were displayed.
gpE1/gpE2 binds to more diverse broadly cross-neutralising antibodies than gpE2 alone and elicits a broader profile of cross-neutralising antibodies in animals, especially against more heterologous, non-1a genotypes. While not all heterologous HCV strains can be potently inhibited in vitro by gpE1/gpE2 antisera derived from a single HCV strain, the breadth of heterologous cross-neutralisation is shown to be substantial.
Our work supports the inclusion of gpE1/gpE2 in an HCV vaccine in order to maximise the cross-neutralisation of heterogenous HCV isolates. Our data also offers future directions in formulating a cocktail of gpE1/gpE2 antigens from a small selection of HCV genotypes to further enhance cross-neutralisation of global HCV strains and hopefully advance the development of a globally effective HCV vaccine.
An HCV vaccine is urgently required to prevent the high global incidence of HCV infection and disease. Since HCV is a highly heterogeneous virus, it is desirable for a vaccine to elicit antibodies that neutralise the infectivity of most global strains. To this end, we have compared the immunoreactivity and antigenicity of recombinant H77C E1E2 heterodimer with that of H77C E2 alone and show that the former exhibits more cross-neutralising epitopes and demonstrates a broader cross-neutralisation profile in vitro. In addition, our data suggests a way to further broaden cross-neutralisation using a combination of E1E2 antigens derived from a few different HCV clades. Our work is relevant for the development of an effective global HCV vaccine.
一种理想的 HCV 疫苗需要诱导能够中和多种异源病毒分离株感染性的抗体。在本研究中，我们专注于确定最佳的重组包膜糖蛋白成分，以诱导针对全球 HCV 基因型的交叉中和抗体。我们比较了 HCV 1a 株 H77C 衍生的包膜糖蛋白异二聚体 gpE1/gpE2 与单独的重组 gpE2 的免疫原性和抗原性。
通过确定其与广泛交叉中和单克隆抗体结合的能力来对包膜糖蛋白进行表征。通过测试疫苗抗血清在体外中和代表主要全球 HCV 基因型的代表性分离株衍生的假型 HCV 颗粒的感染性的能力来确定免疫原性。
gpE1/gpE2 与更多不同的广泛交叉中和抗体结合，并且在动物中诱导更广泛的交叉中和抗体谱，特别是针对更多的异源、非 1a 基因型。虽然并非所有异源 HCV 株都可以被源自单个 HCV 株的 gpE1/gpE2 抗血清在体外强烈抑制，但显示出广泛的异源交叉中和作用。
我们的工作支持在 HCV 疫苗中包含 gpE1/gpE2，以最大程度地中和异源 HCV 分离株的感染性。我们的数据还为从少数 HCV 基因型中制定 gpE1/gpE2 抗原混合物提供了未来的方向，以进一步增强对全球 HCV 株的交叉中和作用，并有望推进全球有效 HCV 疫苗的开发。
迫切需要 HCV 疫苗来预防全球 HCV 感染和疾病的高发病率。由于 HCV 是一种高度异质性病毒，理想的疫苗应诱导出能够中和大多数全球株感染性的抗体。为此，我们比较了重组 H77C E1E2 异二聚体与 H77C E2 单独的免疫原性和抗原性，结果表明前者具有更多的交叉中和表位，并在体外显示更广泛的交叉中和谱。此外，我们的数据表明使用源自少数不同 HCV 进化枝的 E1E2 抗原组合进一步拓宽交叉中和的方法。我们的工作与有效全球 HCV 疫苗的开发有关。
