Altered Glycosylation Patterns Increase Immunogenicity of a Subunit Hepatitis C Virus Vaccine, Inducing Neutralizing Antibodies Which Confer Protection in Mice
Altered Glycosylation Patterns Increase Immunogenicity of a Subunit Hepatitis C Virus Vaccine, Inducing Neutralizing Antibodies Which Confer Protection in Mice
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DOI：
10.1128/jvi.01462-16
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发表时间：
2016-12-01
影响因子：
5.4
通讯作者：
Huang, Zhong
中科院分区：
文献类型：
--
作者：
Li, Dapeng;von Schaewen, Markus;Huang, Zhong
丙型肝炎病毒(丙型肝炎病毒)感染是一个全球健康问题，目前还没有疫苗可用。丙型肝炎病毒具有高度异质性的RNA基因组，可分为七种基因类型。由于不同基因型别之间存在高度的遗传变异和由此产生的抗原性差异，通过实验性疫苗接种来诱导能够中和大多数丙型肝炎病毒基因型别的抗体一直是具有挑战性的。以往的研究主要集中在用哺乳动物细胞产生的重组丙型肝炎病毒包膜蛋白来启动体液免疫应答。在这里，我们报告了在昆虫细胞中产生的一种可溶性形式的丙型肝炎病毒E2(SE2)具有不同的糖基化模式，并且更具免疫原性，这是通过诱导针对细胞培养来源的丙型肝炎病毒(HCVcc)的更高滴度的广谱中和抗体(BNAbs)来证明的，该抗体含有来自多种丙型肝炎病毒基因型的结构蛋白。我们确认特征良好的bNAbs的连续和不连续表位是保守的，这表明昆虫细胞产生的SE2是正确折叠的。在基因人源化的小鼠模型中，SE2的主动免疫有效地防止了异源丙型肝炎病毒的攻击。这些数据不仅表明SE2是一个很有前途的候选丙型肝炎病毒疫苗，而且也突显了糖基化模式在亚单位病毒疫苗开发中的重要性。全球控制丙型肝炎病毒感染迫切需要一种高效、低成本的预防性疫苗。由于丙型肝炎病毒基因组的抗原性多样性，针对大多数丙型肝炎病毒的广谱中和抗体的诱导一直是具有挑战性的。在这里，我们提炼了一种高产量的丙型肝炎亚单位疫苗，该疫苗在临床前试验中引起了广泛的中和抗体反应。我们发现，在昆虫细胞中产生的可溶性丙型肝炎病毒E2蛋白(SE2)是明显糖基化的，并且比在哺乳动物细胞中产生的SE2更具免疫原性，这表明在研制基于抗体的重组抗丙型肝炎疫苗时应考虑糖基化模式。我们进一步证明，在基因人源化的小鼠模型中，SE2疫苗对丙型肝炎病毒感染具有保护作用。因此，我们的工作确定了一种具有广泛保护性的有前景的候选丙型肝炎病毒疫苗，应该考虑用于进一步的临床前和临床开发。
Hepatitis C virus (HCV) infection is a global health problem for which no vaccine is available. HCV has a highly heterogeneous RNA genome and can be classified into seven genotypes. Due to the high genetic and resultant antigenic variation among the genotypes, inducing antibodies capable of neutralizing most of the HCV genotypes by experimental vaccination has been challenging. Previous efforts focused on priming humoral immune responses with recombinant HCV envelope E2 protein produced in mammalian cells. Here, we report that a soluble form of HCV E2 (sE2) produced in insect cells possesses different glycosylation patterns and is more immunogenic, as evidenced by the induction of higher titers of broadly neutralizing antibodies (bNAbs) against cell culture-derived HCV (HCVcc) harboring structural proteins from a diverse array of HCV genotypes. We affirm that continuous and discontinuous epitopes of well-characterized bNAbs are conserved, suggesting that sE2 produced in insect cells is properly folded. In a genetically humanized mouse model, active immunization with sE2 efficiently protected against challenge with a heterologous HCV genotype. These data not only demonstrate that sE2 is a promising HCV vaccine candidate, but also highlight the importance of glycosylation patterns in developing subunit viral vaccines.IMPORTANCEA prophylactic vaccine with high efficacy and low cost is urgently needed for global control of HCV infection. Induction of broadly neutralizing antibodies against most HCV genotypes has been challenging due to the antigenic diversity of the HCV genome. Here, we refined a high-yield subunit HCV vaccine that elicited broadly neutralizing antibody responses in preclinical trials. We found that soluble HCV E2 protein (sE2) produced in insect cells is distinctly glycosylated and is more immunogenic than sE2 produced in mammalian cells, suggesting that glycosylation patterns should be taken into consideration in efforts to generate antibody-based recombinant vaccines against HCV. We further showed that sE2 vaccination confers protection against HCV infection in a genetically humanized mouse model. Thus, our work identified a promising broadly protective HCV vaccine candidate that should be considered for further preclinical and clinical development.