Recombinant Hepatitis C Virus Envelope Glycoprotein Vaccine Elicits Antibodies Targeting Multiple Epitopes on the Envelope Glycoproteins Associated with Broad Cross-Neutralization
Recombinant Hepatitis C Virus Envelope Glycoprotein Vaccine Elicits Antibodies Targeting Multiple Epitopes on the Envelope Glycoproteins Associated with Broad Cross-Neutralization
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DOI：
10.1128/jvi.01911-14
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发表时间：
2014-12-01
影响因子：
5.4
通讯作者：
Houghton, Michael
中科院分区：
文献类型：
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作者：
Alexander, Jason;Wong, Ji-Xhin;Houghton, Michael
虽然有效的丙型肝炎病毒（HCV）抗病毒药物即将问世，但全球预防性HCV疫苗仍然难以捉摸。病毒的多样性是疫苗开发的主要关注点;全球发现的HCV有7种主要基因型。因此，成功的疫苗需要保护所有基因型的HCV感染。尽管存在多样性，但已描述了许多具有广泛交叉中和活性的单克隆抗体（MAb），这表明存在可靶向以预防感染的保守表位。类似地，包含源自基因型1a HCV-1毒株的重组包膜糖蛋白（rE 1 E2）的疫苗已显示能够在豚鼠、黑猩猩和健康人类志愿者中引发交叉中和抗体。为了研究这种交叉中和的基础，通过肽图谱和竞争研究，用一组靶向E1 E2内各种表位的交叉中和MAb，对用HCV-1 rE 1 E2免疫的山羊和人的抗血清中存在的抗E1 E2抗体进行表位图谱分析。免疫的山羊抗血清显示与所有测试的MAb（AP 33、HC 33.4、HC 84.26、1：7、AR 3B、AR 4A、AR 5A、IGH 526和A4）竞争结合。抗血清显示对HC 84.26和AR 3B的最佳竞争，对AR 4A的最弱竞争。此外，来自五种免疫的人疫苗接种者的抗血清显示与五种预选的MAb（AP 33、AR 3B、AR 4A、AR 5A和IGH 526）竞争。这些数据表明，用HCV-1 rE 1 E2免疫可激发靶向多个交叉中和表位的抗体。我们的研究结果进一步支持使用这样的疫苗抗原，以诱导跨基因型neutralization.IMPORTANCEAn有效的预防性疫苗HCV是需要最佳控制的疾病负担。HCV的高度多样性对开发疫苗提出了挑战，这些疫苗可以引发中和抗体以保护免受感染。尽管如此，我们先前已经表明，包含来源于单一基因型1a菌株的重组包膜糖蛋白的疫苗能够在人类志愿者中引发交叉中和抗体应答。在这里，我们已经使用竞争结合试验和肽结合试验，以显示存在于接种疫苗的山羊和人的抗血清中的抗体结合与各种充分表征的交叉中和单克隆抗体的表位重叠的表位。这为交叉中和人抗血清提供了一种机制：抗血清中存在的抗体与交叉中和相关的保守区域结合。重要的是，这项工作为包含重组包膜糖蛋白的疫苗提供了进一步的支持，可能在具有引发强抗HCV CD 4（+）和CD 8（+）T细胞应答的疫苗组分的制剂中。
Although effective hepatitis C virus (HCV) antivirals are on the horizon, a global prophylactic vaccine for HCV remains elusive. The diversity of the virus is a major concern for vaccine development; there are 7 major genotypes of HCV found globally. Therefore, a successful vaccine will need to protect against HCV infection by all genotypes. Despite the diversity, many monoclonal antibodies (MAbs) with broadly cross-neutralizing activity have been described, suggesting the presence of conserved epitopes that can be targeted to prevent infection. Similarly, a vaccine comprising recombinant envelope glycoproteins (rE1E2) derived from the genotype 1a HCV-1 strain has been shown to be capable of eliciting cross-neutralizing antibodies in guinea pigs, chimpanzees, and healthy human volunteers. In order to investigate the basis for this cross-neutralization, epitope mapping of anti-E1E2 antibodies present within antisera from goats and humans immunized with HCV-1 rE1E2 was conducted through peptide mapping and competition studies with a panel of cross-neutralizing MAbs targeting various epitopes within E1E2. The immunized-goat antiserum was shown to compete with the binding of all MAbs tested (AP33, HC33.4, HC84.26, 1:7, AR3B, AR4A, AR5A, IGH526, and A4). Antisera showed the best competition against HC84.26 and AR3B and the weakest competition against AR4A. Furthermore, antisera from five immunized human vaccinees were shown to compete with five preselected MAbs (AP33, AR3B, AR4A, AR5A, and IGH526). These data show that immunization with HCV-1 rE1E2 elicits antibodies targeting multiple cross-neutralizing epitopes. Our results further support the use of such a vaccine antigen to induce cross-genotype neutralization.IMPORTANCEAn effective prophylactic vaccine for HCV is needed for optimal control of the disease burden. The high diversity of HCV has posed a challenge for developing vaccines that elicit neutralizing antibodies for protection against infection. Despite this, we have previously shown that a vaccine comprising recombinant envelope glycoproteins derived from a single genotype 1a strain was capable of eliciting a cross-neutralizing antibody response in human volunteers. Here, we have used competition binding assays and peptide binding assays to show that antibodies present in the antisera from vaccinated goats and humans bind epitopes overlapping with those of a variety of well-characterized cross-neutralizing monoclonal antibodies. This provides a mechanism for the cross-neutralizing human antisera: antibodies present in the antisera bind to conserved regions associated with cross-neutralization. Importantly, this work provides further support for a vaccine comprising recombinant envelope glycoproteins, perhaps in a formulation with a vaccine component eliciting strong anti-HCV CD4(+) and CD8(+) T cell responses.