Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine
Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine
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DOI：
10.1128/jvi.02141-17
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发表时间：
2018-06-01
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：
Law, John L. M.;Logan, Michael;Houghton, Michael
目前的证据支持病毒中和抗体在抗丙型肝炎病毒（HCV）感染的免疫中的保护作用。已经鉴定了许多交叉中和单克隆抗体。这些抗体已被证明在动物模型中提供保护或清除感染。先前的临床试验表明，gpE 1/gpE 2疫苗可以诱导抗体，中和世界各地所有主要细胞培养衍生的HCV（HCV-HCV）基因型的体外感染性。然而，交叉中和似乎有利于某些基因型，对其他基因型的中和显著但较低。HCV可采用表位掩蔽以避免抗体介导的中和。糖蛋白E2氨基末端的高变区1（HVR 1）已被证明限制了许多中和抗体的进入。与此相一致，其他研究组报道了缺乏HVR 1的重组病毒对中和反应高度敏感。已经提出缺乏该结构域的gpE 1/gpE 2可以是诱导广泛中和抗体的更好的疫苗抗原。在这项研究中，我们研究了缺乏HVR 1的重组gpE 1/gpE 2（Δ HVR 1）的免疫原性。我们的研究结果表明，野生型（WT）和Delta HVR 1 gpE 1/gpE 2抗原诱导的抗体靶向许多充分表征的跨基因型中和表位。然而，尽管WT gpE 1/gpE 2疫苗可以诱导针对HCV和/或HCV假型病毒（HCVpp）的各种基因型的交叉基因型保护，但来自Delta HVR 1 gpE 1/gpE 2免疫动物的抗血清显示出与WT相比降低的同源中和活性或与WT相似的异源中和活性。这些数据表明Delta HVR 1 gpE 1/gpE 2不是上级疫苗抗原。基于先前报道的使用野生型gpE 1/gpE 2的黑猩猩保护数据和我们目前的研究结果，我们正在准备一种包括野生型重组gpE 1/gpE 2的组合疫苗用于未来的临床测试。重要信息HCV疫苗是一种未满足的医疗需求。目前的证据表明，中和抗体在病毒清除中发挥重要作用，沿着细胞免疫应答。以往的临床资料表明，gpE 1/gpE 2可以有效地诱导交叉中和抗体，尽管它们有利于某些基因型。HCV利用gpE 2内的HVR 1逃避宿主免疫控制。据推测，去除该结构域将改善交叉中和抗体的产生。在这项研究中，我们比较了WT和Delta HVR 1 gpE 1/gpE 2抗原作为候选疫苗的免疫原性。我们的结果表明，与WT抗原相比，Delta HVR 1 gpE 1/gpE 2抗原在中和HCV方面没有优势。以前，我们表明这种WT抗原仍然是保护黑猩猩免受慢性感染的唯一候选疫苗，含有多个交叉中和表位，并且在人类中具有良好的耐受性和免疫原性。目前的数据支持该疫苗抗原组分的进一步临床开发。
Current evidence supports a protective role for virus-neutralizing antibodies in immunity against hepatitis C virus (HCV) infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to provide protection or to clear infection in animal models. Previous clinical trials have shown that a gpE1/gpE2 vaccine can induce antibodies that neutralize the in vitro infectivity of all the major cell culture-derived HCV (HCVcc) genotypes around the world. However, cross-neutralization appeared to favor certain genotypes, with significant but lower neutralization against others. HCV may employ epitope masking to avoid antibody-mediated neutralization. Hypervariable region 1 (HVR1) at the amino terminus of glycoprotein E2 has been shown to restrict access to many neutralizing antibodies. Consistent with this, other groups have reported that recombinant viruses lacking HVR1 are hypersensitive to neutralization. It has been proposed that gpE1/gpE2 lacking this domain could be a better vaccine antigen to induce broadly neutralizing antibodies. In this study, we examined the immunogenicity of recombinant gpE1/gpE2 lacking HVR1 (Delta HVR1). Our results indicate that wild-type (WT) and Delta HVR1 gpE1/gpE2 antigens induced antibodies targeting many well-characterized cross-genotype-neutralizing epitopes. However, while the WT gpE1/gpE2 vaccine can induce cross-genotype protection against various genotypes of HCVcc and/or HCV-pseudotyped virus (HCVpp), antisera from Delta HVR1 gpE1/gpE2-immunized animals exhibited either reduced homologous neutralization activity compared to that of the WT or heterologous neutralization activity similar to that of the WT. These data suggest that Delta HVR1 gpE1/gpE2 is not a superior vaccine antigen. Based on previously reported chimpanzee protection data using WT gpE1/gpE2 and our current findings, we are preparing a combination vaccine including wildtype recombinant gpE1/gpE2 for clinical testing in the future.IMPORTANCE An HCV vaccine is an unmet medical need. Current evidence suggests that neutralizing antibodies play an important role in virus clearance, along with cellular immune responses. Previous clinical data showed that gpE1/gpE2 can effectively induce cross-neutralizing antibodies, although they favor certain genotypes. HCV employs HVR1 within gpE2 to evade host immune control. It has been hypothesized that the removal of this domain would improve the production of cross-neutralizing antibodies. In this study, we compared the immunogenicities of WT and Delta HVR1 gpE1/gpE2 antigens as vaccine candidates. Our results indicate that the Delta HVR1 gpE1/gpE2 antigen confers no advantages in the neutralization of HCV compared with the WT antigen. Previously, we showed that this WT antigen remains the only vaccine candidate to protect chimpanzees from chronic infection, contains multiple cross-neutralizing epitopes, and is well tolerated and immunogenic in humans. The current data support the further clinical development of this vaccine antigen component.