Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.
Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site.
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DOI：
10.1016/j.cell.2015.07.043
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发表时间：
2015-08-27
期刊：
影响因子：
64.5
通讯作者：
Nabel GJ
中科院分区：
文献类型：
--
作者：
Kanekiyo M;Bu W;Joyce MG;Meng G;Whittle JR;Baxa U;Yamamoto T;Narpala S;Todd JP;Rao SS;McDermott AB;Koup RA;Rossmann MG;Mascola JR;Graham BS;Cohen JI;Nabel GJ
EB病毒（EBV）是一种严重的全球性健康问题。虽然它与传染性单核细胞增多症和全世界每年200，000例癌症有关，但没有疫苗可用。免疫的主要靶点是EBV糖蛋白350/220（gp 350），其通过补体受体2（CR2/CD 21）介导与B细胞的附着。在这里，我们创建了自组装纳米颗粒，以对称阵列显示gp 350的不同结构域。通过将CR2结合结构域集中呈现在纳米颗粒上，在小鼠和非人灵长类动物中引发了有效的中和抗体。与可溶性gp 350相比，结构设计的纳米颗粒疫苗通过靶向功能保守的脆弱性位点，提高了中和性10至100倍，改善了小鼠模型中疫苗诱导的保护作用。EBV疫苗设计的这种合理方法通过保守的病毒进入结构域的阵列呈递引起有效的中和抗体应答，这是一种可应用于其他病毒的策略。自组装纳米颗粒呈现保守的gp 350受体结合结构域纳米颗粒比可溶性gp 350引发更有效的中和抗体这些中和抗体主要靶向gp 350上的CR2结合位点纳米颗粒在小鼠和非人灵长类动物中引发有效的中和抗体基于自组装纳米颗粒的结构设计的EBV候选疫苗引发有效和持久的病毒-中和抗体靶向病毒包膜蛋白gp 350上的受体结合位点，即脆弱性位点，用作开发EBV疫苗的模板，并通过合理的疫苗设计为免疫聚焦提供基础。
Epstein-Barr virus (EBV) represents a major global health problem. Though it is associated with infectious mononucleosis and ∼200,000 cancers annually worldwide, a vaccine is not available. The major target of immunity is EBV glycoprotein 350/220 (gp350) that mediates attachment to B cells through complement receptor 2 (CR2/CD21). Here, we created self-assembling nanoparticles that displayed different domains of gp350 in a symmetric array. By focusing presentation of the CR2-binding domain on nanoparticles, potent neutralizing antibodies were elicited in mice and non-human primates. The structurally designed nanoparticle vaccine increased neutralization 10- to 100-fold compared to soluble gp350 by targeting a functionally conserved site of vulnerability, improving vaccine-induced protection in a mouse model. This rational approach to EBV vaccine design elicited potent neutralizing antibody responses by arrayed presentation of a conserved viral entry domain, a strategy that can be applied to other viruses. Self-assembling nanoparticles present the conserved gp350 receptor-binding domain The nanoparticles elicit more potent neutralizing antibodies than soluble gp350 These neutralizing antibodies predominantly target the CR2-binding site on gp350 The nanoparticles elicit potent neutralizing antibodies in mice and non-human primates Structurally designed EBV vaccine candidates based on self-assembling nanoparticles elicit potent and durable virus-neutralizing antibodies that target the receptor-binding site on the viral envelope protein gp350, a site of vulnerability, serving as a template to develop an EBV vaccine and providing a basis for immunofocusing through rational vaccine design.