A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice
A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice
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DOI：
10.1126/scitranslmed.abf3685
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发表时间：
2022-05-04
影响因子：
17.1
通讯作者：
Nabel，Gary J.
中科院分区：
文献类型：
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作者：
Wei，Chih-Jen;Bu，Wei;Nabel，Gary J.
EB病毒（EBV）是传染性单核细胞增多症的主要原因，并与几种人类癌症和最近的多发性硬化症有关。尽管它的流行和健康影响，目前没有疫苗或治疗方法。四种病毒糖蛋白（gp）gp 350和gH/gL/gp 42介导进入病毒复制的主要位点、B细胞和上皮细胞。在这里，我们设计了一种展示这些蛋白质的纳米颗粒疫苗，并表明它能产生有效的中和抗体，在体内保护免受感染。我们设计了单链gH/gL和gH/gL/gp 42蛋白，它们各自与细菌铁蛋白融合以形成自组装纳米颗粒。结构分析表明，单链gH/gL和gH/gL/gp 42采取了类似的构象的野生型蛋白，并通过电子显微镜观察到的蛋白尖峰。构建单链gH/gL或gH/gL/gp 42纳米颗粒疫苗以确保临床开发所需的产品均一性。这些疫苗在小鼠、雪貂和非人灵长类动物中引发中和抗体，抑制EBV进入B细胞和上皮细胞。当与先前报道的gp 350纳米颗粒疫苗gp 350 D123混合时，没有观察到免疫竞争。为了证实其在体内的功效，在从用对照、gH/gL/gp 42 + gp 350 D123或gH/gL+ gp 350 D123纳米颗粒接种的小鼠被动转移IgG后，用EBV攻击人源化小鼠。尽管所有对照动物都被感染，但每个接受免疫IgG的疫苗组中只有一只小鼠具有可检测的短暂病毒血症。此外，在免疫动物中未检测到EBV淋巴瘤。这种二价EBV纳米颗粒疫苗代表了预防人类EBV感染和EBV相关恶性肿瘤的有希望的候选物。
Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several human cancers and, more recently, multiple sclerosis. Despite its prevalence and health impact, there are currently no vaccines or treatments. Four viral glycoproteins (gp), gp350 and gH/gL/gp42, mediate entry into the major sites of viral replication, B cells, and epithelial cells. Here, we designed a nanoparticle vaccine displaying these proteins and showed that it elicits potent neutralizing antibodies that protect against infection in vivo. We designed single-chain gH/gL and gH/gL/gp42 proteins that were each fused to bacterial ferritin to form a self-assembling nanoparticle. Structural analysis revealed that single-chain gH/gL and gH/gL/gp42 adopted a similar conformation to the wild-type proteins, and the protein spikes were observed by electron microscopy. Single-chain gH/gL or gH/gL/gp42 nanoparticle vaccines were constructed to ensure product homogeneity needed for clinical development. These vaccines elicited neutralizing antibodies in mice, ferrets, and nonhuman primates that inhibited EBV entry into both B cells and epithelial cells. When mixed with a previously reported gp350 nanoparticle vaccine, gp350D123, no immune competition was observed. To confirm its efficacy in vivo, humanized mice were challenged with EBV after passive transfer of IgG from mice vaccinated with control, gH/gL/gp42+gp350D123, or gH/gL+gp350D123nanoparticles. Although all control animals were infected, only one mouse in each vaccine group that received immune IgG had detectable transient viremia. Furthermore, no EBV lymphomas were detected in immune animals. This bivalent EBV nanoparticle vaccine represents a promising candidate to prevent EBV infection and EBV-related malignancies in humans.