Wayne D Harshbarger, Genevieve Holzapfel, Nishat Seraj, Sai Tian, Chelsy Chesterman, Zongming Fu, Yan Pan, Claire Harelson, Dongjun Peng, Ying Huang, Sumana Chandramouli, Enrico Malito, Matthew James Bottomley, James Williams
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Importantly, gE is the sole antigen in Shingrix, a highly efficacious, AS01<sub>B</sub>-adjuvanted vaccine approved in multiple countries for the prevention of HZ, yet the three-dimensional (3D) structure of gE remains elusive. <b>Objectives</b>: We sought to determine the structure of VZV gE and to understand in detail its interactions with neutralizing antibodies. <b>Methods</b>: We used X-ray crystallography and cryo-electron microscopy to elucidate structures of gE bound by recombinant Fabs of antibodies previously elicited through vaccination with Zostavax, a live, attenuated vaccine. <b>Results</b>: The 3D structures resolve distinct central and C-terminal antigenic domains, presenting an array of diverse conformational epitopes. The central domain has two beta-sheets and two alpha helices, including an IgG-like fold. 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These results yield insights to VZV gE structure and immunogenicity, provide a framework for future studies, and may guide the design of additional herpesvirus vaccine antigens. <b>Teaser:</b> Structures of varicella zoster virus glycoprotein E reveal distinct antigenic domains and define epitopes for vaccine-elicited human antibodies.</p>","PeriodicalId":23634,"journal":{"name":"Vaccines","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511291/pdf/","citationCount":"0","resultStr":"{\"title\":\"Structures of the Varicella Zoster Virus Glycoprotein E and Epitope Mapping of Vaccine-Elicited Antibodies.\",\"authors\":\"Wayne D Harshbarger, Genevieve Holzapfel, Nishat Seraj, Sai Tian, Chelsy Chesterman, Zongming Fu, Yan Pan, Claire Harelson, Dongjun Peng, Ying Huang, Sumana Chandramouli, Enrico Malito, Matthew James Bottomley, James Williams\",\"doi\":\"10.3390/vaccines12101111\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> Varicella zoster virus (VZV) is the causative agent for chickenpox and herpes zoster (HZ, shingles). 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引用次数: 0
摘要
背景:水痘带状疱疹病毒(VZV)是水痘和带状疱疹(HZ,带状疱疹)的病原体。带状疱疹是一种使人衰弱的疾病,多发于老年人和免疫力低下的人群。糖蛋白 E(gE)是病毒复制和细胞间传播不可或缺的物质,也是抗 VZV 抗体的主要靶点。重要的是,gE是Shingrix中的唯一抗原,Shingrix是一种高效的AS01B佐剂疫苗,已被多个国家批准用于预防HZ,但gE的三维(3D)结构仍然难以捉摸。我们的目标是我们试图确定 VZV gE 的结构,并详细了解它与中和抗体的相互作用。方法:我们使用 X 射线晶体学和低温电子显微镜阐明了 gE 与重组 Fabs 结合的结构,这些 Fabs 是以前通过接种减毒活疫苗 Zostavax 引起的抗体。结果:三维结构解析了不同的中心和 C 端抗原结构域,呈现出一系列不同的构象表位。中心结构域有两个β片和两个α螺旋,包括一个类似IgG的折叠。C 端结构域有 3 个贝塔片和一个 Ig 样折叠,与 HSV1 gE 的结构高度相似。结论:来自 VZV 感染细胞的 gE 会引起人类抗体反应,并偏好 gE 的 gI 结合域。这些结果揭示了 VZV gE 的结构和免疫原性,为今后的研究提供了一个框架,并可能为设计更多的疱疹病毒疫苗抗原提供指导。预告:水痘带状疱疹病毒糖蛋白 E 的结构揭示了不同的抗原结构域,并确定了疫苗诱导的人类抗体的表位。
Structures of the Varicella Zoster Virus Glycoprotein E and Epitope Mapping of Vaccine-Elicited Antibodies.
Background: Varicella zoster virus (VZV) is the causative agent for chickenpox and herpes zoster (HZ, shingles). HZ is a debilitating disease affecting elderly and immunocompromised populations. Glycoprotein E (gE) is indispensable for viral replication and cell-to-cell spread and is the primary target for anti-VZV antibodies. Importantly, gE is the sole antigen in Shingrix, a highly efficacious, AS01B-adjuvanted vaccine approved in multiple countries for the prevention of HZ, yet the three-dimensional (3D) structure of gE remains elusive. Objectives: We sought to determine the structure of VZV gE and to understand in detail its interactions with neutralizing antibodies. Methods: We used X-ray crystallography and cryo-electron microscopy to elucidate structures of gE bound by recombinant Fabs of antibodies previously elicited through vaccination with Zostavax, a live, attenuated vaccine. Results: The 3D structures resolve distinct central and C-terminal antigenic domains, presenting an array of diverse conformational epitopes. The central domain has two beta-sheets and two alpha helices, including an IgG-like fold. The C-terminal domain exhibits 3 beta-sheets and an Ig-like fold and high structural similarity to HSV1 gE. Conclusions: gE from VZV-infected cells elicits a human antibody response with a preference for the gI binding domain of gE. These results yield insights to VZV gE structure and immunogenicity, provide a framework for future studies, and may guide the design of additional herpesvirus vaccine antigens. Teaser: Structures of varicella zoster virus glycoprotein E reveal distinct antigenic domains and define epitopes for vaccine-elicited human antibodies.
VaccinesPharmacology, Toxicology and Pharmaceutics-Pharmacology
CiteScore
8.90
自引率
16.70%
发文量
1853
审稿时长
18.06 days
期刊介绍:
Vaccines (ISSN 2076-393X) is an international, peer-reviewed open access journal focused on laboratory and clinical vaccine research, utilization and immunization. Vaccines publishes high quality reviews, regular research papers, communications and case reports.