Structures of the Varicella Zoster Virus Glycoprotein E and Epitope Mapping of Vaccine-Elicited Antibodies

被引:0
|
作者
Harshbarger, Wayne D. [1 ]
Holzapfel, Genevieve [1 ]
Seraj, Nishat [1 ]
Tian, Sai [1 ]
Chesterman, Chelsy [1 ]
Fu, Zongming [1 ]
Pan, Yan [1 ]
Harelson, Claire [1 ]
Peng, Dongjun [1 ]
Huang, Ying [1 ,2 ]
Chandramouli, Sumana [1 ,3 ]
Malito, Enrico [1 ,4 ]
Bottomley, Matthew James [1 ,5 ]
Williams, James [1 ]
机构
[1] GSK, Rockville, MD 20850 USA
[2] WuXi Biol, Cranbury, NJ 08512 USA
[3] Moderna Therapeut Inc, Cambridge, MA 02142 USA
[4] Schrodinger Inc, New York, NY 10036 USA
[5] Dynavax Technol Corp, Emeryville, CA 94608 USA
关键词
vaccines; herpes zoster; antibodies; pathogen-host interaction; HERPES-ZOSTER; SUBUNIT VACCINE; EFFICACY; GE; PHOSPHORYLATION; REPLICATION; INFECTION; SHINGLES; FUSION; SAFETY;
D O I
10.3390/vaccines12101111
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页数:18
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