{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:29:58Z","timestamp":1792013398699,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GlaxoSmithKline Biologicals SA"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Vaccines"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/vaccines12101111","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T11:19:33Z","timestamp":1727435973000},"page":"1111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Structures of the Varicella Zoster Virus Glycoprotein E and Epitope Mapping of Vaccine-Elicited Antibodies"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-0679","authenticated-orcid":false,"given":"Wayne D.","family":"Harshbarger","sequence":"first","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3265-4216","authenticated-orcid":false,"given":"Genevieve","family":"Holzapfel","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3292-377X","authenticated-orcid":false,"given":"Nishat","family":"Seraj","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Tian","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsy","family":"Chesterman","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongming","family":"Fu","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Pan","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0958-4092","authenticated-orcid":false,"given":"Claire","family":"Harelson","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6474-5138","authenticated-orcid":false,"given":"Dongjun","family":"Peng","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0603-5568","authenticated-orcid":false,"given":"Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"},{"name":"WuXi Biologics, Cranbury, NJ 08512, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-506X","authenticated-orcid":false,"given":"Sumana","family":"Chandramouli","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"},{"name":"Moderna Therapeutics Inc., Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1669-5607","authenticated-orcid":false,"given":"Enrico","family":"Malito","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"},{"name":"Schr\u00f6dinger, Inc., New York City, NY 10036, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9734-5694","authenticated-orcid":false,"given":"Matthew James","family":"Bottomley","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"},{"name":"Dynavax Technologies Corporation, Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4998-6571","authenticated-orcid":false,"given":"James","family":"Williams","sequence":"additional","affiliation":[{"name":"GSK, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35324","DOI":"10.18632\/oncotarget.6117","article-title":"Insights into the role of immunosenescence during varicella zoster virus infection (shingles) in the aging cell model","volume":"6","author":"Kim","year":"2015","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e004833","DOI":"10.1136\/bmjopen-2014-004833","article-title":"Systematic review of incidence and complications of herpes zoster: Towards a global perspective","volume":"4","author":"Kawai","year":"2014","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1586\/erv.10.30","article-title":"Herpes zoster and postherpetic neuralgia","volume":"9","author":"Johnson","year":"2010","journal-title":"Expert Rev. Vaccines"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Johnson, R.W., Bouhassira, D., Kassianos, G., Leplege, A., Schmader, K.E., and Weinke, T. (2010). The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med., 8.","DOI":"10.1186\/1741-7015-8-37"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1093\/cid\/cir970","article-title":"Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years","volume":"54","author":"Schmader","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"545","DOI":"10.7326\/0003-4819-152-9-201005040-00004","article-title":"Safety of herpes zoster vaccine in the shingles prevention study: A randomized trial","volume":"152","author":"Simberkoff","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1093\/cid\/ciab125","article-title":"Recombinant Zoster Vaccine (Shingrix): Real-World Effectiveness in the First 2 Years Post-Licensure","volume":"73","author":"Izurieta","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1056\/NEJMoa1501184","article-title":"Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults","volume":"372","author":"Lal","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1056\/NEJMoa1603800","article-title":"Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older","volume":"375","author":"Cunningham","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1080\/21645515.2018.1442162","article-title":"Persistence of immune response to an adjuvanted varicella-zoster virus subunit vaccine for up to year nine in older adults","volume":"14","author":"Schwarz","year":"2018","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.vaccine.2015.09.073","article-title":"Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults","volume":"34","author":"Chlibek","year":"2016","journal-title":"Vaccine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/infdis\/157.5.882","article-title":"Western blot analysis of antibody to varicella-zoster virus","volume":"157","author":"Dubey","year":"1988","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sullivan, N.L., Reuter-Monslow, M.A., Sei, J., Durr, E., Davis, C.W., Chang, C., McCausland, M., Wieland, A., Krah, D., and Rouphael, N. (2018). Breadth and Functionality of Varicella-Zoster Virus Glycoprotein-Specific Antibodies Identified after Zostavax Vaccination in Humans. J. Virol., 92.","DOI":"10.1128\/JVI.00269-18"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3643","DOI":"10.1128\/jvi.66.6.3643-3651.1992","article-title":"Receptor properties of two varicella-zoster virus glycoproteins, gpI and gpIV, homologous to herpes simplex virus gE and gI","volume":"66","author":"Litwin","year":"1992","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1128\/jvi.71.1.110-119.1997","article-title":"Varicella-zoster virus Fc receptor gE glycoprotein: Serine\/threonine and tyrosine phosphorylation of monomeric and dimeric forms","volume":"71","author":"Olson","year":"1997","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4464","DOI":"10.1128\/jvi.67.8.4464-4473.1993","article-title":"Identification of the phosphorylation sequence in the cytoplasmic tail of the varicella-zoster virus Fc receptor glycoprotein gpI","volume":"67","author":"Yao","year":"1993","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12406","DOI":"10.1128\/JVI.78.22.12406-12415.2004","article-title":"Functions of the C-terminal domain of varicella-zoster virus glycoprotein E in viral replication in vitro and skin and T-cell tropism in vivo","volume":"78","author":"Moffat","year":"2004","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/rmv.377","article-title":"Membrane fusion mediated by herpesvirus glycoproteins: The paradigm of varicella-zoster virus","volume":"13","author":"Cole","year":"2003","journal-title":"Rev. Med. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9483","DOI":"10.1128\/JVI.75.19.9483-9492.2001","article-title":"Varicella-zoster Virus gB and gE coexpression, but not gB or gE alone, leads to abundant fusion and syncytium formation equivalent to those from gH and gL coexpression","volume":"75","author":"Maresova","year":"2001","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8279","DOI":"10.1128\/jvi.71.11.8279-8288.1997","article-title":"Mutational analysis of the role of glycoprotein I in varicella-zoster virus replication and its effects on glycoprotein E conformation and trafficking","volume":"71","author":"Mallory","year":"1997","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.cell.2006.08.046","article-title":"Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread","volume":"127","author":"Li","year":"2006","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1128\/JVI.01902-10","article-title":"Varicella-zoster virus glycoprotein E is a critical determinant of virulence in the SCID mouse-human model of neuropathogenesis","volume":"85","author":"Zerboni","year":"2011","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sprague, E.R., Wang, C., Baker, D., and Bjorkman, P.J. (2006). Crystal structure of the HSV-1 Fc receptor bound to Fc reveals a mechanism for antibody bipolar bridging. PLoS Biol., 4.","DOI":"10.1371\/journal.pbio.0040148"},{"key":"ref_24","first-page":"341","article-title":"VZV T cell-mediated immunity","volume":"342","author":"Weinberg","year":"2010","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4429","DOI":"10.1172\/JCI121484","article-title":"Th1 memory differentiates recombinant from live herpes zoster vaccines","volume":"128","author":"Levin","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1093\/infdis\/jiaa300","article-title":"Immunogenicity of the Adjuvanted Recombinant Zoster Vaccine: Persistence and Anamnestic Response to Additional Doses Administered 10 Years After Primary Vaccination","volume":"224","author":"Hastie","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Norden, R., Nilsson, J., Samuelsson, E., Risinger, C., Sihlbom, C., Blixt, O., Larson, G., Olofsson, S., and Bergstrom, T. (2019). Recombinant Glycoprotein E of Varicella Zoster Virus Contains Glycan-Peptide Motifs That Modulate B Cell Epitopes into Discrete Immunological Signatures. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040954"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1016\/j.vaccine.2021.02.074","article-title":"Correlation of protection against varicella in a randomized Phase III varicella-containing vaccine efficacy trial in healthy infants","volume":"39","author":"Habib","year":"2021","journal-title":"Vaccine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1038\/nprot.2006.468","article-title":"In-gel digestion for mass spectrometric characterization of proteins and proteomes","volume":"1","author":"Shevchenko","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1107\/S0907444906019949","article-title":"HKL-3000: The integration of data reduction and structure solution--from diffraction images to an initial model in minutes","volume":"62","author":"Minor","year":"2006","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"J. Appl. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1093\/bioinformatics\/btn341","article-title":"PIGS: Automatic prediction of antibody structures","volume":"24","author":"Marcatili","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: A comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF ChimeraX: Meeting modern challenges in visualization and analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"key":"ref_36","unstructured":"The PyMOL Molecular Graphics System, Version 2.5.5 Schr\u00f6dinger, LLC."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1107\/S1600577520016173","article-title":"FMX\u2014The Frontier Microfocusing Macromolecular Crystallography Beamline at the National Synchrotron Light Source II","volume":"28","author":"Schneider","year":"2021","journal-title":"J. Synchrotron Radiat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jsb.2015.08.008","article-title":"CTFFIND4: Fast and accurate defocus estimation from electron micrographs","volume":"192","author":"Rohou","year":"2015","journal-title":"J. Struct. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e06980","DOI":"10.7554\/eLife.06980","article-title":"Measuring the optimal exposure for single particle cryo-EM using a 2.6 A reconstruction of rotavirus VP6","volume":"4","author":"Grant","year":"2015","journal-title":"Elife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/bioinformatics\/btaa1071","article-title":"PROSS 2: A new server for the design of stable and highly expressed protein variants","volume":"37","author":"Weinstein","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41541-022-00545-2","article-title":"Development of antibody-dependent cellular cytotoxicity in response to recombinant and live-attenuated herpes zoster vaccines","volume":"7","author":"Park","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.vaccine.2016.02.007","article-title":"A highly conserved epitope-vaccine candidate against varicella-zoster virus induces neutralizing antibodies in mice","volume":"34","author":"Zhu","year":"2016","journal-title":"Vaccine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1128\/JCM.38.6.2447-2449.2000","article-title":"Comparison of quantitations of viral load in varicella and zoster","volume":"38","author":"Kimura","year":"2000","journal-title":"J. Clin. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1073\/pnas.0912373107","article-title":"Functions of the unique N-terminal region of glycoprotein E in the pathogenesis of varicella-zoster virus infection","volume":"107","author":"Berarducci","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"}],"updated-by":[{"DOI":"10.3390\/vaccines14090746","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000}}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/10\/1111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:44:01Z","timestamp":1787921041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/10\/1111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,27]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["vaccines12101111"],"URL":"https:\/\/doi.org\/10.3390\/vaccines12101111","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,27]]}}}