{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:29:54Z","timestamp":1792013394961,"version":"4.4.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2017,7,1]],"date-time":"2017-07-01T00:00:00Z","timestamp":1498867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The incidence and severity of herpes zoster (HZ) increases with age. The live attenuated zoster vaccine generates immune responses similar to HZ. We compared the immune responses to zoster vaccine in young and older to adults to increase our understanding of the immune characteristics that may contribute to the increased susceptibility to HZ in older adults. Young (25\u201340 y; n = 25) and older (60\u201380 y; n = 33) adults had similar magnitude memory responses to varicella-zoster virus (VZV) ex vivo restimulation measured by responder cell-frequency and flow cytometry, but the responses were delayed in older compared with young adults. Only young adults had an increase in dual-function VZV-specific CD4+ and CD8+ T cell effectors defined by coexpression of IFN-\u03b3, IL-2, and CD107a after vaccination. In contrast, older adults showed marginal increases in VZV-specific CD8+CD57+ senescent T cells after vaccination, which were already higher than those of young adults before vaccination. An increase in VZV-stimulated CD4+CD69+CD57+PD1+ and CD8+CD69+CD57+PD1+ T cells from baseline to postvaccination was associated with concurrent decreased VZV-memory and CD8+ effector responses, respectively, in older adults. Blocking the PD1 pathway during ex vivo VZV restimulation increased the CD4+ and CD8+ proliferation, but not the effector cytokine production, which modestly increased with TIM-3 blockade. We conclude that high proportions of senescent and exhausted VZV-specific T cells in the older adults contribute to their poor effector responses to a VZV challenge. This may underlie their inability to contain VZV reactivation and prevent the development of HZ.<\/jats:p>","DOI":"10.4049\/jimmunol.1700290","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T00:20:22Z","timestamp":1497313222000},"page":"604-612","source":"Crossref","is-referenced-by-count":53,"title":["Varicella-Zoster Virus\u2013Specific Cellular Immune Responses to the Live Attenuated Zoster Vaccine in Young and Older Adults"],"prefix":"10.1093","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6920-0623","authenticated-orcid":false,"given":"Adriana","family":"Weinberg","sequence":"first","affiliation":[{"name":"Section of Pediatric Infectious Diseases, Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"},{"name":"Department of Pathology, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"},{"name":"Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Canniff","sequence":"additional","affiliation":[{"name":"Section of Pediatric Infectious Diseases, Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Rouphael","sequence":"additional","affiliation":[{"name":"Hope Clinic of the Emory Vaccine Center and Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University , Decatur, GA 30030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6552-9162","authenticated-orcid":false,"given":"Aneesh","family":"Mehta","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University , Atlanta, GA 30307"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Mulligan","sequence":"additional","affiliation":[{"name":"Hope Clinic of the Emory Vaccine Center and Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University , Decatur, GA 30030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1072-1058","authenticated-orcid":false,"given":"Jennifer A","family":"Whitaker","sequence":"additional","affiliation":[{"name":"Hope Clinic of the Emory Vaccine Center and Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University , Decatur, GA 30030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myron J","family":"Levin","sequence":"additional","affiliation":[{"name":"Section of Pediatric Infectious Diseases, Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"},{"name":"Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,7,15]]},"reference":[{"key":"2025030614193154700_r1","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1111\/j.1525-1497.2005.0150.x","article-title":"The incidence of herpes zoster in a United States administrative database","volume":"20","author":"Insinga","year":"2005","journal-title":"J. Gen. Intern. Med."},{"key":"2025030614193154700_r2","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.4065\/82.11.1341","article-title":"A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction","volume":"82","author":"Yawn","year":"2007","journal-title":"Mayo Clin. Proc."},{"key":"2025030614193154700_r3","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1056\/NEJM199607043350107","article-title":"Postherpetic neuralgia--pathogenesis, treatment, and prevention","volume":"335","author":"Kost","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"2025030614193154700_r4","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1001\/archinte.1997.00440320117011","article-title":"Risk factors for postherpetic neuralgia","volume":"157","author":"Choo","year":"1997","journal-title":"Arch. Intern. 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Virol."},{"key":"2025030614193154700_r14","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1002\/jmv.23605","article-title":"Varicella zoster virus quantitation in blood from symptomatic and asymptomatic individuals","volume":"85","author":"Toi","year":"2013","journal-title":"J. Med. Virol."},{"key":"2025030614193154700_r15","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1101\/sqb.78.019869","article-title":"Programmed cell death 1-directed immunotherapy for enhancing T-cell function","volume":"78","author":"Araki","year":"2014","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"2025030614193154700_r16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/ni.1679","article-title":"Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection","volume":"10","author":"Blackburn","year":"2009","journal-title":"Nat. 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Neurovirol."},{"key":"2025030614193154700_r19","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1093\/infdis\/jiu500","article-title":"Altered phenotype and functionality of varicella zoster virus-specific cellular immunity in individuals with active infection","volume":"211","author":"Schub","year":"2015","journal-title":"J. Infect. Dis."},{"key":"2025030614193154700_r20","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1038\/jid.2015.63","article-title":"The characterization of varicella zoster virus-specific T Cells in skin and blood during aging","volume":"135","author":"Vukmanovic-Stejic","year":"2015","journal-title":"J. Invest. Dermatol."},{"key":"2025030614193154700_r21","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jim.2010.09.032","article-title":"Optimization of storage and shipment of cryopreserved peripheral blood mononuclear cells from HIV-infected and uninfected individuals for ELISPOT assays","volume":"363","author":"Weinberg","year":"2010","journal-title":"J. Immunol. Methods"},{"key":"2025030614193154700_r22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0022-1759(94)90242-9","article-title":"Clinical application of responder cell frequency estimates with four years of follow up","volume":"170","author":"Hayward","year":"1994","journal-title":"J. Immunol. 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Microbiol."},{"key":"2025030614193154700_r29","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/j.1749-6632.1991.tb33450.x","article-title":"Development of a treatment regimen for human cytomegalovirus (CMV) infection in bone marrow transplantation recipients by adoptive transfer of donor-derived CMV-specific T cell clones expanded in vitro","volume":"636","author":"Greenberg","year":"1991","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2025030614193154700_r30","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1073\/pnas.0610847104","article-title":"Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia","volume":"104","author":"Verjans","year":"2007","journal-title":"Proc. Natl. Acad. Sci. 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Cancer"},{"key":"2025030614193154700_r34","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1128\/JVI.03445-13","article-title":"Analysis of T cell responses during active varicella-zoster virus reactivation in human ganglia","volume":"88","author":"Steain","year":"2014","journal-title":"J. Virol."},{"key":"2025030614193154700_r35","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1128\/JVI.06623-11","article-title":"Immune correlates of herpes zoster in HIV-infected children and youth","volume":"86","author":"Weinberg","year":"2012","journal-title":"J. Virol."},{"key":"2025030614193154700_r36","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1093\/cid\/ciu918","article-title":"Long-term persistence of zoster vaccine efficacy","volume":"60","author":"Morrison","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"2025030614193154700_r37","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1093\/cid\/cis638","article-title":"Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy","volume":"55","author":"Schmader","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"2025030614193154700_r38","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/infdis\/jiv480","article-title":"Cellular and humoral responses to a second dose of herpes zoster vaccine administered 10 years after the first dose among older adults","volume":"213","author":"Levin","year":"2016","journal-title":"J. Infect. Dis."},{"key":"2025030614193154700_r39","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.vaccine.2011.11.096","article-title":"Safety, tolerability, and immunogenicity after 1 and 2 doses of zoster vaccine in healthy adults \u226560 years of age","volume":"30","author":"Vermeulen","year":"2012","journal-title":"Vaccine"},{"key":"2025030614193154700_r40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nri3790","article-title":"Clinical blockade of PD1 and LAG3--potential mechanisms of action","volume":"15","author":"Nguyen","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614193154700_r41","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2025030614193154700_r42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.it.2013.10.001","article-title":"Tolerance and exhaustion: defining mechanisms of T cell dysfunction","volume":"35","author":"Schietinger","year":"2014","journal-title":"Trends Immunol."},{"key":"2025030614193154700_r43","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030614193154700_r44","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1172\/JCI26856","article-title":"Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection","volume":"116","author":"Brooks","year":"2006","journal-title":"J. Clin. Invest."},{"key":"2025030614193154700_r45","doi-asserted-by":"crossref","first-page":"977","DOI":"10.4049\/jimmunol.1201331","article-title":"Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans","volume":"190","author":"Vukmanovic-Stejic","year":"2013","journal-title":"J. Immunol."},{"key":"2025030614193154700_r46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1086\/375828","article-title":"Identification of CD8+ T cell epitopes in the immediate early 62 protein (IE62) of varicella-zoster virus, and evaluation of frequency of CD8+ T cell response to IE62, by use of IE62 peptides after varicella vaccination","volume":"188","author":"Frey","year":"2003","journal-title":"J. Infect. Dis."},{"key":"2025030614193154700_r47","doi-asserted-by":"crossref","first-page":"9772","DOI":"10.1128\/JVI.00564-06","article-title":"Persistent high frequencies of varicella-zoster virus ORF4 protein-specific CD4+ T cells after primary infection","volume":"80","author":"Jones","year":"2006","journal-title":"J. Virol."},{"key":"2025030614193154700_r48","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1002\/eji.200737648","article-title":"Phenotypic analysis of human CD4+ T cells specific for immediate-early 63 protein of varicella-zoster virus","volume":"37","author":"Jones","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025030614193154700_r49","doi-asserted-by":"crossref","first-page":"874","DOI":"10.3324\/haematol.2011.052597","article-title":"Varicella-zoster virus glycoproteins B and E are major targets of CD4+ and CD8+ T cells reconstituting during zoster after allogeneic transplantation","volume":"97","author":"Kleemann","year":"2012","journal-title":"Haematologica"},{"key":"2025030614193154700_r50","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1086\/511274","article-title":"Rapid effector function of varicella-zoster virus glycoprotein I-specific CD4+ T cells many decades after primary infection","volume":"195","author":"Malavige","year":"2007","journal-title":"J. Infect. 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