{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T09:55:17Z","timestamp":1779184517308,"version":"3.51.4"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009947","name":"Merck Sharp and Dohme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cytomegalovirus (CMV) can cause congenital infection and is the leading cause of nongenetic newborn disabilities. V160, a conditionally replication-defective virus, is an investigational vaccine under evaluation for prevention of congenital CMV. The vaccine was well tolerated and induced both humoral and cellular immunity in CMV-seronegative trial participants. T-cell\u2013mediated immunity is important for immune control of CMV. Here we describe efforts to understand the quality attributes of the T-cell responses induced by vaccination.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using multicolor flow cytometry, we analyzed vaccine-induced T cells for memory phenotype, antigen specificity, cytokine profiles, and cytolytic potential. Moreover, antigen-specific T cells were sorted from 4 participants, and next-generation sequencing was used to trace clonal lineage development during the course of vaccination using T-cell receptor \u03b2-chain sequences as identifiers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The results demonstrated that vaccination elicited polyfunctional CD4 and CD8 T cells to 2 dominant antigens, pp65 and IE1, with a predominantly effector phenotype. Analysis of T-cell receptor repertoires showed polyclonal expansion of pp65- and IE1-specific T cells after vaccination.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>V160 induced a genetically diverse and polyfunctional T-cell response and the data support further clinical development of V160 for prevention of CMV infection and congenital transmission.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical Trials Registration<\/jats:title>\n                  <jats:p>NCT01986010.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiaa631","type":"journal-article","created":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T19:10:53Z","timestamp":1601579453000},"page":"2001-2012","source":"Crossref","is-referenced-by-count":8,"title":["Functional Evaluation and Genetic Evolution of Human T-Cell Responses After Vaccination With a Conditionally Replication-Defective Cytomegalovirus Vaccine"],"prefix":"10.1093","volume":"223","author":[{"given":"Kara S","family":"Cox","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Strategic Planning and Research Informatics, MSD, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel C","family":"Freed","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aimin","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shifang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Abhelix, LLC., South Plainfield, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I-Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Pharmacogenomics, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E","family":"Rupp","sequence":"additional","affiliation":[{"name":"Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart P","family":"Adler","sequence":"additional","affiliation":[{"name":"CMV Research Foundation, Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luwy K","family":"Musey","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalpit A","family":"Vora","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-2271","authenticated-orcid":false,"given":"Tong-Ming","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Vaccines, Merck & Co., Inc. Kenilworth, New Jersey, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,10,8]]},"reference":[{"key":"2021060422092438100_CIT0001","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1093\/infdis\/jiu019","article-title":"Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection","volume":"209","author":"Pereira","year":"2014","journal-title":"J Infect Dis"},{"key":"2021060422092438100_CIT0002","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jcv.2005.09.015","article-title":"Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome","volume":"35","author":"Pass","year":"2006","journal-title":"J Clin Virol"},{"key":"2021060422092438100_CIT0003","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1093\/cid\/ciy1128","article-title":"Sequelae of congenital cytomegalovirus following maternal primary infections are limited to those acquired in the first trimester of pregnancy","volume":"69","author":"Faure-Bardon","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2021060422092438100_CIT0004","first-page":"253","article-title":"TORCH infections. toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus (CMV), and herpes infections","volume":"2","author":"Stegmann","year":"2002","journal-title":"Curr Womens Health Rep"},{"key":"2021060422092438100_CIT0005","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/jp.2017.41","article-title":"Long-term outcomes of children with symptomatic congenital cytomegalovirus disease","volume":"37","author":"Lanzieri","year":"2017","journal-title":"J Perinatol"},{"key":"2021060422092438100_CIT0006","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1128\/CMR.00062-12","article-title":"The \u201csilent\u201d global burden of congenital cytomegalovirus","volume":"26","author":"Manicklal","year":"2013","journal-title":"Clin Microbiol Rev"},{"key":"2021060422092438100_CIT0007","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1001\/jama.289.8.1008","article-title":"Maternal immunity and prevention of congenital cytomegalovirus infection","volume":"289","author":"Fowler","year":"2003","journal-title":"JAMA"},{"key":"2021060422092438100_CIT0008","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3390\/v10080405","article-title":"Maternal immunity and the natural history of congenital human cytomegalovirus infection","volume":"10","author":"Britt","year":"2018","journal-title":"Viruses"},{"key":"2021060422092438100_CIT0009","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1086\/512245","article-title":"Development of human cytomegalovirus-specific T cell immunity during primary infection of pregnant women and its correlation with virus transmission to the fetus","volume":"195","author":"Lilleri","year":"2007","journal-title":"J Infect Dis"},{"key":"2021060422092438100_CIT0010","doi-asserted-by":"crossref","first-page":"e59863","DOI":"10.1371\/journal.pone.0059863","article-title":"Fetal human cytomegalovirus transmission correlates with delayed maternal antibodies to gH\/gL\/pUL128-130-131 complex during primary infection","volume":"8","author":"Lilleri","year":"2013","journal-title":"PLoS One"},{"key":"2021060422092438100_CIT0011","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1016\/j.vaccine.2014.03.057","article-title":"Progress on pursuit of human cytomegalovirus vaccines for prevention of congenital infection and disease","volume":"32","author":"Fu","year":"2014","journal-title":"Vaccine"},{"key":"2021060422092438100_CIT0012","doi-asserted-by":"crossref","first-page":"362ra145","DOI":"10.1126\/scitranslmed.aaf9387","article-title":"A replication-defective human cytomegalovirus vaccine for prevention of congenital infection","volume":"8","author":"Wang","year":"2016","journal-title":"Sci Transl Med"},{"key":"2021060422092438100_CIT0013","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/infdis\/jiz141","article-title":"Phase 1 clinical trial of a conditionally replication-defective human cytomegalovirus (CMV) vaccine in CMV-seronegative subjects","volume":"220","author":"Adler","year":"2019","journal-title":"J Infect Dis"},{"key":"2021060422092438100_CIT0014","doi-asserted-by":"crossref","first-page":"553","DOI":"10.3389\/fimmu.2015.00553","article-title":"Effector and central memory poly-functional CD4+ and CD8+ T cells are boosted upon ZOSTAVAX(\u00ae) vaccination","volume":"6","author":"Sei","year":"2015","journal-title":"Front Immunol"},{"key":"2021060422092438100_CIT0015","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/cyto.a.21015","article-title":"SPICE: exploration and analysis of post-cytometric complex multivariate datasets","volume":"79","author":"Roederer","year":"2011","journal-title":"Cytometry A"},{"key":"2021060422092438100_CIT0016","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jim.2004.01.001","article-title":"The interferon gamma secretion assay: a reliable tool to study interferon gamma production at the single cell level","volume":"286","author":"Desombere","year":"2004","journal-title":"J Immunol Methods"},{"key":"2021060422092438100_CIT0017","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/nbt.2938","article-title":"Linking T-cell receptor sequence to functional phenotype at the single-cell level","volume":"32","author":"Han","year":"2014","journal-title":"Nat Biotechnol"},{"key":"2021060422092438100_CIT0018","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: summarize analysis results for multiple tools and samples in a single report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"2021060422092438100_CIT0019","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1471-2105-13-31","article-title":"PANDAseq: paired-end assembler for illumina sequences","volume":"13","author":"Masella","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"2021060422092438100_CIT0020","first-page":"D256-61","article-title":"IMGT\/GENE-DB: a comprehensive database for human and mouse immunoglobulin and T cell receptor genes","volume":"33","author":"Giudicelli","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"2021060422092438100_CIT0021","doi-asserted-by":"crossref","first-page":"W34","DOI":"10.1093\/nar\/gkt382","article-title":"IgBLAST: an immunoglobulin variable domain sequence analysis tool","volume":"41","author":"Ye","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2021060422092438100_CIT0022","first-page":"265","article-title":"Nonparametric estimation of the number of classes in a population","volume":"11","author":"Chao","year":"1984","journal-title":"Scand J Stat"},{"key":"2021060422092438100_CIT0023","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2307\/2531532","article-title":"Estimating the population size for capture-recapture data with unequal catchability","volume":"43","author":"Chao","year":"1987","journal-title":"Biometrics"},{"key":"2021060422092438100_CIT0024","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0022-1759(03)00265-5","article-title":"Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation","volume":"281","author":"Betts","year":"2003","journal-title":"J Immunol Methods"},{"key":"2021060422092438100_CIT0025","doi-asserted-by":"crossref","first-page":"e1002889","DOI":"10.1371\/journal.ppat.1002889","article-title":"Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years","volume":"8","author":"Klarenbeek","year":"2012","journal-title":"PLoS Pathog"},{"key":"2021060422092438100_CIT0026","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.1111\/ajt.12431","article-title":"TCR repertoire analysis by next generation sequencing allows complex differential diagnosis of T cell-related pathology","volume":"13","author":"Dziubianau","year":"2013","journal-title":"Am J Transplant"},{"key":"2021060422092438100_CIT0027","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1084\/jem.20051357","article-title":"Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses","volume":"202","author":"Price","year":"2005","journal-title":"J Exp Med"},{"key":"2021060422092438100_CIT0028","doi-asserted-by":"crossref","first-page":"e0141561","DOI":"10.1371\/journal.pone.0141561","article-title":"Multiplex identification of antigen-specific T cell receptors using a combination of immune assays and immune receptor sequencing","volume":"10","author":"Klinger","year":"2015","journal-title":"PLoS One"},{"key":"2021060422092438100_CIT0029","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.celrep.2017.03.072","article-title":"Sequence and structural analyses reveal distinct and highly diverse human CD8+ TCR repertoires to immunodominant viral antigens","volume":"19","author":"Chen","year":"2017","journal-title":"Cell Rep"},{"key":"2021060422092438100_CIT0030","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1093\/bioinformatics\/btx286","article-title":"McPAS-TCR: a manually curated catalogue of pathology-associated T cell receptor sequences","volume":"33","author":"Tickotsky","year":"2017","journal-title":"Bioinformatics"},{"key":"2021060422092438100_CIT0031","doi-asserted-by":"crossref","first-page":"979","DOI":"10.4049\/jimmunol.1801401","article-title":"Antigen-specific TCR signatures of cytomegalovirus infection","volume":"202","author":"Huth","year":"2019","journal-title":"J Immunol"},{"key":"2021060422092438100_CIT0032","doi-asserted-by":"crossref","first-page":"eaaw2607","DOI":"10.1126\/scitranslmed.aaw2607","article-title":"A live-attenuated RhCMV\/SIV vaccine shows long-term efficacy against heterologous SIV challenge","volume":"11","author":"Hansen","year":"2019","journal-title":"Sci Transl Med"},{"key":"2021060422092438100_CIT0033","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.4049\/jimmunol.1302523","article-title":"A novel murine cytomegalovirus vaccine vector protects against Mycobacterium tuberculosis","volume":"193","author":"Beverley","year":"2014","journal-title":"J Immunol"},{"key":"2021060422092438100_CIT0034","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.3390\/ijms20184457","article-title":"Promising cytomegalovirus-based vaccine vector induces robust CD8+ T-cell response","volume":"20","author":"Liu","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2021060422092438100_CIT0035","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10875-015-0139-3","article-title":"Reduced frequencies of polyfunctional CMV-specific T cell responses in infants with congenital CMV infection","volume":"35","author":"Gibson","year":"2015","journal-title":"J Clin Immunol"},{"key":"2021060422092438100_CIT0036","doi-asserted-by":"crossref","first-page":"877","DOI":"10.4049\/jimmunol.1501589","article-title":"IL-12-dependent cytomegalovirus-specific CD4+ T cell proliferation, T-bet induction, and effector multifunction during primary infection are key determinants for early immune control","volume":"196","author":"Popescu","year":"2016","journal-title":"J Immunol"},{"key":"2021060422092438100_CIT0037","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1002\/jmv.24449","article-title":"Comparative magnitude and kinetics of human cytomegalovirus-specific CD4+ and CD8+ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pregnancy","volume":"88","author":"Fornara","year":"2016","journal-title":"J Med Virol"},{"key":"2021060422092438100_CIT0038","doi-asserted-by":"crossref","first-page":"e00747-19","DOI":"10.1128\/JVI.00747-19","article-title":"A replication defective human cytomegalovirus vaccine elicits humoral immune responses analogous to those with natural infection","volume":"93","author":"Liu","year":"2019","journal-title":"J Virol"},{"key":"2021060422092438100_CIT0039","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00430-019-00608-7","article-title":"The hallmarks of CMV-specific CD8 T-cell differentiation","volume":"208","author":"van den Berg","year":"2019","journal-title":"Med Microbiol Immunol"},{"key":"2021060422092438100_CIT0040","doi-asserted-by":"crossref","first-page":"7919","DOI":"10.4049\/jimmunol.0803903","article-title":"The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response","volume":"183","author":"Akondy","year":"2009","journal-title":"J Immunol"},{"key":"2021060422092438100_CIT0041","doi-asserted-by":"crossref","first-page":"128ra42","DOI":"10.1126\/scitranslmed.3003647","article-title":"T cell receptor \u03b1\u03b2 diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection","volume":"4","author":"Wang","year":"2012","journal-title":"Sci Transl Med"},{"key":"2021060422092438100_CIT0042","doi-asserted-by":"crossref","first-page":"15054","DOI":"10.1038\/mtm.2015.54","article-title":"Rapid cloning, expression, and functional characterization of paired \u03b1\u03b2 and \u03b3\u03b4 T-cell receptor chains from single-cell analysis","volume":"3","author":"Guo","year":"2016","journal-title":"Mol Ther Methods Clin Dev"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiaa631\/34366299\/jiaa631.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/223\/11\/2001\/38488634\/jiaa631.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/article-pdf\/223\/11\/2001\/38488634\/jiaa631.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T23:42:42Z","timestamp":1622850162000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/223\/11\/2001\/5919748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,8]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,10,8]]},"published-print":{"date-parts":[[2021,6,4]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiaa631","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,6,1]]},"published":{"date-parts":[[2020,10,8]]}}}