{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:31:02Z","timestamp":1791412262275,"version":"4.3.3"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The reactivation of herpes simplex virus 2 (HSV-2) from latency causes viral shedding that develops into recurrent genital lesions. The role of tissue-resident T cells and the nature of viral antigens associated with protection against recurrent genital herpes remain to be fully elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this preclinical study, we investigated the protective therapeutic efficacy, in the guinea pig model of recurrent genital herpes, of five recombinant adenovirus-based therapeutic vaccine candidates (rAd-Ags), each expressing different HSV-2 envelope and tegument proteins: RR1 (UL39), RR2 (UL40), gD (glycoprotein D), VP16 (UL48), or VP22 (UL49). We compared the frequency and function of dorsal root ganglia (DRG)- and vaginal mucosa (VM)-resident CD4+ and CD8+ T cells induced by each vaccine and their effect on the frequency and severity of recurrent genital herpes. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HSV-2 latent-infected guinea pigs immunized with rAd-RR2 and rAd-gD vaccines showed high frequencies of DRG- and VM-tissue-resident IFN-g-producing CD4+ and CD8+ TRM cells associated with significant reductions in viral shedding and genital herpetic lesions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Taken together, these preclinical results provide new insights into the T cell mechanisms of protection against recurrent genital herpes and confirm the tegument RR2 protein and glycoprotein D as viable candidate antigens to be incorporated in future genital herpes therapeutic vaccines.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1568258","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T10:53:03Z","timestamp":1742986383000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Therapeutic mucosal vaccination of herpes simplex virus type 2 infected guinea pigs with an adenovirus-based vaccine expressing the ribonucleotide reductase 2 and glycoprotein D induces local tissue-resident CD4+ and CD8+ TRM cells associated with protection against recurrent genital herpes"],"prefix":"10.3389","volume":"16","author":[{"given":"Afshana","family":"Quadiri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swayam","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hawa","family":"Vahed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy Medhat","family":"Tadros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy K.","family":"Hormi-Carver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swena Jignesh","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lbachir","family":"BenMohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"B1","volume-title":"What you need to know about infectious disease","author":"Drexler","year":"2010"},{"key":"B2","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1002\/iid3.v8.1","article-title":"Identification and characterization of protective CD8(+) T-epitopes in a malaria vaccine candidate SLTRiP","volume":"8","author":"Quadiri","year":"2020","journal-title":"Immun Inflammation Dis"},{"key":"B3","first-page":"198","article-title":"Management of oral manifestations of herpes simplex virus, varicella zoster virus, and human papillomavirus","volume":"45","author":"Elkada","year":"2024","journal-title":"Compend Contin Educ Dent"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s11908-009-0066-7","article-title":"New concepts in understanding genital herpes","volume":"11","author":"Schiffer","year":"2009","journal-title":"Curr Infect Dis Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.19.237149","article-title":"Herpes simplex virus: global infection prevalence and incidence estimates, 2016","volume":"98","author":"James","year":"2020","journal-title":"Bull World Health Organ"},{"key":"B6","doi-asserted-by":"publisher","first-page":"149135","DOI":"10.1155\/2012\/149135","article-title":"Mucosal herpes immunity and immunopathology to ocular and genital herpes simplex virus infections","author":"Chentoufi","year":"2012","journal-title":"Clin Dev Immunol 2012"},{"key":"B7","article-title":"An insight into current treatment strategies, their limitations, and ongoing developments in vaccine technologies against herpes simplex infections","volume":"11","author":"Sharma","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/jam.15428","article-title":"Role of HrcA in stress management in Mycobacterium tuberculosis","volume":"132","author":"Hakiem","year":"2022","journal-title":"J Appl Microbiol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00545-11","article-title":"CMX001 potentiates the efficacy of acyclovir in herpes simplex virus infections","volume":"55","author":"Prichard","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/82_2018_102","article-title":"Successful vaccines","volume":"428","author":"Amanna","year":"2020","journal-title":"Curr Top Microbiol Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"01.07.425694","DOI":"10.1101\/2021.01.07.425694","article-title":"SLTRiP induces long lasting and protective T-cell memory response","volume":"2021","author":"Quadiri","year":"2021","journal-title":"bioRxiv"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2024.2367640","article-title":"Targeting HIF-1alpha in sickle cell disease and cancer: unraveling therapeutic opportunities and risks","volume":"28","author":"Ubaid","year":"2024","journal-title":"Expert Opin Ther Targets"},{"key":"B13","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.trsl.2021.12.006","article-title":"An mRNA vaccine to prevent genital herpes","volume":"242","author":"Awasthi","year":"2022","journal-title":"Transl Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06054","article-title":"Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease","volume":"4","author":"Petro","year":"2015","journal-title":"Elife"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01596-23","article-title":"Therapeutic prime\/pull vaccination of HSV-2-infected Guinea pigs with the ribonucleotide reductase 2 (RR2) protein and CXCL11 chemokine boosts antiviral local tissue-resident and effector memory CD4(+) and CD8(+) T cells and protects against recurrent genital herpes","volume":"98","author":"Quadiri","year":"2024","journal-title":"J Virol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02309-18","article-title":"Therapeutic mucosal vaccination of herpes simplex virus 2-infected Guinea pigs with ribonucleotide reductase 2 (RR2) protein boosts antiviral neutralizing antibodies and local tissue-resident CD4(+) and CD8(+) T(RM) cells associated with protection against recurrent genital herpes","volume":"93","author":"Srivastava","year":"2019","journal-title":"J Virol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2014.00052","article-title":"Ribonucleotide reductases: essential enzymes for bacterial life","volume":"4","author":"Torrents","year":"2014","journal-title":"Front Cell Infect Microbiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)00547-7","article-title":"The R1 subunit of herpes simplex virus ribonucleotide reductase has chaperone-like activity similar to Hsp27","volume":"545","author":"Chabaud","year":"2003","journal-title":"FEBS Lett"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.8.6083-6093.1997","article-title":"Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry","volume":"71","author":"Whitbeck","year":"1997","journal-title":"J Virol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s13205-020-02452-6","article-title":"Generation of oligomers of subunit vaccine candidate glycoprotein D of Herpes Simplex Virus-2 expressed in fusion with IgM Fc domain(s) in Escherichia coli: A strategy to enhance the immunogenicity of the antigen","volume":"10","author":"Singh","year":"2020","journal-title":"3 Biotech"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.000078","article-title":"VP22 core domain from Herpes simplex virus 1 reveals a surprising structural conservation in both the Alpha- and Gammaherpesvirinae subfamilies","volume":"96","author":"Hew","year":"2015","journal-title":"J Gen Virol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.01908","article-title":"Alphaherpesvirus major tegument protein VP22: its precise function in the viral life cycle","volume":"11","author":"Wu","year":"2020","journal-title":"Front Microbiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines13010047","article-title":"A spike-based mRNA vaccine encapsulated in phospholipid 1,2-dioleoyl-sn-glycero-3-phosphoEthanolamine containing lipid nanoparticles induced potent B- and T-cell responses associated with protection against SARS-coV-2 infection and COVID-19-like symptoms in hamsters","volume":"13","author":"Quadiri","year":"2025","journal-title":"Vaccines (Basel)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.ijpara.2024.04.011","article-title":"Optimized plasmid loading of human erythrocytes for Plasmodium falciparum DNA transfections","volume":"54","author":"Mohammad","year":"2024","journal-title":"Int J Parasitol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.849515","article-title":"Combinatorial herpes simplex vaccine strategies: from bedside to bench and back","volume":"13","author":"Chentoufi","year":"2022","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3347\/kjp.2022.60.4.295","article-title":"Comparative assessment of diagnostic performance of cytochrome oxidase multiplex PCR and 18S rRNA nested PCR","volume":"60","author":"Kumari","year":"2022","journal-title":"Korean J Parasitol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"S82","DOI":"10.1016\/j.vaccine.2024.01.044","article-title":"Vaccine value profile for herpes simplex virus","volume":"42","author":"Johnston","year":"2024","journal-title":"Vaccine"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2300093","article-title":"Mucosal CCL28 Chemokine Improves Protection against Genital Herpes through Mobilization of Antiviral Effector Memory CCR10+CD44+ CD62L-CD8+ T Cells and Memory CCR10+B220+CD27+ B Cells into the Infected Vaginal Mucosa","volume":"211","author":"Dhanushkodi","year":"2023","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.699887","article-title":"Plasmodium berghei-released factor, pbTIP, modulates the host innate immune responses","volume":"12","author":"Kalia","year":"2021","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI179483","article-title":"Therapeutic vaccines for herpesviruses","volume":"134","author":"Cohen","year":"2024","journal-title":"J Clin Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11020325","article-title":"Insights into the Novel Therapeutics and Vaccines against Herpes Simplex Virus","volume":"11","author":"Malik","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02745-12","article-title":"An adjuvanted herpes simplex virus 2 subunit vaccine elicits a T cell response in mice and is an effective therapeutic vaccine in Guinea pigs","volume":"87","author":"Skoberne","year":"2013","journal-title":"J Virol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1332939","article-title":"The next-generation DNA vaccine platforms and delivery systems: advances, challenges and prospects","volume":"15","author":"Lu","year":"2024","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.798927","article-title":"Developments in vaccination for herpes simplex virus","volume":"12","author":"Krishnan","year":"2021","journal-title":"Front Microbiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199911043411904","article-title":"A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group","volume":"341","author":"Langenberg","year":"1999","journal-title":"N Engl J Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s40011-021-01330-2","article-title":"Antibody responses against plasmodium falciparum MSP3 protein during natural malaria infection in individuals living in malaria-endemic regions of India","volume":"92","author":"Quadiri","year":"2022","journal-title":"Proc Natl Acad Sci India Sect B Biol Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/v15010219","article-title":"An adenovirus-based recombinant herpes simplex virus 2 (HSV-2) therapeutic vaccine is highly protective against acute and recurrent HSV-2 disease in a Guinea pig model","volume":"15","author":"Wan","year":"2023","journal-title":"Viruses"},{"key":"B38","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.gendis.2017.04.001","article-title":"Adenovirus-mediated gene delivery: potential applications for gene and cell-based therapies in the new era of personalized medicine","volume":"4","author":"Lee","year":"2017","journal-title":"Genes Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242216519","article-title":"Adenoviral gene therapy vectors in clinical use-basic aspects with a special reference to replication-competent adenovirus formation and its impact on clinical safety","volume":"24","author":"Leikas","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1101\/2023.05.23.542024","article-title":"A multi-epitope\/CXCL11 prime\/pull coronavirus mucosal vaccine boosts the frequency and the function of lung-resident memory CD4(+) and CD8(+) T cells and enhanced protection against COVID-19-like symptoms and death caused by SARS-CoV-2 infection","volume":"97","author":"Zayou","year":"2023","journal-title":"J Virol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1328905","article-title":"Cross-protection induced by highly conserved human B, CD4(+), and CD8(+) T-cell epitopes-based vaccine against severe infection, disease, and death caused by multiple SARS-CoV-2 variants of concern","volume":"15","author":"Prakash","year":"2024","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11020432","article-title":"Adenoviral vector-based vaccine platform for COVID-19: current status","volume":"11","author":"Chavda","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1556\/EuJMI.4.2014.1.2","article-title":"Human adenovirus: Viral pathogen with increasing importance","volume":"4","author":"Ghebremedhin","year":"2014","journal-title":"Eur J Microbiol Immunol (Bp)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/s41541-021-00356-x","article-title":"Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic","volume":"6","author":"Mendonca","year":"2021","journal-title":"NPJ Vaccines"},{"key":"B45","volume-title":"Background document on the CanSinoBIO Ad5-nCoV-S [recombinant] vaccine (ConvideciaTM) against COVID-19: Background document to the WHO Interim recommendations for use of the CanSinoBIO Ad5-nCoV-S vaccine (ConvideciaTM) against COVID-19","author":"World Health","year":"2022"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/v16091476","article-title":"Toward the eradication of herpes simplex virus: vaccination and beyond","volume":"16","author":"Chang","year":"2024","journal-title":"Viruses"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3103","article-title":"Rapid host immune response and viral dynamics in herpes simplex virus-2 infection","volume":"19","author":"Schiffer","year":"2013","journal-title":"Nat Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02279-14","article-title":"Vaginal memory T cells induced by intranasal vaccination are critical for protective T cell recruitment and prevention of genital HSV-2 disease","volume":"88","author":"Sato","year":"2014","journal-title":"J Virol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.724618","article-title":"Immunoregulatory functions of interferons during genital HSV-2 infection","volume":"12","author":"Feng","year":"2021","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000338","article-title":"CD8+ T cell responses following replication-defective adenovirus serotype 5 immunization are dependent on CD11c+ dendritic cells but show redundancy in their requirement of TLR and nucleotide-binding oligomerization domain-like receptor signaling","volume":"185","author":"Lindsay","year":"2010","journal-title":"J Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2017.10.011","article-title":"Intramuscular delivery of replication-defective herpes simplex virus gives antigen expression in muscle syncytia and improved protection against pathogenic HSV-2 strains","volume":"513","author":"Diaz","year":"2018","journal-title":"Virology"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1086\/jid.2005.192.issue-12","article-title":"Impact of immunization with glycoprotein D2\/AS04 on herpes simplex virus type 2 shedding into the genital tract in Guinea pigs that become infected","volume":"192","author":"Bourne","year":"2005","journal-title":"J Infect Dis"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy415","article-title":"Effects of different doses of GEN-003, a therapeutic vaccine for genital herpes simplex virus-2, on viral shedding and lesions: results of a randomized placebo-controlled trial","volume":"218","author":"Van Wagoner","year":"2018","journal-title":"J Infect Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2015.10.137","article-title":"A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and Guinea pigs","volume":"34","author":"Odegard","year":"2016","journal-title":"Vaccine"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.9.1459","article-title":"CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons","volume":"191","author":"Liu","year":"2000","journal-title":"J Exp Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.09.018","article-title":"Recombinant adenovirus vaccines can successfully elicit CD8+ T cell immunity under conditions of extreme leukopenia","volume":"13","author":"Grinshtein","year":"2006","journal-title":"Mol Ther"},{"key":"B57","doi-asserted-by":"publisher","first-page":"23640","DOI":"10.1038\/s41598-021-03059-4","article-title":"Essential role of a Plasmodium berghei heat shock protein (PBANKA_0938300) in gametocyte development","volume":"11","author":"Kashif","year":"2021","journal-title":"Sci Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1568258\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T10:53:15Z","timestamp":1742986395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1568258\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":57,"alternative-id":["10.3389\/fimmu.2025.1568258"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1568258","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]},"article-number":"1568258"}}