{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:53:00Z","timestamp":1782888780678,"version":"3.54.5"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T00:00:00Z","timestamp":1650585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21EY019739"],"award-info":[{"award-number":["R21EY019739"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>We previously isolated an HSV-1 mutant, KOS-NA, that contains two non-synonymous mutations in UL39. One of the mutations, resulting in an R950H amino acid substitution in ICP6, renders KOS-NA severely neuro-attenuated and significantly reduces HSV-1 latency. Vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated eye diseases even at a very low immunizing dose, indicating its utility as a vaccine scaffold. Because KOS-NA contains a neuro-attenuating mutation in a single gene, we sought to improve its safety by deleting a portion of the UL29 gene whose protein product, ICP8, is essential for viral DNA replication. Whereas KOS-NA reduced replication of HSV-1 challenge virus in the corneal epithelium and protected mice against blepharitis and keratitis induced by the challenge virus, KOS-NA\/8- and an ICP8- virus were significantly less efficacious except at higher doses. Our results suggest that the capacity to replicate, even at significantly reduced levels compared with wild-type HSV-1, may be an important feature of an effective vaccine. Means to improve safety of attenuated viruses as vaccines without compromising efficacy should be sought.<\/jats:p>","DOI":"10.3390\/v14050869","type":"journal-article","created":{"date-parts":[[2022,4,24]],"date-time":"2022-04-24T02:22:02Z","timestamp":1650766922000},"page":"869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy of an HSV-1 Neuro-Attenuated Vaccine in Mice Is Reduced by Preventing Viral DNA Replication"],"prefix":"10.3390","volume":"14","author":[{"given":"Hong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Davido","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba H.","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynda A.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA"},{"name":"Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,22]]},"reference":[{"key":"ref_1","unstructured":"Knipe, D.M., and Howley, P.M. (2007). Herpes simplex viruses. Fields Virology, Lippincott Williams & Wilkins."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1097\/00003226-200009000-00008","article-title":"Twenty-five-year panorama of corneal immunology: Emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection","volume":"19","author":"Dana","year":"2000","journal-title":"Cornea"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00003226-200101000-00001","article-title":"Herpes simplex virus epidemiology and ocular importance","volume":"20","author":"Liesegang","year":"2001","journal-title":"Cornea"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/S0161-6420(13)31155-5","article-title":"Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis","volume":"101","author":"Barron","year":"1994","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"665","DOI":"10.2147\/TCRM.S58242","article-title":"Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: Background, effectiveness, tolerability, safety, and future applications","volume":"10","author":"Chou","year":"2014","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_6","first-page":"CD002898","article-title":"Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis","volume":"1","author":"Wilhelmus","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ike, A.C., Onu, C.J., Ononugbo, C.M., Reward, E.E., and Muo, S.O. (2020). Immune response to herpes simplex virus infection and vaccine development. Vaccines, 8.","DOI":"10.3390\/vaccines8020302"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1056\/NEJMoa1103151","article-title":"Herpevac Trial for Women. Efficacy results of a trial of a herpes simplex vaccine","volume":"366","author":"Belshe","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Awasthi, S., Hook, L.M., Shaw, C.E., Pahar, B., Stagray, J.A., Liu, D., Veazey, R.S., and Friedman, H.M. (2017). An HSV-2 trivalent vaccine is immunogenic in rhesus macaques and highly efficacious in guinea pigs. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006141"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eaaw7083","DOI":"10.1126\/sciimmunol.aaw7083","article-title":"Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes","volume":"4","author":"Awasthi","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_11","first-page":"1352","article-title":"Protection against herpes simplex virus-induced eye disease after vaccination with seven individually expressed herpes simplex virus 1 glycoproteins","volume":"36","author":"Ghiasi","year":"1995","journal-title":"Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1128\/JVI.72.1.65-72.1998","article-title":"The gH-gL complex of herpes simplex virus (HSV) stimulates neutralizing antibody and protects mice against HSV type 1 challenge","volume":"72","author":"Peng","year":"1998","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.vaccine.2018.11.076","article-title":"A trivalent gC2\/gD2\/gE2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gC2 better than natural infection","volume":"37","author":"Hook","year":"2019","journal-title":"Vaccine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3930","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":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1006\/viro.1997.8926","article-title":"Modulation of mucosal and systemic immunity by enteric administration of nonreplicating herpes simplex virus expressing cytokines","volume":"240","author":"Kuklin","year":"1998","journal-title":"Virology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.virol.2015.10.033","article-title":"Protection from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus","volume":"488","author":"Diaz","year":"2016","journal-title":"Virology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1093\/infdis\/jiz225","article-title":"A randomized, double-blinded, placebo-controlled, phase 1 study of a replication-defective herpes simplex virus (HSV) type 2 vaccine, HSV529, in adults with or without HSV infection","volume":"220","author":"Dropulic","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4586","DOI":"10.1128\/JVI.07203-11","article-title":"Live attenuated herpes simplex virus 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread","volume":"86","author":"Awasthi","year":"2012","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1128\/jvi.68.2.927-932.1994","article-title":"Vaccine potential of a herpes simplex virus type 1 mutant with an essential glycoprotein deleted","volume":"68","author":"Farrell","year":"1994","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00335-20","DOI":"10.1128\/JVI.00335-20","article-title":"A single-cycle glycoprotein D deletion viral vaccine candidate, DeltagD-2, elicits polyfunctional antibodies that protect against ocular herpes simplex virus","volume":"94","author":"Ramsey","year":"2020","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e06054","DOI":"10.7554\/eLife.06054","article-title":"Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease","volume":"10","author":"Petro","year":"2015","journal-title":"eLife"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Naidu, S.K., Nabi, R., Cheemarla, N.R., Stanfield, B.A., Rider, P.J., Jambunathan, N., Chouljenko, V.N., Carter, R., Del Piero, F., and Langohr, I. (2020). Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0228252"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.1128\/JVI.00517-16","article-title":"A highly efficacious herpes simplex virus 1 vaccine blocks viral pathogenesis and prevents corneal immunopathology via humoral immunity","volume":"90","author":"Royer","year":"2016","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e01654-17","DOI":"10.1128\/JVI.01654-17","article-title":"Herpes simplex virus 1 mutant with point mutations in UL39 is impaired for acute viral replication in mice, establishment of latency, and explant-induced reactivation","volume":"92","author":"Mostafa","year":"2018","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e01036-18","DOI":"10.1128\/JVI.01036-18","article-title":"Attenuated herpes simplex virus 1 (HSV-1) expressing a mutant form of ICP6 stimulates a strong immune response that protects mice against HSV-1-induced corneal disease","volume":"92","author":"Davido","year":"2018","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5258","DOI":"10.1128\/jvi.63.12.5258-5267.1989","article-title":"Genetic evidence for multiple nuclear functions of the herpes simplex virus ICP8 DNA-binding protein","volume":"63","author":"Gao","year":"1989","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1128\/jvi.43.1.314-324.1982","article-title":"Definition of a series of stages in the association of two herpesviral proteins with the cell nucleus","volume":"43","author":"Knipe","year":"1982","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1006\/viro.1998.9047","article-title":"Influence of mucosal and parenteral immunization with a replication-defective mutant of HSV-2 on immune responses and protection from genital challenge","volume":"243","author":"Morrison","year":"1998","journal-title":"Virology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0264-410X(97)00164-3","article-title":"Protection from primary infection and establishment of latency by vaccination with a herpes simplex virus type 1 recombinant deficient in the virion host shutoff (vhs) function","volume":"16","author":"Walker","year":"1998","journal-title":"Vaccine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11137","DOI":"10.1128\/JVI.74.23.11137-11144.2000","article-title":"Disruption of virion host shutoff activity improves the immunogenicity and protective capacity of a replication-incompetent herpes simplex virus type 1 vaccine strain","volume":"74","author":"Geiss","year":"2000","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1128\/JVI.79.1.410-418.2005","article-title":"Comparative efficacy and immunogenicity of replication-defective, recombinant glycoprotein, and DNA vaccines for herpes simplex virus 2 infections in mice and guinea pigs","volume":"79","author":"Hoshino","year":"2005","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1086\/605645","article-title":"Protection from herpes simplex virus (HSV)-2 infection with replication-defective HSV-2 or glycoprotein D2 vaccines in HSV-1-seropositive and HSV-1-seronegative guinea pigs","volume":"200","author":"Hoshino","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Schrimpf, J.E., Tu, E.M., Wang, H., Wong, Y.M., and Morrison, L.A. (2011). B7 costimulation molecules encoded by replication-defective, vhs-deficient HSV-1 improve vaccine-induced protection against corneal disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022772"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0167-5699(97)01114-6","article-title":"Immunity causing blindness: Five different paths to herpes stromal keratitis","volume":"18","author":"Streilein","year":"1997","journal-title":"Immunol. 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