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In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0\u0394NLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0\u0394NLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. Moreover, 0\u0394NLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechanosensory function. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0\u0394NLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>HSV-1 manifests in a variety of clinical presentations ranging from a rather benign \u201ccold sore\u201d to more severe forms of infection, including necrotizing stromal keratitis and herpes simplex encephalitis. The present study was undertaken to evaluate a novel vaccine to ocular HSV-1 infection not only for resistance to viral replication and spread but also for maintenance of the visual axis. The results underscore the necessity to reconsider strategies that utilize attenuated live virus as opposed to subunit vaccines against ocular HSV-1 infection.<\/jats:p>","DOI":"10.1128\/jvi.00517-16","type":"journal-article","created":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T03:17:51Z","timestamp":1459394271000},"page":"5514-5529","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity"],"prefix":"10.1128","volume":"90","author":[{"given":"Derek J.","family":"Royer","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hem R.","family":"Gurung","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy K.","family":"Jinkins","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoms, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Geltz","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoms, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Halford","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J. 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