JVI Accepts, published online ahead of print on 18 June 2008

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J. Virol. doi:10.1128/JVI.00551-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Replication Competent, Neuronal Spread Defective, Live Attenuated Herpes Simplex Virus Type-1 Vaccine

Elizabeth E. Brittle, Fushan Wang, John M. Lubinski, Ralph M. Bunte, and Harvey M. Friedman^*

Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6073; University Laboratory Animal Resources, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Suite 177E, Philadelphia, PA 19104-6009

^* To whom correspondence should be addressed. Email: hfriedma{at}mail.med.upenn.edu.

Herpes simplex virus type 1 (HSV-1) produces oral lesions, encephalitis, keratitis and severe infections in the immunocompromised host. HSV-1 is almost as common as HSV-2 in causing first episodes of genital herpes, a disease that is associated with an increased risk of HIV acquisition and transmission. No approved vaccines are currently available to protect against HSV-1 or HSV-2 infection. We developed a novel HSV vaccine strategy that uses a replication competent strain of HSV-1, NS-gEnull, that has a defect in anterograde and retrograde directional spread and cell-to-cell spread. Following scratch inoculation on the mouse flank, NS-gEnull replicated at the site of inoculation without causing disease. Importantly, the vaccine strain was not isolated from dorsal root ganglia (DRG). We used the flank model to challenge vaccinated mice and demonstrated that NS-gEnull was highly protective against wild-type HSV-1. The challenge virus replicated to low titers at the site of inoculation; therefore, the vaccine strain did not provide sterilizing immunity. Nevertheless, challenge by HSV-1 or HSV-2 resulted in less severe disease at the inoculation site, and vaccinated mice were totally protected against zosteriform disease and death. After HSV-1 challenge, latent virus was recovered by DRG explant co-cultures from < 10% of vaccinated mice compared with 100% of mock-vaccinated mice. The vaccine provided protection against disease and death after intravaginal challenge, and markedly lowered the titers of the challenge virus in the vagina. Therefore, the HSV-1 gEnull strain is an excellent candidate for further vaccine development.

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