G enital herpes simplex is one of the most prevalent sexually transmitted diseases. In 2012, more than 417 million persons worldwide were reported to be infected with herpes simplex virus 2 (HSV-2), with more than 19.2 million new persons infected in that year alone (1). While HSV-2 disease is mild in most cases, infection can be severe and life threatening in immunocompromised patients and neonates. In addition, genital herpes increases the risk of acquisition of HIV infection 3-fold (2). While HSV-2 traditionally has been the principal cause of genital herpes, more recent studies have shown that HSV-1 may be replacing HSV-2 as the most frequent cause of genital herpes in the United States (3, 4). While both HSV-1 and HSV-2 cause primary and recurrent genital herpes, genital recurrences are much more frequent with HSV-2 than with HSV-1 (5).HSV-2 infects epithelial cells in the vaginal mucosa, replicates in the cells, and enters the nerve endings innervating the mucosa. Viral capsids travel retrograde in axons to the cell body in sensory ganglia, where HSV establishes a latent infection in the nuclei of neurons. Latent HSV can be reactivated by multiple stimuli, such as stress, fever, and exposure to UV light. Viral capsids travel anterograde from the ganglion down the axons to the mucosa, where the virus replicates and is shed in the presence or absence of symptomatic genital lesions. This allows the virus to spread to unin- Citation Wang K, Goodman KN, Li DY, Raffeld M, Chavez M, Cohen JI. 2016. A herpes simplex virus 2 (HSV-2) gD mutant impaired for neural tropism is superior to an HSV-2 gD subunit vaccine to protect animals from challenge with HSV-2.