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Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.
Introduction
Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that infects more than 500 million people worldwide and causes an estimated 23 million new infections each year (1). HSV-2 seroprevalence ranges from 16% among 14-49 year olds in the United States (2) to greater than 80% in some areas of subsanaran Africa (3); seroprevalence in women is up to twice as high as men, and increases with age (2, 4). Although HSV-2 is the leading cause of genital ulcer disease worldwide (5, 6), most people are not aware of the infection (7), and may transmit the virus during periods of subclinical shedding (8, 9). In contrast to other sexually transmitted infections (STIs) that may be concentrated among "core groups," such as gonorrhea (10), HSV-2 is widespread even among people with low or moderate levels of sexual activity. For instance, 18.8% of American women with 2-4 lifetime sexual partners are HSV-2 seropositive (2).
Although incident genital herpes is increasingly caused by HSV type 1 (HSV-I; ref. 1 1), and HSV-I may also cause significant eye and brain disease, almost all HSV vaccine candidates reaching clinical trials have targeted HSV-2. As HSV-I and HSV-2 have similar pathogenesis and host interactions, many of the concepts for development of an effective vaccine are likely relevant to both viruses. In addition, infection with HSV-2 provides partial protection against HSV-I (12), although the reverse does not appear to be true (13), and thus there is potential for generation of cross-reactive immunity (14). The possibility that an HSV-2 vaccine may provide protection against HSV-I increases its potential value and may shift the optimal time...