Genital herpes increases the risk of acquiring and transmitting Human Immunodeficiency Virus (HIV), is a source of anxiety for many about transmitting infection to intimate partners, and is life-threatening to newborns. A vaccine that prevents genital herpes infection is a high public health priority. An ideal vaccine will prevent both genital lesions and asymptomatic subclinical infection to reduce the risk of inadvertent transmission to partners, will be effective against genital herpes caused by herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and will protect against neonatal herpes. Three phase 3 human trials were performed over the past 20 years that used HSV-2 glycoproteins essential for virus entry as immunogens. None achieved its primary endpoint, although each was partially successful in either delaying onset of infection or protecting a subset of female subjects that were HSV-1 and HSV-2 uninfected against HSV-1 genital infection. The success of future vaccine candidates may depend on improving the predictive value of animal models by requiring vaccines to achieve near-perfect protection in these models and by using the models to better define immune correlates of protection. Many vaccine candidates are under development, including DNA, modified mRNA, protein subunit, killed virus, and attenuated live virus vaccines. Lessons learned from prior vaccine studies and select candidate vaccines are discussed, including a trivalent nucleoside-modified mRNA vaccine that our laboratory is pursuing. We are optimistic that an effective vaccine for prevention of genital herpes will emerge in this decade.
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