Towards an effective genital herpes vaccine: past lessons and future prospects.

In 2007, the most effective means to acquire lifelong immunity to genital herpes will be to engage in romantic activity with a partner who is infected with herpes simplex virus (HSV)-2. Three out of four people who acquire HSV-2 in this manner are blissfully unaware of the molecular hitchhikers that they will carry for life, hidden away in neurons of their peripheral nervous system. Such persons derive a huge benefit from these molecular hitchhikers: life-long immunity from the disease of genital herpes. The natural approach to acquiring HSV-2 has a serious downside: 2–5% of HSV-2infected people endure considerable pain and distress, as they may experience recurrent outbreaks of genital herpes every 3–12 months for the rest of their lives. Approximately 1.5 billion people worldwide are infected with HSV-2, and approximately 50 million suffer from recurrent outbreaks of genital herpes. It is absurd to suggest that unprotected sex is the best means to vaccinate against HSV-2 and genital herpes. Yet, the sad reality in 2007 is that the medical community has about as much power to prevent genital herpes as doctors who practiced in ancient Rome. The development of acyclovir in the late 1970s was a major breakthrough. It has provided a tool by which doctors and patients can restrict the severity and frequency of genital herpes outbreaks. However, a preventative vaccine that confers life-long protection against genital herpes continues to elude us. Tens of thousands of studies have been published on HSV-1 and HSV-2 in the past 50 years. These studies provide a wealth of information about the epidemiology, clinical presentation, immunology, molecular biology and animal biology of HSV-1. Given that HSV-1 and HSV-2 share a nearly identical set of 75 genes, we possess an amazingly detailed knowledge about the biology of the infectious agents that cause recurrent herpes. So, how is it possible that progress in treating genital herpes has remained at a standstill for 30 years? I have grappled with this question for the past decade, and summarize my conclusions herein. My personal view is that a dichotomy in logic exists between the approaches being most seriously considered to prevent genital herpes, and the biology of HSV infections. As the most thoroughly studied herpes vaccine candidate, the glycoprotein D subunit vaccine merits specific attention. However, I believe that the larger questions are: Why has an effective herpes vaccine eluded us for so long? and What approaches are most likely to lead to an effective herpes vaccine?