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

In 2007, the most effective means to acquire life-long immunity to genital herpes is to engage in romantic activity with a partner who is infected with herpes simplex virus 2 (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 to 5% of HSV-2 infected people endure considerable pain and distress, as they may experience recurrent outbreaks of genital herpes every three to twelve months for the rest of their lives. About 1.5 billion people worldwide are infected with HSV-2, and ~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 did 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 herpes simplex virus 1 (HSV-1) and HSV-2 in the past fifty 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 1. the approaches being most seriously considered to prevent genital herpes, and 2. the biology of herpes simplex virus 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? What approaches are most likely to lead to an effective herpes vaccine? HSV-2 subunit vaccines: what have we learned? If one thinks of vaccine development in purely molecular terms, then an ideal HSV-2 vaccine would be a protein subunit of the virus that “jump starts” the adaptive immune response to HSV-2. Thus, HSV-2 vaccine development has focused on how to deliver immunodominant epitopes of HSV-2 to the immune system (1, 6, 25, 32, 38). Glycoprotein D is an immunodominant protein of HSV-1 and HSV-2. Clinical trials have been performed to determine if HSV-2 glycoprotein D can be used to protect people from HSV-2 infection and genital herpes. On both counts, the glycoprotein D subunit vaccine is marginally effective (29–31). Likewise, glycoprotein 120 subunit vaccines fail to protect people against human immunodeficiency virus infection and AIDS (5, 33, 39). Other attempts to produce HSV-2 vaccines have included killed, inactivated HSV-2 vaccines (27, 28), and replication-defective viral vectors (3, 7, 9, 20). In each case, I have reservations about the likelihood of success of the approach. Before proceeding, I wish to make clear my respect for the scientists who performed the studies on the HSV-2 glycoprotein D subunit vaccine. These individuals blazed a trail that simply did not exist ten years earlier. The glycoprotein D subunit may not be critical to the final formulation of a genital herpes vaccine, but what we have learned is invaluable. These studies have lifted a veil from the eyes of the scientific community, and have served as a catalyst that has scientists today asking the question, “What is necessary to attain an effective genital herpes vaccine?” There is no bigger success in science than to change (for the better) how your peers look at the natural world.