Current Thinking on Genital Herpes

Annika M. Hofstetter; Susan L. Rosenthal; Lawrence R. Stanberry


Curr Opin Infect Dis. 2014;27(1):75-83. 

In This Article

Prophylactic Vaccines

A prophylactic HSV vaccine, particularly one that confers 'sterilizing immunity' by preventing acute disease and establishment of latent infection, holds greatest promise in reducing, if not eliminating, the global burden of genital herpes infection. Over the past few decades, researchers have made important advances, yet encountered new roadblocks in the design of an effective prophylactic HSV vaccine. Although two HSV-2 glycoprotein-D-subunit vaccine efficacy trials found no effect among men or HSV-1 seropositive women, they demonstrated 73–74% efficacy against genital herpes disease among women seronegative for both HSV-1 and HSV-2.[75] On the basis of this promising finding, a follow-up trial was conducted among HSV-1 and HSV-2 seronegative women.[130] However, unlike the preceding trials, it failed to show a vaccine effect on HSV-2 infection or disease. Although these results were disappointing, important lessons were learned that may guide future investigations. First, the discrepancy in findings may relate to differences between study populations: the earlier trials included HSV-discordant couples with higher HSV-2 attack rates among uninfected women, whereas the follow-up trial included a more representative group of study participants. The study population should be considered closely in subsequent clinical trial design. Moreover, immunologic priming could have contributed to these differential results, again highlighting the need for improved understanding of host immunity against HSV.

The follow-up trial was able to assess HSV-1 outcomes, given the greater number of observed cases of HSV-1 genital infection and disease, likely reflecting different recruitment strategies[125,130] and perhaps changing epidemiology.[35] Interestingly, it found 35 and 58% efficacy against HSV-1 genital infection and disease, respectively. Homology between the HSV-1 and HSV-2 glycoprotein-D antigens as well as differences in immunobiology, transmission route, viral load and infection site could explain this finding.[125,130] One recent study[131] similarly observed differential efficacy of HSV-2 vaccine candidates in preventing infection against a U.S. viral strain compared with an African strain, although some protection was afforded for both. Further investigation of type and strain-specific immune responses as well as potential for cross-reactive immunity[132] is warranted. Moreover, HSV type(s) and strain(s)to be included in future vaccines should be considered carefully.

Building upon our current understanding of HSV pathogenesis and the host immune response, future vaccine candidates may be most effective when acting locally at mucocutaneous sites or within sensory ganglia, potentially by establishing a local pool of protective memory T cells[133] or inducing neutralizing and/or antibody-dependent cell-mediated cytotoxicity responses, particularly in areas of low T cell presence. Improved understanding of T cell antigen specificity and identification of broadly immunogenic viral gene products are also needed for developing an effective vaccine.[125]