The results of a large-scale double-blind, randomized field trial of a glycoprotein D (gD)-based vaccine against herpes simplex virus type 2 (HSV-2) have been reported in the New England Journal of Medicine and, to the surprise of many in the field, have proved disappointing. Previous efficacy trials had shown that, in HSV-discordant couples, the vaccine conferred >70% protection against HSV-2-mediated genital disease in HSV-seronegative women. The current trial recruited 8,323 HSV-seronegative women between 18 and 30 years of age, who were given three doses of either the test vaccine, comprising 20 μg of HSV-2 gD combined with an alum and monophosphorylated lipid A adjuvant, or a control, which was an inactivated hepatitis A virus vaccine. Although the vaccine provided 58% protection against HSV-1-mediated genital disease and 35% protection against HSV-1 infection, only 20% of participants were protected against HSV-2-mediated disease, the primary end point of the trial, and there was no protection against HSV-2 infection. The authors concluded that the failure of this study compared with previous studies could be due to differences in the study populations.