A vaccine for a chronic or recurrent viral infection should induce immune responses that protect against primary disease or that augment preexisting defenses sufficiently to diminish the likelihood of disease recurrence or progression. Such a vaccine was sought for genital herpes, a sexually transmitted infection of epidemic proportion. Vaccine containing recombinant herpes simplex virus type 2 glycoprotein D expressed in CHO cells was given repeatedly and safely to 24 human volunteers. In previously uninfected subjects, the vaccine induced primary antigen-specific and neutralizing antibody responses nearing or exceeding those seen at entry in subjects with genital herpes. Primary cellular immune responses were also evoked. Vaccination of previously seropositive subjects boosted antibody titers to levels that remained, for > or = 1 year, severalfold above those attained in recurrent genital herpes. Either the quantity or mode of presentation of antigen permitted this vaccine to exhibit previously unachieved immunogenicity, which may prove adequate for antiviral immunoprophylaxis or treatment of genital herpes.