A vaginal microbicide able to protect against HSV-2 transmission could contribute significantly to controlling sexually transmitted diseases. We previously found that gene silencing is sustained for several weeks in vivo in slowly dividing cells, including the genital tract of progesterone-treated mice. To investigate the onset and duration of protection, mice were treated at various times with nectin-1 and/or UL29 chol-siRNAs, given either before or after HSV-2 infection and followed for 14 days for clinical signs of disease, using a well-established scoring system, and survival. Genital herpes is caused by herpes simplex virus 1 (HSV-1) and HSV-2, and its incidence is constantly increasing in the human population. Two of the eight fully protected vaccinees underwent subclinical HSV-2 infection, as demonstrated by deep immunosuppression and other analyses. Palliser D, et al. 2006. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Ther., 14(3):336-42 (2006)) in the genital tract and protected against challenge from herpes simplex virus (Palliser, et al., Nature, 439(7072):89-94 (2006)).