Direct comparison of three herpes simplex virus-2 vaccine candidates using peripheral or mucosal routes of vaccination

Despite decades of research, no vaccine has been approved for herpes simplex virus-2 (HSV-2). While HSV-2 subunit vaccines have been more extensively studied, various HSV-2 mutants have also been tested. We compared three types of HSV-2 mutant viruses (replication-defective, single-cycle replication, and replication-competent) using five routes of vaccination (intramuscular, subcutaneous at two different sites, intrarectal, or intravaginal) for their ability to protect mice from intravaginal challenge with HSV-2. The replication-competent virus vaccine gave the best protection compared to the other vaccines after intravaginal vaccination of mice resulting in complete prevention of disease, and 90 % of the animals had no detectable shedding after challenge despite very low serum neutralizing titers. The replication-competent virus vaccine was also superior to the other vaccines when given intrarectally, although less effective than when given intravaginally. In contrast, when given subcutaneously in the scruff of the neck, the replication-defective vaccine was more effective than the replication-competent vaccine and the replication-defective vaccine tended to be more effective than the live vaccine when given intramuscularly. The highest levels of serum neutralizing antibody were observed with the replication-defective and single-cycle replication vaccines given intramuscularly. Thus, excellent protection from genital herpes was obtained after intravaginal vaccination with the replication-competent vaccine providing evidence that a replication-competent vaccine given by the natural route of HSV-2 infection is superior to replication-defective or single-cycle replication vaccines to reduce virus infection and spread in the genital mucosa.