Model of vaccine efficacy against HSV-2 superinfection of HSV-1 seropositive mice demonstrates protection by antibodies mediating cellular cytotoxicity

A majority of the world’s population is infected with HSV-1, highlighting the need for vaccines that are effective in HSV-1-seropositive hosts. We established a superinfection model by infecting mice intranasally with a sublethal dose of HSV-1, which results in high rates of seropositive, latently infected mice susceptible to HSV-2 superinfection. Sublethal HSV-1 induced a predominantly neutralizing antibody response. Vaccination of HSV-1-seropositive mice with recombinant adjuvanted glycoprotein D (rgD-2) failed to significantly boost HSV total or neutralizing antibody responses and provided no significant increased protection against HSV-2 superinfection compared to control-vaccinated HSV-1-seropositive mice. In contrast, immunization with a single-cycle virus deleted in gD (ΔgD-2) significantly boosted total HSV-specific antibody titers and elicited new antibody-dependent cell-mediated cytotoxicity responses, providing complete protection from death following HSV-2 superinfection. This model recapitulates clinical responses to natural infection and the rgD-2 vaccine trial outcomes and suggests that ΔgD-2 may prove protective in HSV-1-seropositive hosts.