Comparison of different forms of herpes simplex replication-defective mutant viruses as vaccines in a mouse model of HSV-2 genital infection

Abstract

Some subunit vaccines composed of herpes simplex virus (HSV) glycoproteins have been shown to protect guinea pigs against primary and recurrent genital infection by HSV-2. However, these vaccines were ineffective or only marginally effective in clinical trials. To attempt to define an animal model that would better discriminate the protective capacity of different vaccine formulations, we have examined the requirements for vaccine-induced protection against HSV-2 infection and disease in a mouse genital model. Unlike the guinea pig model where inactivated viral vaccines can protect nearly as well as live viral vaccines, inactivated viral vaccine afforded little protection in this mouse model. Using replication-defective mutant viruses as a form of live viral vaccine, we found that the extent of protection conferred by live vaccine was proportional to the amount of replication-defective mutant virus inoculated, over doses from 10(4) to 10(6) PFU. Furthermore, the mouse genital model showed quantitative differences in the degree of protection induced by various viral vaccine constructs. An HSV-2 replication-defective mutant virus protected better than an HSV-1 replication-defective mutant that expressed HSV-2 glycoprotein D, which in turn protected better than an HSV-2 replication-defective mutant virus. We conclude that this mouse genital model can rank different vaccine constructs for their capacity to induce protective immunity. Thus, genital infection of the mouse with HSV-2 may provide a stringent animal model that can predict the relative capacity of viral vaccines to stimulate protective immunity against HSV-2.