Therapeutic vaccination with vhs− herpes simplex virus reduces the severity of recurrent herpetic stromal keratitis in mice

Abstract

Virion host shutoff (vhs)-deficient herpes simplexvirus (HSV) was tested as a therapeutic vaccine in a mouse model of UV light-induced recurrent herpetic stromal keratitis. Four weeks after primary corneal infection, mice were vaccinated intraperitoneally with vhs N vaccine or control. Four weeks after vaccination, the eyes of latently infected mice were UV-B irradiated to induce recurrent virus shedding and disease. Post-irradiation corneal opacity in latently infected, vhs N -vaccinated mice was significantly reduced compared to control-vaccinated mice (P l 0n007 to 0n035). The incidence and duration of recurrent virus shedding were the same in both groups. Antibody titres were increased (P l 0n05) and delayed type hypersensitive responses were unaffected by vhs N vaccination. Combined with studies using different vaccination timing and vhs N genotypes, these data suggest that deletion of vhs is a useful strategy in the development of a therapeutic HSV vaccine, and that temporal and genetic factors influence vaccination outcome.

Recurrent Herpetic Stromal Keratitis in Mice, a Model for Studying Human HSK

“…As shown in Figure 3, mice lacking IFNγ displayed worse corneal disease than did wildtype mice 14 . It was also used successfully to define the therapeutic value of several different vaccine constructs 6,10,11 . Note that in one case the vaccine tested worked well prophylactically but did not prove to be therapeutically effective 6 .…”

“…Note that in one case the vaccine tested worked well prophylactically but did not prove to be therapeutically effective 6 . However, when a replication-incompetent viral vaccine was tested, it was not only effective prophylactically, but was also very effective therapeutically 10,11 , see Figure 5 in reference 10. More recently we have used this model to determine if gender differences were detectable in mice undergoing recurrent HSK.…”

“…They tested and our laboratory has been using a modified version of this model to publish many manuscripts over the years [4][5][6][7][8][9][10][11][12][13][14][15] . The model was used to define the role that the cytokine interferon-γ plays in recurrent HSV-1 disease 10 .…”

“…Since these mice already have an immune response to HSV-1, the factors that reactivate that immune response are likely different from those that originally generated it. Therefore, therapeutic intervention to prevent primary HSK will not always lead to amelioration of recurrent HSK, which we have shown in various publications when evaluating differences between primary and recurrent HSK 6,8,[10][11][12][13]15 . As indicated previously, this is particular the case when developing vaccines to prevent human HSK.…”

“…As indicated previously, this is particular the case when developing vaccines to prevent human HSK. Most vaccines will prevent the development of primary HSK but very few have been shown to be effective in reducing recurrent HSK 6,10,11 .…”