Abstract
Glycoprotein D (gD-2) is the entry receptor of herpes simplex virus 2 (HSV-2), and is the immunogen in the pharmaceutical industry's lead HSV-2 vaccine candidate. Efforts to prevent genital herpes using gD-2 subunit vaccines have been ongoing for 20 years at a cost in excess of $100 million. To date, gD-2 vaccines have yielded equivocal protection in clinical trials. Therefore, using a small animal model, we sought to determine if a live-attenuated HSV-2 ICP0 − virus would elicit better protection against genital herpes than a gD-2 subunit vaccine. Mice immunized with gD-2 and a potent adjuvant (alum+monophosphoryl lipid A) produced high titers of gD-2 antibody. While gD-2-immunized mice possessed significant resistance to HSV-2, only 3 of 45 gD-2-immunized mice survived an overwhelming challenge of the vagina or eyes with wild-type HSV-2 (MS strain). In contrast, 114 of 115 mice immunized with a live HSV-2 ICP0 − virus, 0ΔNLS, survived the same HSV-2 MS challenges. Likewise, 0ΔNLS-immunized mice shed an average 125-fold less HSV-2 MS challenge virus per vagina relative to gD-2-immunized mice. In vivo imaging demonstrated that a luciferase-expressing HSV-2 challenge virus failed to establish a detectable infection in 0ΔNLS-immunized mice, whereas the same virus readily infected naïve and gD-2-immunized mice. Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if it contained a live-attenuated HSV-2 virus rather than a single HSV-2 protein.
Highlights
Infections with herpes simplex virus 2 (HSV-2) are exceedingly common;,1 billion people serve as carriers of HSV-2 and,20 million people acquire new HSV-2 infections each year [1]
Wild-type HSV-2 MS (ICP0+) virus was included as a control to verify that the 0DNLS mutation was necessary to attenuate the pathogenesis of HSV-2 infection
The 0DNLS mutation in the ICP0 gene allowed a mild HSV-2 infection to be established in ICR mice that did not produce any overt symptoms of disease following inoculation of the eyes, nose, vagina, or footpads
Summary
Infections with herpes simplex virus 2 (HSV-2) are exceedingly common; ,1 billion people serve as carriers of HSV-2 and ,20 million people acquire new HSV-2 infections each year [1]. HSV-2 viruses that are overattenuated and/or unable to replicate in neurons [26,27,28,29,30,31] Of these approaches, subunit vaccines based on a combination of HSV-2 glycoprotein D (gD-2) and a potent adjuvant have received the greatest level of consideration. Two clinical trials of gD-2 subunit vaccines were completed in the late 1990s and early 2000s [36,41] In the latter trial, it was noted that HSV-1 seronegative women responded to a gD-2 subunit vaccine with significant reductions in the rate of acquiring HSV-2 genital herpes [36]. These results offered hope that vaccine-induced protection against HSV-2 genital herpes was possible, but would need to be further improved
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