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© 2019 Bernstein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Although herpes simplex viruses (HSV) are a major target for vaccine development no vaccine is currently licensed. Methods A live attenuated HSV virus vaccine, VC2 was compared to a subunit HSV vaccine, glycoprotein D (gD2) administered with the adjuvant, MPL/Alum using the Guinea pig model of genital herpes. Three doses of intramuscular (IM) vaccine were provided followed by intravaginal challenge with HSV-2 at either 3 weeks or six months after the last vaccination. Results Both VC2 and gD2 vaccines reduced acute genital disease. VC2 was somewhat more effective in reducing acute vaginal replication, the amount of virus in neural tissue, subsequent recurrent disease and recurrent virus shedding following challenge at 3 weeks post vaccination. Both vaccines continued to provide protection at 6 months after vaccination but the differences between the vaccines became more pronounced in favor of the live attenuated vaccine, VC2. Significant differences in acute disease, acute vaginal virus replication, recurrent disease and recurrent virus shedding (P<0.05 for each) was observed comparing the vaccines. Re-examination of protection for this study using criteria similar to those used in recent clinical trials (inclusion of recurrent disease) showed that efficacy may not be as high in this model as previously thought prompting a need to assess the best predictive outcomes for protection in humans. Conclusion While both the live attenuated vaccine, VC2, and the gD2 subunit vaccine provided protection, the duration of protection appeared to be greater for VC2. Using the same evaluation criteria as used in human trials provided unique insights into the utility of the Guinea pig model.

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