Date Published: March 27, 2019
Publisher: Public Library of Science
Author(s): David I. Bernstein, Rhonda D. Cardin, Derek A. Pullum, Fernando J. Bravo, Konstantin G. Kousoulas, David A. Dixon, Edward Gershburg.
Although herpes simplex viruses (HSV) are a major target for vaccine development no vaccine is currently licensed.
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.
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. 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.
Genital herpes infections remain a major target for vaccine development [1, 2]. The most recent large trial of a herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) vaccine showed that it was effective against HSV-1 genital disease and infection but not HSV-2 genital disease or infection . Thus, it appears that protection of the genital mucosa from HSV is possible and since HSV-1 genital infections are more common than genital HSV-2 in some areas [4, 5], this is a significant advance.
We have previously shown that both gD2 [15, 16] and VC2 [12, 14] vaccines effectively limit acute virus replication, modify acute disease and decrease the number of subsequent recurrences. In this paper we extend our analysis to evaluate the duration of protection.
There is a general consensus that live vaccines offer more durable protection than killed or subunit vaccines. However, there are more concerns for the safety of live vaccines. Live attenuated vaccines for viruses that can become latent are perhaps of even more concern because if they persist there is always the possibility of reversion or recombination. Further, the recent link between HSV and neurodegenerative diseases, such as Alzheimer’s [27, 28], raises the possibility of a persistent vaccine virus acting as a risk factor. Therefore, VC2 was chosen as a live attenuated vaccine for these experiments as it was specifically designed to not enter nerve endings, reach the DRG or establish persistence [14, 29–31].