A randomized controlled trial of a replication defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes among immunocompetent subjects
Introduction
Immunization of persons with chronic viral infections has been identified as a potential novel approach to therapy (therapeutic vaccination). Herpes simplex virus (HSV) infections and more recently varicella zoster vaccines have been prime models for demonstrating the potential clinical benefit of such an approach. Two previous trials of subunit vaccines containing the HSV glycoprotein gD2 or gB2, and gD2 have shown modest clinical benefit among persons with recurrent genital herpes. One trial showed a 24% reduction in reactivation rates [1] and one a 25–35% reduction in days that new genital lesions appeared [2]. These glycoprotein vaccines were shown to increase CD4+ T cell antibody responses to HSV after vaccination [3]. Increasingly, evidence has shown the importance of CD8+ T cell responses in reducing reactivation and clearing virus from mucosal lesions [4], [5]. CD8+ T cell responses to HSV are usually directed at internal structural proteins, especially the tegument [6].
In 1992, Forrester et al. described a novel HSV vaccine in which the gH gene from HSV was deleted from the virus creating a replication incompetent mutant expressing all other HSV proteins [7]. This mutant virus was developed as a candidate HSV vaccine (disabled infectious single cycle vaccine). Phase I trials indicated the vaccine was safe and immunogenic (unpublished data). As such, we conducted a randomized clinical trial of this vaccine to evaluate its effects on reducing HSV reactivation and clinical disease among persons with recurrent genital herpes.
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Study population
Men and women with a history of recurrent genital herpes (confirmed by prior HSV-2 culture or serology) with at least six reported recurrences within the prior year or three recurrences in the prior 6 months were enrolled into this multi-center international study. Additionally, participants were required to fulfill the following criteria: age 18–55 years; in good general health; if female, of non-childbearing potential or practicing an effective method of contraception; have discontinued any
Results
Four hundred and eighty-five participants from 14 clinical trial sites were enrolled into the trial. The median number of participants at each site was 29 and ranged from 9 to 93. Two participants for whom it was documented that no study drug was received were excluded from analyses. The intention-to-treat population therefore consisted of 483 persons. Three hundred and sixty-seven participants (76%) completed the primary analysis phase (32 weeks) and 350 participants (72.5%) completed the
Discussion
The hypothesis being examined in the current study was whether vaccination with this replication defective HSV-2 vaccine would alter the frequency of clinically symptomatic genital herpes, reduce the duration of HSV lesions, or reduce the frequency of HSV shedding as measured by PCR. This multi-center clinical trial demonstrated no measurable benefit in any of these parameters from the vaccination scheduled employed in the study.
The results of the trial failed to demonstrate any effect of
Acknowledgement
Supported by a grant from GlaxoSmithKline.
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- 1
Present address: Perinatal HIV Research Unit, ZA, USA.
- 2
Present address: Eli Lilly and Company, Indianapolis, IN, USA.