Elsevier

Vaccine

Volume 24, Issue 7, 13 February 2006, Pages 914-920
Vaccine

A randomized controlled trial of a replication defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes among immunocompetent subjects

https://doi.org/10.1016/j.vaccine.2005.08.088Get rights and content

Abstract

Background

A replication incompetent herpes virus lacking the glycoprotein H gene has been developed as a potential therapeutic vaccine for genital herpes.

Goal

To determine vaccine efficacy on reducing HSV reactivation and clinical disease among immunocompetent persons with recurrent genital HSV-2 infection.

Study design

Randomized multicenter placebo-controlled trial. Healthy volunteers who had six or more recurrences of genital herpes per year were randomized to receive injections of vaccine at 0 and 8 or 0, 4, and 8 or 0, 2, 4, and 8 weeks or placebo and were followed for subsequent recurrences for 1 year.

Results

The median times to first recurrence of genital herpes (40 days versus 30 days versus 37 days versus 42 days, respectively), mean number of recurrences (3 versus 3 versus 2.4 versus 1.9, respectively), and time to lesion healing of the first recurrence (8 days versus 7.8 days versus 7.4 days versus 7.5 days, respectively), were similar for all treatment groups. Asymptomatic viral shedding was detected by PCR in 61/74 (82%) persons performing daily sample collection following completion of the vaccination series. No differences were noted in the proportion of days with shedding between treatment groups (11.9% versus 17.2% versus 13.1% versus 16.4%, respectively).

Conclusion

This replication incompetent HSV-2 vaccine lacking the glycoprotein H gene was safe but had no clinical or virologic benefit in the amelioration of genital HSV-2 disease among immunocompetent men and women.

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.

Section snippets

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.

References (19)

There are more references available in the full text version of this article.

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1

Present address: Perinatal HIV Research Unit, ZA, USA.

2

Present address: Eli Lilly and Company, Indianapolis, IN, USA.

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