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Researchers Report Setbacks on Herpes Simplex Vaccine and Treatment


An experimental herpes simplex virus (HSV) vaccine partially protected women against infection with HSV type 1 but not type 2, according to a recent report in the New England Journal of Medicine. Another recent study found that antiviral treatment with acyclovir (Zovirax) or valacyclovir (Valtrex) did not prevent periodic HSV-2 reactivation and viral shedding.

HSV type 2 (HSV-2) is the usual cause of genital herpes, while HSV type 1 (HSV-1) is typically associated with oral herpes (cold sores); both types, however, can infect either site. The immune system does not usually clear HSV, rather it lies dormant in nerves, ready to cause recurrent outbreaks in response to various triggers. Infected people can transmit HSV even when they do not have obvious lesions.

HSV-2 Vaccine

As described in the January 5, 2012, New England Journal of Medicine, Robert Belshe and fellow investigators with the Herpevac Trial for Women conducted a randomized field trial to test the effectiveness of an HSV-2 subunit vaccine containing glycoprotein D. The study included 8323 women (age 18-30 years) who were negative for antibodies to both HSV-1 and HSV-2.

Two prior studies of HSV-discordant couples showed that the vaccine had 73%-74% efficacy against genital herpes among women who were seronegative for both types of HSV, but it was not effective for men or for HSV-1 seropositive women, the researchers noted as background.

In the current trial, some participants were randomly assigned to receive the investigational vaccine (20 mcg HSV-2 glycoprotein D with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant) at months 0, 1, and 6, while the rest received the hepatitis A vaccine as a control. The primary end point was occurrence of genital herpes lesions due to either HSV-1 or HSV-2 from months 2 through 20.


  • The vaccine was shown to elicit ELISA and neutralizing antibodies against HSV-2.
  • Overall, however, the vaccine was not effective in preventing genital herpes outbreaks.
  • Vaccine efficacy was 20% against genital herpes disease overall, rising to 58% for genital herpes caused by HSV-1.
  • The vaccine demonstrated 35% efficacy against HSV-1 infection (with or without outbreaks).
  • However, it did not show significant efficacy against HSV-2 infection (-8%).
  • People who received the HSV-2 vaccine had an increased risk of local injection site reactions compared with the control vaccine.

Based on these findings, the researchers concluded, "In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection."

Antiviral Treatment

As described in the second report, published in the February 18, 2012, issue of The Lancet, Christine Johnston from the University of Washington and colleagues assessed whether daily antiviral medication could prevent short subclinical episodes of genital HSV-2 reactivation, which are a major contributor to viral shedding and transmission.

The study included HSV-2 seropositive, HIV negative participants enrolled at the University of Washington Virology Research Clinic. Just over half (54%) were women, 76% were white, and the median age was 43 years. Out of 113 randomized participants, 90 were eligible for the primary analysis

In 3 complementary open-label cross-over studies, the researchers compared 5 regimens: no medication vs 400 mg twice-daily acyclovir (standard-dose acyclovir); 500 mg once-daily valacyclovir (standard-dose valacyclovir, an acyclovir pro-drug) vs 800 mg 3-times-daily acyclovir (high-dose acyclovir); and standard-dose valacyclovir vs 1 gram 3-times-daily valacyclovir (high-dose valacyclovir).

Participants used different regimens in sequences determined by a random number generator. Study periods lasted 4 to 7 weeks, separated by 1-week wash-out periods. Patients collected genital swabs 4 times per day for quantitative PCR testing of HSV DNA. The primary endpoint was within-person comparison of shedding in each regimen group.


  • Participants collected a total of 23,605 swabs, of which 1272 (5.4%) were positive for HSV-2, reflecting 344 reactivation episodes.
  • Some viral reactivation or breakthrough occurred with all treatment regimens.
  • The frequency of HSV shedding was found to be lower with standard-dose acyclovir compared with vs no medication (1.2% vs 18.1% of swabs).
  • High-dose acyclovir was associated with slightly less shedding than standard-dose valacyclovir (4.2% vs 4.5% of swabs).
  • Shedding was less frequent in the high-dose valacyclovir group compared with the standard-dose valacyclovir group (3.3% vs 5.8% of swabs).
  • The number of episodes per person-year did not differ significantly for people receiving standard-dose valacyclovir vs high-dose acyclovir (20.2 vs 22.6 episodes), or standard-dose valacyclovir vs high-dose valacyclovir (14.9 vs 16.8 episodes), but was significantly lower for standard-dose acyclovir vs no medication (10.0 vs 28.7 episodes).
  • The median duration of episodes was significantly longer for no medication compared with standard-dose acyclovir (13 vs 7 hours) and for standard-dose valacyclovir vs high-dose valacyclovir (10 vs 7 hours), but not for standard-dose valacyclovir vs high-dose acyclovir (8 hours for both).
  • Maximum HSV DNA viral load was significantly higher for no medication compared with standard-dose acyclovir (3.3 vs 2.9 log copies/mL), and for standard-dose valacyclovir vs high-dose valacyclovir (2.5 vs 3.0 log copies/mL), but not for standard-dose valacyclovir vs high-dose acyclovir (2.7 vs 2.8 log copies/mL).
  • 80% of reactivation episodes were subclinical, or asymptomatic, in all study groups.
  • All regimens were generally well-tolerated, although there was a higher frequency of headaches (30%) in the high-dose valacyclovir group.

"Short bursts of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy," the study authors concluded.

"That we could not eliminate or even alter the frequency of shedding episodes with high-dose valacyclovir suggests that the maximum benefit of shedding reduction has probably been reached for currently available antiviral drugs," they elaborated. "More potent antiviral therapy is needed to eliminate HSV transmission."

Investigator affiliations:

Belshe study: Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University, St. Louis, MO; Department of Epidemiology, University of North Carolina, Chapel Hill, NC; Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Medicine, Epidemiology, and Laboratory Medicine, Fred Hutchinson Cancer Research Center, Vaccine and Infectious Diseases Division, and Children's Hospital Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA; Anschutz Medical Campus, Section of Pediatric Infectious Diseases, University of Colorado Denver, Aurora, CO; Department of Internal Medicine, University of Iowa, and the Veterans Affairs Medical Center, Iowa City, IA; PrimeHealth Clinical Research Organization, Toronto, Canada; EMMES Corporation, Rockville, MD; National Institute of Allergy and Infectious Diseases, Bethesda, MD; GlaxoSmithKline, King of Prussia, PA.

Johnston study: Department of Medicine, Department of Laboratory Medicine, Department of Global Health, and Department of Epidemiology, University of Washington, Seattle, WA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.



RB Belshe, PA Leone, DI Bernstein, et al (Herpevac Trial for Women). Efficacyresults of a trial of a herpes simplex vaccine. New England Journal of Medicine 366(1):34-43. January 5, 2012.

C Johnston, M Saracino, S Kuntz, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: Three randomised, open-label, cross-over trials. The Lancet 379(9816):641-617. February 18, 2012.

P Van de Perre and N Nagot. Herpes simplex virus: a new era? The Lancet379(9816):598-599. February 18, 2012.