Herpes Simplex Virus (HSV) Vaccine Update Carl Whittaker, M.D. Family Medicine Grand Rounds November 16, 2005 Learning Objectives • Be aware of the most recent evidence regarding the HSV vaccine • Know the current status of vaccine development and timing of projected approval • Identify in which patient populations this vaccine will be applicable Why Develop a Vaccine? • Genital herpes simplex virus (HSV) infection is a recurrent, lifelong disease with no cure whose only known hosts are humans • HSV-1 normally is associated with oral infections and HSV-2 with genital infections, but either type can infect a person anywhere on the skin • Since the late 1970s, the seroprevalence rates for HSV-2 in the United States have increased by 30 percent • At least 50 million persons in the United States have genital HSV infection • An estimated 500,000 to 700,000 cases of symptomatic first- episode genital HSV infections occur annually Why Develop a Vaccine? • Concerning relationship between human immunodeficiency virus (HIV) and genital HSV infection because the interaction of HSV-2 and HIV-1 may result in more efficient transmission of HIV-1 and an increased rate of HIV replication during HSV reactivation • Strongest predictor for genital HSV infection is a person's number of lifetime sex partners • Subclinical viral shedding has been documented in more than 80 percent of HSV-2-seropositive persons who report no lesions • One in four persons 30 years of age or older in the United States has HSV-2, although most do not realize that they have been infected Why Develop a Vaccine? • Only 10 to 25 percent of persons who are HSV-2 seropositive report a history of genital herpes, which suggests that most infected persons have unrecognized symptomatic or completely asymptomatic infections • It is thought that viral shedding in persons who are unaware that they are infected is responsible for at least 70 percent of HSV transmission Glycoprotein-D-Adjuvant Vaccine to Prevent Genital Herpes Stanberry, Lawrence R et al. The New England Journal of Medicine, November 21 2002; Vol 347 (21): 1652-1661. Objective: To evaluate whether an effective prophylactic vaccine would help control the spread of genital herpes. Design: Two Double-blind, Randomized Controlled Trials Study 1 • Phase 3, double-blind, randomized efficacy trial involving subjects who were seronegative for HSV-1 and HSV-2. • In1995 and 1996, 2486 adults 18 to 45 years of age were screened, and 847 of them (268 women) underwent randomization and were vaccinated at 57 centers in Australia, Canada, the United Kingdom, and the United States. • The primary end point was the occurrence of genital herpes disease. Study 2 • Phase 3, double-blind, randomized trial that was initially designed to evaluate the safety of the vaccine in subjects of any HSV serologic status • In 1996 and 1997, 2834 adults 18 years of age or older were screened, and 2491 of them (1867 of them seronegative for HSV-2, 710 of them HSV-2–negative women) underwent randomization and were vaccinated at 61 centers in Australia, Canada, Italy, and the United States. • In 1998, when the results from Study 1 became available and before the results from Study 2 had been examined, the prevention of genital herpes disease during months 0 through 19 was added as a primary efficacy end point in female subjects who were seronegative for HSV-2 at base line and as a secondary end point in female subjects who were seronegative for both HSV-1 and HSV-2 at base line. Vaccination and Design of the Studies • All subjects had a regular sexual partner (the "source partner") with clinically confirmed genital herpes • All subjects were randomly assigned to receive either vaccine or a control preparation by intramuscular injection in the deltoid area at months 0, 1, and 6, and were followed for a total of 19 months • The primary efficacy end point, the occurrence of genital herpes disease, was defined as genital signs or symptoms (e.g., pain, itching, swelling, papules, vesicles, ulcers, or crusts) with either a positive HSV culture or detection of HSV DNA by polymerase chain reaction (PCR) and HSV seroconversion • A secondary efficacy end point, HSV infection, was defined as genital herpes disease or asymptomatic seroconversion to HSV antigens not contained in the vaccine. • Visits were scheduled at months 0, 1, 6, 7, 13, and 19 and, in Study 1, also at months 4, 10, and 16. Blood samples for serologic analysis were obtained at all visits in Study 1 and at months 0, 7, and 19 in Study 2 • Source partners agreed (after giving written informed consent) not to use suppressive antiviral therapy during Study 1; in Study 2, they were allowed to use such therapy Figure 1. Kaplan–Meier Plots for Study 1, Showing Time to Occurrence of Genital Herpes Disease in Subjects Who Were Seronegative for Herpes Simplex Virus Type 1 (HSV-1) and Herpes Simplex Virus Type 2 (HSV-2) at Base Line. Broken vertical lines represent the scheduled time of the third and final vaccine or control injection. Figure 2. Kaplan–Meier Plots for Study 2, Showing Time to Occurrence of Genital Herpes Disease. Panels A and B are for subjects in Study 2 who were seronegative for herpes simplex virus type 2 (HSV-2) at base line; Panel C is for the subgroup of female subjects who were seronegative for herpes simplex virus type 1 (HSV-1) as well as for HSV-2 at base line. Broken vertical lines represent the scheduled time of the third and final vaccine or control injection. Vaccine Efficacy • In Study 1, no significant efficacy of the vaccine was observed against the acquisition of genital herpes in subjects who were seronegative for HSV-1 and HSV-2 at base line (efficacy, 38 percent [95 percent confidence interval, –18 to 68]; P=0.14). • Time-to-event analyses indicated that the vaccine was efficacious against genital herpes disease in female subjects (efficacy, 73 percent; 95 percent confidence interval, 19 to 91; P=0.01) but not in male subjects (efficacy, –11 percent; 95 percent confidence interval, –161 to 53; P=0.81). Vaccine Efficacy • In Study 2, no significant efficacy of the vaccine was observed against the acquisition of genital herpes disease in HSV-2– seronegative female subjects (efficacy, 42 percent; 95 percent confidence interval, –31 to 74; P=0.19). • Subgroup analysis indicated that the vaccine had significant efficacy against disease in female subjects seronegative for both HSV-1 and HSV-2 (efficacy, 74 percent; 95 percent confidence interval, 9 to 93; P=0.02) but not in female subjects who were seropositive for HSV-1 and seronegative for HSV-2 at base line (efficacy, –106 percent; 95 percent confidence interval, –723 to 49; P=0.30) or in HSV-2–seronegative male subjects (efficacy, –10 percent; 95 percent confidence interval, –127 to 47; P=0.80). • Although not statistically significant, both studies showed trends toward protection against HSV infection in female subjects who were seronegative for HSV-1 and HSV-2 • Vaccine efficacy against HSV infection in Study 1 was 46 percent (95 percent confidence interval, –2 to 71; P=0.08) among female subjects, as compared with –7 percent (95 percent confidence interval, –108 to 45; P=0.86) among male subjects • Vaccine efficacy against infection in Study 2 was 39 percent (95 percent confidence interval, –6 to 65; P=0.08) among female subjects who were seronegative for HSV-1 and HSV-2, as compared with –19 percent (95 percent confidence interval, –128 to 38; P=0.70) among male subjects who were seronegative for HSV-1 and HSV-2. The potential epidemiological impact of a genital herpes vaccine for women Garnett, G P et al. Sexually Transmitted Infections, Februrary 2004; Vol 80 (1): 24-29. Objective: To evaluate the epidemiological impact of the partial protection provided by an HSV vaccine. Design: A sex and sexual activity stratified deterministic differential and partial differential equation model of the natural history of herpes simplex virus type 2 (HSV-2) and the impact of vaccination is developed and analyzed. Assumptions for this model are consistent with the results of the vaccine trial. Figure 2 The modelled transient and long term impact of a vaccine introduced over years 50–55 that causes a 42% reduction in the risk of infection and a further reduction in the risk of disease so that overall the reduced risk of disease is 73%. Before the introduction HSV-2 is assumed to be at steady state. (A) The prevalence of HSV-2 in men and women. (B) The incidence of HSV-2 infections in men and women. (C) The prevalence of disease (the proportion of the population with genital ulcers with a HSV-2 etiology). Figure 3 Transient impact of a vaccine with observed efficacy for three sets of assumptions about the behaviour of the vaccine: (1) that it prevents disease (73% efficacy) and the episodes of viral shedding that would normally accompany disease episodes (that is, asymptomatic viral shedding continues even those who are protected from disease by the vaccine); (2) that the vaccine provides a 42% efficacy in protecting against infection, without any protection from disease or viral shedding beyond this; (3) that the vaccine provides a 42% protection from infection and an additional protection from disease and asymptomatic viral shedding to generate a 73% protection in total. Key Messages • A vaccine against genital herpes which only works in women who are HSV-1-/2- can have a substantial impact on genital herpes epidemiology (should be used almost universally) • The impact extends from women to men • The magnitude of the impact of genital herpes vaccine depends on whether it prevents asymptomatic shedding which can occur in two ways: Prevention of disease is likely to correlate with prevention of asymptomatic shedding Prevention of infection implicitly prevents asymptomatic shedding • The impact of previous HSV-1 infection on the risk of HSV-2 infection is an important mediator of the vaccine’s action Current HSV vaccine development (as of November 2003) HerpeVac Trial for Women This study is currently recruiting patients. Verified by National Institute of Allergy and Infectious Diseases (NIAID) May 2005 Purpose: The primary purpose of this study is to see if the vaccine is safe and prevents genital herpes disease in women who are not infected. Condition: Herpes Simplex Intervention: Vaccine: glycoprotein D GSK Adjuvant System 04 (Alum-MPL), Havrix (control) Phase: Phase III Official Title: A Double-Blind, Randomized, Controlled Phase III Study to Assess the Prophylactic Efficacy and Safety of gD-Alum/MPL Vaccine in the Prevention of Genital Herpes Disease in Young Women Who Are HSV-1 and -2 Seronegative. Study Type: Interventional, Pivotal Phase III efficacy study Study Design: Prevention, Randomized, Double-Blind, Active Control, Parallel Assignment, Efficacy Study Expected Total Enrollment: 7550 healthy females, 18-30 yo Study start: January 2003; Expected completion: April 2008 • Study participants will be vaccinated at the start of the trial and at one and six months after the first injection, for a total of three injections. • The women will be followed for 20 months after the initial vaccination to determine the efficacy of the vaccine. INCLUSION CRITERIA 1. Female between, and including, 18 and 30 years of age 2. Written informed consent obtained from the subject 3. Free of obvious health problems 4. Seronegative for HSV-1 and HSV-2 by Western blot 5. Subject must be non-childbearing potential, i.e. either surgically sterilized or, if of child bearing potential, she must be using a highly effective method of birth control. 6. A subject for whom the investigator believes can and will comply with the requirements of the protocol The Relationship between Condom Use and Herpes Simplex Virus Acquisition Wald, Anna et al. Annals of Internal Medicine, November 15, 2005; Vol 143 (10): 707-713. Objective: To assess the relationship between condom use and acquisition of HSV-2 and HSV-1 among men and women. Design: Analysis of data collected as part of a clinical trial of an ineffective candidate vaccine for HSV-2. Participants: Men and women at risk for HSV-2 acquisition, defined as having 4 or more sexual partners or having a sexually transmitted disease in the past year. Conclusions: Consistent use of condoms is associated with lower rates of infection with HSV-2 and should be routinely recommended. Conclusions • Most recent vaccine study shows significant efficacy in reducing genital herpes disease, but only a trend in reducing acquisition of genital herpes. • Epidemiological models substantiate the assumptions of this vaccine’s efficacy in reducing genital herpes disease. • Current HerpeVac Trial is studying efficacy in HSV-1-/2- females and is projected to end its Phase III trial in 2008. • This vaccine projects to be most efficacious in HSV-1-/2- females, with effects spreading to greater population. • Currently, consistent condom use is the most effective method for preventing HSV-2 infection. Resources for Patients with Genital Herpes Infection American Social Health Association Web site: http://www.ashastd.org Centers for Disease Control and Prevention Web site: http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm Herpes Web Web site: http://www.herpesweb.net International Herpes Management Forum Web site: http://www.ihmf.org/Patient/PatientResources.asp National Herpes Hotline Telephone: (919) 361-8488 (9 a.m. to 6 p.m. EST, Monday through Friday) National STD & AIDS Hotline Telephone: (800) 227-8922 or (800) 342-2437 (24 hours per day, 7 days per week) En Español: (800) 344-7432 (8 a.m. to 2 a.m. EST, 7 days per week) Bibliography Stanberry, Lawrence et al. Glycoprotein-D-Adjuvant Vaccine to Prevent Genital Herpes. The NEJM, November 21 2002; Vol 347 (21): 1652-1661. Garnett, G P et al. The potential epidemiological impact of a genital herpes vaccine for women. Sexually Transmitted Infections, February 2004; Vol 80 (1): 24-29. Berstein, David I. et al. Safety and Immunogenicity of the Glycoprotein D-Advjuvant Genital Herpes Vaccine. Clinical Infectious Diseases, 1 May 2005; Vol 40 (9): 1271-1281. Jones, Cheryl A et al. Herpes simplex virus vaccines. Pediatric Infectious Disease Journal, November 2003; Vol 22 (11): 1003-1005. ClinicalTrials.gov HerpeVac Trial for Women. Wald, Anna et al. The Relationship between Condom Use and Herpes Simplex Virus Acquisition. Annals of Internal Medicine, November 15, 2005; Vol 143 (10): 707-713.
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