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Herpes Simplex Virus _HSV_ Vaccine Update

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Herpes Simplex Virus _HSV_ Vaccine Update Powered By Docstoc
					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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