Human Papillomavirus (HPV) Vaccine The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or

1
Human Papillomavirus (HPV) Vaccine The
findings and conclusions in this presentation
have not been formally disseminated by the
Centers for Disease Control and Prevention and
should not be construed to represent any agency
determination or policy.June 6,
2006NVACLauri Markowitz, MDDSTD/NCHHSTPCenter
s for Disease Control and Prevention
2
Candidate Prophylactic HPV Vaccines
Vaccine/ Manufacturer HPV Types FDA Filing FDA Decision ACIP Vote
Quadrivalent Merck 6/11/16/18 Dec 2005 June 2006 June 2006?
Bivalent GSK 16/18 Dec 2006? 2007? 2007?
3
Outline

• Background on HPV and cervical cancer
• HPV vaccine
• Acceptability
• Proposed recommendations

4
Background Human Papillomavirus

• Non enveloped DNA virus
• gt100 different types
• 40 types are sexually transmitted
• Low-risk types (6,11, 42, 43, 44)
• High-risk types (16, 18, 31, 33, 35, 39, 45,
  51, 52, 56, 58.)

5
gt100 HPV types
Cutaneous
Mucosal
(40 types)
(60 types)
Common
high-risk
low-risk
warts
types (16,18)
types (6,11)
(hands/feet)

• low grade cervical abnormalities
• high grade abnormalities/
• cancer precursors
• anogenital cancers

• low grade cervical abnormalities
• genital warts
• respiratory papillomas

6
Genital HPV Infection

• HPV is the most common sexually transmitted
  infection in the US
• First infection is usually acquired soon after
  sexual debut. Infection with multiple types
  common
• Infection is usually transient and not associated
  with symptoms 90 of infections clear within 2
  years
• Persistent HPV infection is cause of cervical
  cancer as well as other anogenital cancers

7
Natural History of HPV Infection and Cervical
Cancer
Up to 20 years
1 year
Up to 5 years
Persistent infection
CIN 2/3
Initial HPV infection
CANCER
CIN 1
CLEARED HPV INFECTION
cervical intraepithelial neoplasia
8
Age-Adjusted Invasive Cancer Incidence Rates,
Among Women, U. S., 2000
United States Cancer Statistics 2000 Incidence
NPCR
9
Cervical Cancer Mortality Rates U.S., 1946-1984
Source Program for Improving Clinical Pap Smear
Programs and Management, Office of Population
Affairs, DHHS, 1987.
10
HPV-Related Disease Burden, U.S.

• Cervical cancer 9,710 cases 3,700 deaths (2006
  estimate)
• 70 caused by types 16,18
• Pap tests 50 million 2.8 million abnormal
• Genital warts .5 to 1million
• 90 caused by types 6,11
• Recurrent respiratory papillomatosis (rare)
• 90 caused by types 6,11
• Other anogenital cancers (anal, penile, vaginal,
  vulvar)

11
Percentage of Adolescents Who Have Had Vaginal
Sex, by Gender and Age National Survey of Family
Growth (NSFG), 2002
90
77
80
70
70
69
60
49
62
50
Females
40
46
Males
40
26
37
30
25
20
10
0
15
16
17
18
19
Age
Mosher et al., 2005 Vital and Health Statistics
No. 362
12
High Risk HPV Prevalence, by AgeSentinel
Surveillance, U.S.2003-2004 (N5555)
CDC, unpublished data
13
Cumulative Incidence of HPV Infection among
Female College Students, by Time Since Sexual
Debut
4 years, gt 50
Winer et al. Am J Epidemiol 2003157
14
HPV Prevalence
Population Estimates, U.S.

• 20 million people are infected
• 15 of persons age 15-49 currently infected
• 6.2 million new infections each year
• gt 50 of sexually active men women acquire
  genital HPV infection

Cates, STD 1999 Weinstock, Perspectives on
Sexual and Reproductive Health 2004 Koutsky Am
J Med 1997
15
Candidate HPV VLP Vaccines

• HPV L1 major capsid protein of the virus is
  antigen used for immunization
• Expression of L1 protein uses recombinant
  technology
• L1 proteins self-assemble into virus-like
  particles (VLP)

HPV VLP
16
Candidate HPV VLP Vaccines
Vaccine/ Manufacturer HPV Types Schedule Schedule Adjuvant Target Groups
Quadrivalent Merck 6/11/16/18 0,1,6 mos Alum Alum females males
Bivalent GSK 16/18 0,1,6 mos Alum and MPL(ASO4) Alum and MPL(ASO4) females
17
HPV Vaccine Initial Clinical Development Programs
Vaccine/ Manufacturer Efficacy Trials Adolescent Immunogenicity Safety Trials
Quadrivalent Merck females 16-26 yrs females and males 9-15 yrs
Bivalent GSK females 15-25 yrs females 10-14 yrs
endpoints include CIN 2/3 or AIS
18
HPV Vaccine Additional Clinical Development
Vaccine/ Manufacturer Efficacy in Females gt26 Long Term Follow-up Efficacy in Men
Quadrivalent Merck X X X
Bivalent GSK X X
19
HPV Vaccine Phase II TrialsPrevention of
Persistent Infection

• Manufacturer
• Vaccine Vaccine Placebo VE (95 CI)
• N cases N cases
  
• Merck
• HPV 16 768 0 765 41
  100 (90,100)
• GSK
• HPV 16/18 366 0 355 16 100
  (77,100)
• Koutsky et al. NEJM 2002, 347
• Harper et al. Lancet 2004, 364

20
Efficacy - Phase III TrialQuadrivalent HPV
Vaccine HPV 16/18 Related Cervical Cancer
Precursors
Endpoint Vaccine(N5301) Placebo (N5258) Efficacy (97.5 CI)
HPV 16/18 related CIN 2/3 or AIS 0 21 100 (76,100)
Mean 17 Months of Follow-Up in Per Protocol
Population
Merck, unpublished data, ACIP presentation,
February 2006
21
Efficacy - Phase III TrialQuadrivalent HPV
Vaccine HPV 6/11/16/18 Related External Genital
Lesions
Endpoint Vaccine (N 2261) Placebo (N 2279) Efficacy (97.5 CI)
HPV 6/11/16/18 EGL 0 40 100 (88,100)
Mean 20 Months of Follow-Up in the Per Protocol
Population External genital lesions includes
genital warts, VIN, VaIN
Merck, unpublished data, ACIP presentation,
February 2006
22
Populations in Quadrivalent HPV Vaccine Phase
III Clinical Trials
Day 1 Seronegative Seropositive
PCR (-) Prophylactic efficacy in HPV-naïve women (Per protocol population) Prevention of recurrence of infection?
PCR () Post exposure prophylaxis in women with early infection? Treatment of chronic HPV infection?
23
Anti-HPV 16 GMTs Through 3.5 Years Postdose 3
HPV 16 L1 VLP Vaccine
Placebo recipients previously infected with HPV 16
Geometric Mean Titer (mMU/mL)
Mao et al. Obstetrics and Gynecology 2006,107
24
Anti-HPV 6 Antibody Titers after 3 Doses by Age
at Enrollment (Quadrivalent HPV vaccine)
Efficacy Program
Immunogenicity Bridge
1600
1500
1300
1100
900
Serum GMT with 95 CI, mMU/mL
700
500
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Age at Enrollment (Years)
Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n) Number of Subjects Evaluable (n)
Age 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
n 68 129 166 141 166 148 109 85 137 440 511 624 576 564 400
25
Quadrivalent HPV VaccineSummary

• High efficacy in 16 to 26 year-old females who
  are naïve to the respective vaccine HPV types
• HPV 16,18 related CIN 2/3
• HPV 6,11,16,18 related CIN
• HPV 6,11,16,18 related external genital lesions
• Efficacy data available through 5 years duration
  of protection and need for booster unknown
• No evidence of therapeutic efficacy
• Safe side effects mainly local reactions

26
Quadrivalent HPV VaccineSummary

• gt99 seroconversion rates in 9-26 year-olds
• Antibody titers decline over time after 3rd
  injection, but plateau by 18 months
• Antibody titers substantially higher than after
  natural infection highest in those vaccinated at
  younger ages
• No serologic correlate of immunity

27
HPV Vaccineand Cervical Cancer Screening

• Even with 100 coverage, current generation HPV
  vaccines will not eliminate need for cervical
  cancer screening in the US
• Types other than HPV 16 and 18 cause 30 of
  cervical cancers

28
Pediatricians Intention to Recommend HPV Vaccine
for Female and Male Patients, by Age
Kahn J et al. Journal of Adolescent Health 2005
29
Potential Unintended Consequences of HPV Vaccine

• Increase in sexual risk unlikely
• Research shows generally low levels of HPV
  knowledge
• Multiple influences on adolescent sexual behavior
• Fear of STD not apparent major motivation for
  abstinence
• No evidence of behavioral disinhibition in other
  similar fields

30
Family Research Council and HPV Vaccines

• FRC welcomes the news that vaccines are in
  development for preventingHPV
• Media reports suggesting that FRC opposes all
  development or distribution of such vaccines are
  false
• While we welcome medical advances such as an HPV
  vaccine, it remains clear that practicing
  abstinence until marriage and fidelity within
  marriage is the single best way of preventing the
  full range of STD.
• www.frc.org Press release, 10/18/05

31
Advisory Committee on Immunization Practices
(ACIP)

• Provides guidance to Secretary, HHS and Director,
  CDC on vaccine preventable diseases in the US
• Develops recommendations and publishes written
  guidance for use of vaccines
• Makes recommendations for the Vaccines for
  Children (VFC) Program

32
ACIP HPV Vaccine WorkgroupFDA Licensure
Assumptions

• Quadrivalent HPV 6,11,16,18 vaccine will be
  licensed for use in females 9-26 years of age in
  mid 2006
• Quadrivalent HPV vaccine may be licensed for use
  in males at a later date
• Bivalent HPV 16,18 vaccine will be licensed for
  use in females at a later date

33
Vaccines and Related Biological Products
Advisory Committee May 18, 2006

• Do the data from studies 005, 007, 013, and 015
  support the efficacy of Gardasil for the
  prevention of HPV 16/18 related cervical cancer,
  cervical AIS, and CIN 2/3 or worse in females
  16-26 years of age?
• Do the data from studies 007, 013, and 015
  support the efficacy of Gardasil for the
  prevention of HPV 6/11/16/18 related VIN 2/3 and
  VaIN 2/3 in females 16-26 years of age?
• Do the data from studies 007, 013, and 015
  support the efficacy of Gardasil for the
  prevention of HPV 6/11/16/18 related condyloma
  acuminata, VIN 1 and VaIN 1?
• Do the immunogenicity data support bridging of
  the younger female population (9-15 years of age)
  to the efficacy population (females 16-26 years
  of age)?
• Do the safety data from studies 007, 013, 015,
  016 and 018 support the safety of Gardasil for
  use in females 9-26 years of age?

Committee members voted (13/13) yes to all
34
ACIP HPV Vaccine WorkgroupProposed
Recommendations (2/06) Routine Vaccination

• ACIP recommends routine vaccination of females
  11-12 years of age with three doses of
  quadrivalent HPV vaccine. The vaccination series
  can be started as young as 9 years of age at the
  discretion of the physician.
• Presented at February 2006 ACIP meeting
• depends on FDA indication 

35
Rationale Routine Vaccination of Females at
11-12 Years

• Routine
• Prevalent infection, targeting high risk groups
  not possible
• Modeling shows more impact
• 11-12 years
• More females vaccinated prior to sexual debut
  than at older ages
• Implementation advantages consistent with young
  adolescent health care visit
• Although duration of protection not known, no
  evidence of waning immunity ongoing studies will
  monitor duration

36
ACIP HPV Vaccine WorkgroupProposed
Recommendations Vaccination of Females 13-26
years

• Vaccination is also recommended for females
  13-26 years of age who have not been previously
  vaccinated. Ideally vaccine should be
  administered before onset of sexual activity, but
  females who are sexually active should still be
  vaccinated.

37
Rationale Vaccination of Females 13-26 years

• Older females not yet sexually active can be
  expected to have the full benefit of vaccination
  
• Studies evaluating type-specific prevalence in
  the US indicate a small percentage of sexually
  active females have been infected with all HPV
  vaccine types
• Infection with one HPV type does not appear to
  adversely impact the protection afforded by the
  vaccine against other vaccine HPV types
• Overall vaccine effectiveness would be lower when
  administered to a population of females who are
  sexually active most females will derive benefit
  from vaccination

38
Summary

• Two HPV vaccines are in development FDA approval
  for the quadrivalent HPV vaccine may be in June
  2006
• If licensed, ACIP will consider recommendations
  for quadrivalent vaccine at the June 29-30
  meeting
• Vaccines have high efficacy for prevention of HPV
  infection, cervical cancer precursor lesions,
  external genital lesions in females
• Recommendations need to take into consideration
  multiple factors, including epidemiology,
  acceptability, impact and cost effectiveness
• Vaccine would be most efficacious administered to
  young adolescent females

39
Cumulative probability of Incident HPV type 6,
11, 16, 18 Infection 24 months after sexual
initiation, Women
HPV Type Cumulative Incidence at 24 months (95 CI) Cumulative Incidence at 24 months (95 CI)
6 7.5 (7.0, 12.6)
11 0.9 (0.3, 2.3)
16 10.4 (7.8, 13.8)
18 4.1 (2.6, 6.4)
Winer et al. Am J Epidemiol 2003157
40
Two types of Cost Effectiveness Models in HPV
Vaccine Literature

• Markov models
• model natural history of HPV infection
• Dynamic models
• model transmission of HPV natural history of
  HPV infection

41
Models and cost-effectiveness of HPV vaccine in
the U.S. Vaccination of females against types
16/18 at 12 years compared with cervical cancer
screening alone

• Markov Models Cost/QALY
• Goldie et al. 24,300
• Sanders Taira 22,800
• Kulasingam and Myers n/a
• Dynamic Models
• Taira et al. (2004) 14,600
• Elbasha (with HPV 6/11 benefits) lt0

Goldie SJ, et al. Journal of the National
Cancer Institute 200496604-15. Sanders GD,
Taira AV. Emerging Infectious Diseases
2003937-48. Kulasingam SL, Myers ER. JAMA
2003290781-89. Taira AV et al. Emerging
Infectious Diseases 200419,1915-23 unpublished