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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, 2006
NVAC
Lauri Markowitz, MD
DSTD/NCHHSTP
Centers for Disease Control and Prevention
Candidate Prophylactic
HPV Vaccines
Vaccine/ FDA
Manufacturer HPV Types FDA Filing Decision ACIP Vote
Quadrivalent 6/11/16/18 Dec June June
Merck 2005 2006 2006?
Bivalent 16/18 Dec 2007? 2007?
GSK 2006?
Outline
• Background on HPV and cervical cancer
• HPV vaccine
• Acceptability
• Proposed recommendations
Background
Human Papillomavirus
• Non enveloped DNA virus
• >100 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….)
>100 HPV types
Mucosal Cutaneous
(~40 types) (~60 types)
“Common”
“high-risk” “low-risk”
warts
types types
(16,18) (6,11) (hands/feet)
• low grade cervical • low grade cervical
abnormalities abnormalities
• high grade abnormalities/ • genital warts
cancer precursors • respiratory papillomas
• anogenital cancers
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
Natural History of HPV Infection
and Cervical Cancer
1 year Up to 5 years Up to 20 years
Persistent
infection CIN* 2/3
Initial
HPV
infection
CIN* 1
CANCER
CLEARED HPV INFECTION
*cervical intraepithelial neoplasia
Age-Adjusted Invasive Cancer Incidence
Rates, Among Women, U. S., 2000
Breast 128.9
Lung & Bronchus 52.5
Colon & Rectum 47.0
Corpus & Uterus, NOS 23.5
Ovary 15.8
Non-Hodgkin Lymphoma 15.4
Melanomas of the Skin 12.4
Thyroid 10.7
Urinary Bladder 9.8
Pancreas 9.5
Cervix Uteri 9.2
Leukemias 8.7
Kidney & Renal Pelvis 8.4
Oral Cavity & Pharynx 6.0
Brain & CNS 5.5
0 20 40 60 80 100 120 140
Rate per 100,000
United States Cancer Statistics: 2000 Incidence; NPCR
Cervical Cancer Mortality Rates
U.S., 1946-1984
12
Mortality Rate (per 100,000)
10
8
6
4
2
0
46
48
50
52
54
56
58
60
62
64
66
68
70
72
74
76
78
80
82
84
Year
Source: Program for Improving Clinical Pap Smear Programs and Management, Office of
Population Affairs, DHHS, 1987.
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)
Percentage of Adolescents Who Have
Had Vaginal Sex, by Gender and Age
National Survey of Family Growth (NSFG), 2002
90
80 77
70
70
69
60
49 62
50 Females
40
40 46 Males
30 26 37
20 25
10
0
15 16 17 18 19
Age
Mosher et al., 2005; Vital and Health Statistics: No. 362
High Risk HPV Prevalence, by Age
Sentinel Surveillance, U.S.
2003-2004 (N=5555)
50
40
30
%
20
10
0
14-19 20-29 30-39 40-49 50-65
Age in years
CDC, unpublished data
Cumulative Incidence of HPV Infection
among Female College Students,
by Time Since Sexual Debut
4 years, > 50%
Winer et al. Am J Epidemiol 2003;157
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
• > 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
Candidate HPV VLP Vaccines
• HPV L1 major capsid protein HPV VLP
of the virus is antigen used for
immunization
• Expression of L1 protein uses
recombinant technology
• L1 proteins self-assemble into
virus-like particles (VLP)
Candidate HPV VLP Vaccines
Vaccine/ Target
Manufacturer HPV Types Schedule Adjuvant Groups
Quadrivalent 6/11/16/18 0,1,6 mos Alum females
Merck & males
Bivalent 16/18 0,1,6 mos Alum females
GSK and MPL
(ASO4)
HPV Vaccine
Initial Clinical Development
Programs
Adolescent
Vaccine/ Immunogenicity
Manufacturer Efficacy Trials* Safety Trials
Quadrivalent females females and males
Merck 16-26 yrs 9-15 yrs
Bivalent females females
GSK 15-25 yrs 10-14 yrs
*endpoints include CIN 2/3 or AIS
HPV Vaccine
Additional Clinical Development
Vaccine/ Efficacy in Long Term
Manufacturer Females >26 Follow-up Efficacy in Men
Quadrivalent X X X
Merck
Bivalent X X
GSK
HPV Vaccine Phase II Trials
Prevention 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
Efficacy - Phase III Trial
Quadrivalent HPV Vaccine
HPV 16/18 Related Cervical Cancer Precursors
Vaccine Placebo
Endpoint (N=5301) (N=5258) Efficacy (97.5% CI)
HPV 16/18 related 0 21 100% (76,100)
CIN 2/3 or AIS
Mean 17 Months of Follow-Up in Per Protocol Population
Merck, unpublished data, ACIP presentation, February 2006
Efficacy - Phase III Trial
Quadrivalent HPV Vaccine
HPV 6/11/16/18 Related External Genital Lesions
Vaccine Placebo
Endpoint (N = 2261) (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
Populations in
Quadrivalent HPV Vaccine
Phase III Clinical Trials
Day 1 Seronegative Seropositive
Prophylactic efficacy in
HPV-naïve women Prevention of recurrence
PCR (-)
of infection?
(Per protocol population)
PCR (+) Post exposure
Treatment of chronic
prophylaxis in women
HPV infection?
with early infection?
Anti-HPV 16 GMTs Through 3.5 Years Postdose 3
3000 HPV 16 L1 VLP Vaccine
2000 Placebo recipients previously infected with
Geometric Mean Titer (mMU/mL)
1000 HPV 16
100
10
Vaccination
1
0 7 12 18 30 42 48
Mao et al. Obstetrics and Gynecology 2006,107
Months Since
Enrollment
Anti-HPV 6 Antibody Titers after 3 Doses
by Age at Enrollment (Quadrivalent HPV vaccine)
1600 Immunogenicity Bridge Efficacy Program
1500
Serum GMT with 95% CI, mMU/mL
1300
1100
900
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)
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
Quadrivalent HPV Vaccine
Summary
• 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
Quadrivalent HPV Vaccine
Summary
• >99% 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
HPV Vaccine
and 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
Pediatricians’ Intention to
Recommend HPV Vaccine for
Female and Male Patients, by Age
100
90 female
% somewhat or extremely likely
male
80
70
60
50
40
30
20
10
0
11 year olds 14 year olds 17 year olds
Kahn J et al. Journal of Adolescent Health 2005
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
Family Research Council
and HPV Vaccines
FRC welcomes the news that vaccines are in development
for preventing…HPV
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
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
ACIP HPV Vaccine Workgroup
FDA 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
Vaccines and Related Biological Products
Advisory Committee
May 18, 2006
1. 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?
2. 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?
3. 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?
4. 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)?
5. 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
ACIP HPV Vaccine Workgroup
Proposed 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
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
ACIP HPV Vaccine Workgroup
Proposed 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.
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
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
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)
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 2003;157
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
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) <$0
Goldie SJ, et al. Journal of the National Cancer Institute 2004;96:604-15.
Sanders GD, Taira AV. Emerging Infectious Diseases 2003;9:37-48.
Kulasingam SL, Myers ER. JAMA 2003;290:781-89.
Taira AV et al. Emerging Infectious Diseases 2004;19,1915-23
*unpublished
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