Title: Human Papillomavirus HPV Vaccine Background and Overview Lauri Markowitz, MD DSTDP, NCHHSTP, CDC Tit
1 Human Papillomavirus (HPV) VaccineBackground
and OverviewLauri Markowitz, MDDSTDP,
NCHHSTP, CDCTitle X Grantee MeetingSeptember
2006
2- 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.
3Background 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.) -
4gt100 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
5Genital 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
6Natural 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
7HPV-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)
8Cervical Cancer Mortality Rates U.S., 1946-1984
Source Program for Improving Clinical Pap Smear
Programs and Management, Office of Population
Affairs, DHHS, 1987.
9Most Common Cancers in Women
Less developed countries
More developed countries
Breast
Cervix
Ovary
Endometrium
Colon/rectum
Lung
Stomach
600
200
400
600
0
400
200
Annual number of cases (thousands)
Adapted from Parkin et al. Eur J Cancer 2001,
37S4
10Percentage 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
11Cumulative Incidence of Any HPV Infection among
Female College Students, by Time Since Sexual
Debut
4 years, gt 50
Winer et al. Am J Epidemiol 2003,157
12HPV 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
W. Cates, STD April 1999, Weinstock, Perspectives
on Sexual and Reproductive Health 2004, Koutsky
Am J Med 1997
13Licensed Candidate Prophylactic HPV Vaccines
Types 16/18 cause 70 cervical cancer Types 6/11
cause 90 genital warts
14Licensed Candidate Prophylactic HPV Vaccines
Advisory Committee on Immunization Practices
15HPV 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
16Quadrivalent HPV Vaccine Initial Clinical Studies
- Efficacy studies in females 16 - 26 years
- Safety and immunogenicity studies in
- 9 - 15 year olds
17Quadrivalent HPV Vaccine FDA Licensure June
2006
- Indicated in girls and women 9-26 years of age
for the prevention of the following diseases
caused by HPV types 6, 11, 16, and 18 - Cervical cancer
- Genital warts (condyloma acuminata)
- Cervical, vaginal and vulvar precancerous or
dysplastic lesions
18Quadrivalent HPV Vaccine additional clinical
development
- Efficacy trials in males
- Efficacy trials in females older than 26 yrs
- Long term follow-up studies
Results expected in next few years
19Efficacy Analysis Populations for Quadrivalent
Vaccine
- Per Protocol Population for Efficacy (PPE)
- Received all 3 vaccinations, naïve to
relevant vaccine HPV type through Month 7, did
not deviate from protocol cases counted after
Month 7.
20Efficacy for Prevention of Clinical HPV Disease
Due to HPV 6/11/16/18 among 16-26 year-old
females
Package insert Gardasil Integrated dataset
results in the per-protocol populations CIN
cervical intraepithelial neoplasia AIS
adenocarcinoma in situ
21Quadrivalent HPV Vaccine
- High efficacy against outcomes due to HPV vaccine
types among females without evidence of infection
with the relevant HPV type - No evidence of efficacy against disease due to
existing infection - Infection with one HPV type does not diminish
efficacy of vaccine against other vaccine HPV
types
22Efficacy Analysis Populations for Quadrivalent
Vaccine
- Per Protocol Population for Efficacy
- Received all 3 vaccinations, naïve to
relevant vaccine HPV type through Month 7, did
not deviate from protocol cases counted after
Month 7.
- Modified Intent to Treat-Population
- Received at least one vaccination and had any
follow-up visit one month after dose 1. Subjects
were included regardless of baseline HPV status.
Cases were counted from 30 days after dose 1.
23Time to Detection of HPV 16/18 CIN 2/3 or AIS
Intention to Treat Population
Phase II and III Database for GARDASIL and HPV
16 Vaccine
Merck, unpublished data, Presented at ACIP
meeting, June 2006
v501p5p7p13p15c2w Apr. 28, 2006
24Anti-HPV 16 GMTs Through 5 Years
Protocol 007
10000
â
GARDASIL
1000
GMT (Log Scale)
100
10
Placebo (Sero () and PCR (-)
to HPV 16 at Day 1)
Vaccination
0
7
12
18
24
30
36
54
60
Time Since Vaccination 1 (Months)
Merck, unpublished data, Presented at ACIP
meeting, June 2006
25Antibody Titers by Age at Enrollment Anti-HPV 6
GMTs (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)
Merck, unpublished data, Presented at ACIP
meeting, February 2006
26Quadrivalent HPV VaccineSummary
- High efficacy in 16 to 26 year-old females who
are naïve to the HPV vaccine type - HPV 16,18 related CIN 2/3
- HPV 6,11,16,18 related CIN
- HPV 6,11,16,18 related external genital lesions
- No evidence of therapeutic efficacy
- Efficacy data available through 5 years duration
of protection and need for booster unknown - Safe side effects mainly local reactions
27 28Advisory Committee on Immunization Practices
(ACIP)
- US Federal advisory committee
- Coordinated and organized by the Centers for
Disease Control and Prevention (CDC) - Provides guidance to Secretary, Health and Human
Services and Director, CDC on vaccine preventable
diseases in the US
29Functions Advisory Committee on Immunization
Practices (ACIP)
- Develop recommendations and publish written
guidance for use of vaccines -
- Make recommendations for the Vaccines for
Children (VFC) Program
30Vaccines for Children ( VFC) Program
- Provides vaccine at no cost to eligible children
lt19 years - Medicaid eligible, uninsured, underinsured,
Native Americans or Alaskan Natives - VFC Act passed in 1993
- Funding for new vaccines occurs through a vote by
ACIP - Federal government establishes contract with
manufacturer -
- Saves parents and enrolled providers expenses for
vaccine - Provides cost savings to states by purchase of
vaccine through CDC contracts
31Childhood Vaccine Doses Distributed by Funding
Source, 2004
Source Biologics Surveillance Data 2004
32Federal Contract Prices for Vaccines Recommended
Universally for Children and Adolescents 1985
2006
837
155
45
Federal contract price shown for 1985 and 1995
are averages that account for price changes
within that year. Analysis accounts for market
share of specific products. Analysis current as
of May 1, 2006.
33HPV vaccine
- ACIP voted to include HPV vaccine in VFC
- Private sector price 120 per dose
- VFC contract not yet established
34 Background Information for HPV Vaccine
Recommendations
- Vaccine and clinical trials
- HPV epidemiology and HPV related disease
- Sexual behavior
- Vaccine acceptability
- Impact and cost effectiveness
- Program/implementation issues
35Provisional ACIP Recommendations
- Routine vaccination
- Catch-up vaccination
- Special situations
- Precautions and contraindications
36Routine Vaccination Provisional Recommendation
- Routine vaccination is recommended for 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 -
37Rationale Routine Vaccination Females at 11-12
Years
- Prevalent infection, targeting high risk groups
not possible - Vaccination prior to sexual debut
- Implementation advantages consistent with young
adolescent health care visit - High antibody titers after vaccination at this
age - Data through 5 years show no evidence of waning
immunity ongoing studies will monitor duration
of protection
38Females 13-26 Years Provisional Recommendation
- At the beginning of the vaccination program,
there will be females older than 12 years who
could benefit from HPV vaccine - Vaccination is 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
39Rationale Vaccination of Females 13-26 Years
- Females not yet sexually active can be expected
to have the full benefit of vaccination - Sexually active females may not have full benefit
because they may have been infected with vaccine
HPV types, however - Only a small percentage are likely to have been
infected with all four vaccine HPV types - For those already infected with gt1 vaccine HPV
types, vaccine would provide protection against
disease caused by the other vaccine HPV types - Overall vaccine effectiveness would be lower
most females will still derive some benefit from
vaccination
40Special Situations
- Equivocal or abnormal Pap test
- Positive HPV test
- Genital warts
- Vaccine does not have any therapeutic efficacy
and will not treat existing infection or disease - Vaccine would prevent acquisition of new
infections
41Vaccination during Pregnancy Provisional
Recommendation
- Initiation of the vaccine series should be
delayed until after completion of pregnancy - If a woman is found to be pregnant after
initiating the vaccination series, remaining
doses should be delayed until after the pregnancy
- If a vaccine dose has been administered during
pregnancy, there is no indication for
intervention - Exposures to vaccine in pregnancy should be
reported - (800) 986-8999
42Precautions and Contraindications
- Moderate or severe acute illnesses should be
deferred until after the illness improves - History of immediate hypersensitivity or severe
allergic reaction to yeast or to any vaccine
component contraindication
43Cervical Cancer Screening
- Cervical cancer screening no change
- 30 of cervical cancers caused by HPV types not
prevented by the quadrivalent HPV vaccine - Vaccinated females could subsequently be infected
with non-vaccine HPV types - Sexually active females could have been infected
prior to vaccination - Providers should educate women about the
importance of cervical cancer screening
44Future Data and Issues
- Further analyses of phase III quadrivalent HPV
vaccine trials - New epidemiologic data on HPV
- Consideration of vaccine for males
- Data from bivalent HPV vaccine trials
- Second generation HPV vaccines
- Monitoring impact of HPV vaccine
45 46Populations in Quadrivalent HPV Vaccine Phase
III Clinical Trials
47Age-Adjusted Invasive Cancer Incidence Rates,
Among Women, U. S., 2000
United States Cancer Statistics 2000 Incidence
NPCR