Title: HPV Vaccine: - More than Cervical Cancer Prevention -
1HPV Vaccine - More than Cervical Cancer
Prevention -
Tam Kar Fai Department of Obstetrics and
Gynaecology University of Hong Kong
2Quadrivalent HPV Vaccine(4 in 1 HPV vaccine)
Human Papillomavirus
Zoster (live)
Rotavirus
2006
2006
2006
2005
1996
The First Cancer Vaccine of the World
Measles, mumps, rubella, varicella
Haemophilus influenzae type b / Hepatitis B
3Cervical Cancer Is Essentially Caused by
Oncogenic HPV (????HPV?????????)
- HPV is a main cause (??) of cervical cancer
- Analysis of 932 specimens from women in 22
countries indicated prevalence of HPV DNA in
cervical cancers worldwide 99.7.
(????? 99.7)
1. Muñoz N, Bosch FX, de Sanjosé, et al. N Engl J
Med. 2003348518527. 2. Walboomers JM, Jacobs
MV, Manos MM, et al. J Pathol. 19991891219.
4Importance of Cervical Cancer
Effort to reduce cervical cancer began 50 years
ago Various evidences suggested cervical
screening led to a reduction in incidence up to
75 Second most common cancer among females
worldwide1
1.WHO 2003
5Cervical Cancer in Hong Kong1
5th most common cancer 9th leading cause of
cancer death Cervical Screening Program in HK
since March 2004
450 new cases per year 120 deaths per year
1.Hong Kong Cancer Registry, 2005
6GARDASIL ??? MSDs Quadrivalent HPV L1 VLP
Vaccine1
- Quadrivalent HPV L1 VLP vaccine
- (Types 6, 11, 16, 18)
- VLPs manufactured in
- Yeast
- Recombinant VLPs (empty shell protein L1)
- Do not contain Virus DNA (not infectious)
-
- Amorphous Aluminum Hydroxyphosphate Sulfate
Adjuvant (225 µg per dose) - No Mercury preservative (thimerosal)
- Storage 2 to 8 OC
GARDASIL is a trademark of Merck Co., Inc.,
Whitehouse Station, NJ, USA. VLP Virus-like
particle. 1. Villa LL, Costa RL, Petta CA, et
al. Lancet Oncol. 20056271278.
7GARDASIL
8Approved in 86 Countries/Territories
Europe (EU) Austria, Belgium, Bulgaria,
Cyprus, Czech Republic, Denmark,
Estonia, Finland, France, Germany, Greece,
Hungary, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, The Netherlands, Poland,
Portugal, Romania, Slovakia, Slovenia, Spain,
Sweden, UK Europe (non-EU) Bosnia, Croatia,
Iceland, Liechtenstein, Norway, Russia, Serbia,
Switzerland, Turkey
North America Canada, Mexico, USA
3
36
Caribbean Aruba, Bahamas, Bermuda, Barbados,
Cayman Island, Curacao, Dominican Republic,
Jamaica, Puerto Rico, Trinidad, Tobago
11
Middle East and Africa Central African Republic,
Chad, Congo Kinshasa, Guinea Equatorial, Gabon,
Ethiopia, Israel, Jordan, Kenya, Mauritania,
Mauritius, Morocco, Togo, United Arab Emirates
Asia Pacific
Australia, Hong Kong, Indonesia , Macau,
Malaysia, New Zealand, Philippines, Taiwan,
Thailand , Singapore, Korea
14
Central America Costa Rica, El Salvador,
Honduras, Guatemala, Nicaragua
11
5
South America Argentina, Brazil, Chile,
Colombia, Ecuador, Peru
6
as of 2 October 07
9HPV Vaccine National Immunization Program
15 countries
Eleven European countries (Germany, France,
Italy, Belgium, Austria, Norway, Sweden, Greece,
Denmark, Luxemburg and Switzerland), as well as
the United States, Canada, Australia and UK have
already reviewed the positive public health
impact and recommended the quadrivalent HPV
vaccine for universal human papillomavirus
vaccination with accelerated reviews.
10GARDASIL
- The only vaccine registered in Hong Kong in the
moment - Indication 9 26 year old females
11Dosage Administration
- 3 doses within 6 months
- (0, 2, 6 months)
- 0.5 mL volume IM injection
- Package
- Prefilled syringe
- Shake well before use
- Injection Site
- Upper arm (Deltoid region)
- Thigh (higher anterolateral area)
12Natural History of HPV InfectionSurrogate
Markers for Cervical Cancer
0 to 5 Years
Up to 20 Years
Sq. Cell Carcinoma
CIN 2
CIN 3
InitialHPV Infection
PersistentInfection
Adeno- Carcinoma
AIS
CIN 1
Cleared HPV Infection
13Natural History of HPV InfectionSurrogate
Markers for Cervical Cancer
0 to 5 Years
Up to 20 Years
Sq. Cell Carcinoma
CIN 2
CIN 3
InitialHPV Infection
PersistentInfection
Adeno- Carcinoma
AIS
CIN 1
Cleared HPV Infection
14Clinical Program Combined Efficacy Analysis
Ph IIP005 (N2392)1Proof of Principle 16- to
23-year-old women
- 33,000 subjects enrolled
- Multinational
Ph IIP007 (N1158)2 Dose-ranging 16- to
23-year-old women
Yr 5 Immune MemoryEvaluation
Ph IIIFUTURE I CIN/EGL (N5455)3 16- to
24-year-old women
Ph IIIFUTURE II CIN 2/3 (N12,167)4 15- to
26-year-old women
Duration of Efficacy Registry StudyNordic Region
Norwegian HPV Surveillance and Disease
Burden/Population Effectiveness Study
Ph IIIP016, P018 (N4836) Safety/Immunogenicity
9- to 15-year-old boys and girls5,6
Efficacy in women up to 45 years old6
Efficacy in 16- to 26-year-old men6
Jan2003
Jan2004
Jan2005
Jan2009
Jan2006
Jan2008
Jan2007
Jan2010
EGL external genital lesions.
1. Koutsky LA, Ault KA, Wheeler CM et al. N Engl
J Med. 200234716451651. 2. Villa LL, Costa
RLR, Petta CA, et al. Lancet Oncol.
20056271278. 3. Garland SM, Hernandez-Avila M,
Wheeler CM, et al. Submitted. 2006 4. FUTURE II
study group. Submitted. 2006. 5. Block SL, Nolan
T, Sattler C, et al. Submitted. 2006. 6. Data on
file, MSD.
15HPV 6/11/16/18-Related High Grade Disease
(Cervix, Vulva, Vagina, Genital Warts)
Per-Protocol Efficacy Population - Protocols 007,
013, 015 (n18780)
HPV 6/11/16/18-Related Gardasil Placebo Efficacy 95 CI
CIN 2/3 or AIS 1 73 99 92, 100
Vulval and Vaginal Lesions (incl. Genital Warts) 2 189 99 96, 100
VIN 2/3 or VaIN 2/3 0 15 100 72, 100
PP received 3 vaccinations within 1 year no
major protocol violations HPV 16/18 sero(-) at
day 1 and HPV 16/18 DNA(-) day 1 to month 7
cases counted starting after month 7. CIN
cervical intraepithelial neoplasia AIS
adenocarcinoma in situ. Eliav Barrs
Presentation to ACIP (CDC) FEB 2007
Average follow up for 3 years
16HPV disease burden More than Cancer Prevention
Cervical cancer 0.500 million in 2002 1
HPV 16, 18 and others
High-grade precancerous lesions 10 million 2
Very high global burden of HPV-related diseases
Low-grade cervical lesions 30 million 2
Genital warts 30 million 3
Attributable to oncogenic HPV types
HPV 6, 11 and others
Attributable to non-oncogenic HPV types
HPV infection without detectable abnormalities
300 million 2
1.Parkin et al. 2005 2.WHO 1999 3.WHO 1990
17HPV-6/11 related diseases
18HPV and Anogenital Warts
- HPV 6 and 11 responsible for gt90 of anogenital
warts1 - Clinically apparent in 1 of sexually active US
adult population2 - Estimated lifetime risk of developing genital
warts 103,4
Images top left and top right Reprinted with
permission from NZ DermNet (www.dermnetnz.org)
1. Jansen KU, Shaw AR. Annu Rev Med.
200455319331. 2. Koutsky L. Am J Med.
199710238. 3. Franco EL, Villa LL, Richardson
H, Rohan TE, Ferenczy A. In Franco EL, Monsonego
J, eds. Oxford, UK Blackwell Science
19971422. 4. Tortolero-Luna G. Hematol Oncol
Clin North Am. 199913245257, x.
19- In Hong Kong, between 3 4 thousand patients
with genital warts attended the Social Hygiene
Clinic every year in the past decade, which
account for about 9 of all attendances
20- Incubation period 3 weeks to 8 months, majority
around 2-3 months - Reported spontaneous complete clearance rate was
low 5 - No report on the rate of spontaneous regression
in long term - Recurrence is common after treatment, 25 occurs
within 3 months
21Treatment
- Antiproliferative agents podophlyllin
- Destructive therapies trichloroacetic acid,
electrosurgery, laser, excision - Immunomodulators - Imiquimod
22HPV-6/11 related cervical neoplasia
- HPV-6 and 11 are associated with LSIL
- A meta-analysis of 55 studies HPV-6 and -11
were present in 8.1 and 3.2 of HPV-positive
LSIL - Causal relationship still not clear
23Recurrent Respiratory Papillomatosis(RRP)
- A rare condition
- Can occur anywhere in the respiratory tract, most
commonly in the larynx - Hoarseness of voice and respiratory obstruction
are the commonest presentations - Commonly recurrent after treatment
- HPV-6 and -11 are the causative agents for almost
all the RRP
24Juvenile onset RRP
- Before age of 4
- Source of virus - most probably from the genital
tract during birth - Condyloma during pregnancy increases the risk for
more than 200 folds - Risk still lt 1
25Adult onset RRP
- Peak at 21 - 30
- Adult onset RRP result from sexual or
non-sexual contact with an infected lesion
26Treatment
- Surgical
- In case of multiple recurrence, surgical excision
is still the mainstay of the treatment - Use of other therapies remain controversial
27- GARDSIL is highly effective in the prevention of
HPV-6 and -11 related genital warts in women - Cost-effectiveness of including GARDSIL as part
of the immunization programme for the prevention
of genital warts among different countries,
public acceptability and efficacy in men have to
be evaluated - Role of GARDSAIL in RRP has to be evaluated
28- Vaginal and Vulval
- Intraepithelial Neoplasia
29Vaginal Intraepithelial Neoplasia (VaIN)
- Main predisposing factor for VaIN is likely
exposure to HPV.1 - VaIN is often found in conjunction with cervical
intraepithelial neoplasia (CIN). - Average age of women with VaIN 3550 years2
- On average, older than those presenting with CIN
- True incidence unknown, but lower than for CIN1
- Incidence expected to rise due to wider use of
cytological screening and colposcopy, as well as
increased awareness of disease2 - VaIN is often asymptomatic and difficult to
diagnose.2 - While untreated VaIN can spontaneously regress,
there is a potential for VaIN to progress to
invasive vaginal cancer.2
1. Winter-Roach B, Monaghan JM, de Lopes A.
Colposcopy of the vagina. In Bosze P, Luesley D,
eds. EAGC Course Book on Colposcopy. Budapest
Primed-X Press 2004120123. 2. Dodge JA,
Eltabbakh GH, Mount SL, et al. Gynecol Oncol. Nov
200183363369.
30Vulval Intraepithelial Neoplasia (VIN)
- Incidence of VIN is increasing in the United
States and worldwide.1 - In the United States, the incidence has nearly
doubled between 1973 and 1987 (1.1 to 2.1 per
100,000 woman year)2 - Mean age of women with VIN is decreasing24
- The peak incidence has shifted from women 50 to
women aged gt35 to 50. - Symptoms occur and may be present for a long time
prior to diagnosis (median of 1 year)4 - The most common symptoms include pruritus (56),
vulval pain and soreness (29), and vulval
swelling (16).
1. Joura EA. Curr Opin Obstet Gynecol.
2002143943. 2. Sturgeon SR, Brinton LA, Devesa
SS, Kurman RJ. Am J Obstet Gynecol.
199216614821485. 3. Jones RW, Rowan DM,
Stewart AW. Obstet Gynecol. 200510613191326.
4. Herod JJ, Shafi MI, Rollason TP, et al. Br J
Obstet Gynaecol. May 1996103446452.
31Vulval Intraepithelial Neoplasia (VIN)
- No biological continuum between histological
grades of VIN has been shown1 - Rarely has progression from VIN 1 to VIN 3 been
documented. - The annual progression rate of untreated VIN 3 to
invasive cancer is at least 10. - Surgically treated VIN have a high rate of
recurrence, and in untreated women gt30 years
there is an appreciable invasive potential.2 - HPV 16 appears to be the dominant HPV type
associated with high-grade VIN (up to 81 in VIN
3)3 - Majority of VIN 1 cases are associated with HPV
types 6 and 113 - HPV 6, 11, 16, or 18 can be found in VIN 2 or 34
1. Jones RW. Eur J Gynaecol Oncol.
200122393402. 2. Jones RW, Rowan DM, Stewart
AW. Obstet Gynecol. 200510613191326. 3.
Buscema J, Naghashfar Z, Sawada E, et al. Obstet
Gynecol. 198871601606. 4. Koutsky L. Am J Med.
199710238.
32- VaIN and VIN are of concern because they are
considered as precancerous lesions with about 40
- 50 associated with HPV infection - In UK, vulval cancer is 6 times and vaginal
cancer 20 times less common than cervical cancer1 - No screening programme exists
1. Gonzalez Inchaurraga MA et al. HPV and
carcinogenesis. Acta Dermatovenerol.
200211-8. 2. Parkins DM et al. International
Agency for Research on Cancer, 20028.
33HPV 6/11/16/18-Related High Grade Disease
(Cervix, Vulva, Vagina, Genital Warts)
Per-Protocol Efficacy Population - Protocols 007,
013, 015 (n18780)
HPV 6/11/16/18-Related Gardasil Placebo Efficacy 95 CI
CIN 2/3 or AIS 1 73 99 92, 100
Vulvar and Vaginal Lesions (incl. Genital Warts) 2 189 99 96, 100
VIN 2/3 or VaIN 2/3 0 15 100 72, 100
PP received 3 vaccinations within 1 year no
major protocol violations HPV 16/18 sero(-) at
day 1 and HPV 16/18 DNA(-) day 1 to month 7
cases counted starting after month 7. CIN
cervical intraepithelial neoplasia AIS
adenocarcinoma in situ. Eliav Barrs
Presentation to ACIP (CDC) FEB 2007
Average follow up for 3 years
34Updates on HPV Vaccines
35- Safety
- Duration of protection
- Cross protection
- Age
36Safety
37Safety
- VACCINE ADVERSE EVENT REPORTING SYSTEM (VAERS)
http//vaers.hhs.gov/info.htm - - A passive reporting system which records any
hearsays and Adverse Events (AEs) from any
sources - - CDC Will investigate the casual relationship
of AEs and vaccines -
- Deaths 11 cases from VAERS (9 from the FUTURE
studies) - Guillain-Barre Syndrome 13 cases
38Deaths
- 11 deaths in recipients of GARDSIL among
approximately 18.3 million doses of distribution
(another 9 cases in FUTURE I II) - Causal relationship between the events and the
vaccination has not been established - From the studies, number of death cases were not
different between vaccine groups and placebo
groups
39Cases in FUTURE I II
- 4 cases of traffic accident
- 1 case of suicide
- 1 case of drug overdose
- 1 case of pneumonia and sepsis
- 1 case of pulmonary embolism
- 1 case of infective thrombosis
40Other cases
- Several of these reports are hearsay and did not
have first hand information and may be duplicates
(one case was confirmed as false report and the
subject is still alive). These cases generally
were associated with underlying life threatening
or chronic cardiovascular diseases - 1 died before vaccination
- 1 due to pulmonary embolism
- 1 died of influenza B viral infection with
secondary staphylococcal infection - 1 had severe heart problems, died of myocarditis
6 days after vaccination of 3 vaccines including
Gardasil
41Guillain-Barre Syndrome
- 13 reports of GBS are within the numbers of
reports that could be expected to occur by chance
alone with or without a vaccination - 6 of 13 reports also involved simultaneous
injection of Menactra (meningococcal vaccine).
Current studies are underway to evaluate the
small increased risk of GBS, which might be
associated with Menactra - Only 2 reports met the case definition of GBS,
occurred within six weeks after vaccination, and
had received Gardasil alone
42Summary Safety of Gardasil
- CDC and FDA were satisfied with the safety data
in the context of more than 18 millions doses of
Gardasil distributed. - Large scale clinical trials have also shown well
tolerated safety profile. - Therefore, CDC and FDA continue to support the
universal vaccination program of Gardasil. There
are no changes of recommendations.
43Duration of Protection
44Sustained clinical efficacy and antibody titer
for at least 5 years
GMT (mMU/mL)
GARDASIL
100
10 000
GARDASIL
1 000
Neutralising antibodies (HPV type 16)
Clinical efficacy
100
10
Natural infection
0
7
12
18
24
30
36
54
60
18
5 years
months
1st
2nd
3rd
Dose
against infection, CIN (Cervical
intraepithelial neoplasia) and genital warts due
to HPV types 6,11,18 5 yrs follow up (after
dose 1) of a subset (241 women, vaccine
placebo) from a phase II efficacy study
Villa L High Sust Eff Proph Quad HPV Vacc 5 Year
Followup Br J Can 2006 95 1459
45Vaccines Long-Term Protection 3 ExamplesAt
licensing, vaccines are typically used broadly,
despite that full knowledge of their duration of
protection is unknown.
1. Mast E, Mahoney F, Kane M, Margolis H.
Hepatitis B vaccine. In Vaccine, 4th Ed. Plotkin
SA, Orenstein WA editors. Elsevier Inc. USA
publisher 2004. 2. Bottiger M. Vaccine.
19908443445. 3. McMahon BJ, Bruden DL,
Petersen KM, et al. Ann Intern Med.
2005142333341. 4. Ni Y-H, Chang M-H, Huang
L-M, et al. Ann Intern Med. 2001135796800. 5.
Van Herck K, Van Damme P, Lievens M, et al. J Med
Virol. 200472194196.
46Hepatitis B Immune Response Level Through 5
Years Post-Vaccination1
- Protection against hepatitis B virus (HBV) is
based on the presence of specific antibodies
against anti-HBs antigen.2 - Anti-HBs levels disappear in 10-50 of vaccinees
after a few years.2 - No booster has been recommended to date.3
6
24
36
48
60
12
Months After First Vaccine Dose
1. Wainwright RB, McMahon BJ, Bulkow LR, et al.
JAMA. 198926123622366. 2. Bauer T and Jilg W.
Vaccine. 200624572-577. 3. Mast E, Mahoney F,
Kane M, Margolis H. Hepatitis B vaccine. In
Vaccine, 4th Ed. Plotkin SA, Orenstein WA
editors. Elsevier Inc. USA publisher 2004.
47Anti-HBs After Immune Challenge1
- Immune memory persists beyond the time at which
anti-HBs levels may no longer be detectable. - Immune memory leads to a rapid anamnestic
response after exposure to HBV, which prevents
acute infection (and disease). - To demonstrate this, a typical anamnestic
response is observed to immune challenge.
In vivo anti-HBs response
105
104
Anti-HBs IU/I
103
102
101
100
28
10
0
Days
Immune Challenge
1. Bauer T, Jilg W. Vaccine. 200624572577.
48Immune Memory Study of Gardasil
- Vaccine 25 (2007) 49314939
49Principle
- Vaccines that induce long-term protection are
usually characterized by the generation of immune
memory - Gardasil have demonstrated high efficacy through
5 years of follow-up - Evaluated whether Gardasil is able to generate
HPV type-specific immune memory
50Neutralizing Antibodies Suggest an Anamnestic
Response (Immune Memory) to GARDASIL 1
Ph IIP007 Dose-Ranging 16- to 23-year-old women
Challenge by vaccine
The hallmark of long term protection
HPV 11
HPV 6
HPV 18
HPV 16
In subjects naïve to the relevant HPV type from
Day 1 through Month 60. Sven-Eric Olsson
Induction of immune memory of quadrivalent
vaccine Vaccine 25 (2007) 49314939
51Durable Protection Through at least 5 Years
Ph IIP007 Dose-Ranging 16- to 23-year-old women
PPE Population Efficacy Results
HPV 6, 11, 16, or 18-Related Vaccine Vaccine Placebo Placebo
HPV 6, 11, 16, or 18-Related Vaccine Vaccine Placebo Placebo
HPV 6, 11, 16, or 18-Related N Cases N Cases Efficacy () 95 CI
Persistent Infection 235 2 233 45 96 83100
Disease 235 0 233 6 100 12100
CIN 1, 2, or 3 235 0 233 3 100 lt0100
Vulvar/vaginal neoplasias or genital warts 235 0 233 3 100 lt0100
.
A total of 241 subjects were entered into the
5-year extension phase of Protocol 007. One case
of confirmed persistent infection HPV 18 DNA
detected at months 12 and 18 only not a case in
the 5-year extension phase. One case of HPV 16
DNA detected at the last visit (month 36) not a
case in the 5-year extension phase.
52Follow-up Through Nordic Registries Provides a
Sentinel Cohort1
Clinical program
Phase III Study
Registry-based Monitoring
Reports from clinical program
4 years
7 years
10 years
Routine use postlaunch
1 year
7 years
4 years
Launch
United States, Mexico, Australia, Canada, Togo
1. Data on file, MSD.
53Cross Protection
54What is being shown on the poster presentation at
ICAAC?
- First analysis of data assessing whether
GARDASIL is efficacious against disease caused by
10 additional cancer-causing HPV types (in
addition to 6, 11, 16 and 18). Specifically - The cross-protection analysis evaluated disease
endpoints - Reductions in CIN 2 /3 and AIS
- CIN 2/3 and AIS are the immediate and obligate
precursors of cervical cancer as recommend by WHO
and FDA - The 10 additional HPV types evaluated were 31,
33, 35, 39, 45, 51, 52, 56, 58 and 59
55(No Transcript)
56What endpoints did this analysis evaluate?
- The first study endpoint was the combined
incidence of HPV 31/45-related CIN 2/3 or AIS
after three years of follow-up. - The second endpoint was the combined incidence of
HPV 31-, 33-, 45-, 52- and 58-related CIN 2/3 or
AIS after three years of follow-up. - An analysis of reductions in CIN 2/3 and AIS
caused by all 10 HPV types (31, 33, 35, 39, 45,
51, 52, 56, 58 and 59) also was conducted.
57Phylogenetic Tree of HPV Family
HPV 16 Related
HPV18 Related
58 - Beyond HPV 6, 11, 16, 18 - Gardasil
potentially offers disease protection against
additional oncogenic HPV types
59For the bivalent HPV vaccine
- HPV type 45, 31, 52
- (6 months persistent infection)
60- Currently available HPV vaccines potentially
offer cross protection against other HPV types,
efficacy has to be confirmed by further studies
61Age
62Interim analysis of a study
- Safety, Efficacy, and Immunogenicity of
Quadrivalent HPV Vaccine (GARDASILTM) in Women
Aged 24 45 - Poster oral presentation in the 24th
International Papillomavirus Congress in Nov. 2007
63(No Transcript)
64(No Transcript)
65Combined incidence of persistent infection, CIN,
or external genital lesions (EGLs) caused by HPV
6, 11, 16, or 18 Ref IPV congress 2007 NOV
Presentation PA1-04
66(No Transcript)
67(No Transcript)
68Gardasil in 24-45 women
- Generally well tolerated
- - Injection site AEs higher than placebo
69Eradication of Cervical Cancer and HPV Related
Diseases
Not a Dream Anymore
70Thank you!