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Title: HPV Vaccine: - More than Cervical Cancer Prevention -


1
HPV Vaccine - More than Cervical Cancer
Prevention -
Tam Kar Fai Department of Obstetrics and
Gynaecology University of Hong Kong
2
Quadrivalent 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
3
Cervical 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.
4
Importance 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
5
Cervical 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
6
GARDASIL ??? 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.
7
GARDASIL
  • Prophylactic vaccine

8
Approved 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
9
HPV 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.
10
GARDASIL
  • The only vaccine registered in Hong Kong in the
    moment
  • Indication 9 26 year old females

11
Dosage 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)

12
Natural 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
13
Natural 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
14
Clinical 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.
15
HPV 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
16
HPV 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
17
HPV-6/11 related diseases
18
HPV 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

21
Treatment
  • Antiproliferative agents podophlyllin
  • Destructive therapies trichloroacetic acid,
    electrosurgery, laser, excision
  • Immunomodulators - Imiquimod

22
HPV-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

23
Recurrent 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

24
Juvenile 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

25
Adult onset RRP
  • Peak at 21 - 30
  • Adult onset RRP result from sexual or
    non-sexual contact with an infected lesion

26
Treatment
  • 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

29
Vaginal 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.
30
Vulval 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.
31
Vulval 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.
33
HPV 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
34
Updates on HPV Vaccines
35
  • Safety
  • Duration of protection
  • Cross protection
  • Age

36
Safety
37
Safety
  • 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

38
Deaths
  • 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

39
Cases 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

40
Other 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

41
Guillain-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

42
Summary 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.

43
Duration of Protection
44
Sustained 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
45
Vaccines 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.
46
Hepatitis 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.
47
Anti-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.
48
Immune Memory Study of Gardasil
  • Vaccine 25 (2007) 49314939

49
Principle
  • 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

50
Neutralizing 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
51
Durable 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.
52
Follow-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.
53
Cross Protection
54
What 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
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56
What 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.

57
Phylogenetic 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
59
For 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

61
Age
62
Interim 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
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64
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65
Combined 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
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67
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68
Gardasil in 24-45 women
  • Generally well tolerated
  • - Injection site AEs higher than placebo

69
Eradication of Cervical Cancer and HPV Related
Diseases
Not a Dream Anymore
70
Thank you!
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