Human Papillomavirus HPV Vaccines

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Human Papillomavirus (HPV) Vaccines
Darron R. Brown, MD Professor of Medicine,
Microbiology, and Immunology Division of
Infectious Diseases Indiana University School of
Medicine Indianapolis, Indiana
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Disclosures

• Dr. Brown serves on the Womens Health Advisory
  Board at Merck and Co., Inc. and is compensated
  for his time.
• Dr. Brown has received honoraria from Merck and
  Co., Inc. for lectures related to HPV and
  vaccines.
• Dr. Browns laboratory has receives research
  funding from Merck and Co., Inc.
• Indiana University and Merck and Co., Inc. have a
  confidential agreement that pays the University,
  based on certain landmarks related to
  intellectual property and development of the HPV
  vaccine. Dr. Brown receives a portion of these
  funds as income.

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HPV is an infectious virus that causes
Immunocompromised patients
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HPV prevalence and CxCa incidence by age
Bosch FX et al. J Clin Path 200255244
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Cervical cancer

• United States
• Annual incidence 10,000
• 4,000 women die each year, 10 each day of
  cervical cancer
• 2 billion per year spent on screening and
  treatment of pre-malignant lesions
• Worldwide
• Annual incidence 500,000
• Second most common cause of cancer death in all
  women, the most common cause of cancer death in
  women in poor countries
• 250,000 deaths each year (800 deaths each day)

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Cervical cancer most common in poor countries
EUROPE 59,931
N. AMERICA 14,670
ASIA 265,884
C-S. AMERICA 71,862
AFRICA 78,897
Globocan 2002.
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HPV

• gt120 types identified (80 cutaneous, 40
  anogenital)
• Oncogenic (high risk) anogenital types include
  16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
• HPV 16 (50) and HPV 18 (20) account for the
  majority of cervical cancers worldwide.
• Other cancers caused HR-HPV types anal, vulvar,
  vaginal, penile, oropharyngeal
• Non-oncogenic (low risk) anogenital types
  include 6, 11, 40, 42, 43, 44, 54
• HPV 6 and 11 cause 90 of external
  anogenital warts, 10 - 20 CIN 1, 90 of
  laryngeal papillomatosis

Non-enveloped, double-stranded DNA virus (seven
genes), 50 nm diameter
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Infectious Virus Particle of HPV
Capsid proteins L1 L2
Viral DNA
Viral interior
Viral exterior
1. Baker TS, et al. Biophys J. 19916014451456.
2. Chen XS, et al. Mol Cell. 20005557567.
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HPV 83 particles in lesion
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HPV Genome (ds DNA, 8 kb)
L1 encodes major capsid protein, 54 kDa

• E6

• URR

• E7

L1

• 7000

• 1000

• E1

• 2000

• 6000

• 5000

• 3000

• 4000

• L2

• E2

• E5a

• E4

• E5b

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HPV L1 Virus-Like Particles (VLPs)
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HPV 11VLP
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Pre-clinical studies

• In preclinical animal studies using
  species-specific VLPs
• Vaccination induced protection from infection and
  disease.
• Efficacy was associated with development of
  neutralizing antibodies.
• Passive transfer confers protection

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Antibody response in HPV 11
VLP-vaccinated monkeys
V
V
V
Serum Vaginal secretions
(blood-free)
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Phase I trial HPV 11 VLP vaccine (young
women)Month 7 RIA titers by neutralization status
Neutralization positive
Neutralization negative
1000
RIA titer (mMu/mL)
100
10
1
Placebo
10 mcg
20 mcg
50 mcg
100 mcg
Treatment group
Brown DR et al. J Infect Dis. 20011841183-1186.

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Vaginal lumen
antibody to VLP
Cervical epithelium
Basal layer
Basement membrane
Dermis
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HPV vaccines

• Quadrivalent (Gardasil) HPV 6/11/16/18 L1 VLPs
  with aluminum hydroxyphosphate sulfate as
  adjuvant
• Bivalent (Cervarix) HPV 16/18 L1 VLPs with an
  adjuvant known as ASO4 that contains aluminium
  hydroxide and deacylated monophosphoryl lipid A
  (MPL)

Submitted to FDA, but not yet approved for use
in USA
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Quadrivalent Vaccine Clinical Protocols (Women
Aged 16-26 Women Aged 24-45 Men Aged 16-26)

• Multi-center, international studies
• 1 1 randomization (vaccine or placebo) day 1,
  month 2, month 6
• Comprehensive anogenital examinations and
  specimens for HPV, (Pap testing at enrollment and
  6-12 month intervals thereafter)
• Cytology, histology, HPV detection conducted
  centrally
• Colposcopy algorithm-based

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Prevention of Cervical Lesions in Women 16 26
years.
100 95 CI 31 100 0 vs 7 cases
97 95 CI 88 100 2 vs 63 cases
96 95 CI 91 98 7 vs 170 cases
100 95 CI 95 100 0 vs 71 cases
n (quadrivalent vaccine) 7,864 n (placebo)
7,865
Ault K for the FUTURE II Study Group. 2007.
Lancet Jun 2369(9576)1861-8.
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Prophylactic Efficacy Against HPV
6/11/16/18-related VIN 2/3 and VaIN 2/3 (Women
Aged 16 to 26)
100 95 CI 67 100 0 vs 13 cases
100 95 CI 55 100 0 vs 10 cases
n (Quadrivalent) 7,900 n (Placebo) 7,902
Ault K for the FUTURE II Study Group. 2007.
Lancet Jun 2369(9576)1861-8.
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Prophylactic Efficacy Against HPV
6/11/16/18-related Genital Warts (Women Aged 16
to 26).
100 95 CI (80 100) 0 vs 20 cases
99 95 CI (96 100) 2 vs 185 cases
n (Quadrivalent) 7,900 n (Placebo) 7,902
Ault K for the FUTURE II Study Group. 2007.
Lancet Jun 2369(9576)1861-8.
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Combined Incidence of HPV 6/11/16/18-related
Persistent Infection and Cervical/Vulvar/Vaginal
Disease (Women Aged 24 - 45)
Muñoz N, et al., Lancet. 2009 Jun
6373(9679)1949-57.
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Male Study (ages 16 to 23) Efficacy against
persistent HPV-6/11/16/18 infection and external
genital lesions (EGL)
EGL includes external genital warts,
penile/perianal/perineal intraepithelial
neoplasia (PIN), penile, perianal, or perineal
cancer case counting began after month
7. PERSISTENT INFECTION HPV DNA detection in
anogenital specimens from gt2 consecutive visits
gt6 months apart.
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Quadrivalent Vaccine Impact of HPV 6/11/16/18
Vaccine on Abnormal Pap Tests
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Quadrivalent vaccine Reduction in HPV 16 or
18-related abnormal Pap tests
ASC-US (positive by high risk probe), LSIL, or
worse
Placebo (n 1023)
108
?93 (85-97)
Vaccine (n 1021)
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Number of cases
For 5/8 vaccine cases, subject coinfected with a
non-vaccine HR type.
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Cross-Protection

• It is hypothesized that HPV16 and HPV18
  neutralizing antibodies generated by vaccination
  may bind and neutralize virions of HPV types
  related to HPV16 and/or HPV18, thereby preventing
  infection and disease caused by these related
  types (cross-protection)
• Such a capability could potentially increase the
  expected cancer reduction of this vaccine

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Phylogenetic Characterization of Oncogenic HPV
Types
A6 SpeciesHPV 56-Related
A9 SpeciesHPV 16-Related
A7 SpeciesHPV 18-Related
A5 SpeciesHPV 51-Related
de Villiers E-M, et al. Virology 200432417-27.
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Contribution to Cervical Cancer, and L1 Protein
Homology
Munoz et al. NEJM 2003
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L1 Surface Loops (Epitopes) Immune Targets
Antibody Binding Regions
Side view
Top view
Chen XS, et al. Mol Cell. 20005557567.
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Contribution of HPV Types to Cervical Cancer,
world average (varies by region)
2 most common types in cervical cancer after 16
and 18
5 most common types in cervical cancer after
16 and 18
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Quadrivalent HPV VaccineCross-Protection
Against HPV 31/45 CIN 2/3 AIS
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Quadrivalent HPV VaccineCross-Protection
Against HPV31/33/45/52/58 CIN 2/3 AIS
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Quadrivalent HPV VaccineCross-Protection
Against CIN 2/3 AIS
HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
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Safety of quadrivalent vaccine pre-licensure
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Injection-Site AEs
Detailed Safety Population All Ages
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Systemic AEs
Detailed Safety Population All Ages
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AEs Resulting in Death

• Total of 23 subjects died during the studies
• 15 recipients of quadrivalent vaccine (0.1)
• 8 recipients of placebo (0.07)
• None of the deaths was determined to be vaccine
  or placebo related
• General categories of adverse experiences
  resulting in death
• Trauma/suicide 11
• Infection 3
• Thromboembolic events 2
• Cancer 2
• Asphyxia, Arrhythmia, Hyperthroidism,
• Gastrointestinal hemorrhage, Systemic lupus 1
  each

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Vaccine Related SAEs - all subjects
Subjects With Follow-up Subjects With at Least 1
Vaccine-related Serious AE Bronchospasm (Possibly
Related) Gastroenteritis (Possibly
Related) Headache/Hypertension (Definitely
Related) Injection Site Pain/Movement Impairment
(Probably Related) Vaginal Hemorrhage (Probably
Related) Ulcerative Colitis (Possibly
Related) Hypersensitivity (Possibly
Related) Chills/Headache/Fever (Possibly Related)
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Safety of quadrivalent vaccine post-licensure

• Approximately 23 million doses given in USA as of
  12/08
• VAERS 12,424 reports of AEFIs (772 serious)

Slade et al., JAMA 2009, Vol 302, No. 7, pp 750 -
757
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Slade BA et al., Postlicensure safety
surveillance for quadrivalent human
papillomavirus recombinant vaccine. JAMA. 2009
Aug 19302(7)750-7.
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Safety of quadrivalent vaccine conclusions of
study

• The post-licensure reports for the quadrivalent
  vaccine through VAERS were broadly consistent
  with pre-licensure safety data
• Post-licensure monitoring of the quadrivalent
  vaccine will continue, and identifying signals
  may be evaluated using epidemiologic studies

Slade et al., JAMA 2009, Vol 302, No. 7, pp 750 -
757
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Utilization

• Approximately 20 of eligible young women
  vaccinated in US
• Close to 70 in Australia
• Cost, lack of recommendation of physician are
  most important factors in poor vaccine coverage

Leddy et al., J Ped Adol Gyn 2009, 22239-246
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Summary

• The quadrivalent HPV vaccine is safe and
  effective in young women in preventing cervical
  disease protection is long-lasting (data
  available up to 5 years)
• The quadrivalent HPV vaccine has a moderate
  capacity for cross-protection against disease
  caused by vaccine-related types
• The quadrivalent vaccine prevents infection and
  disease in other sites, is effective in adult
  women up to age 44, and can reduce the burden of
  abnormal Pap smears and procedures in women.
• The quadrivalent vaccine reduces infection and
  disease in men

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Challenges

• Utilization of current vaccine(s)
• Development of second generation vaccines
• Delivery to poor countries

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Replacement can occur only if two conditions
apply.

• There exists competition between differing HPV
  types during natural infection
• No cross-protection occurs with HPV vaccination.
• Instead of competition, we see cooperation
  between types.
• Past or present HPV infection appears to favor
  infection with additional HPV types.

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Escape mutants

• Could new escape mutants form once HPV 16 and
  18 are reduced?
• No, because HPV mutates at the same rate as the
  human genome, as it uses cellular (proofreading)
  DNA polymerases for replication.
• Also, all HPV 16 subtypes variants constitute
  a single serotype, and contain the same
  neutralizing epitopes induced by the vaccine.

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Quadrivalent vaccine Prevention of HPV 16 or
18-related Pap tests in women 16 26 years
97 95 CI 82 - 100
92 95 CI 84 - 97
1 cases Vaccine 32 cases Placebo
7 cases Vaccine 90 cases Placebo
ASC-US (positive by HCII high risk probe), LSIL,
or worse
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Reduction in abnormal Pap tests (caused by any
HPV type)
?45
?36
?22
?17
ASC-US HR
LSIL
ASC-H
HSIL
Cases Placebo 357 980
87 40 Cases Vaccine
276 813 55
22
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Reduction in procedures (any HPV type)
?42
?22
?20
Colposcopy
Cervical Biopsy
Definitive therapy
Cases Placebo 1061
935 228
Cases Vaccine 850
728 130

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Bivalent Vaccine Women Aged 15-25

• Multi-center, international studies
• 11 randomization (vaccine or hepatitis A) day
  1, months 1 and 6
• Genital tract specimens for HPV, Pap testing at
  enrollment and 6 -12 month
  intervals thereafter
• Colposcopy algorithm-based

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Efficacy (per-protocol) of Bivalent Vaccine
Paavonen J, et al., Lancet. 2009 Jul
25374(9686)301-14
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Efficacy (per-protocol) of Bivalent vaccine
Paavonen J et al., Lancet. 2009 Jul
25374(9686)301-14
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Cross-protection against CIN 2/3 ( AIS for
quadrivalent)
Paavonen J et al. Lancet. 2009 Jul
25374(9686)301-14 Brown DR et al. J Infect
Dis. 2009 Apr 1199(7)926-35.