Title: Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer
1Human Papillomaviruses (HPV) The Background,
Current Status and Future of Vaccines to Prevent
HPV Infection, Abnormal Genital Lesions and
Cervical Cancer
- Cosette M. Wheeler, PhD
- Departments of Molecular Genetics Microbiology
- And Obstetrics Gynecology
- University of New Mexico Health Sciences Center
- Albuquerque, New Mexico
2Learning Objectives
- Identify risk factors for acquiring HPV infection
- Discuss the causal relationship between HPv and
cervical cancer and HPV and genital warts - Identify recent clinical findings on HPV vaccines
in development
3Papillomaviruses are small DNA viruses that
coevolved with ALL animals HPV Life Cycle
HPV Protein Expression Late
genes L1L2 Early Genes E6 E7
Early Genes E4 E5 Early Genes E1 E2
Stratum Corneum Stratum Granulosum Stratum
Spinosum Stratum Basale Basement Membrane
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5Natural history of CC factors co-factors
- HPV genotypes
- HPV variants
- Multiple types
- Viral load
- Viral integration
- Early AFSI
- High NOSP
- High-risk malepartners
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7Incidence of Cervical HPV Detection in Women From
the Time of Onset of Their First Sexual
Relationship
Collins et al. Brit J Obstet Gynecol 2002109
96 to 98
Time since first intercourse (months)
8Natural History of HPV 16/18-Related Cervical
Neoplasia Estimated Median Age of Events
Menarche
Sexual debut
HPV 16 or 18 cervical infection
CIN
ASC-US (atypical squamous cells of undetermined
significance)
CIS
Micro-invasive Cervix Cancer
Invasive Cervix Cancer
10 20 30
40 50
Age in Years
9Lifetime Risk of HPV Related Disease
- Genital HPV Infection is the Most Common Viral
STI Worldwide - Lifetime risk of HPV infection for sexually
active males and females 50 (80) - Estimated lifetime risk of developing genital
warts 10 1, 2 - Women participating in routine screening
- abnormal Pap smear ?35
- CIN 25
- invasive cervical cancer lt1
- Women without routine screening
- invasive cervical cancer 3 to 4
1) 1 Franco, E. L., et al. in New
Developments in Cervical Screening and
Prevention, Oxford, Blackwell Science, 1997
14-22. 2) 2 Tortolero-Luna, G. Hematology
and Oncology Clinics of North America, 13 (1),
1999 245-257.
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11Prevalence of HPV DNA in over 1,000 cervical
cancer biopsies from 22 countries 99.7 J.
Pathol. 189 12-19, 1999
HPV is a necessary cause of invasive cervical
cancer worldwide
12IARC International prevalence survey of HPV types
in cervical cancer
Poland
Canada
Germany
Spain
USA
Morocco
Algeria
The Philippines
Thailand
Cuba
Mali
Panama
Benin
Guinea
Colombia
Uganda
Tanzania
Brazil
Indonesia
Bolivia
Paraguay
Chile
Argentina
13Prevalence of HPV types in cervical cancer
- Any HPV 99.7
- HPV 16 57.4
- HPV 18 16.6 81
- HPV 45 6.8 89
- HPV 31 4.3 96
- HPV 33 3.7
- HPV 52 2.5
- HPV 58 2.3
- HPV 35 2.2
14Geographical distribution of HPV types in
cervical cancer
OTH
HPV type 16
18
45
31
33
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16- A vaccine that prevents HPV16- and 18-related
intraepithelial lesions and neoplasms will be a
major advance in anogenital cancer control
17HPV Viral-Like Particle (VLP) Vaccines
Electron micrograph of VLP
Schematic of HPV VLP
HPV Neutralizing Epitopes Are Conformational and
Reside in Pentameric (5 x L1) Capsomere Subunits
Connected by Invading C-termini
Modis Y et al (2002) Atomic Model of the
Papillomavirus Capsid. EMBO214754-4762
18HPV Vaccine Programs Conducted in 3 Phases
- Phase I in 300 subjects
- Immunogenicity and tolerability of a range of
doses of monovalent HPV L1 VLP vaccines - Phase II in 3,500 subjects
- Immunogenicity/tolerability of a range of HPV L1
VLP vaccine dose formulations - Preliminary proof of efficacy
- Koutsky LA, Ault KA, Wheeler CM, Jansen KU, Barr
E, Alvarez FB, Chiacchierini LM. Results from a
phase II human papillomavirus virus-like particle
vaccine efficacy trial. New England Journal of
Medicine.2002 3471646-1651. - Diane M Harper, Eduardo L Franco, Cosette
Wheeler, Daron G Ferris, David Jenkins et al.
Efficacy of a bivalent L1 virus-like particle
vaccine in prevention of infection with human
papillomavirus types 16 and 18 in young women a
randomized controlled trial. Lancet.
20043641757-65. - Villa LL, Costa RLR, Petta CA, Andrade RP, Ault
KA, Giuliano AR, Wheeler CM, Koutsky LA et al. A
Double-blind, Placebo-controlled Efficacy Trial
of a Prophylactic Quadrivalent Human
Papillomavirus (Types 6, 11, 16, 18) L1
Virus-Like Particle (VLP) Vaccine in Young Women.
Lancet Oncology. 20056271-278.
19HPV Vaccine Programs Conducted in 3 Phases (cont.)
- Phase III in gt20,000 subjects
- Efficacy of HPV L1 VLP vaccine vs. vaccine
type-related - CIN 1
- Genital warts
- CIN 2/3
20HPV L1 VLP Phase III Vaccines
- Quadrivalent HPV Types 6, 11, 16, 18 L1 VLP
vaccine (Gardasil, Merck Research Laboratories,
West Point, PA.) Phase II and III Reported - Di-valent HPV Types 16 and 18 (Cervarix,
GlaxoSmithKline) Phase II Reported
21GSK Vaccine Efficacy Persistent Infection (all
samples)
Harper DM et al, The Lancet, 2004
22Summary of HPV-001 Efficacy Data HPV 16 and/or
18 Cervical Protection
Persistent Infection
Incident Infection
Cytology
CIN
Harper et al, The Lancet, 2004
Vaccine Efficacy
91
93
100
100
Analysis of incident/persistent infection and
cytology performed in ATP cohort (cervical
samples). Analysis of CIN performed in ITT
cohort (DNA detected in tissue)
23GSK Phase III Efficacy Studies
- GSK efficacy study
- Global North America, Latin America, Asia
Pacific, Europe - N 18,000 (15-25 year old women)
- National Cancer Institute (NCI) efficacy study
- Population-based trial in Guanacaste, Costa Rica
- Clinical trial management Allan Hildesheim
(NCI PI), Rolando Herrero (Costa Rican PI) - N 12,000 (18-25 year old women)
- Both trials assessing CIN 2 endpoints
24- Definitive evaluation of the impact of
prophylactic HPV vaccination on cervical
intraepithelial neoplasia grade 2 and 3 (CIN2/3),
squamous cell carcinoma in situ (CIS),
adenocarcinoma in situ (AIS) and cervical cancer
has been recently reported for Merck quadrivalent
HPV 6, 11, 16, and 18 VLP vaccine
25Merck Quadrivalent HPV (Types 6, 11, 16, 18) L1
VLP Vaccine Dose-Ranging and Phase II Efficacy
Study
- Double-blind, placebo-controlled study
- In 1106 women aged 16 to 23 (U.S., Brazil, E.U.)
- Followed for 3 years, 6 month intervals
- 3 formulations of HPV vaccine or Placebo given at
enrollment, Month 2, and Month 6
Group HPV 6 VLP (mg) HPV 11 VLP (mg) HPV 16 VLP (mg) HPV 18 VLP (mg) Total VLP (mg)
Pbo 0 0 0 0 0
Low 20 40 40 20 120
Med 40 40 40 40 160
High 80 80 40 80 200
GARDASIL formulation
26Quadrivalent HPV Vaccine Study Results of
Dose-Ranging Phase
1000
Geometric Mean Titer (mMU/mL)
Placebo
20/40/40/20 mg
100
40/40/40/40 mg
80/80/40/80 mg
10
Levels after Natural Infection
HPV 11
HPV 16
HPV 18
HPV 6
27Quadrivalent HPV Vaccine StudyAnti-HPV 18
Immunogenicity Over 3.0 Years
10000
Per-Protocol Subjects (Phase III formulation)
Baseline Seropositive PCR Negative Subjects
(Placebo Group)
1000
Serum cLIA GMT, mMU/mL
100
10
0
2
3
6
7
12
18
24
30
36
Time (Months)
28Quadrivalent HPV Vaccine StudyAnti-HPV 16
Immunogenicity Over 3.0 Years
29Quadrivalent HPV Vaccine Study Efficacy
Evaluation by HPV Type
Per-Protocol Efficacy Cohort
- Vaccine cases
- HPV 16 3 cases single positive at the last visit
on record - HPV 18 1 case persistent HPV 18 infection
Villa et al, Lancet Oncology 2005 6 271-78.
30Antibody levels among non-cases vs. single case
of persistent HPV 18 infection (vaccine
recipients)
10000
Non-Cases for HPV 18 combined Subject A
1000
Serum cLIA GMT, mMU/mL
100
Detection of HPV 18 DNA
10
0
2
3
6
7
12
18
24
30
36
Time (Months)
No evidence that HPV vaccine titers are any
different in cases compared to non-cases No
minimum protective antibody level known
31Phase III Trial of Prophylactic Quadrivalent HPV
6, 11, 16, 18 L1 Virus-Like Particle (VLP)
Vaccine - Merck Prevention of Cervical
Intraepithelial Neoplasia (CIN) and External
Genital Lesions (EGL) FUTURE I Prevention of
Cervical Intraepithelial Neoplasia (CIN) 2/3
including Adeno- and Squamous-cell Carcinoma in
situ (CIS)-FUTURE IIGeneral Trial Population
Impact
32FUTURE II Clinical Protocol
- Randomized, double-blind, placebo-controlled
study in 12,167 women aged 16 to 26 enrolled in
13 countries - 11 randomization to Gardasil or placebo
- ThinPrep Pap tests, swabs for HPV DNA taken at
Day 1 and Months 7, 12, 24, 36, 48, and sera
tested at Day 1 in all subjects - Mandatory colposcopy and definitive therapy
algorithm based on standard of care - All Pap tests and biopsies processed and read at
a central laboratory - Expert Pathology panel read all slides for
endpoint determination
33FUTURE I and II Trial Primary Disease
EndpointsHPV 6/11-Rleated Extragenital
Lesions HPV 16/18-Related CIN 2, CIN 3 (includes
CIS), AIS, or Cervical Cancer
Fixation, Processing Paraffin Embedding
CervicalBiopsy
Prepare Consecutive Sections
1
2
12
13
HE Staining and Histology
HPV 6/11/16/18 PCR Positive
Wart/CIN - FUTURE I CIN 2/3, AIS, Cancer
FUTURE II
Vaccine Type PCR Negative
No Case
Case
34Statistical Plan
- Primary Efficacy Evaluation in Per-Protocol (PP)
Population - 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
- Supportive analysis in Modified intention to
treat (MITT) population - received 1 vaccination
- HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1
- Cases were counted starting 30 days after Day 1
- Timing of efficacy analyses
- Interim analyses when ?19 endpoint cases seen in
PP population - PP population efficacy tested at a0.0204
- For the HPV 16/18-related CIN 2, CIN 3 (includes
CIS), AIS, or cervical cancer endpoint in the PP
population, 97.96 CI reported. All other CIs
are 95.
35Subject Characteristics FUTURE II
Vaccine(N 6087) Placebo(N 6080)
Mean age (yrs) 20.0 19.9
Age range (yrs) 15 to 26 15 to 26
Region
North America 460 (8) 456 (7)
Latin America 1599 (26) 1594 (26)
Asia-Pacific 92 (2) 89 (2)
Europe 3936 (64) 3941 (65)
Mean Age 1st intercourse among non-virgins (93.4) 16.6 16.6
Median Lifetime of sex partners 2 2
Using hormonal contraception 3613 (59.4) 3614 (59.5)
36Subject Accounting FUTURE II
Vaccine Placebo Population to which category applies Population to which category applies
(N 6,087) (N 6,080) PP MITT
Received 1 Injection 6,082 6,075
Included in PP 5,301 5,258
Included in MITT 5,736 5,766
Reason for exclusion
General protocol violations 275 315 X
Sero () and/or DNA () to HPV 16
at Day 1 954 964 X X
at or before Month 7 1,012 1,162 X
Sero () and/or DNA () to HPV 18
at Day 1 397 405 X X
at or before Month 7 443 548 X
No post-Month 7 follow-up (16/18) 25/35 25/36 X
37Clinical Serious Adverse Experience (AE)
Summary(Days 1 to 15 Following Any Vaccination
Visit)
Vaccine (N6075) Vaccine (N6075) Placebo (N6076) Placebo (N6076)
n () n ()
Subjects with follow-up 6019 6031
Number () of subjects with
serious AE 17 (0.3) 16 (0.3)
serious vaccine-related AE 3 (lt0.1) 2 (lt0.1)
discontinuation due to a serious AE 2 (lt0.1) 1 (lt0.1)
discontinuation due to a serious vaccine-related AE 0 (lt0.1) 1 (lt0.1)
discontinuation due to death 2 (lt0.1) 0 (0)
Deaths one drug overdose and one traffic
accident
38Efficacy Results in PP Efficacy FUTURE II
Average 17 Months After Completion of the
Vaccination Regimen
Vaccine (N6,082) Vaccine (N6,082) Placebo (N6,075) Placebo (N6,075) Placebo (N6,075) Placebo (N6,075) Efficacy () CI p-Value
Endpoint n Cases n n Cases Cases Efficacy () CI p-Value
CIN 2/3 or AIS
HPV 16/18-related 5,301 0 5,258 5,258 21 21 100 (76 100) lt 0.001
HPV 16-related 4,552 0 4,405 4,405 16 16 100 (75 100)
HPV 18-related 5,051 0 4,968 4,968 8 8 100 (42 100)
By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group By lesion type (worst diagnosis)- All in the Placebo group
CIN 2 CIN 2 CIN 2 CIN 2 5 5
CIN 3 CIN 3 CIN 3 CIN 3 15 15
AIS AIS AIS AIS 1 1
CIN 3 includes squamous-cell carcinoma in situ
(CIS) AIS adenocarcinoma in situ (AIS)
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
39Efficacy Results in MITT Population FUTURE II
Average 24 Months After the First Vaccination
Vaccine (N6,082) Vaccine (N6,082) Placebo (N6,075) Placebo (N6,075) Placebo (N6,075) Placebo (N6,075) Efficacy () CI p-Value
Endpoint n Cases n n Cases Cases Efficacy () CI p-Value
CIN 2/3 or AIS
HPV 16/18-related 5,736 1 5,766 5,766 36 36 97 (83 100) lt 0.001
HPV 16-related 4,944 1 4,957 4,957 28 28 96 (78 100)
HPV 18-related 5,477 0 5508 5508 11 11 100 (60 100)
By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis) By lesion type (worst diagnosis)
CIN 2 CIN 2 CIN 2 CIN 2 10 10
CIN 3 CIN 3 CIN 3 CIN 3 23 23
AIS AIS AIS AIS 4 4
Single case of HPV 16-related CIN 2 (Month 24)
in vaccine group. HPV 16 DNA detected at Month 7.
MITT received 1 vaccination HPV 16/18 sero(-)
and HPV 16/18 DNA(-) at Day 1 Cases were counted
starting 30 days after first vaccination
40Efficacy Results in MITT Population FUTURE I
Average 26 Months After Completion of the
Vaccination Regimen
Vaccine (N2,240) Vaccine (N2,240) Placebo (N2,258) Placebo (N2,258) Efficacy () CI p-Value
Endpoint Cases Cases Efficacy () CI p-Value
HPV6/11/16/18-CIN 2 57 97 87,100 Plt0.001
HPV 6-related CIN 1 12 92 43,100
HPV 11-related CIN 0 6 100 15,100
HPV 16-related CIN 0 32 100 88,100
HPV 18-related CIN 1 13 92 49,100
MITT received 1 vaccination HPV 16/18 sero(-)
and HPV 16/18 DNA(-) at Day 1 Cases were counted
starting 30 days after first vaccination CIN 3
includes squamous-cell carcinoma in situ (CIS)
AIS adenocarcinoma in situ (AIS)
41Efficacy Results in MITT Population FUTURE I
Average 26 Months After Completion of the
Vaccination Regimen
Vaccine (N2,240) Vaccine (N2,240) Placebo (N2,258) Placebo (N2,258) Efficacy () CI p-Value
Endpoint Cases Cases Efficacy () CI p-Value
HPV 6/11/16/18-EGL 3 59 95 84,99 Plt0.001
HPV 6-related EGL 2 34 94 77,99
HPV 11-related EGL 1 14 93 53,100
HPV 16-related EGL 0 10 100 70,100
HPV 18-related EGL 0 7 100 30, 100
42General Clinical Trial Population Impact of
Gardasil
Average 24 Months After the First Vaccination
Vaccine Vaccine Placebo Placebo Reduction() 95 CI
Endpoint n Cases n Cases Reduction() 95 CI
HPV 16/18
CIN 2/3 or AIS 9831 122 9896 201 39 (23 52)
VIN 2/3 and VaIN 2/3 8954 8 8962 26 69 (30 88)
HPV 6,11,16,18-related CIN, CIN 2/3, AIS HPV 6,11,16,18-related genital warts 8814 8954 170 58 8846 8962 317 184 46 69 (3556) (58-77)
General Population received 1 vaccination HPV
16/18 sero(/-) and HPV16/18 DNA(/-) at Day 1 -
Cases were counted starting 30 days after first
vaccination Gardasil Trial Population had no
more than 4 lifetime sex partners AND an average
of only 2
43Summary
- A 3-dose regimen of Gardasil was 100 effective
in preventing HPV 16/18-related CIN 2/3 and AIS
in women who were HPV 16/18-naïve at enrollment
and HPV 16/18 DNA(-) through the vaccination
regimen - Efficacy remained high (97) in MITT population
(received 1 vaccination includes protocol
violators but which excluded women previously
exposed to HPV vaccine types) - General trial population impact of Gardasil was
significantly reduced compared to PP or MITT when
women who had already been exposed to HPV vaccine
types in the past (sero) or who were currently
infected with vaccine types (HPV DNA PCR) were
included - There is no clear evidence that Gardasil or any
other HPV vaccine provides benefit to women who
are currently infected or have been infected in
the past with HPV vaccine types - Administration of Gardasil was generally safe
and well-tolerated
44Other Important Take Home Messages I
- It is critical that vaccinated and un-vaccinated
women continue being screened under current early
detection guidelines - Current first generation HPV vaccines do not
protect against over 12 HPV types that cause 30
of invasive cervical cancer - Duration of HPV vaccine immunity is unknown and
how and when booster immunizations will be
recommended is unknown - Public health and policy efforts are needed to
ensure access and encourage high HPV vaccine
coverage for all racial, ethnic, and
socioeconomic groups, and particularly for
girls/women of color, immigrants, those living in
rural areas, low-income and uninsured women, and
others who have limited access to health care
services
45Other Important Take Home Messages II
- Clinical trials for Gardasil were not conducted
in a general population of women (limited
inclusion for lifetime sex of partners and
abnormal Pap history) although universal
vaccination of women aged 13-26 was recommended - It is likely that the reduction in disease in a
random general population will be less than that
observed in the general Gardasil trial
populations US population average number of sex
partners is 4 for women ages 21-26 - HPV 16/18
- CIN 2/3 or AIS 39 (23 52)
- VIN 2/3 and VaIN 2/3 69 (30 88)
- HPV 6,11,16,18-related CIN, CIN 2/3, AIS 46
(3556) - HPV 6,11,16,18-related genital warts 69
(58-77)
46Other Important Take Home Messages III
- In many cases women may be paying for HPV
vaccines themselves - The potential benefit
diminishes with increasing number of lifetime
sexual partners - Vaccination of women over age 26 and of males is
not currently recommended - HPV testing is not recommended prior to
vaccination current tests are not type-specific
and even if and when type-specific HPV tests
become available, single tests do not accurately
measure current infections and CANNOT assess past
exposure
47Some Remaining Questions
- Given competing health care demands and limited
resources, is it rational to vaccinate the
general population of women ages 19-26 many who
have already been exposed (currently infected )
or whom are presumed immune and who should be
attending screening programs ? - Will HPV vaccination give a false sense of
protection and result in modification of
screening behaviors or practices that will
undermine the anticipated benefits of HPV
vaccines? - There are no data to provide evidence for changes
in screening of vaccinated women - however will
financial constraints or alternate interests
drive lengthening of Pap smear screening
intervals to allow HPV vaccine expenditures ? - As changes in practices continue, will providers
implement somewhat costly active screening
reminders and pursue missed screens in support of
the changing environment and potential problems
as we move forward ?
48Other Key Issues
- If HPV vaccines are shown effective in men, will
they be recommended given cost benefit and
benefit to overall disease outcomes appear to be
minimal based on modeling if penetration in women
is high - Will women at greatest risk for this disease be
provided to access to HPV vaccines developing
world, impoverished
49Required Go-Forward Surveillance and Research
- Ongoing research and surveillance should be
conducted in diverse populations, including
research on - duration of protective immunity,
- population- and lesion-based changes in
type-specific prevalence for the full spectrum of
carcinogenic and non-carcinogenic genital HPV
types, - changes in Pap test performance characteristics,
- changes in screening practices and behaviors,
- comprehensive surveillance for reproductive
toxicities, - increasing vaccine coverage and acceptability,
and impact on safe sexual behavior.