prophylactic quadrivalent human papillomavirus (hpv) (types 6, 11
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Human 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 & MicrobiologyAnd Obstetrics & Gynecology
University of New Mexico Health Sciences CenterAlbuquerque, New Mexico
Learning 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
Papillomaviruses are small DNA viruses that coevolved with ALL animals
HPV Life Cycle
HPV Protein Expression
Late genes L1&L2
Early Genes E6 & E7 Early Genes E4 & E5 Early Genes E1 & E2
Stratum Corneum
Stratum Granulosum
Stratum Spinosum
Stratum Basale
Basement Membrane
Natural history of CC: factors & co-factors
• HPV genotypes• HPV variants• Multiple types• Viral load• Viral integration
• Early AFSI
• High NOSP
• High-risk malepartners
• C. trachomatis
• HSV-2
•Sexual behavior
•Hygiene
•Condom use
•Circumcision• Immunosuppresion
• Cervical inflammation
HPV INFECTION LSIL HSIL INVASIVE
CANCER
NORMAL • Immune
surveillance & response
•Genetic susceptibility
•Viral factors
•Smoking
•Parity
•OC use
•HIV
•Other STIs
Incidence of Cervical HPV Detection in Women From the Time of Onset of Their
First Sexual Relationship
Collins et al. Brit J Obstet Gynecol 2002;109: 96 to 98
Time since first intercourse (months)
0%
10%
20%
30%
40%
50%
60%
70%
0 6 12 18 24 30 36 42 48
Cervical HPV Detection
10 20 30 40 50 Age in Years
HPV 16 or 18 cervical infectionHPV 16 or 18 cervical infectionCINCIN
Sexual debutSexual debut
Invasive Cervix CancerInvasive Cervix Cancer
MenarcheMenarche
CISCIS
Micro-invasive Cervix CancerMicro-invasive Cervix Cancer
Natural History of HPV 16/18-Related Natural History of HPV 16/18-Related Cervical Neoplasia: Cervical Neoplasia:
Estimated Median Age of EventsEstimated Median Age of Events
ASC-US (atypical squamous cells of undetermined significance)
Lifetime 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: <1%
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.
Prevalence 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
Colombia
The Philippines
Brazil
SpainMorocco
MaliThailand
Paraguay
USA
BoliviaChile
Argentina
Panama
Canada GermanyPoland
Guinea Benin
TanzaniaUganda
Indonesia
Cuba Algeria
IARC International prevalence survey of HPV types in cervical cancer
Prevalence 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 %
Geographical distribution of HPV types in cervical cancer
0% 20% 40% 60% 80% 100%
Northern Africa
Subsah. Africa
C.S/ America
S.E.Asia
N.Amer./Europe
HPV type 16 18 45 3133 OTH
A vaccine that prevents HPV16- and 18-related intraepithelial lesions and
neoplasms will be a major advance in anogenital cancer control
HPV Viral-Like Particle (VLP) Vaccines
Schematic of HPV VLP
Electron micrographof 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. EMBO;21:4754-4762
HPV 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; 347:1646-1651.
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. 2004;364:1757-65.
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. 2005;6:271-278.
HPV Vaccine Programs Conducted in 3 Phases (cont.)
Phase III in >20,000 subjects– Efficacy of HPV L1 VLP vaccine vs. vaccine type-related
• CIN 1 • Genital warts • CIN 2/3+
HPV 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
Vaccine Efficacy
Cohort HPV Type Vaccine(N=366)
Placebo (N=355) % 95%CI
16 0 13 100.0 71.5-100 18 0 4 100.0 7.2-100
ATP
16 and/or 18 0 16 100.0 76.8-100
Vaccine Efficacy Cohort HPV Type
Vaccine(N=560)
Placebo (N=553) % 95%CI
16 4 25 84.5 55.2-94.6 18 1 11 91.1 31.0-98.9
ITT
16 and/or 18 4 31 87.5 64.6-95.6
GSK Vaccine Efficacy: Persistent Infection (all samples)
Harper DM et al, The Lancet, 2004
Summary of HPV-001 Efficacy Data: HPV 16 and/or 18 Cervical Protection
0102030405060708090
100
Vacc
ine
Effica
cy
91% 93%100%
Incide
nt Inf
ection
Persis
tent In
fectio
n
Cytolog
y
Harper et al, The Lancet, 2004
*Analysis of incident/persistent infection and cytology performed in ATP cohort (cervical samples). Analysis of CIN performed in ITT cohort (DNA detected in tissue)
100%
CIN
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
GSK Phase III Efficacy Studies
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
Merck Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Vaccine Dose-Ranging and Phase II Efficacy
StudyDouble-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
GroupHPV 6 VLP
(g)HPV 11 VLP (g)
HPV 16 VLP (g)
HPV 18 VLP (g)
Total VLP (g)
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
Quadrivalent HPV Vaccine Study: Results of Dose-Ranging Phase
10
100
1000
HPV 11 HPV 16 HPV 18HPV 6
Geo
met
ric M
ean
Tite
r (m
MU
/mL)
Placebo
40/40/40/40 g 80/80/40/80 g
20/40/40/20 g
Levels after Natural Infection
Quadrivalent HPV Vaccine Study:Anti-HPV 18 Immunogenicity Over 3.0
Years
Ser
um c
LIA
GM
T, m
MU
/mL
0 2 3 6 7 12 18 24 30 36Time (Months)
10
100
1000
10000
Per-Protocol Subjects (Phase III formulation)
Baseline Seropositive & PCR Negative Subjects (Placebo Group)
Quadrivalent HPV Vaccine Study:Anti-HPV 16 Immunogenicity Over 3.0 Years
Ser
um c
LIA
GM
T, m
MU
/mL
0 2 3 6 7 12 18 24 30 36Time (Months)
10
100
1000
10000 Per-Protocol Subjects (Phase III formulation)Baseline Seropositive & PCR Negative Subjects (Placebo Group)
Quadrivalent HPV Vaccine Study: Efficacy Evaluation by HPV Type
VaccineCases
4
0
0
3
1
VaccineEfficacy
90%
100%
100%
86%
89%
71-97%
95%Confidence
IntervalP-
Value
<10–336
13
3
21
9
PlaceboCases Endpoint
HPV 6/11/16/18 Infxn, CIN, or GW
HPV 6-related
HPV 11-related
HPV 16-related
HPV 18-related Vaccine cases:
– HPV 16: 3 cases single positive at the last visit on record– HPV 18: 1 case persistent HPV 18 infection
Per-Protocol Efficacy Cohort
Villa et al, Lancet Oncology 2005; 6: 271-78.
Antibody levels among non-cases vs. single case of persistent HPV 18 infection (vaccine recipients)
0 2 3 6 7 12 18 24 30 36
Time (Months)
10
100
1000
10000
Ser
um c
LIA
GM
T, m
MU
/mL
Non-Cases for HPV 18 combinedSubject A
____
…..
Detection of HPV 18 DNA
No evidence that HPV vaccine titers are any different in cases compared to non-cases – No minimum protective antibody level known
Phase 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 II
General Trial Population Impact
FUTURE II Clinical Protocol
Randomized, double-blind, placebo-controlled study in 12,167 women aged 16 to 26 enrolled in 13 countries
1:1 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
FUTURE I and II Trial Primary Disease Endpoints:HPV 6/11-Rleated Extragenital Lesions
HPV 16/18-Related CIN 2, CIN 3 (includes CIS), AIS, or Cervical Cancer
Prepare Consecutive
Sections
CervicalBiopsy
Fixation, Processing & Paraffin Embedding
H&E Staining and Histology
1 2 12 13
Extraction of DNA for HPV Multiplex PCR
3 75
12
54
3
67
12
98
1311
10
No Case
Wart/CIN - FUTURE I +CIN 2/3, AIS, Cancer – FUTURE II
HPV 6/11/16/18PCR Positive
Case
Vaccine TypePCR Negative
Statistical 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 =0.0204– 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%.
Subject Characteristics FUTURE IIVaccine
(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%)
Subject Accounting FUTURE II
Vaccine Placebo 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 5,766Reason 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
Clinical Serious Adverse Experience (AE) Summary(Days 1 to 15 Following Any Vaccination Visit)
Vaccine (N=6075)
Placebo (N=6076)
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 (<0.1) 2 (<0.1)
discontinuation due to a serious AE 2 (<0.1) 1 (<0.1)discontinuation due to a serious vaccine-related AE
0 (<0.1) 1 (<0.1)
discontinuation due to death* 2 (<0.1) 0 (0)
*Deaths: one drug overdose and one traffic accident
Efficacy Results in PP Efficacy – FUTURE IIAverage 17 Months After Completion of the Vaccination Regimen
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 3 includes squamous-cell carcinoma in situ (CIS); AIS = adenocarcinoma in situ (AIS)
Vaccine(N=6,082)
Placebo(N=6,075)
Efficacy (%)
CI
p-
Value Endpoint n Cases n Cases
CIN 2/3 or AIS
HPV 16/18-related 5,301 0 5,258 21 100 (76– 100)
< 0.001
HPV 16-related 4,552 0 4,405 16 100 (75– 100)
HPV 18-related 5,051 0 4,968 8 100
(42– 100)
By lesion type (worst diagnosis)- All in the Placebo group
CIN 2 5 CIN 3 15 AIS 1
Efficacy Results in MITT Population FUTURE IIAverage 24 Months After the First Vaccination
MITT = received ≥1 vaccination; HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1Cases were counted starting 30 days after first vaccination
Vaccine(N=6,082)
Placebo(N=6,075)
Efficacy (%)
CI
p-
Value Endpoint n Cases n Cases
CIN 2/3 or AIS
HPV 16/18-related 5,736 1 5,766 36 97 (83– 100)
< 0.001
HPV 16-related 4,944 1 4,957 28 96 (78– 100)
HPV 18-related 5,477 0 5508 11 100
(60– 100)
By lesion type (worst diagnosis)
CIN 2 10 CIN 3 23 AIS 4
Single case of HPV 16-related CIN 2 (Month 24) in vaccine group. HPV 16 DNA detected at Month 7.
Efficacy Results in MITT Population FUTURE IAverage 26 Months After Completion of the Vaccination Regimen
MITT = received ≥1 vaccination; HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1Cases were counted starting 30 days after first vaccination
CIN 3 includes squamous-cell carcinoma in situ (CIS); AIS = adenocarcinoma in situ (AIS)
Vaccine(N=2,240)
Placebo(N=2,258)
Efficacy (%)
CI
p-
Value Endpoint Cases Cases
HPV6/11/16/18-CIN 2 57 97 87%,100% P<0.001
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%
Efficacy Results in MITT Population FUTURE I Average 26 Months After Completion of the Vaccination Regimen
Vaccine(N=2,240)
Placebo(N=2,258)
Efficacy (%)
CI
p-Value
Endpoint Cases Cases
HPV 6/11/16/18-EGL 3 59 95 84%,99% P<0.001
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%
General Clinical Trial Population Impact of GardasilAverage 24 Months After the First Vaccination
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
Vaccine PlaceboReduction
(%) 95%
CI Endpoint n Cases n Cases
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, AISHPV 6,11,16,18-related genital warts
8814
8954
170
58
8846
8962
317
184
46
69
(35–56)
(58-77)
SummaryA 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
Other 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
Other 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 16/18CIN 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% (35–56)HPV 6,11,16,18-related genital warts 69% (58-77)
Other 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
Some 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 ?
Other 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
Required 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.