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• The data and opinion expressed in this file were that of the speakers and did not in whatever way represent the opinion of the OGSHK
• In line with usual policy, OGSHK do not encourage or discourage the use of any device or medications
Cervarix TM
The AS04 AdjuvantedCervical Cancer Vaccine
A Step Forward in Cervical Cancer Prevention
Dinner Symposium – Medical Forum26 Feb 2008
Cervarix TM – Clinical Update
Dr Goh Choo-BengRegional Medical Affairs – HPV VaccinesGSK BiologicalsAsia Pacific, Australasia, China/Hong Kong
Presentation Outline
Recognising the Need for Cervical Cancer Prevention and Disease BurdenGSK’s Cervical Cancer Vaccine Development Vision – the AS04 Innovative AdjuvantVaccine Trial DesignEfficacy ResultsUsing Cervarix TM today
5
Hong Kong
• Incidence
− 5th leading cause of cancer in women
− ASR: 9.9 / 100,000
• Mortality
− 9th leading cause of cancer-associated deaths in women
− ASR: 2.2 / 100,000
1. Government of Hong Kong Special Administrative Region, Department of Health http://www.info.gov.hk/dh/diseases/ncd/eng/cervical.htm; 2.http://www.cervicalscreening.gov.hk/english/cc/cc_facts/cc_facts.php; 3. Hong Kong Cancer Registry, Hospital Authority, http://www3.ha.org.hk/cancereg/canstat2002.pdf.
6
Natural History Of HPV and Pre-cancerous Lesions
For every 1 million women with any HPV infection:1
– 100,000 will develop cervical cytological abnormality
– 8000 will develop CIN III (carcinoma in situ) – 1600 will develop invasive cervical cancer
Cancer is a rare outcome of a common infection.2
1. McIntosh N. JHPIEGO strategy paper. 2000; 2. Bosch FX et al. J Clin Pathol 2002; 55: 244−65.
Adenocarcinoma of the Cervix
Adenocarcinomas arise from the glandular epithelia of the endocervix whereas SCCs arise from the squamous epithelia on the ectocervix1
Adenocarcinomas account for approximately 15 – 25% of all invasive cancers2
Up to 30% diagnosed in women <35 years2
Greater likelihood of recurring compared to squamous cell carcinomas2
Adenocarcinomas are strongly associated with HPV-18 infection2,3,4,5
1. Tjalma WA et al. Best Pract Res Clin Obstet Gynaecol. 2005 (19) 4: 469-832. Rohan TE. Ch 8: The Epidemiology of Adenocarcinoma of the Cervix. Cervical Cancer: From Etiology to Prevention. 2004; 206; 3. Altekruse SF et al. Am J Obstet Gynecol 2003;188:657-63; 4. Vizcaino AP et al. Int J Cancer1998; 75:536–545; 5. Bosch XF et al. J Nat Cancer Inst. 1995; 87: 796-802
Two types of CERVICAL CANCERThe 3 most common HPV types - IARC study
De Sanjose et al, Beijing 2007
Squamous cellcarcinoma Adenocarcinoma
HPV type % HPV type %
16 62.14 16 49.07
18 7.91 18 31.02
45 5.00 45 12.04
HPV 16-18-45 are the most aggressive types
Adapted from Smith J S et al. Int J Cancer 2007; 121: 621-632
AdenocarcinomaRecognising the Hidden Killer
F. X. Bosch, A. Lorincz, N. Munoz, C. J. Meijer, K. V. Shah, J Clin Pathol 55, 244 (2002)
Adenocarcinoma
89.7
92.7
94.1
16 + 18 + 45
16 + 18 + 45 + 31
16 + 18 + 45 + 31 + 33
%
1001002020 808060604040
The 5 Most Common HPV Types - IARC Study
The HPV Phylogenetic Tree
Can
ine
Ora
l
Cotton Tail Rabbit
Bovine
Age-specific incidence of oncogenicHPV infection in womenOncogenic HPV incidence is highest in young womenThe risk for infection/reinfection remains throughout life
V. Dalstein et al., Int J Cancer 106, 396 (2003), A. N. Burchell, R. L. Winer, S. de Sanjose, E. L. Franco, Vaccine 24 Suppl 3, S52 (2006), H. Trottier, E. L. Franco, Vaccine 24 Suppl 1, S1 (2006), J. W. Sellors et al., CMAJ 168, 421 (2003), Dunne E et al. JAMA 2007;297:813-19
Age, years
Prev
alen
ce o
f Onc
ogen
icH
PV, %
0
5
10
15
20
25
11 14-19 20-24 25-29 30-39 40-49 50-59
30
Universal Mass Vaccination of Girls
from Age 11 Need for long term protection
NHANES, 2003-2004 (N=1921)
HPV-16/18 are responsible for ~70% of invasive cervical cancers worldwideProphylactic cervical cancer vaccine based on 16 and 18Prophylactic cervical cancer vaccine based on 16 and 18L1 virusL1 virus--like particles like particles
Every sexually active woman is at risk of oncogenic HPVThe objective is to develop a vaccine which targets prevention oThe objective is to develop a vaccine which targets prevention of cervical f cervical cancer in females fromcancer in females from10 years onwards10 years onwards
HPV doesn’t show itself to the immune system – the vaccine will have to induce a better immune response than natural infection does
AS04 Adjuvant System (Alum + MPL) designed toAS04 Adjuvant System (Alum + MPL) designed toenhance the immune responseenhance the immune response
GSK Cervical Cancer Vaccine:Development Vision
Immunogenic antigens- potent activators of APC
+
Cervarix TM : composition
Immune response
Strong & sustained immune response
Baldridge J, et al. Expert Opin Biol Ther (2004) 4(7):1129-1138.; Evans et al. Expert Rev. Vaccines 2(2), 219-229 (2003).
AS04Adjuvant System 04
Immunomodulator
Administered intramuscularly in the deltoid muscle ; over a 0, 1 and 6 months schedule
Cervarix TM
AS04:500 µg Aluminum Hydroxide
50 µg MPL
Adjuvant
0, 1, 6 months
20 µg HPV 16
20 µg HPV 18
Schedule
Composition
MPL in the AS04 adjuvant system
MPL, the detoxified lipopolysacchride in the AS04 adjuvant system, contains a molecular sequence that binds to toll-like receptor 4Found on macrophages and dendritic cellsActivation of toll-like receptor 4 initiates the enhanced immune responses that characterisethe strong and sustained antibody titres seen in the GSK studies
Monophosphoryl Lipid A
AAHS – Amorphous Aluminium Hydroxyphosphate Sulphate adjuvant
Impact of AS04 Adjuvant :High Antibody Titers in Humans
Adapted from Giannini SL, Hanon E, Moris P, et al. Vaccine 2006;24:5937–49
∗
Wilcoxon’s non-Parametric(p<0.05)
V5 epitope is targeted by HPV-16 neutralizing antibodies J4 epitope is targeted by HPV-18 neutralizing antibodies
* *
*
*
*
1000
600
400
200
00 8 16 32 4824 40
Vaccination
= Al(OH)3
= AS04
Anti-V5 HPV-16
GM
T an
tibod
y tit
ers
(EU
/ml) 800
* *
*
**
1000
600
400
200
00 8 16 32 4824 40
Vaccination
= Al(OH)3
= AS04
Anti-J4 HPV-18
800
*
*
months months
0
4000
8000
12000
16000
day 60 day 210
HPV16
pre0
1000
2000
3000
day 60 day 210
HPV18
pre
= [Al(OH)3]= AS04
Median
Median
Q3
Q1
Q3
Q1
3.6 x*
2.2 x
Freq
uenc
y of
HP
V s
peci
fic m
emor
y B
cel
ls
GSK cervical cancer vaccine formulated with AS04induces higher frequency of memory B cells
* statistically significant (p <0.05, Wilcoxon’s test)
vaccination vaccination
Giannini SL, et al. Vaccine 2006; 24: 5937–49
CervarixTM: Does AS04 Enhancethe B cell Memory Pool?
GSK’s Innovative Adjuvant Systems (AS)
First license (European Union) for vaccine with novel adjuvant
FendrixTM : hepatitis B vaccine with MPLcontaining adjuvant system 04 (AS04)
Number of key future GSK ’s vaccines contain AS :– HPV: AS04 (Al + MPL)– HSV: AS04 (Al + MPL) – Malaria: AS02 (MPL + QS21)
Saponin extracted from Quillaria saponaria
– Pandemic influenza vaccine
Presentation Outline
Recognising the Need for Cervical Cancer Prevention and Disease BurdenGSK’s Cervical Cancer Vaccine Development Vision and the AS04 adjuvant systemVaccine Trial DesignEfficacy ResultsUsing Cervarix TM today
GSK’s clinical development programme
Women15-25 years
Women15-25 years
Women10-14 years
Women10-14 years
Women26-55 years
Women26-55 years
Study HPV-012 Study HPV-012
Immunobridge trial
Key endpoints : ImmunogenicitySafety
Studies HPV-001/007“Unexposed” population Studies HPV-001/007
“Unexposed” population
Efficacy trials
Key endpoints : •HPV-16/18 efficacy •Other HPV-types efficacy•Immunogenicity
Study HPV-14Study HPV-14
Immunobridge trial
Key endpoints : ImmunogenicitySafety
in women above 25 yrs (on going)
Study HPV-013 Study HPV-013 Study HPV-015Study HPV-015
Safety trial
Key endpoints : SafetyImmunoginicity
Efficacy trial
Studies HPV-008“General” population*
Studies HPV-008“General” population*
Efficacy trials
Key endpoints : •HPV-16/18 efficacy •Other HPV-types efficacy•Immunogenicity
Study HPV-012 Study HPV-012
Immunobridge trial
Key endpoints : ImmunogenicitySafety
Studies HPV-001/007“Unexposed” population Studies HPV-001/007
“Unexposed” population
Efficacy trials
Key endpoints : •HPV-16/18 efficacy •Other HPV-types efficacy•Immunogenicity
Study HPV-14Study HPV-14
Immunobridge trial
Key endpoints : ImmunogenicitySafety
in women above 25 yrs (on going)
Study HPV-013 Study HPV-013 Study HPV-015Study HPV-015
Safety trial
Key endpoints : SafetyImmunoginicity
Efficacy trial
Studies HPV-008“General” population*
Studies HPV-008“General” population*
Efficacy trials
Key endpoints : •HPV-16/18 efficacy •Other HPV-types efficacy•Immunogenicity
*In some regions, this population is referred to as “women with current or prior infection”
Summary of Ongoing Phase IIb/III Trials 2005 2006 2007 2008 2009
HPV-001/007 (efficacy in 15-25 yr old women) N = 11135.5 yrs 6.5 yrs
HPV-008 (efficacy in 15-25 yr old women) N =18,665
Interim analysis CIN2+
HPV-009 (efficacy in 18-25 yr old women in Costa Rica) N = 7,462
4.5 yrs
HPV-015 (efficacy >25yrs) N=5,700
Interim analyses virological/histopath endpointsImmunogenicityEfficacy
Y1
HPV-014 (immuno 15-55y)
Y2 Y3
LT follow-up
HPV-010 (GSK HPV vaccine vs Gardasil 18-45 yrs)
Y1 Y2 Y3HPV-012 (immuno 10-25y) LT follow-up
LT follow-upHPV-013 (safety/immuno 10-14 yrs)
UP TO 9.5 YEARS
Enrolled1113 women*
Studyentry
Vaccine doses administered and follow up
Initial Efficacy Study*
Study visits and follow-up time
Follow-up Extended Follow upthrough 4.5 yrs**
Extended Follow up through 5.5yrs
Enrolled776 women
Extended follow up study of initial efficacy study through 5.5 years
Median age: 23 years (range 17-29)
Study period: ~ 28 to 65 monthsAverage follow up time: 23.4 months Study period: 0 to 27 months
5.5 year Trial:Initial Efficacy and Extended Follow-up Study
* Harper D et al. Lancet. 2004; 364: 1757-65**Harper D et al. Lancet. 2006; 367: 1247-55
Endpoints*
HPV Vaccine Control Vaccine Efficacy
n n % 95% CI
6 Month Persistence 0 19 100 81-100
12 Month Persistence 0 9 100 54-100
Extended follow-up period: ~ 28 to 65 months HPV-16 & 18 Efficacy
Presentation Gall S, AACR, Los Angeles, April 14-18, 2007
Normal epithelium
Low-grade squamous intraepithelial lesions (LSILs)
High-grade squamous intraepithelial lesions (HSILs)
Invasive cervical cancerHPV infectionkoilocytosis
CIN 1 CIN 2 CIN 3
Screening
Treatment
Monsonego 2006, p159. CIN = Cervical intraepithelial neoplasia
Spontaneous regression
From incident to persistent HPV infection
YearsMonths
Persistent infection with oncogenic HPV is the necessary cause of cervical cancer
“Since persistent infection with the same high-risk type is considered a predictor for moderate or high-grade cervical dysplasias and cancer, they might represent a useful endpoint in future vaccine efficacy studies.”
S.R. Pagliusi, M.T. Aguado WHO REFERENCE PAPER 2004
Enrolled1113 women*
Studyentry
Vaccine doses administered and follow up
Initial Efficacy Study*
Study visits and follow-up time
Follow-up Extended Follow upthrough 4.5 yrs**
Extended Follow up through 5.5yrs
Enrolled776 women
Extended follow up study of initial efficacy study through 5.5 years
Median age: 23 years (range 17-29)
Study period: ~ 28 to 65 monthsAverage follow up time: 23.4 months Study period: 0 to 27 months
5.5 years Trial:Initial Efficacy and Extended Follow-up Study
Total average follow up time initial and EFU phases: 59.9 months (up to 67 months)
* Harper D et al. Lancet. 2004; 364: 1757-65 **Harper D et al. Lancet. 2006; 367: 1247-55§Gall S et al. AACR abstract 2007
Extension to 9.5 years
Endpoints*CervarixTM Control Vaccine Efficacy
n n % 95% CI
6 Month Persistence 0 29 100 87.9 – 10012 Month Persistence 0 14 100 72.3 – 100
CIN1+ 0 11 100 61.5 – 100
CIN2+ 0 7 100 32.7 – 100
Up to 5.5 years Complete Protection Against HPV-16/18 Infections and CIN Outcomes
*Combined analysis initial efficacy study and extended follow-upATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpoints
Presentation Gall S, AACR, Los Angeles, April 14–18, 2007
0
10
2030
40
50
60
7080
90
100
5.5 years follow-upHPV Neg
Broad population 15 mths Interim
Analysis
Up to 100% Efficacy Against CIN2+Caused by HPV-16 and 18
% E
ffica
cy C
IN2+
HPV
-16/
18
Harper D et al. Lancet 2006; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007; Paavonen J et al. Lancet 2007;369:2161–70
95% CI: 32.7 – 100 97.9% CI: 53.4 – 99.3
97.9% CI: 74.2 – 100
Pre-specified analysis
Causality assessment analysis*
*Based on causality assessment case assignment. The pre-specified analysis included 3 CIN2+ cases which were not considered to be causally associated with HPV-16 or HPV-18 infections acquired during the trial. Based on this analysis vaccine efficacy was 90.4% (CI 53.4–99.3)
Vaccination Beyond HPV 16 and 18
Impact on Oncogenic HPV Types Other than HPV 16 and HPV 18
EndpointEndpointCervarixCervarix™™
N=505N=505Al(OH)Al(OH)33N=497N=497 Vaccine EfficacyVaccine Efficacy
nn nn % 95% CI95% CI
≥≥ASCUSASCUS 106106 155155 38.2 20.4 20.4 –– 52.2 52.2
≥≥LSILLSIL 5151 8181 41.8 16 16 –– 5959
CIN1+CIN1+ 1515 3232 55.2 14.9 14.9 ––77.5 77.5
CIN2+CIN2+ 55 1515 67.8 6.8 6.8 –– 90.8 90.8
Up to 5.5 Year Results:Cytological Abnormalities and CIN Outcomes
Efficacy against endpoints independent of HPV DNA status
Harper D et al. Lancet 2006;367:1247–55; Presentation Gall S, AACR, Los Angeles, April 14–18, 20071Clifford et al. Cancer Epi Biom Prev 2005;14(5); 2Muñoz et al. N Engl J Med 2003;348;6
Combined analysis for initial efficacy study and extended follow-up
Estimated prevalence HPV 16/18
20–30%1
25–30%1
25–30%1
50%2
80
90
Time (months)0 6 12 18 24 30 36 42 48 54 60 66
100
HPV-45Related to HPV 18
VaccinePlacebo
Vaccine efficacy: 88% (61–98)
Perc
enta
ge w
ithou
t inf
ectio
n
0 6 12 18 24 30 36 42 48 54 60 66Time (months)
100
90
80
HPV-31Related to HPV 16
VaccinePlacebo
Vaccine efficacy: 54% (15–76)
Globally HPV-45 and 31 are the 3rd and 4th most common oncogenic HPV types
Total cohort; cervical samples only; Cox regression model
Harper D et al. Lancet 2006;367:1247–55; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007
Up to 5.5 years Cross Protection againstIncident Infection with HPV Types 31 and 45
HPV Types In Cervical Cancer Globally
Cancer cases attributed to the most frequent HPV genotypes (%)
HPV genotype
Vaccine types
2.32.21.41.31.21.00.70.60.50.31.2
4.4
53.5
2.6
17.26.7
2.9
0 10 20 30 40 50 60 70 80 90 100
XOther
827368395156593558523331451816 53.5%
70.7%77.4%80.3%
Muñoz N et al. Int J Cancer 2004; 111: 278–85
Phase III Broad Population Study: Cross Protection against 6 Months Persistent Infections
Paavonen J et al. Lancet 2007;369:2161–70
4 - 523211679HPV-52
3 – 85602510HPV-45
0.5 – 60367447HPV-31
97.9% CICervarixTM
Efficacy (%)HAV (cases)CervarixTM
(cases)Type
Analysis on a population that received at least one vaccine/control dose:
Presentation Outline
Recognising the Need for Cervical Cancer Prevention and Disease BurdenGSK’s Cervical Cancer Vaccine Development Vision and the AS04 adjuvant systemVaccine Trial DesignEfficacy ResultsUsing Cervarix TM today
When, Why, How
WHEN can you prescribe CervarixTM?Prescribed now for girls and women, as they remain at risk of infection from oncogenic HPV throughout their lives
WHY prescribe CervarixTM?CervarixTM with novel adjuvant AS04, provides strong and sustained protection against cervical cancer
HOW do you administer CervarixTM?Give 3 doses of CervarixTM at 0, 1, 6 months
Vaccination is by IM injection into the
deltoid area
CervarixTM: safety profile
Large safety database (~30,000 females) in a broad age rangedata up to 5.5 years post-vaccination
– CervarixTM is generally well tolerated across all age groups
– Comparable rates of unsolicited adverse events, SAEs and autoimmune diseases in vaccine and control groups
– Comparable safety profile in women with HPV exposure prior to vaccination and women with no previous exposure
– Similar overall rates of pregnancy outcomes in vaccine and control groups
EPAR Cervarix, Published 03/10/07
Cervical Cancer prevention is a possibility now
Cervarix™ : Approved in 51 countries
EU ( 27)NorwayIceland
AustraliaNew Zealand
KenyaUganda
UAEBahrainTurkey
Philippines(Macau)Thailand
SingaporeMalaysiaIndonesia
Hong KongMyanmar
Mexico
UkraineKazakhstan
Belarus
ArgentinaChileColombiaUruguay
International: Cervarix licensure to date
New ZealandChile
MyanmarColombia
Hong KongMalaysiaMexico
IcelandSingaporeArgentinaKenya
NorwayIndonesiaMacauPhilippines
Europe*Thailand*>26 yr virgins
AustraliaUAE
10-25 years10 – 25 yrs Cross protection
10-45 yrs10 years onwardCross protection
*This depends on individual EU states’ interpretation of the PI
Hong Kong Cervarix TM indication
CERVARIX TM is indicated for the prevention of high-grade cervical intraepithelial neoplasia (CIN grades 2 and 3) and cervical cancer causally related to Human Papillomavirus(HPV) types 16 and 18.
The indication is based on demonstration of efficacy in women aged 15-25 years following vaccination with CERVARIX TM
and on the immunogenicity of the vaccine in girls and women aged 10-25 years.
Section 5.1Study 014 performed in women aged 15 to 55 years,
All subjects seroconverted to both HPV types 16 and 18 after the third dose (at month 7). All subjects remained seropositive for both types throughout the follow-up phase (up to month 18) maintaining antibody levels at an order of magnitude above those encountered after natural infection.
Australia supports vaccination for older women
"If a woman up to the age of 45 years desires protection against cervical disease over and above regular Pap screening, and is prepared to pay for this vaccine, there is considerable potential for individual benefit."
http://www.ama.com.au/web.nsf/doc/WEEN-7BS4WR
The bivalent HPV vaccine has been licensed for use inwomen aged up to 45 years. Older women have robust immune responses to the bivalent HPV vaccine, and so should derive benefit from the vaccine if exposed to HPV type 16 or18 in the future. It is likely that this vaccine will need to be purchased by women in the older age group (27–45 years).
MJA 2008; 188: 238–242
Cervarix™ : Generally safe and well toleratedProtective efficacy– HPV types 16 and 18
• High level of efficacy against persistent infection• High level of efficacy against CIN2+• Sustained for up to 5.5 years with studies ongoing• Substantiated in a broad population
– HPV types 45 and 31• Substantial protection against:
Incident infection for up to 5.5 years Persistent infection
• Substantiated in a broad population
AS04 – How AdjuvantationMakes a Difference in
Cervical Cancer Prevention
Prof Tino SchwarzCentral Laboratory
Yellow fever vaccination centreStiftung Juliusspital Würzburg
www.juliusspital.de
AS04 - How adjuvantationmakes a difference in cervical
cancer preventionTino F. Schwarz
Central LaboratoryYellow fever vaccination centreStiftung Juliusspital Würzburg
www.juliusspital.de
Cervarix™: Safety and Immunogenicity
Safety in vaccine trials
Immunobridging and Long Term Immunogenicity
Mucosal immunity
Implementation of HPV vaccination – European perspective
Vaccination of females >26 years
Up to 100 % protection against HPV-16/18 against virological and histopathological endpoints up to 5.5 years
High protection confirmed in broad population( >18,000 women)
Cross protection beyond HPV-16 and HPV-18– protection broader than expected for ASCUS/LSIL and CIN1/CIN2+
over 5.5 years (68%)
– type specific protection against incident infection sustained over 5.5 years for HPV-45 (88%) and HPV-31 (54%)
Clinical Efficacy
Presentation Gall S, AACR, Los Angeles, April 14–18, 2007
Harper D et al. Lancet. 2004; 364: 1757-65
Vaccine
N = 531
ControlAl(OH)3
N = 538P-value
Pain 496 469 <0.001
Swelling 182 113 <0.001
Redness 189 131 <0.001
Safety and Reactogenicity:Injection Site Symptoms
Solicited Adverse Events (within 7 days following any dose)
Vaccine
N = 531
ControlAl(OH)3
N = 538P-value
Fatigue 308 289 0.175
Gastrointestinal 178 172 0.602
Headache 331 329 0.706
Itching 130 109 0.106
Rash 60 54 0.552
Temp Elevation* 88 73 0.172
Harper D et al. Lancet. 2004;364:1757-65 * Temperature > 37.5 °C (oral)
Safety and Reactogenicity:General Symptoms
Extended Follow-up 5.5 Years: Safety Profile
HPV VaccineN = 373
ControlN = 370
Adverse events
Women with at least one adverse event 83 107
Number of Adverse events 101 161
New Onset Chronic Disease (NOCD)*
Women with at least one NOCD event 11 20
Number of NOCD events 12 22
Serious adverse events (SAE)
Women with at least one SAE 22 30
Number of SAEs reported 27 31ATP analysis. Safety events recorded from the end of the initial efficacy study through month 24 of the extendedfollow-up study*Including, but not exclusively, autoimmune diseases, endocrine, musculoskeletal, connective tissue, metabolism and nutrition, respiratory and thoracic disorders.
Presentation Gall S, AACR, Los Angeles, April 14-18, 2007
Safety and Pregnancy
Pregnancies/Pregnancy outcomes*
CervarixTM
(N = 9,319)Control (HAV)
(N = 9,325)
Number of pregnanciesPregnancy ongoingNormal infantAbnormal infantPremature birthsSpontaneous abortionElective termination Lost to follow-up
66530.2%40.6%0.6%2.3%9.9%13.1%1.5%
68534.0%38.5%1.2%2.5%7.4%13.6%1.9%
*Totals do not include blinded outcomes, ectopic pregnancies
Broad Population Study
Paavonen J et al. Lancet 2007;369:2161–70
Cervarix™Safety and Immunogenicity: Outline
Safety of vaccine trials
Immunobridging and long term immunogenicity data
Mucosal immunity
Implementation of HPV vaccination
Vaccination of females >26 years
Females15-25 yrsFemales15-25 yrs
Females10–14 yrs
GSK study 012Immunogenicity bridgeSafety / reactogenicity
GSK studies 001 / 007Immuno & Efficacy
Findings up to 5.5 yrs
Cervarix™ Data in Adolescents
Immunogenicity BridgeFemales 10–14 → 15–25 Years
1
10
100
1000
10000
100000
10-14 y 15-25 y
HPV-16
GMCs log (EU/ml)
Dubin G, ICAAC, 2005
GMCs at Month 7
1
10
100
1000
10000
100000
10-14 y 15-25 y
HPV-18
Up to 5.5 YearsHigh and Sustained Antibody Levels and Seropositivity
Harper D et al. Lancet 2006;367:1247–55; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007
Anti-HPV-16 IgG
1000
100
10
1
10000
Months70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64
Seroconversion 100% at 7 moSeropositivity ≥98% at 5.5 yrs
Anti-HPV-18 IgG
1000
100
10
1
10000
Months70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64
≥11-fold higher than natural
infection
≥11-fold higher than natural
infection
GM
T (E
U/m
l)G
MT
(EU
/ml)
Seroconversion 100% at 7 moSeropositivity ≥98% at 5.5 yrs
Immune Response against HPV-31 and -45:GMTs and Seropositivity Rates*
HPV-31Related to HPV-16
1000
100
10
1
10000
Months
HPV-45Related to HPV-181000
100
10
1
10000
Months70 12 25–32 33–38 39–44 45–50 51–56
Data on File. GSKBio-WWMA_DoF001_2007 Cut-off level for seropositivity for both HPV-45 and 31: ≥59 EU/ml
*up to 4.5 yrs
70 12 25–32 33–38 39–44 45–50 51–56
GM
T (E
U/m
l)G
MT
(EU
/ml)
Cervarix™ Study 013: Study Design
Cervarix™ vs. a control group receiving a Hepatitis A vaccine
13 countries across Asia, Australia, Europe and Latin America
2,067 girls aged 10-14 years old enrolled
Vaccination schedule: 0, 1 and 6 months
Total duration of study will be up to 48 months
Interim analysis at 18 months
L. Rombo, Poster ESPID 2007
S. Gall, presented at AACR, April 17 2007 L. Rombo, Poster ESPID 2007Months follow up time
HPV 16
NaturalInfection
1
10
100
1000
10000
GM
T (lo
g EL
U/m
l)
63-6457-6251-5645-5039-4433-3825-32181270
> 11 fold higher
Immunobridging Between Girls 10-14 Years and Women 15-25 Years of Age
10000
1000
100
10
1
HPV 18
10-14 year old girls
0 7 12 18 25-32 33-38 39-44 45-50 51-56 57-62 63-64
> 11 fold higher
yOlds Comparable to those
Observed in Efficacy Study HPV-001/007
Assay cut-off: 8 EU/mlATP analysisSeronegative prior to vaccination
NaturalInfection
1
10
100
1000
10000
0 7 12 18 24 39–44 51–56 63–64
Months
GM
T (E
U/m
l)
15–25 yearsEfficacy study
15–25 years26–35 years36–45 years
At least 8-fold
higher than natural
infection
46–55 years
Harper DM et al. Lancet 2006; Paavonen J et al. Lancet 2007; Schwarz TF. ASCO 2006; Gall S. AACR 2007
HPV-16
NaturalInfection
1
10
100
1000
10000
0 7 12 18 24 39–44 51–56 63–64
Months
GM
T (E
U/m
l)
15–25 years26–35 years36–45 years46–55 years
Antibody Levels in 15-55 Year Olds Comparable to those
Observed in Efficacy Study HPV-001/007
Assay cut-off: 7 EU/ml
Harper DM et al. Lancet 2006; Paavonen J et al. Lancet 2007; Schwarz TF. ASCO 2006; Gall S. AACR 2007
ATP analysisSeronegative prior to vaccination
15–25 yearsEfficacy study
HPV-18At least 8-fold
higher than natural
infection
Binding ELISA
InhibitionELISA
Pseudovirionneutralisation
High Correlation (CC) Between GSK’s Binding ELISA and Pseudovirion Neutralisation Assay
H. Clayton et.al. Journal of National Cancer Institute 2001 93(4):284-292.
HPV-16 HPV-18N 557 561
Pearson CC 0.91 0.84
HPV-16 HPV-18N 965 968
Pearson CC 0.90 0.84
HPV-16 HPV-18N 446 443
Pearson CC 0.93 0.93
Importance of Antibodies in the Cervical Mucosa
• High serum antibody responses against HPV-16 and -18 are elicited by Cervarix™
• The presence of antibodies at disease-relevant sites (cervical mucosa) may contribute to protection
• A plausible mechanism is transudation of serum IgG into cervico-vaginal secretions (CVS)
High Correlation between CVS and Serum HPV-16 and -18 IgG Antibodies According to Age
TWO YEARS DATA
Scatterplot between secretion and serum HPV-16 (divided by total IgG) by age and with Hemastix <80
HPV 18HPV 1615 – 25 YEARS R = 0.9026 – 45 YEARS R = 0.7246 – 55 YEARS R = 0.88
15 – 25 YEARS R = 0.9126 – 45 YEARS R = 0.82
46 – 55 YEARS R = 0.93
Summary: Correlation of Antibody in the serum and CVS
Good correlation between antibodies (IgG) in the serum and in the CVS indicates likely transudation to the cervical epithelium
Similar observation irrespective of age groups for antibody against both HPV 16 and HPV 18
– 15-25 years
– 26-45 years
– 45-55 years
Conclusions I
Cervarix™ is highly immunogenic in all age groups– 100% seroconversion– HPV-16 and -18 antibody levels several fold higher
than natural infection antibody levels– Similar range of HPV-16 and -18 antibody titers to
those observed in women 15-25 years old up to 5.5 years • in girls aged 10-14 years• in women aged 26-55 years
Conclusions II
Antibody levels in the mucosa
– High correlation of anti-HPV-16 and -18 levels
between serum and CVS
– Serum IgG antibodies transudate through to cervical
epithelium
Safety
– A good safety profile
Vaccination to Prevent Cervical Cancer:
Public and Individual Health Perspective
EUROPE
Integrating into Clinical Practice
Public Health Perspective
Primarily pre-sexually active adolescents
Individual Perspective
Sexually active women
Vaccination Programmes in Europe9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Austria
Belgium
Denmark
France
Germany*
Greece
Italy
Luxembourg
Norway
Spain
Sweden
Switzerland
UK
TBD
TBD
TBDMain age
Catch up
Age
Last updated October 2007 * Above 17 years of age, vaccination based on individual benefit
Natural Infection
Natural Infection
Gall S, et al. AACR April 2007.Schwarz T, et al. ASCO. June 2006.
Cervical Cancer HPV types: Different quantitative immune
response for 16 /18?
Adapted from S. E. Olsson et al., Vaccine 25, 4931 (2007)
Time (months)
1
10
100
1,000
10,000
1
10
100
1,000 Seropositivity decreased to 68% from 24-60 months
Quadrivalent vaccine HPV 16
HPV 18VaccineNatural Infection
01 12 18 24 30 36 54 60 612 3 6 7
01 12 18 24 30 36 54 60 612 3 6 7
Bivalent vaccine
0 7 12 18
[25–32]
[33–38]
[39–44]
[45–50]
[51–56]
[57–62]
[63–64]
1
0 7 12 18
[25–32]
[33–38]
[39–44]
[45–50]
[51–56]
[57–62]
[63–64]HPV 16
HPV 18
1000
100
10
10000
1
1000
100
10
10000
Placebo
Natural Infection
Natural Infection
Placebo
VaccineNatural Infection
Role of Antibodies:Systemic and local Infection
HPV infects the cervicalmucosa epithelium (localinfection)No systemic infection!
Following infection of the cell, the virus is hidden from a systemic immune response
Transudating neutralisingAb in CVS are important forprotection
Hepatitis B Virus istransported from thesite of infectionvia the blood streamto the liver
By that way, the virus isdetected by the immunesystem
In case of infection=> Activation of memory cells=> Booster of Ab levels
HBV
HPV
0 2 4 6 8anti-HBs response
10
100
1000
10000
100000A
nti-H
Bs
IU/L
days
“anamnestic response” 17 yrs after immunization
Rise of levels of Anti-HBs from 80 IU/L to25000 IU/L
>300 fold increase
mean increase130 IU/L per hour2 IU/L per minute
Immune memoryT, B memory cells
HPV Infections Continue to Occur in Women over 25 Years of Age
Incident infection of oncogenic types is estimated to be 5.3% in women 25-55 years of age (range 5-10%)1
Although new infections decrease with age, risk of persistence increases with age2
Immune function declines with age resulting in decreased capacity to respond to both new and previously encountered infections
1. Munoz N et al. JID 2004. 2. Castle PE et al. JID 2005.
Sexually active women may remain at risk of acquiring HPV throughout their lives1-7
HPV prevalence was measured by Hybrid Capture® 2 in the Portland study and by consensus primer polymerase chain reaction in the Guanacaste study. Adapted from Schiffman & Krüger 2003.
1. Baseman & Koutsky, 2005; 32S:S16-24. 2. Brown et al, 2005; 191: 182-92. 3. Munoz et al, J Infect Dis 2004; 190: 2077-874. Herrero et al, 2000; 92(6): 464-474. 5. Franco et al, 1999; 180: 1415-23. 6. Sellors et al, 2003; 168(4): 421-5. 7. Schiffman & Kruger Kjaer, 2003; 31: 14-19
Age specific prevalence of HPV Infection in Portland USA & Guanacaste Costa Rica
Ongoing risk for HPV infection over 26 years
Grainge MJ et al.: Emerg Infect Dis 11: 1680-1685 (2005)
This retrospective study shows that HPV-negative women >50 years of age can acquire HPV and, therefore, require cervical screening
Cervical Cancer Vaccines„That´s one small „prick“for woman, one giant leap
for womankind“
Expert Forum
What is the importance of high Antibody titres?
Natural antibody levels to HPV infection are unreliable (No immunity).
No confirmed immune correlate for protection.
The vaccine induced Abs are neutralising.
Strong correlation between Ab levels between serum and CVS – protection would be site specific for HPV infection.
Presentation by T. Schwarz – Eurogin 2007
The importance of High Antibody levels
The Hepatitis B vaccinology experienceBoosting with a vaccine is not the same as natural infection 1
Natural HPV infection occurs at the cervical mucosa – unlike systemic HBV infectionIt takes about 15 minutes for HPV to attach to the target cells
– Two days to mount immune memory response 2
This illustrates the importance of high and sustained Ab level to combat lifelong HPV infection
1. S. E. Olsson et al., Vaccine 25, 4931 (2007)2. Ozbun MA et al, Virol. 2002 Nov;76(22):11291-300.
Natural Infection
Natural Infection
Gall S, et al. AACR April 2007.Schwarz T, et al. ASCO. June 2006.
Cervical Cancer HPV types: Different quantitative immune
response for 16 /18?
Adapted from S. E. Olsson et al., Vaccine 25, 4931 (2007)
Time (months)
1
10
100
1,000
10,000
1
10
100
1,000 Seropositivity decreased to 68% from 24-60 months
QuadrivalentVaccine HPV 16
HPV 18VaccineNatural Infection
01 12 18 24 30 36 54 60 612 3 6 7
01 12 18 24 30 36 54 60 612 3 6 7
Cervarix TM
0 7 12 18
[25–32]
[33–38]
[39–44]
[45–50]
[51–56]
[57–62]
[63–64]
1
0 7 12 18
[25–32]
[33–38]
[39–44]
[45–50]
[51–56]
[57–62]
[63–64]HPV 16
HPV 18
1000
100
10
10000
1
1000
100
10
10000
Placebo
Natural Infection
Natural Infection
Placebo
VaccineNatural Infection
Role of Antibodies Systemic / local Infection
HPV infects the cervicalmucosa epithelium (localinfection)No systemic infection!
Following infection of the cell, the virus is hidden from a systemic immune response
Transudating neutralisingAb in CVS are important forprotection
Hepatitis B Virus istransported from thesite of infectionvia the blood streamto the liver
By that way, the virus isdetected by the immunesystem
In case of infection=> Activation of memory cells=> Booster of Ab levels
HBV
HPV
0 2 4 6 8anti-HBs response
10
100
1000
10000
100000A
nti-H
Bs
IU/L
days
“Anamnestic response” 17 yrs after immunization
Rise of levels of Anti-HBs from 80 IU/L to 25 000 IU/L
>300 fold increase
mean increase130 IU/L per hour2 IU/L per minute
immunologicmemory
T, B memory cells
What is the difference between B cell Memory and vaccine induced Antibody levels?
Giannini study shows high memory B cell response to HPV 16 and 18 compared to alum based antigen.
B cell memory is important for durable Abresponse – long term protection
High systemic Ab levels correlate with mucosal Ab levels
This ties in with the need for a strong Ab level and B cell memory
Giannini SL, Hanon E, Moris P, et al. Vaccine 2006;24:5937–49
The Value of Immunobridging Data
Recognised by regulatory authorities in Malaysia, Australia and others.
In mature women, there is an unmet medical need – should not delay the availability of the cervical cancer vaccine.
Paavonen J et al. Lancet 2007
The importance of HPV 18 and cross protection
Adenocarcinoma and HPV 18 and 45.
Cross protection data for CervarixTM.
5.5 year data and on-going follow up.
Paavonen J et al. Lancet 2007
The importance of cervical mucosa protection
Neutralising IgG – first line of defense to HPV infection at the site of infection
Slower response from immune memory
Correlation data available for CervarixTM
Poncelet S et al.. European Society of Paediatric Infectious Diseases (ESPID), 2-7 May 2007: Abstract presented
Presentation by T. Schwarz – Eurogin 2007
Two Years Data –High Correlation between CVS and Serum
HPV-16 and -18 IgG Antibodies According to Age
Scatterplot between secretion and serum HPV-16 (divided by total IgG) by age and with Hemastix <80
HPV 18HPV 16
Presentation by T. Schwarz – Eurogin 2007
Testing HPV status before vaccination
HPV DNA status versus Serostatus
Not routinely done even in countries with universal vaccination programmes.
No recommendations for routine HPV testing
Coinfection with both HPV 16 and 18 rare
Skinner R et al. Presented at EUROGIN 2007.
Safety of Vaccine
Localised reaction to vaccine –recognised adverse effect
Nevertheless compliance in trials is high
Self limiting and generally well tolerated
EPAR Cervarix, Published 03/10/07
What is the Level of Protection to Natural HPV Infection?
Natural boosters when in contact with wild Hepatitis B viruses seen – lifelong protection despite declining Ab levels over time.
No similar response following natural HPV infection seen in HPV vaccinated subjects or naturally infected subjects.
Importance of strong and sustained Ab levels in CervarixTM data up to 5.5 years
EPAR Cervarix, Published 03/10/07
The need for a Booster?
From vaccinology experience (mathematical model for 50 years) with such a high and sustained Ab levels seen, the protection is expected to be long lasting
Due to induction of memory B cell clones
Follow up in GSK trials extended till 9.5 years
International Papilloma virus Conference 2007 - Beijing
Differences between the two vaccines
Immune profiles
Cross protection
Duration of protection – booster
Natural Infection
Natural Infection
Gall S, et al. AACR April 2007.Schwarz T, et al. ASCO. June 2006.
Cervical Cancer HPV types: Different quantitative immune
response for 16 /18?
Adapted from S. E. Olsson et al., Vaccine 25, 4931 (2007)
Time (months)
1
10
100
1,000
10,000
1
10
100
1,000 Seropositivity decreased to 68% from 24-60 months
QuadrivalentVaccine HPV 16
HPV 18VaccineNatural Infection
01 12 18 24 30 36 54 60 612 3 6 7
01 12 18 24 30 36 54 60 612 3 6 7
Cervarix TM
0 7 12 18
[25–32]
[33–38]
[39–44]
[45–50]
[51–56]
[57–62]
[63–64]
1
0 7 12 18
[25–32]
[33–38]
[39–44]
[45–50]
[51–56]
[57–62]
[63–64]HPV 16
HPV 18
1000
100
10
10000
1
1000
100
10
10000
Placebo
Natural Infection
Natural Infection
Placebo
VaccineNatural Infection
Antibody concentrations in seronegative and seropositivewomen after complete vaccination at month 7
GM
T (E
U/m
l)
GM
T (E
U/m
l)
HPV 16 HPV 18
Seroconversion 100% 100% 100% 100% 100% 100% 100% 100%
Presentation by T. Schwarz – Eurogin 2007
Vaccination in males
Recognised as source for transmission of HPV
Burden of disease is still cervical cancer
Ongoing studies
Guiliano AR, Gynecol Oncol. 2007 Nov;107(2 Suppl):S24-6
Can we interchange vaccines?
Seropositivity vs seroconversion?
Seroconversion is the mechanism by which a patient becomes seropositive.
Medical Forum
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