hpv vaccine talk on 26 02 08 · 2/26/2008 · presentation outline recognising the need for...

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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


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


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*


Efficacy trials


Study HPV-012 Study HPV-012

Immunobridge trial


Studies HPV-001/007“Unexposed” population Studies HPV-001/007

“Unexposed” population

Efficacy trials


Study HPV-14Study HPV-14

Immunobridge trial


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



Efficacy trials


*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:


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


HPV-16 HPV-18N 446 443


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





Time (months)

1

10

100

1,000

10,000

1

10

100


QuadrivalentVaccine HPV 16


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


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


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


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


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


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





Time (months)

1

10

100

1,000

10,000

1

10

100


QuadrivalentVaccine HPV 16


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


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%


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

We welcome all for your questions

Let share your concerns and queries

hpv vaccine talk on 26 02 08 · 2/26/2008 · presentation outline recognising the need for...

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