Disclaimer. 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

Transcription

1 Disclaimer 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

2 Cervarix TM The AS04 Adjuvanted Cervical Cancer Vaccine A Step Forward in Cervical Cancer Prevention Dinner Symposium Medical Forum 26 Feb 2008

3 Cervarix TM Clinical Update Dr Goh Choo-Beng Regional Medical Affairs HPV Vaccines GSK Biologicals Asia Pacific, Australasia, China/Hong Kong

4 Presentation Outline Recognising the Need for Cervical Cancer Prevention and Disease Burden GSK s Cervical Cancer Vaccine Development Vision the AS04 Innovative Adjuvant Vaccine Trial Design Efficacy Results Using Cervarix TM today

5 Hong Kong Incidence 5 th leading cause of cancer in women ASR: 9.9 / 100,000 Mortality 9 th leading cause of cancer-associated deaths in women ASR: 2.2 / 100, Government of Hong Kong Special Administrative Region, Department of Health al.htm; 2. c_facts/cc_facts.php; 3. Hong Kong Cancer Registry, Hospital Authority, 5

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 McIntosh N. JHPIEGO strategy paper. 2000; 2. Bosch FX et al. J Clin Pathol 2002; 55:

7 Adenocarcinoma of the Cervix Adenocarcinomas arise from the glandular epithelia of the endocervix whereas SCCs arise from the squamous epithelia on the ectocervix 1 Adenocarcinomas account for approximately 15 25% of all invasive cancers 2 Up to 30% diagnosed in women <35 years 2 Greater likelihood of recurring compared to squamous cell carcinomas 2 Adenocarcinomas are strongly associated with HPV-18 infection 2,3,4,5 1. Tjalma WA et al. Best Pract Res Clin Obstet Gynaecol (19) 4: 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 Cancer 1998; 75: ; 5. Bosch XF et al. J Nat Cancer Inst. 1995; 87:

8 Two types of CERVICAL CANCER The 3 most common HPV types - IARC study Squamous cell carcinoma Adenocarcinoma HPV type % HPV type % De Sanjose et al, Beijing 2007

9 HPV are the most aggressive types Adapted from Smith J S et al. Int J Cancer 2007; 121:

10 Adenocarcinoma Recognising the Hidden Killer The 5 Most Common HPV Types - IARC Study Adenocarcinoma % F. X. Bosch, A. Lorincz, N. Munoz, C. J. Meijer, K. V. Shah, J Clin Pathol 55, 244 (2002)

11 The HPV Phylogenetic Tree Canine Oral Bovine Cotton Tail Rabbit

12 Age-specific incidence of oncogenic HPV infection in women Prevalence of Oncogenic HPV, % Oncogenic HPV incidence is highest in young women The risk for infection/reinfection remains throughout life Universal Mass Vaccination of Girls from Age Need for long term protection Age, years NHANES, (N=1921) 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

13 GSK Cervical Cancer Vaccine: Development Vision HPV-16/18 are responsible for ~70% of invasive cervical cancers worldwide Prophylactic cervical cancer vaccine based on 16 and 18 L1 virus-like particles Every sexually active woman is at risk of oncogenic HPV The objective is to develop a vaccine which targets prevention of cervical cancer in females from 10 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 to enhance the immune response

14 Cervarix TM : composition Immunogenic antigens - potent activators of APC + Immunomodulator Strong Immune & sustained immune response response AS04 Adjuvant System 04 Administered intramuscularly in the deltoid muscle ; over a 0, 1 and 6 months schedule Baldridge J, et al. Expert Opin Biol Ther (2004) 4(7): ; Evans et al. Expert Rev. Vaccines 2(2), (2003).

15 Cervarix TM Composition 20 µg HPV µg HPV 18 Schedule Adjuvant 0, 1, 6 months AS04: 500 µg Aluminum Hydroxide 50 µg MPL

16 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 4 Found on macrophages and dendritic cells Activation of toll-like receptor 4 initiates the enhanced immune responses that characterise the strong and sustained antibody titres seen in the GSK studies Monophosphoryl Lipid A AAHS Amorphous Aluminium Hydroxyphosphate Sulphate adjuvant

17 Impact of AS04 Adjuvant : High Antibody Titers in Humans V5 epitope is targeted by HPV-16 neutralizing antibodies J4 epitope is targeted by HPV-18 neutralizing antibodies 1000 * Anti-V5 HPV * Anti-J4 HPV-18 GMT antibody titers (EU/ml) * * * = AS04 = Al(OH) 3 * * * * * = AS04 = Al(OH) 3 * * Vaccination months Vaccination months Wilcoxon s non-parametric (p<0.05) Adapted from Giannini SL, Hanon E, Moris P, et al. Vaccine 2006;24:

18 Frequency of HPV specific memory B cells Cervarix TM : Does AS04 Enhance the B cell Memory Pool? 0 pre = AS04 = [Al(OH) 3 ] HPV16 GSK cervical cancer vaccine formulated with AS04 induces higher frequency of memory B cells 3.6 x* day 60 day 210 Q Median Q1 0 pre HPV x day 60 day 210 Q3 Median Q1 vaccination vaccination Giannini SL, et al. Vaccine 2006; 24: * statistically significant (p <0.05, Wilcoxon s test)

19 GSK s Innovative Adjuvant Systems (AS) First license (European Union) for vaccine with novel adjuvant Fendrix TM : hepatitis B vaccine with MPL containing 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) Pandemic influenza vaccine Saponin extracted from Quillaria saponaria

20 Presentation Outline Recognising the Need for Cervical Cancer Prevention and Disease Burden GSK s Cervical Cancer Vaccine Development Vision and the AS04 adjuvant system Vaccine Trial Design Efficacy Results Using Cervarix TM today

21 GSK s clinical development programme Women years Women years Women years Study HPV-012 Immunobridge trial Key endpoints : Immunogenicity Safety Studies HPV-001/007 Unexposed population Efficacy trials Key endpoints : HPV-16/18 efficacy Other HPV-types efficacy Immunogenicity Study HPV-14 Immunobridge trial Key endpoints : Immunogenicity Safety Study HPV-013 Safety trial Key endpoints : Safety Immunoginicity Studies HPV-008 General population* Efficacy trials Key endpoints : HPV-16/18 efficacy Other HPV-types efficacy Immunogenicity Study HPV-015 Efficacy trial in women above 25 yrs (on going) *In some regions, this population is referred to as women with current or prior infection

22 Summary of Ongoing Phase IIb/III Trials HPV-012 (immuno 10-25y) HPV-013 (safety/immuno yrs) HPV-014 (immuno 15-55y) LT follow-up Y1 Y2 Y3 LT follow-up LT follow-up HPV-001/007 (efficacy in yr old women) N = yrs 5.5 yrs 6.5 yrs Interim analyses virological/histopath endpoints HPV-009 (efficacy in yr old women in Costa Rica) N = 7,462 HPV-008 (efficacy in yr old women) N =18,665 HPV-010 (GSK HPV vaccine vs Gardasil yrs) UP TO 9.5 YEARS Efficacy Immunogenicity Interim analysis CIN2+ HPV-015 (efficacy >25yrs) N=5,700

23 5.5 year Trial: Initial Efficacy and Extended Follow-up Study Initial Efficacy Study* Extended follow up study of initial efficacy study through 5.5 years Enrolled 1113 women* Enrolled 776 women Median age: 23 years (range 17-29) Study visits and follow-up time Study entry Vaccine doses administered and follow up Follow-up Extended Follow up through 4.5 yrs** Extended Follow up through 5.5yrs Study period: 0 to 27 months Study period: ~ 28 to 65 months Average follow up time: 23.4 months * Harper D et al. Lancet. 2004; 364: **Harper D et al. Lancet. 2006; 367:

24 Extended follow-up period: ~ 28 to 65 months HPV-16 & 18 Efficacy Endpoints* HPV Vaccine Control Vaccine Efficacy n n % 95% CI 6 Month Persistence Month Persistence Presentation Gall S, AACR, Los Angeles, April 14-18, 2007

25 Persistent infection with oncogenic HPV is the necessary cause of cervical cancer Months Years Normal epithelium HPV infection koilocytosis CIN 1 CIN 2 CIN 3 Spontaneous regression Invasive cervical cancer Since persistent Low-grade squamous infection with High-grade the same squamous high-risk type is intraepithelial lesions (LSILs) intraepithelial lesions (HSILs) considered a predictor for moderate or high-grade cervical dysplasias From and incident cancer, to persistent they HPV infection might represent a useful endpoint in future vaccine efficacy studies. Screening Monsonego 2006, p159. Treatment S.R. Pagliusi, M.T. Aguado WHO REFERENCE PAPER 2004 CIN = Cervical intraepithelial neoplasia

26 5.5 years Trial: Initial Efficacy and Extended Follow-up Study Extension to 9.5 years Initial Efficacy Study* Extended follow up study of initial efficacy study through 5.5 years Enrolled 1113 women* Enrolled 776 women Median age: 23 years (range 17-29) Study visits and follow-up time Study entry Vaccine doses administered and follow up Follow-up Extended Follow up through 4.5 yrs** Extended Follow up through 5.5yrs Study period: 0 to 27 months Study period: ~ 28 to 65 months Average follow up time: 23.4 months Total average follow up time initial and EFU phases: 59.9 months (up to 67 months) * Harper D et al. Lancet. 2004; 364: **Harper D et al. Lancet. 2006; 367: Gall S et al. AACR abstract 2007

27 Up to 5.5 years Complete Protection Against HPV-16/18 Infections and CIN Outcomes Cervarix TM Control Vaccine Efficacy Endpoints* n n % 95% CI 6 Month Persistence Month Persistence CIN CIN *Combined analysis initial efficacy study and extended follow-up ATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpoints Presentation Gall S, AACR, Los Angeles, April 14 18, 2007

28 Up to 100% Efficacy Against CIN2+ Caused by HPV-16 and 18 % Efficacy CIN2+ HPV-16/ years follow-up HPV Neg Broad population 15 mths Interim Analysis 97.9% CI: % CI: % CI: 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 ) Harper D et al. Lancet 2006; Presentation Gall S, AACR, Los Angeles, April 14 18, 2007; Paavonen J et al. Lancet 2007;369:

29 Vaccination Beyond HPV 16 and 18 Impact on Oncogenic HPV Types Other than HPV 16 and HPV 18

30 Up to 5.5 Year Results: Cytological Abnormalities and CIN Outcomes Efficacy against endpoints independent of HPV DNA status Estimated prevalence HPV 16/18 Endpoint Cervarix N=505 Al(OH) 3 N=497 Vaccine Efficacy n n % 95% CI 20 30% % % 1 50% 2 ASCUS LSIL CIN CIN Combined analysis for initial efficacy study and extended follow-up Harper D et al. Lancet 2006;367: ; Presentation Gall S, AACR, Los Angeles, April 14 18, Clifford et al. Cancer Epi Biom Prev 2005;14(5); 2 Muñoz et al. N Engl J Med 2003;348;6

31 Up to 5.5 years Cross Protection against Incident Infection with HPV Types 31 and 45 HPV-31 Related to HPV 16 HPV-45 Related to HPV 18 Percentage without infection Vaccine Placebo Time (months) Vaccine efficacy: 54% (15 76) Time (months) Vaccine Placebo Vaccine efficacy: 88% (61 98) Total cohort; cervical samples only; Cox regression model Globally HPV-45 and 31 are the 3 rd and 4 th most common oncogenic HPV types Harper D et al. Lancet 2006;367: ; Presentation Gall S, AACR, Los Angeles, April 14 18, 2007

32 HPV Types In Cervical Cancer Globally HPV genotype % Other X Cancer cases attributed to the most frequent HPV genotypes (%) 70.7% 77.4% 80.3% Vaccine types Muñoz N et al. Int J Cancer 2004; 111:

33 Phase III Broad Population Study: Cross Protection against 6 Months Persistent Infections Type Cervarix TM (cases) Cervarix HAV (cases) TM Efficacy (%) 97.9% CI HPV HPV HPV Analysis on a population that received at least one vaccine/control dose: Paavonen J et al. Lancet 2007;369:

34 Presentation Outline Recognising the Need for Cervical Cancer Prevention and Disease Burden GSK s Cervical Cancer Vaccine Development Vision and the AS04 adjuvant system Vaccine Trial Design Efficacy Results Using Cervarix TM today

35 When, Why, How WHEN can you prescribe Cervarix TM? Prescribed now for girls and women, as they remain at risk of infection from oncogenic HPV throughout their lives WHY prescribe Cervarix TM? Cervarix TM with novel adjuvant AS04, provides strong and sustained protection against cervical cancer HOW do you administer Cervarix TM? Give 3 doses of Cervarix TM at 0, 1, 6 months Vaccination is by IM injection into the deltoid area

36 Cervarix TM : safety profile Large safety database (~30,000 females) in a broad age range data up to 5.5 years post-vaccination Cervarix TM 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

37 Cervical Cancer prevention is a possibility now

38 Cervarix : Approved in 51 countries Mexico EU ( 27) Norway Iceland Ukraine Kazakhstan Belarus UAE Bahrain Turkey Philippines (Macau) Thailand Singapore Malaysia Indonesia Hong Kong Myanmar Kenya Uganda Australia New Zealand Argentina Chile Colombia Uruguay

39 International: Cervarix licensure to date 10 years onward yrs yrs years Cross protection Cross protection UAE Australia Thailand Europe* *>26 yr virgins Philippines Macau Indonesia Norway Kenya Argentina Singapore Iceland Mexico Malaysia Hong Kong Colombia Myanmar Chile New Zealand *This depends on individual EU states interpretation of the PI

40 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 years following vaccination with CERVARIX TM and on the immunogenicity of the vaccine in girls and women aged years. Section 5.1 Study 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 followup phase (up to month 18) maintaining antibody levels at an order of magnitude above those encountered after natural infection.

41 Australia supports vaccination for older women The bivalent HPV vaccine has been licensed for use in women 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 or 18 in the future. It is likely that this vaccine will need to be purchased by women in the older age group (27 45 years). "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." MJA 2008; 188:

42 Cervarix : Generally safe and well tolerated Protective 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

43 AS04 How Adjuvantation Makes a Difference in Cervical Cancer Prevention Prof Tino Schwarz Central Laboratory Yellow fever vaccination centre Stiftung Juliusspital Würzburg

44 AS04 - How adjuvantation makes a difference in cervical cancer prevention Tino F. Schwarz Central Laboratory Yellow fever vaccination centre Stiftung Juliusspital Würzburg

45 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

46 Clinical Efficacy 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%) Presentation Gall S, AACR, Los Angeles, April 14 18, 2007

47 Safety and Reactogenicity: Injection Site Symptoms Solicited Adverse Events (within 7 days following any dose) Vaccine N = 531 Control Al(OH) 3 N = 538 P-value Pain <0.001 Swelling <0.001 Redness <0.001 Harper D et al. Lancet. 2004; 364:

48 Safety and Reactogenicity: General Symptoms Vaccine N = 531 Control Al(OH) 3 N = 538 P-value Fatigue Gastrointestinal Headache Itching Rash Temp Elevation* Harper D et al. Lancet. 2004;364: * Temperature > 37.5 C (oral)

49 Extended Follow-up 5.5 Years: Safety Profile HPV Vaccine N = 373 Control N = 370 Adverse events Women with at least one adverse event Number of Adverse events New Onset Chronic Disease (NOCD)* Women with at least one NOCD event Number of NOCD events Serious adverse events (SAE) Women with at least one SAE Number of SAEs reported ATP analysis. Safety events recorded from the end of the initial efficacy study through month 24 of the extended follow-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

50 Safety and Pregnancy Broad Population Study Pregnancies/Pregnancy outcomes* Number of pregnancies Pregnancy ongoing Normal infant Abnormal infant Premature births Spontaneous abortion Elective termination Lost to follow-up Cervarix TM (N = 9,319) % 40.6% 0.6% 2.3% 9.9% 13.1% 1.5% Control (HAV) (N = 9,325) % 38.5% 1.2% 2.5% 7.4% 13.6% 1.9% *Totals do not include blinded outcomes, ectopic pregnancies Paavonen J et al. Lancet 2007;369:

51 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

52 Cervarix Data in Adolescents Females yrs Females yrs GSK study 012 Immunogenicity bridge Safety / reactogenicity GSK studies 001 / 007 Immuno & Efficacy Findings up to 5.5 yrs

53 Immunogenicity Bridge Females Years GMCs log (EU/ml) GMCs at Month HPV HPV y y y y Dubin G, ICAAC, 2005

54 Up to 5.5 Years High and Sustained Antibody Levels and Seropositivity GMT (EU/ml) Anti-HPV-16 IgG Seroconversion 100% at 7 mo Seropositivity 98% at 5.5 yrs 11-fold higher than natural infection Months GMT (EU/ml) Anti-HPV-18 IgG Months Seroconversion 100% at 7 mo Seropositivity 98% at 5.5 yrs 11-fold higher than natural infection Harper D et al. Lancet 2006;367: ; Presentation Gall S, AACR, Los Angeles, April 14 18, 2007

55 Immune Response against HPV-31 and -45: GMTs and Seropositivity Rates* GMT (EU/ml) GMT (EU/ml) *up to 4.5 yrs Months Months HPV-31 Related to HPV-16 HPV-45 Related to HPV-18 Data on File. GSKBio-WWMA_DoF001_2007 Cut-off level for seropositivity for both HPV-45 and 31: 59 EU/ml

56 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 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

57 Immunobridging Between Girls Years and Women Years of Age year old girls HPV 16 GMT (log ELU/ml) > 11 fold higher Natural Infection HPV > 11 fold higher Months follow up time S. Gall, presented at AACR, April L. Rombo, Poster ESPID 2007

58 y Olds Comparable to those Observed in Efficacy Study HPV- GMT (EU/ml) /007 HPV-16 At least 8-fold higher than natural infection years Efficacy study years years years years 10 Natural Infection ATP analysis Seronegative prior to vaccination Months Assay cut-off: 8 EU/ml Harper DM et al. Lancet 2006; Paavonen J et al. Lancet 2007; Schwarz TF. ASCO 2006; Gall S. AACR 2007

59 Antibody Levels in Year Olds Comparable to those Observed in Efficacy Study HPV- GMT (EU/ml) /007 HPV-18 At least 8-fold higher than natural infection years Efficacy study years years years years 10 Natural Infection ATP analysis Seronegative prior to vaccination Months 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

60 High Correlation (CC) Between GSK s Binding ELISA and Pseudovirion Neutralisation Assay Pseudovirion neutralisation HPV-16 HPV-18 N Pearson CC HPV-16 HPV-18 N Pearson CC Inhibition ELISA HPV-16 HPV-18 N Pearson CC Binding ELISA H. Clayton et.al. Journal of National Cancer Institute (4):

61 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)

62 High Correlation between CVS and Serum HPV-16 and -18 IgG Antibodies According to Age TWO YEARS DATA HPV YEARS R = YEARS R = YEARS R = 0.88 HPV YEARS R = YEARS R = YEARS R = 0.93 Scatterplot between secretion and serum HPV-16 (divided by total IgG) by age and with Hemastix <80

63 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 years years years

64 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 years old up to 5.5 years in girls aged years in women aged years

65 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

66 Vaccination to Prevent Cervical Cancer: Public and Individual Health Perspective EUROPE

67 Integrating into Clinical Practice Public Health Perspective Primarily pre-sexually active adolescents Individual Perspective Sexually active women

68 Vaccination Programmes in Europe Age Austria Belgium Denmark France Germany* Greece Italy Luxembourg Norway Spain Sweden Switzerland UK TBD TBD TBD Main age Catch up Last updated October 2007 * Above 17 years of age, vaccination based on individual benefit

69 Cervical Cancer HPV types: Different quantitative immune 10,000 1, response for 16 /18? Quadrivalent vaccine HPV 16 Vaccine Natural Infection Bivalent vaccine HPV 16 Natural Infection 10 Placebo Vaccine Natural Infection HPV [25 32] [33 38] [39 44] [45 50] [51 56] [63 64] [57 62] HPV 18 1,000 Seropositivity decreased to 68% from months Natural Infection 10 Placebo Time (months) [25 32] [33 38] [39 44] [45 50] [51 56] [57 62] [63 64] Adapted from S. E. Olsson et al., Vaccine 25, 4931 (2007) Gall S, et al. AACR April Schwarz T, et al. ASCO. June 2006.

70 Role of Antibodies: Systemic and local Infection HBV Hepatitis B Virus is transported from the site of infection via the blood stream to the liver By that way, the virus is detected by the immune system In case of infection => Activation of memory cells => Booster of Ab levels HPV HPV infects the cervical mucosa epithelium (local infection) No systemic infection! Following infection of the cell, the virus is hidden from a systemic immune response Transudating neutralising Ab in CVS are important for protection

71 anamnestic response 17 yrs after immunization Anti-HBs IU/L days anti-hbs response Rise of levels of Anti- HBs from 80 IU/L to IU/L >300 fold increase mean increase 130 IU/L per hour 2IU/L per minute Immune memory T, B memory cells

72 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 years of age (range 5-10%) 1 Although new infections decrease with age, risk of persistence increases with age 2 Immune function declines with age resulting in decreased capacity to respond to both new and previously encountered infections 1. Munoz N et al. JID Castle PE et al. JID 2005.

73 Sexually active women may remain at risk of acquiring HPV throughout their lives 1-7 Age specific prevalence of HPV Infection in Portland USA & Guanacaste Costa Rica 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 Baseman & Koutsky, 2005; 32S:S Brown et al, 2005; 191: Munoz et al, J Infect Dis 2004; 190: Herrero et al, 2000; 92(6): Franco et al, 1999; 180: Sellors et al, 2003; 168(4): Schiffman & Kruger Kjaer, 2003; 31: 14-19

74 Ongoing risk for HPV infection over 26 years This retrospective study shows that HPV-negative women >50 years of age can acquire HPV and, therefore, require cervical screening Grainge MJ et al.: Emerg Infect Dis 11: (2005)

75 Cervical Cancer Vaccines That s one small prick for woman, one giant leap for womankind

76 Expert Forum

77 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

78 The importance of High Antibody levels The Hepatitis B vaccinology experience Boosting with a vaccine is not the same as natural infection 1 Natural HPV infection occurs at the cervical mucosa unlike systemic HBV infection It 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 Nov;76(22):

79 Cervical Cancer HPV types: 10,000 1, Different quantitative immune Quadrivalent response for 16 /18? HPV 16 Cervarix TM Vaccine Vaccine Natural Infection HPV 16 Natural Infection 10 Placebo Vaccine Natural Infection HPV [25 32] [33 38] [39 44] [45 50] [51 56] [63 64] [57 62] HPV 18 1,000 Seropositivity decreased to 68% from months Natural Infection 10 Placebo Time (months) [25 32] [33 38] [39 44] [45 50] [51 56] [57 62] [63 64] Adapted from S. E. Olsson et al., Vaccine 25, 4931 (2007) Gall S, et al. AACR April Schwarz T, et al. ASCO. June 2006.

80

81 Role of Antibodies Systemic / local Infection HBV Hepatitis B Virus is transported from the site of infection via the blood stream to the liver By that way, the virus is detected by the immune system In case of infection => Activation of memory cells => Booster of Ab levels HPV HPV infects the cervical mucosa epithelium (local infection) No systemic infection! Following infection of the cell, the virus is hidden from a systemic immune response Transudating neutralising Ab in CVS are important for protection

82 Anamnestic response 17 yrs after immunization Anti-HBs IU/L days anti-hbs response Rise of levels of Anti- HBs from 80 IU/L to IU/L >300 fold increase mean increase 130 IU/L per hour 2IU/L per minute immunologic memory T, B memory cells

83 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 Ab response 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:

84 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

85 The importance of HPV 18 and cross protection Adenocarcinoma and HPV 18 and 45. Cross protection data for Cervarix TM. 5.5 year data and on-going follow up. Paavonen J et al. Lancet 2007

86 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 Cervarix TM Poncelet S et al.. European Society of Paediatric Infectious Diseases (ESPID), 2-7 May 2007: Abstract presented Presentation by T. Schwarz Eurogin 2007

87 Two Years Data High Correlation between CVS and Serum HPV-16 and -18 IgG Antibodies According to Age HPV 16 HPV 18 Presentation by T. Schwarz Eurogin 2007 Scatterplot between secretion and serum HPV-16 (divided by total IgG) by age and with Hemastix <80

88 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.

89 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

90 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 Cervarix TM data up to 5.5 years EPAR Cervarix, Published 03/10/07

91 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 Beijing

92 Differences between the two vaccines Immune profiles Cross protection Duration of protection booster

93 Cervical Cancer HPV types: 10,000 1, Different quantitative immune Quadrivalent response for 16 /18? HPV 16 Cervarix TM Vaccine Vaccine Natural Infection HPV 16 Natural Infection 10 Placebo Vaccine Natural Infection HPV [25 32] [33 38] [39 44] [45 50] [51 56] [63 64] [57 62] HPV 18 1,000 Seropositivity decreased to 68% from months Natural Infection 10 Placebo Time (months) [25 32] [33 38] [39 44] [45 50] [51 56] [57 62] [63 64] Adapted from S. E. Olsson et al., Vaccine 25, 4931 (2007) Gall S, et al. AACR April Schwarz T, et al. ASCO. June 2006.

94 Antibody concentrations in seronegative and seropositive women after complete vaccination at month 7 GMT (EU/ml) GMT (EU/ml) Seroconversion 100% 100% 100% 100% 100% 100% 100% 100% HPV 16 HPV 18 Presentation by T. Schwarz Eurogin 2007

95 Vaccination in males Recognised as source for transmission of HPV Burden of disease is still cervical cancer Ongoing studies Guiliano AR, Gynecol Oncol Nov;107(2 Suppl):S24-6

96 Can we interchange vaccines?

97 Seropositivity vs seroconversion? Seroconversion is the mechanism by which a patient becomes seropositive.

98 Medical Forum We welcome all for your questions Let share your concerns and queries