1. Prophylactic HPV Vaccines Achievements & Challenges Henry C. Kitchener Lisbon December 2007

2. Cumulative incidence of HPV infection from time of first sexual intercourse

4. E6 E7 E2 E1 E4 E5 L1 L2 Adapted from Doorbar 2005

5. Model of HPV Carcinogenesis 15 – 20 HPV Infection 20 – 25 CIN1/2 AGE25 – 35 CIN3 30+ Cancer PersistsIntegrates & Cofactors Clears FREQUENCY50%1% Genomic Damage

6. Human Papillomavirus Small DNA Virus 7 early and 2 late genes Oncogenic and non-oncogenic types Non-oncotypes include 6 and 11 – genital and respiratory papillomavirus Fifteen oncotypes found in 99% of cervical cancers Five oncotypes are associated with 80% of cancers Two oncotypes 16/18 are associated with 70% of cancers Cervical Cancer

7. Prophylactic Vaccination L1 Capsid proteins can self assemble into virus like particles (VPLs) VPLs are highly immunogenic – up to 100 fold level of neutralising antibody associated with natural infection

8. Cervarix (HPV 16-18) Vaccine Mean Titres & Seropositivity Rates According to HPV Type & Group Harper et al, Lancet, 2006

9. Rationale for Vaccination Programme To prevent type specific infection, thus ultimately preventing type specific associated CIN3 Prevention of infection by 2 types could prevent most cancers Primary prevention of cervical cancer by vaccination could be more cost effective than secondary prevention Vaccination offers a primary prevention strategy for countries without effective screening programmes

10. Definitions used in randomised trials of HPV vaccines Per Protocol Cervix HPV –ve/Sero –ve/16/18 lesions Unrestricted Susceptible Cervix HPV –ve/Sero –ve/± all 3 doses/16/18 lesions Intention to Treat All randomised subjects (real world) All lesions

11. Quadrivalent vaccine against human papillomavirus to prevent high grade cervical lesions. The FUTURE II study Group NEJM (2007) 356: 1915-27

12. Quadrivalent HPV Vaccine to prevent Cervical Lesions(15-26yrs) Future II NEJM (2007) Per Protocol Unrestricted ITT Population 4408 4970 4559 5055 (HPV16) (HPV18) 5043 5602 5054 5602 (HPV16) (HPV18) 60806087 PlaceboVaccine

13. Quadrivalent HPV Vaccine to prevent Cervical Lesions(16/18) Quadrivalent HPV Vaccine to prevent Cervical Lesions(16/18) Future II NEJM (2007) 161127192149ITT (any HPV) 104579641ITT 432401Unrestricted 291280Per protocol PlacVaccPlacVacc CIN3CIN2

14. Quadrivalent Vaccine Efficacy to Prevent Cervical Lesions (16/18) Vaccine Efficacy(%) Per Protocol 98 Unrestricted susceptible 95 ITT Population 44 ITT (Any Type) 17 Future II NEJM (2007)

15. Prevalence rates for four of the commonest five types and HPV 45 by cytological grade

16. Impact of Quadrivalent Vaccine on Vulval Condylomata 78%Intention to treat 97% Unrestricted Susceptible 100%Per protocol Vaccine Efficacy

17. Impact of quadrivalent vaccine (6, 11, 16 & 18) on VAIN and VIN 49% 51% 43% 53 33 21 27 16 12 Intention to treat - all high grade lesions - all VIN - All VAIN 71%319 Intention to treat population HPV 16/18 related VIN 2/3 or VAIN 2/3 97%291 Unrestricted susceptible population HPV 16/18 related VIN 2/3 or VAIN 2/3 100%150 Pre protocol susceptible population HPV 16/18 related VIN 2/3 or VAIN 2/3 EfficacyPlaceboVaccine Joura et al, Lancet (2007)

18. Efficacy of a prophylactic adjuvanted bivalent L1 virus like particle vaccine against infection with HPV16 and 18 in young women: An interim analysis of a phase III double blind randomised trial. Paavonen et al, Lancet (2007) 369:2161-70

19. CIN2+ lesions with HPV16 or HPV18 DNA 100% (74.2 – 100.0)20 0CIN2+ with HPV16 or 18 DNA in lesion and in preceding cytology sample 90.4% (53.4 – 99.3)23 17 6 21 16 5 211211 CIN2+ with HPV16 or 18 CIN2 with HPV16 or 18 CIN3 with HPV16 or 18 Vaccine EfficacyTotal Control Group Vaccine Group Paavonen et al, Lancet (2007)

20. Efficacy of Cervarix in Women initially seropositive or seronegative for HPV 16/18 in a Phase II Trial 10023831908293Additional** 91.624831928293Pre-specified* Seropositive or seronegative 10020783807788Additional** 90.421783827788Pre-specified* Seronegative 1 nNnN Vaccine Efficacy % HAV Control HPV Vaccine Analysis of HPV- 16/18 CIN2+ HPV-16/18 baseline (DNA negative) *Assignment of cases according to HPV DNA in lesion ** Causality assignment considering preceding infection in case of multiple HPV types in lesion 1 Paavonen et al; Lancet 2007; 369:2161-70

21. Cervarix (HPV 16/18) Vaccine Vaccine Efficacy Against Incident Infection with HPV 45, HPV 31, HPV 52, HPV 33 and HPV 58 in Cervical Samples from Intention-to-Treat Analyses 1651714529HPV58 4851540524HPV52 1351912529HPV33 3051614528HPV31 175181528HPV45 Women Reporting event of HPV 45, 31, 33, 52 or 58 who did not report the same event in initial study Total WomenWomen Reporting event of HPV 45, 31, 33, 52 or 58 who did not report the same event in initial study Total Women PlaceboVaccine Harper et al, Lancet (2006)

22. Key Issues (1) Who to Vaccinate Females aged 11-13 –Sexually naive; good immunogenicity Catch up of older adolescents –Will be less cost effective Women up to 25 years –Would be less protective Should boys be vaccinated? –Will the vaccine be protective? –Herd immunity but male HPV-related cancer is rare

23. Key Issues (2) Vaccine Specific Duration of protection –Follow-up of current/previous studies Cross protection –Other oncotypes Cost effectiveness

24. Key Issues (3) Implementation Education –Key messages for children and parents Co-existence with cervical screening –Scope for de-intensifying screening How to reach women in underdeveloped countries –Expense/cold chain/acceptability

25. Chronology of Vaccination & Changes to Screening

26. Impact of the Vaccines 50-60% of CIN2/3 will be prevented and perhaps only 20% of low grade cytological abnormalities The majority of VAIN and VIN may be prevented Prevention of genital warts (Gardasil) Less lower genital tract disease will result in less treatment associated morbidity There should be an impact on other HPV associated cancer e.g. head and neck

27. Impact of the Vaccines Prevention of 70% cervical cancers 450,000 cases per year, worldwide –Infertility –Suffering 250,000 deaths per year worldwide Uptake of vaccine in developing world will save many thousands of lives

28. The incidence of this disease might, in great measure, be prevented by inoculation. From ignorance and prejudices the parents …. instead of inoculating their children, crowd into houses …. when the disease is at its most contagious. Every argument is in support of inoculation, however conclusive, makes no impression upon their minds. Small pox, 1791 Thomas Pollock