1. Cervical Cancer, HPV and Prophylactic Vaccines Paulo Naud

2. 1. Epidemiology of HPV and Cervical Cancer

3. Age-standardized incidence rate for cervical cancer (2008)

4. Cervical Cancer Prevention is the key to avoid this cancer Cervical cancer: this is the only one gynecological cancer that may be eliminated as a public health problem

5. Oncogenic and low-risk HPV types At least 30 HPV types target the genital mucosa 1 At least 15 HPV types are classified as oncogenic (high risk) 1 –Globally, HPV types 16 and 18 together account for > 70% of cervical cancer cases 1,2 –The next most common oncogenic HPV types are 45, 31 and 33, which together account for an additional ~10% of cancers worldwide* 1,2 Low-risk (non-oncogenic) types cause benign genital warts/lesions –HPV type 6 is most commonly detected in genital warts (~90% of warts) followed by HPV type 11 (10–30% of warts) 3,4 1. Muñoz N, et al. N Engl J Med 2003; 348:518–527; 2. Bosch FX, et al. Vaccine. 2008; 26S:K1–K16; 3. Greer CE, et al. J Clin Microbiol 1995; 33:2058; 4. Brown DR, et al. J Clin Microbiol 1999; 37:3316–3322.

6. HPV and Oncogenesis

7. The five most common HPV types associated with invasive cervical cancer by region * HPV genotype 68 or 73 de Sanjosé S, et al. Lancet Oncol 2010; 11:1048–1056. HPV types associated with the development of cervical cancer World (N = 8,977) Africa (n = 544) Asia (n = 2,641) Europe (n = 2,058) Central South America (n = 3,404) North America (n = 160) Oceania (n = 170) HPV% % % % % % % HPV 16 61 HPV 16 48HPV 1660 HPV 16 66 HPV 16 59 HPV 16 72 HPV 16 5959 HPV 18 10 HPV 18 23HPV 1811 HPV 18 7 9 7 2020 HPV 45 6 10HPV 456 HPV 33 6 HPV 45 7 6 5 HPV 33 4 HPV 35 5HPV 584 HPV 45 4 HPV 31 5 HPV 31/33/ 52 3 HPV 68* 4 HPV 31 4 HPV 52 3 4 HPV 31 3 HPV 33 3 HPV 58 2 HPV 35 2

8. Epidemiology of HPV and cervical cancer: summary (I) The global burden of cervical cancer is ~530,000 cases, with ~ 275,000 deaths per year Virtually all cervical cancers are attributable to HPV At least 30 different types of HPV target the genital mucosa; ~15 of these are cancer causing or oncogenic Up to 80% of women will acquire an HPV infection in their lifetime HPV 16, 18, 45, 31 and 33 are the most common types associated with cervical cancer, worldwide HPV 16, 18 and 45 are the most common types associated with adenocarcinom, worldwide

9. Epidemiology of HPV and cervical cancer: summary (II) Phylogenetically, HPV 16 is closely related to HPV 31 and HPV 18 is closely related to HPV 45 Approximately 6% of cervical cancers are associated with multiple HPV infections, but most current methods for detection of cervical lesions do not assign causal HPV type Women remain at risk for developing HPV infections throughout their sexual lifetime

10. Important attributes of an effective cervical cancer vaccine Antigens (virus-like particles [VLPs]) that closely mimic the native virus structure Generation of neutralizing antibodies – a likely mediator of protection Generation of a cell-mediated immune response (T helper cells), which supports antibody production through generation of long-lived plasma cells and memory B cells High levels of antibodies in the serum that can transude to the site of infection, resulting in: –An immune response that improves on natural immunity, as natural immunity may not reliably protect against HPV re-infection –Effective protection against cervical cancer-causing HPV types

11. HPV vaccines generate neutralizing antibodies which prevent infection

12. The adjuvant concept Adjuvants are compounds that enhance the specific immune response to vaccine antigens 1 –Ramon et al. (1925) noted that horses generated higher specific immune responses when co-injected with unrelated substances –Glenny et al. (1926) demonstrated the adjuvant activity of aluminium compounds with diphtheria toxoid absorbed to alum Alum-adjuvanted vaccines are the most widely used today 1 New adjuvant systems, such as AS04, have been designed to achieve a strong immune response with the goal of providing effective and sustained protection against challenging diseases and for subjects with immunologically challenging conditions 2,3 Adjuvant systems, such as AS04, can mimic the danger signals normally provided by pathogens in order to stimulate innate immunity, ultimately enhancing the adaptive immune response 2–4 1. Petrovsky N & Auguilar JC. Immunol Cell Biol 2004; 82:488–496; 2. Garcon N, et al. Immunopotentiators in Modern Vaccines, 2006; pp. 161–178. London: Elsevier Academic Press; 3. Garcon N. Methods Mol Biol 2010; 626:15–27; 4. Giannini SL, et al. Vaccine 2004; 24:5937–5949.

13. Composition of the AS04-adjuvanted bivalent and quadrivalent HPV vaccines

14. Vaccine development: summary HPV vaccine development has focused on generating high and sustained levels of serum neutralizing antibodies in order to prevent infection –Higher circulating antibody levels result in higher levels at the site of infection Both vaccine antigen and adjuvant can have an important impact on vaccine immunogenicity Adjuvants are designed to enhance the specific immune response to vaccine antigens –Aluminium-based compounds are the most widely used adjuvants –AS04 was designed to enhance the immune response even more than traditional adjuvants by incorporating the immunostimulant, MPL The bivalent HPV vaccine comprises HPV 16 and HPV 18 vaccine antigens adjuvanted with AS04 –AS04-adjuvanted bivalent HPV vaccine induced antibodies which were sustained at higher levels, and a higher frequency of specific memory B-cells, than the same vaccine formulated with Al(OH) 3 The quadrivalent HPV vaccine comprises HPV 16, 18, 6 and 11 vaccine antigens adjuvanted with AAHS Both AS04 and AAHS vaccine adjuvants are generally well tolerated and have no evidence of toxicity

15. Antibody response following natural infection

16. Neutralizing antibodies prevent HPV infection

17. Comparison of the immunogenicity and safety of the AS04-adjuvanted bivalent and the quadrivalent HPV vaccines in healthy women aged 18–45 years Phase IIIb –Blinded, randomized (1:1) study Study population –Healthy women 18–45 years –N = 1,106 –Stratified: 18–26 years/27–35 years/36–45 years Two treatment groups –Bivalent HPV vaccine (HPV 16/18 L1 AS04-adjuvanted vaccine) –Quadrivalent HPV vaccine (HPV 6,11,16,18 L1 AAHS-adjuvanted vaccine) Vaccination –Three doses according to the respective vaccination schedules Evaluation of immunogenicity and safety Evaluation –Final analysis: 1 month after the completion of three-dose schedule (M7) –Extended follow-up to 48 months post-dose 1 –Safety was monitored throughout the study Einstein MH, et al. Hum Vaccin 2009; 5:705–719

18. Phase III efficacy analysis of the AS04-adjuvanted bivalent HPV vaccine in young women (PATRICIA trial)

19. PATRICIA (HPV-008): study objectives Primary objective: –Vaccine efficacy against CIN2+ lesions associated with HPV 16/18 –Other objectives included: –Vaccine efficacy against CIN3+ lesions associated with HPV-16/18 –Vaccine efficacy against 6- and 12-month persistent infections associated with HPV-16/18 –Vaccine efficacy against 6- and 12-month persistent infections associated with oncogenic non-vaccine HPV types –Vaccine efficacy against CIN2+ and CIN3+ lesions associated with oncogenic non-vaccine HPV types –Vaccine efficacy against CIN2+ and CIN3+ (irrespective of HPV type in the lesion) –Reduction of colposcopy referrals and cervical excision procedures –Immunogenicity and Safety CIN = cervical intraepithelial neoplasia Paavonen J, et al. Lancet 2007; 369: 2161–70; Paavonen J, et al. Lancet 2009; 374:301–314; Lehtinen M, et al. Lancet Oncol 2012;13:89–99.

20. PATRICIA (HPV-008): study design Randomized 1:1, double-blind, controlled Phase III trial involving 18,644 young women aged 15–25 years (TVC) Subjects received AS04-adjuvanted bivalent HPV vaccine (n = 9,319) or hepatitis A control vaccine (n = 9,325) at 0, 1 and 6 months Procedures: –Gynaecological examination and routine cervical cytological sampling (every 12 months) –Cytological sampling for HPV DNA testing (every 6 months) –Serum samples for assessment of immunogenicity Interim analysis previously reported at mean follow-up of 14.8 months 1 Final analysis conducted at mean follow-up of 39.4 months post-dose 1 2 End-of-study analysis conducted at mean follow-up of 43.7 months post- dose 1 3 1. Paavonen J, et al. Lancet 2007; 369:2161–2170; 2. Paavonen J, et al. Lancet 2009; 374:301–314. 3. Lehtinen M, et al. Lancet Oncol 2012;13:89–99.

21. AS04-adjuvanted bivalent HPV vaccine: efficacy against CIN2+ – final analysis of Phase III trial (34.9 months post-dose 3)

22. AS04-adjuvanted bivalent HPV vaccine: efficacy against CIN3+ – final analysis of Phase III trial (34.9 months post-dose 3)

23. Efficacy of the quadrivalent HPV vaccine: clinical data

24. Quadrivalent HPV vaccine: Phase III study cohorts

25. Quadrivalent HPV vaccine: efficacy against HPV 6/11/16/18-related CIN2/3 or AIS (Phase III)

26. Quadrivalent HPV vaccine: efficacy against HPV 16/18-related CIN2/3 or AIS (Phase III)

27. Quadrivalent HPV vaccine: efficacy in women with previous infection with HPV 6/11/16/18 (Phase III)

28. Quadrivalent HPV vaccine: efficacy in women aged 24–45 years (per-protocol population, 3.8 years’ mean follow-up)

29. Quadrivalent HPV vaccine: safety profile 18,083 subjects aged 9–45 years were monitored using vaccination report card-aided surveillance –10,088 received the quadrivalent HPV vaccine; 7,995 received placebo The quadrivalent HPV vaccine is generally well tolerated with a clinically acceptable safety profile –Most common vaccine-related adverse reactions were pyrexia, and erythema, pain, swelling, bruising and pruritus at the injection site –Data on the quadrivalent HPV vaccine administered during pregnancy did not indicate any safety signal but are insufficient to recommend use of the quadrivalent HPV vaccine during pregnancy –In clinical studies, subjects in the safety population (15,706 received quadrivalent HPV vaccine; 13,617 received placebo) reported any new medical conditions during a 4-year follow-up 39 cases of non-specific arthritis/arthropathy were reported; 24 in the quadrivalent HPV vaccine group and 15 in the placebo group EMA. Gardasil ®. European Summary of Product Characteristics 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000703/WC500021142.pdf (accessed March 2012).

30. AS04-adjuvanted bivalent HPV vaccine: safety profile In clinical studies enrolling subjects aged 10–72 years, AS04-adjuvanted bivalent HPV vaccine was administered to 16,142 subjects whilst 13,811 subjects received control. These subjects were followed for serious adverse events (SAEs) over the entire study period –In a predefined subset of subjects (vaccine = 8,130 vs control = 5,786), adverse events (AEs) were followed for 30 days after each injection The majority of vaccine-related adverse reactions were of mild to moderate severity and were not long lasting –Most common was injection site pain, after 78% of all doses –Other common vaccine-related AEs included headache, nausea, vomiting, diarrhoea, abdominal pain, itching/pruritus, rash, urticaria, myalgia, arthralgia, fatigue, fever, other infection site reactions including redness and swelling –Data on AS04-adjuvanted bivalent HPV vaccine administered during pregnancy did not indicate any safety signal but are insufficient to recommend use of the vaccine during pregnancy EMA. Cervarix ®. European Summary of Product Characteristics, 2012. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000721/WC500024632.pdf (accessed March 2012).

31. Summary: immunogenicity with the AS04- adjuvanted bivalent HPV vaccine The AS04-adjuvanted bivalent HPV vaccine induced sustained serum antibody levels against HPV 16 and 18, which remained several fold higher than those following natural infection for up to 9.4 years (Phase IIb) The AS04-adjuvanted bivalent HPV vaccine induced HPV 16 and 18 antibody levels in serum which correlated with those in cervicovaginal secretions (CVS) (Phase III) Immunogenicity with the AS04-adjuvanted bivalent HPV vaccine was comparable in females aged 10–14 years, 15–25 years and > 25 years (HPV 16 and HPV 18) (Phase III)

32. Summary: immunogenicity with the quadrivalent HPV vaccine The quadrivalent HPV vaccine induced serum antibody levels against HPV 16, which were several fold higher than those following natural infection for up to 5 years (Phase II) –Antibody levels against HPV 18 dropped to similar levels to those following natural infection 18 months after vaccination Immunogenicity for HPV 16 with the quadrivalent HPV vaccine was comparable in women aged 16–23 years and 24–45 years (Phase III) Immunogenicity for HPV 18 with the quadrivalent HPV vaccine reduced with increasing age in women 16–45 years (Phase III)

33. Public Health Implications of HPV Vaccination Cervical screening (traditionally using the Pap smear and more recently by liquid-based cytology [LBC]) is used to detect existing cervical abnormalities and precancerous disease 1 –Screening programmes vary widely between countries and may be completely absent in developing countries due to the cost of implementation –HPV DNA testing may be used to detect existing HPV infection Neither method offers primary prevention; HPV infection and development of cervical disease can still occur –Deaths from cervical cancer still occur in countries with established screening programmes 2 Vaccination offers an important new management option in the primary prevention of cervical cancer 1. Sankaranarayanan R, et al. Int J Gynaecol Obstet 2005; 89(Suppl 2):S4–S12; 2. WHO/ICO Information Centre on Human Papilloma Virus (HPV) and Cervical Cancer. Available at: http://www.who.int/hpvcentre/statistics (accessed May 2012)

34. Cervical cancer screening programmes The effectiveness of a cervical cancer screening programme depends on the overall programme sensitivity Programme sensitivity is the probability that tests repeated at specified intervals will detect underlying disease over a period of time 1 Programme sensitivity depends on: 2 –Natural history of cervical disease –Sensitivity of screening test(s) –Screening policy Target age group, screening interval, procedures for follow-up of positive screens Estimated reduction in cumulative incidence of cervical squamous cell carcinoma (SCC) for well-organized cytological screening programmes: 2,* –Screen every year = 93% –Screen every 3 years = 91% –Screen every 5 years = 84% * Women aged 20–64 years. 1. Saslow D, et al. CA Cancer J Clin 2002; 52:342–362; 2. Arbyn M, et al. European guidelines for quality assurance in cervical cancer screening. Luxembourg: European Communities, 2008 (2nd Ed).

35. Potential impact of an HPV 16/18 vaccine

36. Conclusions

37. Conclusions (I) The global burden of cervical disease and cancer is substantial –~100% of cervical cancer cases are caused by HPV HPV infections are very common and women remain at risk from HPV infection throughout their sexually active lives The HPV lifecycle in the cervix is confined to the epithelium Most HPV-related lesions resolve naturally; progression to cervical cancer is a relatively rare event –A key factor in allowing disease to progress is the ability of HPV to evade the immune system and establish a persistent infection Approximately 50% of infected individuals fail to demonstrate, or produce a detectable antibody response to HPV –In those who do respond, the low antibody levels produced do not guarantee protection from future HPV infection Prophylactic HPV vaccines have been developed to induce HPV-specific immune responses that prevent infection

38. Conclusions (II) The AS04-adjuvanted bivalent HPV vaccine incorporates a novel adjuvant system, AS04 The AS04-adjuvanted bivalent HPV vaccine induced sustained serum antibody levels against HPV 16 and 18 which remain several fold higher than those following natural infection for up to 9.4 years The AS04-adjuvanted bivalent HPV vaccine has demonstrated high efficacy for up to 6.4 years against CIN1+ and CIN2+ lesions caused by HPV 16/18 –At 9.4 years, no breakthrough cases of CIN lesions were detected in the AS04-adjuvanted bivalent HPV vaccine group The AS04-adjuvanted bivalent HPV vaccine provided efficacy against 6 month persistent infection and CIN2+ associated with individual types, HPV 31, 33 and 45* (TVC-naïve and TVC) The AS04-adjuvanted bivalent HPV vaccine has a clinically acceptable safety profile

39. Conclusions (III) The quadrivalent HPV vaccine utilizes the aluminium salt adjuvant, AAHS The quadrivalent HPV vaccine induces serum antibody levels against HPV 16 which are several fold higher than those following natural infection after 5 years –Antibody levels against HPV 18 drop to similar levels to those following natural infection, 18 months after vaccination The quadrivalent HPV vaccine has demonstrated 98% efficacy for up to 3.6 years against HPV 6/11/16/18-related CIN2/3 or AIS The quadrivalent HPV vaccine provided efficacy against 6 month persistent infection and CIN2+ associated with HPV type 31 (subjects naïve to 14 oncogenic HPV types) The quadrivalent HPV vaccine has a clinically acceptable safety profile

40. Conclusions (IV) Before the advent of vaccines, cervical screening was the principal means of preventing cervical cancer –Even with effective screening, deaths from cervical cancer still occur Vaccination plus screening is the most effective approach to reduce the incidence of cervical cancer Modelling studies predict that high antibody titres could be sustained for decades The actual duration of protection will only be established by long-term efficacy studies