1. Update on HPV vaccines and recommendations - Lauri Markowitz Plans for monitoring impact of HPV vaccine - Eileen Dunne Uptake of HPV vaccine, ISS Sentinel Sites - Diana Bartlett National Immunization Conference March 2008 HPV Vaccines: New Developments and Current Assessments

2. Update on HPV Vaccines and Recommendations National Immunization Conference March 2008 Lauri Markowitz, MD NCHHSTP/ CDC

3. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention

4. June 2006 Advisory Committee on Immunization Practices (ACIP) Recommendations for Quadrivalent HPV Vaccine Routine vaccination Females age 11-12 years Catch-up Females age 13-26 years

5. Upcoming Issues for HPV Vaccine Recommendations Bivalent HPV vaccine HPV vaccines for females >26 yrs HPV vaccine for males

6. Prophylactic HPV VLP Vaccines Quadrivalent (Merck)Bivalent (GSK) Vaccine TypeHPV 6/11/16/18HPV 16/18 ManufacturingYeast - S. cerevisiaeBaculovirus Schedule0,2,6 months0,1,6 months Adjuvant Alum: 225 µg Aluminum Hydroxyphosphate Sulfate AS04: 500 µg Aluminum Hydroxide 50 µg 3-deacylated Monophosphoryl Lipid A Availability in US Licensed in June 2006 Application submitted to FDA in March 2007

7. HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials* Phase III Efficacy Trials** Adolescent Immunogenicity Safety Trials Quadrivalent Merck females 16-23 yrs females 16-26 yrs 9-15 yrs Bivalent GSK females 15-25 yrs females 15-25 yrs 10-14 yrs *powered to detected incident and persistent infection endpoints **powered to detect CIN 2/3 or AIS endpoints

8. HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials* Phase III Efficacy Trials** Adolescent Immunogenicity Safety Trials Immunogenicity and efficacy in females > 25 years Quadrivalent Merck females 16-23 yrs females 16-26 yrs 9-15 yrs24-45 yrs Bivalent GSK females 15-25 yrs females 15-25 yrs 10-14 yrs25-55 yrs *powered to detected incident and persistent infection endpoints **powered to detect CIN 2/3 or AIS endpoints

9. Quadrivalent HPV Vaccine Efficacy Phase III Trials Prevention of HPV 6,11,16,18-related outcomes Endpoint Vaccine N cases Placebo N cases Efficacy(95% CI) CIN 2/3 or AIS5305 15260 42 98%(86-100) Condyloma2261 02279 48 100%(92, 100) VIN or VaIN 2/37811 07785 15 100%(72-100) Per Protocol Population; mean follow-up 3 years CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ; VIN – vulvar intraepithelial neoplasia; VaIN – vaginal intraepithelial neoplasia NEJM 2007;356 NEJM 2007;356 Lancet 2007;369

10. Quadrivalent HPV Vaccine Intent-to-Treat Analysis HPV 6,11,16,18-related outcomes Endpoint Vaccine cases Placebo cases Efficacy(95% CI) CIN2/3 or AIS13723241%(27, 53) VIN or VaIN 2/393171%(37, 88) Vulvar and vaginal lesions (including genital warts) 7231978%(71, 83) Barr, Presented at ACIP – February 2007; mean follow up 2.8 years No ‘therapeutic efficacy’ – therefore, efficacy lower in intent-to-treat population

11. Bivalent HPV Vaccine Efficacy Phase III Trial Prevention of HPV 16/18 CIN2/3 and AIS Endpoint Vaccine N cases Control N cases Efficacy(97.9%CI) CIN2/3 or AIS7788 27838 21 90%(53-99) Total vaccinated population,15-25 year old females; mean follow-up 15 months CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ Lancet 2007;369

12. Duration of protection How long will the vaccines provide protection?

13. Mean Follow-up Time in Clinical Trials to Date TrialsQuadrivalentBivalent Phase III4 years15 months Phase II5 years~6 years Published or presented 90-100% efficacy found for all endpoints No evidence of waning protection against disease

14. Quadrivalent Vaccine HPV 16 GMTs and Response to Dose 4 Olsson, et al. Vaccine 2007

15. Cross Protection Do the HPV vaccines provide protection against related HPV types?

16. HPV Types in Cervical Cancer Worldwide Cancer cases attributed to the most frequent HPV genotypes (%) HPV genotype Vaccine types 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 1.2 4.4 53.5 2.6 17.2 6.7 2.9 01020 30 405060708090 100 X Other 82 73 68 39 51 56 59 35 58 52 33 31 45 18 16 53.5% 70.7% Munoz N et al. Int J Cancer 2004; 111: 278–85.

17. Phylogenetic Characterization of Oncogenic HPV Types HPV 16 related HPV 18 related

18. Cross-protection: Bivalent Vaccine 6 month Persistent Infection HPV Type Efficacy(97.9% CI) Type 45*59.9(2.6 - 85.2) Type 31 + 36.1(.5 - 59.5) Type 33 + 36.5(-9.9 - 64.0) Type 52 + 31.6(3.5 - 51.9) Type 58 + -31.4(-132 – 24.7) Paavonen, et al. Lancet 2007;369 * HPV 18 related; + HPV 16 related Significant protection against combination of (12) non-vaccine oncogenic types using 12 mos persistent infection: VE = 27%; CI: 0.5-47%

19. Cross Protection: Quadrivalent Vaccine CIN 2/3 and AIS HPV TypesEfficacy(95% CI) A9 Species (16 related) 45%(10, 68) HPV 31, 33, 35, 52, 58 A7 Species (18 related) 46%(-35, 80) HPV 39, 45, 59 Villa, et al. Presented at Eurogin 2007

20. Ongoing or Planned Studies QuadrivalentBivalent Follow-up phase II and III trials xx Immuno/efficacy in females >25 yrs xx Efficacy trials in men 16-26 yrs x Simultaneous administration xx Comparative immunogenicity xx Safety & immunogenicity in HIV+ women (and men - Quadrivalent) xx Phase 4: long term follow-up xx

21. HPV Vaccine Recommendations Upcoming Issues Projected Dates for ACIP Review Issue June/Oct 2008 Quadrivalent vaccine: females 27-45 yrs 2008 - 2009 Bivalent vaccine: females 2009 Quadrivalent vaccine: males

22. Quadrivalent HPV Vaccine Efficacy in Women 24-45 years Per-Protocol Efficacy Endpoint Vaccine (N=1910) Placebo (N=1907)Efficacy95% CI HPV 6/11/16/18-related persistent infection, CIN or EGL 44191%(74, 98) HPV 16/18-related persistent infection, CIN or EGL 42383%(51, 96) HPV 6/11-related persistent infection, CIN or EGL 019100%(79, 100) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ, EGL – external genital lesions Haupt – presented at Feb 2008 ACIP meeting

23. Quadrivalent HPV Vaccine in women 27- 45 years If FDA approved, what recommendations should be made for vaccine use in women in this age group? –Efficacy in women naïve to respective vaccine type –With increasing age, the rate of new HPV infections decrease and the likelihood of prior infection increases –Cost effectiveness of vaccination decreases with increasing age

24. Bivalent HPV Vaccine If FDA approved, there will be two HPV vaccines on market –How should recommendations be stated for the two vaccines? –Can the vaccines be used interchangeably in the vaccination series (for protection against HPV 16/18)?

25. Comparison of HPV Vaccines AttributeQuadrivalentBivalent Protection against HPV 16/18 related CIN/AIS* Similar Protection against HPV 6/11 related genital lesions YesNo Cross-protection against high risk types other than HPV 16,18 ? Similar Duration of protection? Similar Safety and adverse events? Similar Cost of vaccine series~$360? * Quadrivalent vaccine - also demonstrated protection against VIN and VaIN

26. Quadrivalent HPV Vaccine for Men No efficacy data available – studies ongoing Considerations for recommendations include impact on reduction of disease in women, benefit to men, cost effectiveness

27. Summary Data on HPV vaccines continue to show high efficacy and good duration of protection New data for HPV vaccines will be available over the coming months and years Upcoming HPV vaccine recommendations to consider –Quadrivalent HPV vaccine for women >26 years –Bivalent HPV vaccine for females –Quadrivalent HPV vaccine for males

28. Thank you

29. Acknowledgments Eileen Dunne Mona Saraiya Deblina Datta Herschel Lawson Beth Unger Harrell Chesson Richard Haupt Gary Dubin

31. Upcoming Issues for ACIP Considerations DateIssue June 2006 Quadrivalent vaccine: females 9-26 yrs June/Oct 2008 Quadrivalent vaccine: females 27-45 yrs 2008 - 2009 Bivalent vaccine: females 2009 Quadrivalent vaccine: males

32. Immunogenicity Main basis of protection is neutralizing antibody Minimum protective antibody titer is not known Serologic tests for HPV antibody not standardized Merck - competitive Luminex immunoassay (cLIA) GSK - type specific ELISA

33. Quadrivalent HPV Vaccine Adolescent Bridging Immunogenicity

34. 34 Seropositivity at Months 7 and 36 Post Vaccination Vaccine/ HPV typeMonth 7Month 36 Quadrivalent* Anti-HPV 6 100%96% Anti-HPV 11 100%98% Anti-HPV 16 100%99% Anti-HPV 18 100%74% Bivalent + Anti-HPV 16 100%99% Anti-HPV 18 100%99% * Villa, et al. Vaccine 2006 - competitive Luminex immunoassay (cLIA) + Harper, et al. Lancet 2006 - type specific ELISA

35. Efficacy Analysis Populations In phase III trials, most females were sexually active and were enrolled without regard to PCR or antibody status Per Protocol Population for Efficacy Naïve to relevant vaccine HPV type through month 7 Cases counted after dose 3 Unrestricted susceptible populations (or total vaccinated) Naïve to relevant vaccine HPV type Cases counted day one after dose 1 Intent-to-Treat Population All subjects regardless of baseline status Cases counted day one after dose 1

36. Bivalent HPV Vaccine Immunogenicity in Women >25 Years Immunogenicity and safety study –Designed to compare titers in women 26-55 yrs and 15-25 years 1 10 100 1000 10000 ATP cohort, Seronegative at entry GMT (EU/ml) Month 7 HPV-16 HPV-18 100% [15-25] [26-35] [36-45] [46-55] Non-inferiority of the immune response was demonstrated for both the 26-45 and 46-55 years age groups

37. Ongoing or Planned Studies Quadrivalent HPV Vaccine Efficacy trials –Women 24-45 yrs (N ~ 3800) –Men 16-26 yrs (N ~ 4000) –Follow-up of adolescent trials (N~1500) Phase IV program –Long term follow-up of phase III Nordic cancer registry –Demonstrate population impact of mass vaccination programs on overall rates of disease - General population of Norway –Post marketing surveillance in US (N ~ 44,000) Alternative dosing schedules

38. Ongoing or Planned Studies Bivalent HPV Vaccine Efficacy trials –Women >25 yrs of age (N ~ 5700) –Women 18-25 yrs Costa Rica (NCI sponsored; N~7500) –Follow-up of adolescent trials (N~1200) Phase IV program –Long term pre-cancer/cancer surveillance in Finland of phase III cohort –Community randomized trial to evaluate herd immunity (60-70,000) –Other phase IV studies under development Comparative Immunogenicity –Bivalent vs quadrivalent (N~ 1000)

39. HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/Analysis Vaccine N cases Control N cases Efficacy( CI ) Quadrivalent Per protocol5305 15260 42 98%(86-100) Unrestricted5865 35863 62 95%(85-99) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ The Future II Study Group. NEJM 2007;356. 16-26 year old females; mean follow-up 3 years

40. Safety Integrated prelicensure database - Injection site events occur more often in vaccine than control recipients No significant increase in serious adverse events or new onset chronic diseases No difference in overall pregnancy outcomes in vaccine or control groups

41. Serious Adverse Events Vaccine Total n (%) Control Total n (%) Quadrivalent*11778 101 (0.9%)9680 97 (1.0%) Bivalent** 9319 330 (3.5%) 9235 323 (3.5%) *Source: /www.fda.gov/ohrms/dockets/ac/06/slides/2006-4222S-2 protocols 007, 013, 015, 016, 018 ** Paavonen; Lancet 2007; 369

42. Bivalent Vaccine Viral Clearance for HPV 16/18 Endpoint Vaccine N cleared Control N cleared Efficacy (95% CI) 6 months241 81288 93 2.6%(−10.1 to 13.8) 12 months149 98196 98 -7%(−31.7 to 13.0) Hildesheim, et al. JAMA 2007

43. HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/Analysis Vaccine N cases Control N cases Efficacy( CI ) Quadrivalent Per protocol5305 15260 42 98(86-100) Unrestricted5865 35863 62 95(85-99) Bivalent Unrestricted7788 27838 21 90(53-99) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ The Future II Study Group. NEJM 2007;356. 16-26 year old females; mean follow-up 3 years Paavonen, et al. Lancet 2007;369 15-25 year old females; mean follow-up 15 months

44. HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/HPV type Vaccine N Cases Control N Cases Efficacy( CI ) Quadrivalent HPV 16 HPV 18 5054 3 5602 0 5043 51 5602 16 94 100 (82-99) (74-100) Bivalent HPV 16 HPV 18 6701 1 7221 1 6717 15 7258 6 93 83 (47-100) (-78-100) Unrestricted susceptible or total vaccinated populations The Future II Study Group. NEJM 2007;356. 16-26 year old females; mean follow-up 3 years Paavonen, et al. Lancet 2007;369 15-25 year old females; mean follow-up 15 months

45. Quadrivalent Vaccine Prevention of HPV 16/18 Related CIN 2/3 or AIS by Baseline HPV Status Baseline Status Vaccine N cases Placebo N cases Efficacy(95% CI) PCR + Sero -423 33402 35 10.0%(<0-46) PCR + Sero +298 47332 52 1.2%(<0-100) PCR - Sero +498 0524 4 100% (<0-35) The Future II Study Group. NEJM 2007;356 – supplementary appendix At baseline, 16% sero or PCR positive to HPV 16; 7% sero or PCR positive to HPV 18

46. HPV-Related Cancers United States, 2003 Anatomic siteTotal Cancers% due to HPV Cervix11,820100 Anus4,18785 Vaginal/vulvar4,57740 Penis1,05940 Oral/Pharyngeal29,62715

47. Safety Multiple safety outcomes evaluated in clinical trials including: –Injection site reactions –Serious adverse events –New onset chronic diseases including new onset of autoimmune diseases –Pregnancy and pregnancy related outcomes

48. Summary: Immune Response Serum antibodies induced in all vaccinees Vaccine induced antibody levels are higher than those seen after natural infection Duration of antibody through ~5 years. Loss of detectable antibody to HPV 18 not associated with loss of protection (Quadrivalent) Challenge produces anamnestic response (Quadrivalent) Antibody titers are non inferior in young adolescents (9 or 10-15 years) compared with women in efficacy trials

49. Summary: Efficacy High efficacy against vaccine HPV type CIN endpoints among females ~16-26 yrs naïve to the relevant vaccine type High efficacy against vaccine HPV type related genital warts, VIN and VaIN (Quadrivalent) Some cross protection against non vaccine types No evidence of therapeutic efficacy

50. Adolescent Bridging Immunogenicity Data Immunogenicity in adolescents non-inferior to older females in phase III efficacy trials Seropositivity similar (>99%) GMTs 2- fold higher

51. HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/Analysis Vaccine N cases Control N cases Efficacy( CI ) Quadrivalent Per protocol5305 15260 42 98%(86-100) Unrestricted5865 35863 62 95%(85-99) Bivalent Unrestricted7788 27838 21 90%(53-99) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ The Future II Study Group. NEJM 2007;356. 16-26 year old females; mean follow-up 3 years Paavonen, et al. Lancet 2007;369 15-25 year old females; mean follow-up 15 months

52. Time to HPV 16/18-Related CIN 2/3 or AIS Intent to treat populations – protocols 07, 013, 015

53. Efficacy for Prevention of HPV Disease, by Baseline Status Quadrivalent HPV Vaccine SeronegativeSeropositive PCR (-)Prophylactic efficacy Few cases 100% efficacy PCR (+) No evidence of efficacy against respective type