1. Update on HPV Vaccines National Immunization Conference April 1, 2009 Lauri E. Markowitz, MD Centers for Disease Control and Prevention

2. The findings and conclusions in this presentation are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention

3. Selected Developments in Past Year Nobel Prize in Medicine 2008 - Professor Harald zur Hausen for discovery of HPV causing cervical cancer First national HPV vaccine coverage data from the National lmmunization Survey and safety data from Vaccine Safety Datalink First efficacy data for quadrivalent HPV vaccine in males WHO recommendation for HPV vaccination

4. Overview US Vaccination program HPV Vaccines and Policy Issues International

5. US HPV Vaccination Program

6. Quadrivalent HPV Vaccine Introduction Timeline in the US FDA licensure ACIP recommendationJune 2006 Vaccines for Children vote Vaccines for Children contract Oct 2006 ACIP statement published March 2007 All states purchased VFC vaccineApril 2007 > 23 million doses distributed in the US through 1/09

7. Estimated ≥ 1 Dose HPV Vaccine Coverage, Females 13-17 Years, 2007 National Immunization Survey. MMWR 2008;57 *Molinari et al. National Immunization Conference 2009 No significant differences by race; public insurance associated with higher coverage*

8. National Survey of Physicians 18 Months Post-Licensure Percentage of Pediatricians Recommending HPV Vaccine to Females, by Age Group Daley, presented at Oct 2008 ACIP meeting and NIC 2009

9. Most Common Reported Reasons for Vaccine Refusal/Deferral Daley et al. Oct 2008 ACIP meeting and NIC 2009

11. State Legislation and School Immunization Requirements Legislation to fund, educate the public, or for school requirements –~41 states have introduced legislation –>19 states have enacted some type of legislation School Immunization requirements –Virginia –District of Columbia –Will be implemented in 2009-10 academic year –Require girls entering 6 th grade to have HPV vaccine –Opt out provisions –Information sent to parents of 5 th grade girls

12. Post-Licensure Vaccine Safety Monitoring CDC –Vaccine Adverse Events Reporting System* (VAERS) –Clinical Immunization Safety Assessment (CISA) –Vaccine Safety Datalink (VSD) Manufacturer –Post marketing study in managed care organization –Vaccine in Pregnancy Registry –Nordic Cancer Registry *with FDA

13. U.S. Vaccine Safety Datalink Evaluation of Quadrivalent Vaccine Tests hypotheses suggested by VAERS & prelicensure data Large database that collects medical and vaccine information > 9 million people annually from 8 MCOs Evaluated events after > 470,000 HPV vaccine doses included in Rapid Cycle Analysis GBS, seizures, syncope, venous thromboembolic events, anaphylaxis, and stroke Findings do not support causal association

14. Monitoring Impact of HPV Vaccination in the United States Cervical cancer –Established cancer registries –HPV typing to be initiated at several sites Cervical Precancers –New sentinel projects with HPV typing of lesions –Administrative data Genital warts –Network of STD clinics Type-specific HPV prevalence –Self-collected vaginal swabs - National Survey –Routine Pap specimens

15. HPV Vaccines and Future Policy Issues

16. Upcoming HPV Vaccine Policy Issues Policy IssuePossible Decision Date* Bivalent vaccine, femalesOct 2009 Quadrivalent vaccine, malesOct 2009 Quadrivalent vaccine, females >26 yrs2010 *By Advisory Committee on Immunization Practices (ACIP)

17. Prophylactic HPV VLP Vaccines Quadrivalent (Merck)Bivalent (GSK) Availability in US Licensed in June 2006Application submitted HPV Types HPV 6/11/16/18HPV 16/18 Manufacturing Yeast - S. cerevisiaeBaculovirus Schedule 0,2,6 months0,1,6 months Adjuvant Alum 225 µg Aluminum Hydroxyphosphate Sulfate AS04 500 µg Aluminum Hydroxide 50 µg 3-deacylated Monophosphoryl Lipid A

18. HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials females Phase III Efficacy Trials females “Bridging” Adolescent Immunogenicity Safety Trials Efficacy (and immunogenicity) females > 25 years Quadrivalent Merck 16-23 yrs16-26 yrs9-15 yrs24-45 yrs Bivalent GSK Powered to detect: 15-25 yrs Persistent Infection 15-25 yrs CIN 2/3 and AIS 10-14 yrs26-55 yrs CIN 2/3 = moderate/high-grade cervical intraepithelial neoplasia AIS = adenocarcinoma in situ

19. HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials females Phase III Efficacy Trials females “Bridging” Adolescent Immunogenicity Safety Trials Efficacy (and immunogenicity) females > 25 years Quadrivalent Merck Follow-up to date 16-23 yrs 5 years 16-26 yrs 3.7 years 9-15 yrs24-45 yrs Bivalent GSK Follow-up to date 15-25 yrs 6.4 years 15-25 yrs 15 months 10-14 yrs26-55 yrs

20. Efficacy and Immunogenicity 90-100% efficacy for vaccine type related CIN2/3 or AIS among those without evidence of prior infection No evidence of waning protection through follow-up period Almost all vaccinees develop antibody, with titers higher than those after natural infection Minimum protective antibody titer is not known Some participants who received quadrivalent HPV vaccine lost detectable antibody to HPV 18; no evidence of waning protection

21. HPV Vaccine Cross Protection? Some data suggest the vaccines may provide protection against HPV types other than those in the vaccine Feasible since some HPV types have similar L1 proteins Types examined are those related to HPV 16 and 18

22. 8 most common HPV types in 14,097 cases of invasive cervical cancer by region 70% 72% 67%74% 76% 65% IARC

23. Cross-Protection against 6 month Persistent Infection Efficacy (CI), % TypeQuadrivalentBivalent A9 species (16 related) 31 46 (14, 59) 36 (0.5, 60) 33 29 (-45, 66) 36 (-10, 64) 52 18 (-21, 45) 32 (4, 52) 58 6 (-54, 42) -31 (-132, 25) A7 species (18 related) 45 8 (-67, 49) 60 (3, 85) Brown et al. JID 2009;199 Paavonen et al. Lancet 2007;369

24. Cross-Protection against CIN2/3 Outcomes Efficacy (CI), % TypeQuadrivalentBivalent A9 species (16 related) 31 70 (32, 88) 33 24 (-71,67) 52 25 (-46,62)NA 58 19 (-65, 61) A7 species (18 related) 45 -52 (-1717, 83) Brown et al. JID 2009;199 Paavonen et al. Lancet 2007;369

25. Policy issue: 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)?

26. 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 ?? Duration of protection?? Reactogenicity/safety?? Cost of vaccine dose$130? * Quadrivalent vaccine also demonstrated protection against VIN and VaIN

27. Policy issue: Quadrivalent HPV Vaccine for Males Considerations: –epidemiology of HPV in males –burden of disease –vaccine acceptability –vaccine efficacy and immunogenicity –cost effectiveness

28. Partridge JID 2007 Cumulative Incidence of HPV Infection Males 18-23 years, Seattle, WA

29. HPV-associated Cancers and Attributable Fraction due to HPV Cancer% due to any HPV Infection % of HPV-related which are types 16/18 Cervical10070 Vaginal4080 Vulvar4080 Anal9092 Penile4063 Oral Cavity & Oropharyngeal 25-3589 Parkin DM et al. The burden of HPV-related cancers. Vaccine 2006. Kreimer A et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epid Biomarkers Prev 2005.

30. HPV-associated* Invasive Cervical Carcinomas and Other Squamous Cell Carcinomas, 1998-2003 Anatomic Area Average Annual Incidence Count Cervix10,846 Vagina 601 Vulva2,266 Anus & rectum1,935 Oropharynx & oral cavity1,702 Total (Women)17,350 Penis 828 Anus & Rectum1,083 Oropharynx & oral cavity5,658 Total (Men)7,568 *Defined by histology and anatomic site Watson M et al. Using Population-based Cancer Registry Data to Assess the Burden of Human Papillomavirus-associated Cancers in the United States: Overview of Methods. Cancer 2008. Data source: National Program of Cancer Registries and SEER, covering 83% coverage of US population.

31. Genital Wart Diagnoses by Age Group Men and Women, Medstat, 2000 Cases./1000 py Age in years Insigna R, CID 2003

32. Quadrivalent HPV Vaccine Efficacy Study in Men Heterosexual men (HM) –3400: 16-23 year olds Men having sex with men (MSM) –600: 16-26 year olds Primary Objectives : Efficacy for 6/11/16/18 ‑ related –Main study: HM + MSM External genital warts Penile/perianal/perineal precancers lesions and cancer –Sub-study: MSM Anal precancer lesions and cancer

33. Quadrivalent HPV Vaccine Efficacy in Men: Interim Results HPV 6,11,16 18 related Vaccine (n= 1390) Placebo (n=1400) Efficacy95% CI External genital lesions*33990%(69, 98) Per-Protocol Efficacy Population Palefsky and Giuliano, presented at EUROOGIN meeting, November 2008 *Genital warts and penile/perineal/perianal intraepithelial neoplasia

34. Quadrivalent HPV Vaccine for Males: Issues to Consider HPV prevalent infection in males HPV vaccine has potential for impact on males and their partners High efficacy data for prevention of genital warts; no data on precancer lesions Existing cost effectiveness models: with high coverage in females, vaccination of males may not be cost effective for prevention of cervical cancer –Disease burden in males needs to be considered

35. International Issues

36. Estimated Number of Cervical Cancer Cases and Incidence - 2002 < 87.3 < 16.2 < 32.6 < 9.3 < 26.2 N. AMERICA 14,670 C-S. AMERICA 71,862 AFRICA 78,897 ASIA 265,884 EUROPE 59,931 Age-adjusted incidence rates per 100,000 women per year GLOBOCAN 2002

37. HPV Vaccine International Progress GAVI board agreed to prioritize HPV vaccines along with other new vaccines - Oct 2008 (no funding yet) WHO recommended that HPV vaccination should be included in national immunization programs – Nov 2008* While vaccines are licensed in >90 countries, implementation limited outside of Europe, North America and Australia Costs of the vaccines are major barrier *Weekly Epidemiologic Record No. 1-2, January 2009

38. School-Based Vaccination Programs Australia* –Quadrivalent HPV vaccine –School-based component started in April 2007 –Target group: 12-13 year old girls –Catch up 14-26 yrs (through 18 yrs in schools) –Coverage for year 1 –64%-82% initiation –50%-72% all three doses United Kingdom –Bivalent HPV vaccine –School-based component started in 2008 –Target age group: 12-13 year old girls *Brotherton et al. Commun Dis Intell 2008;32

39. School-based HPV Vaccination Campaign in the UK

40. Summary (con’t) US vaccination program –Progress is being made in vaccine implementation; post licensure vaccine monitoring is ongoing. Further efforts are needed to increase uptake. Information and educations efforts as well as other strategies will be helpful. Vaccines and policy issues –Policy issues that may need to be addressed in the next year include the bivalent HPV vaccine for females and the quadrivalent HPV vaccine for males.

41. Summary (con’t) International –Largest burden of cervical cancer is in developing countries and efforts are underway to make HPV vaccine available. –Several developed countries have had success in school-based vaccine delivery programs.

42. Thank you