1. HPV Vaccines Update on ACIP Recommendations National Immunization Conference April 20, 2010 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. Background Human Papillomavirus > 100 different types identified ~40 types are sexually transmitted “High-risk” types (16, 18, and others) Cervical and other anogenital cancers; subset of oral cavity and oropharyngeal cancers “ Low-risk” types (6, 11, and others) Genital warts and recurrent respiratory papillomatosis

4. Percentage of Cervical Cancers Attributed to HPV types, Worldwide Smith et al. Int J Cancer 2007

5. Human Papillomavirus (HPV) Vaccines Licensed in the US QuadrivalentBivalent HPV Types6, 11, 16, 1816, 18 Schedule3 dose series ManufacturerMerckGlaxoSmithKline Brand nameGardasilCervarix Licensed 2006 - females 9-26 yrs 2009 - males 9-26 yrs2009 - females 10-25 yrs

6. Licensure and Recommendations for HPV Vaccine Quadrivalent vaccine Routine, females 11-12 yrs Catch-up, females 13-26 yrs Quadrivalent or Bivalent vaccine Routine, females 11-12 yrs Catch-up, females 13-26 yrs Quadrivalent vaccine May be given, males 9-26 yrs ACIP, Advisory Committee on Immunization Practices Licensure of Bivalent Vaccine for females Licensure of Quadrivalent vaccine for males

7. Characteristics of Licensed L1 VLP HPV Vaccines QuadrivalentBivalent Composition 20 µg HPV 6 40 µg HPV 11 40 µg HPV 16 20 µg HPV 18 20 µg HPV 16 20 µg HPV 18 Producer cells Saccharomyces cerevisiae (yeast) - expressing L1 Trichoplusia ni insect cell line infected with L1 recombinant baculovirus Adjuvant Alum: 225 µg aluminum hydroxyphosphate sulfate AS04: 500 µg aluminum hydroxide 50 µg 3-O-deacyl-4’- monophosphoryl lipid A Schedule0,2,6 months0,1,6 months VLP, virus-like particle

8. HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials females Phase III Efficacy Trials females Bridging Immunogenicity Safety Trials Efficacy and Immunogenicity females > 25 years Quadrivalent 16-23 yrs16-26 yrs9-15 yrs24-45 yrs Bivalent 15-25 yrs 10-14 yrs>25 yrs *In ATP or per protocol cohorts

9. HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials females Phase III Efficacy Trials females Bridging Immunogenicity Safety Trials Efficacy and Immunogenicity females > 25 years Quadrivalent Mean Follow-up* 16-23 yrs 5 years 16-26 yrs 3.5 years 9-15 yrs24-45 yrs Bivalent Mean Follow-up* 15-25 yrs 5.9 years 15-25 yrs 2.9 years 10-14 yrs>25 yrs Differences: study populations, control group, serologic & PCR assays, colposcopy evaluations *In ATP or per protocol cohorts

10. HPV Vaccine Efficacy Against Vaccine HPV Type-Related CIN2+ Vaccine/ HPV type Vaccine N cases Placebo N cases Vaccine Efficacy % (CI) Bivalent* HPV 16/187344 47312 56 93% (80, 98) HPV 166303 26165 4696% (83,100) HPV 186794 26746 1587% (40, 99) Quadrivalent** HPV 16/187738 27714 100 98% (93,100) HPV 166647 26455 8198%(91,100) HPV 187382 07316 29100% (87,100) *According to protocol population: received all three doses, cases counted day one after dose 3, normal or low grade cytology at baseline; mean follow-up: 2.9 yrs. 96.1% CIs. **Per protocol population: received all three doses, cases counted day one after dose 3; mean follow-up: 3.5 yrs; 95% CIs CIN2+: cervical intraepithelial neoplasia grade 2 or higher or adenocarcinoma in situ Paavonen et al. Lancet 2009; Kjaer et al. Cancer Prev Res 2009; Haupt R. personal communication

11. HPV Vaccine Efficacy Against Vaccine Type-Related Endpoints Vaccine/ Endpoints Vaccine N cases Placebo N cases Vaccine Efficacy % 95% (CI) Quadrivalent* VIN/VaIN2+7900 07902 23 100% (83,100) Condyloma6932 26856 189 99% (96,100) *HPV 6,11,16,18 related; Per protocol population: received all three doses, cases counted day one after dose 3; mean follow-up: 3.5 yrs CIN2+: cervical intraepithelial neoplasia grade 2 or higher or adenocarcinoma in situ VIN: vulvar intraepithelial neoplasia; VaIN: vaginal intraepithelial neoplasia Kjaer et al. Cancer Prev Res 2009. FDA. Label Gardasil

12. HPV Vaccine Cross Protection Some data suggest vaccines may provide protection against types other than those in the vaccine (cross protection) Types examined are those phylogenetically related to HPV 16 and 18 Difficult to assess due to co-infections with vaccine types Data suggest bivalent vaccine may have more cross protection than the quadrivalent vaccine Direct comparisons difficult because of differences in trial methods

13. Bivalent HPV Vaccine Safety Assessment Evaluations for solicited symptoms unsolicited symptoms medically significant conditions new onset autoimmune disorders and chronic diseases serious adverse events pregnancy outcomes Integrated safety analysis from 11 trials of bivalent HPV vaccine involving ~30,000 females Meta-analysis of autoimmune diseases from trials of AS04 containing vaccines involving ~68,000 subjects

14. Bivalent HPV Vaccine SAEs and New Onset Autoimmune Disorders Pooled Safety Database*, Females 10-25 years SAE – serious adverse event *Entire observation period

15. Comparative Trial Bivalent & Quadrivalent HPV Vaccines Serum Neutralizing HPV 16 & 18 Antibody Titers 3.7-fold 7.3-fold Bivalent vaccine induced significantly higher serum neutralizing antibody titers than quadrivalent (p<0.0001) at Month 7. Since both vaccines produce antibody titers higher than those after natural infection, clinical significance of this unclear. Einstein et al. Human Vaccines 2009

16. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

17. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

18. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- Cross-protection against CIN2+ due to high risk types other than HPV 16,18 Some types phylogenetically related to HPV 16? Some types phylogenetically related to HPV 16 and 18? *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

19. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- Cross-protection against CIN2+ due to high risk types other than HPV 16,18 Some types phylogenetically related to HPV 16? Some types phylogenetically related to HPV 16 and 18? Seroconversion to vaccine types>99% *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

20. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- Cross-protection against CIN2+ due to high risk types other than HPV 16,18 Some types phylogenetically related to HPV 16? Some types phylogenetically related to HPV 16 and 18? Seroconversion to vaccine types>99% Geometric mean antibody titersbivalent > quadrivalent *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

21. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- Cross-protection against CIN2+ due to high risk types other than HPV 16,18 Some types phylogenetically related to HPV 16? Some types phylogenetically related to HPV 16 and 18? Seroconversion to vaccine types>99% Geometric mean antibody titersbivalent > quadrivalent Duration of protectionunclear if any differences *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

22. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- Cross-protection against CIN2+ due to high risk types other than HPV 16,18 Some types phylogenetically related to HPV 16? Some types phylogenetically related to HPV 16 and 18? Seroconversion to vaccine types>99% Geometric mean antibody titersbivalent > quadrivalent Duration of protectionunclear if any differences Local reactogenicitybivalent > quadrivalent *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

23. Current Understanding of HPV Vaccines in Females AttributeQuadrivalent Bivalent Protection against HPV 16/18 related CIN2+*>98%>93% Protection against HPV 6/11 related genital lesions ~99%- Cross-protection against CIN2+ due to high risk types other than HPV 16,18 Some types phylogenetically related to HPV 16? Some types phylogenetically related to HPV 16 and 18? Seroconversion to vaccine types>99% Geometric mean antibody titersbivalent > quadrivalent Duration of protectionunclear if any differences Local reactogenicitybivalent > quadrivalent Cost of vaccine dose** ~$130 private ~$108 CDC contract ~$128 private ~$96 CDC contract *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm

24. Provisional ACIP Recommendations for Vaccination of Females Routine vaccination of females aged 11 or 12 years Catch-up vaccination of females aged 13 through 26 years who have not been previously vaccinated Vaccination with either bivalent HPV vaccine or quadrivalent HPV vaccine for prevention of cervical cancers and precancers Vaccination with quadrivalent HPV vaccine for prevention of cervical cancers, precancers and genital warts* * quadrivalent vaccine has also demonstrated efficacy against vulvar and vaginal precancers and is recommended for the prevention of vulvar and vaginal cancers and precancers http://www.cdc.gov/vaccines/recs/provisional/downloads/hpv-vac-dec2009-508.pdf

25. Harmonization of Age Groups, Dosing Schedule and Minimal Intervals The quadrivalent HPV vaccine and bivalent HPV vaccines administered in a 3-dose schedule –Can be given as young as 9 years and catch-up through age 26 yrs Second dose,1-2 months after first dose; third dose, 6 months after first dose Minimal intervals similar for two vaccines

26. Interchangeability of HPV Vaccines ACIP recommends that the HPV vaccine product be used for the entire vaccination series If vaccination provider does not know or have available the HPV vaccine product previously administered, either HPV vaccine product can be used to complete the series to provide protection against HPV 16 & 18

27. Precautions and Contraindications Not recommended for use in pregnant women; pregnancy testing is not needed before vaccination –Any exposure to vaccine during pregnancy should be reported to the appropriate vaccine pregnancy registry: 1-800-986-8999 (quadrivalent HPV vaccine) 1-888-452-9622 (bivalent HPV vaccine) Contraindicated for persons with immediate hypersensitivity to any vaccine component –Quadrivalent HPV vaccine - yeast –Bivalent HPV vaccine in prefilled syringes - latex

28. Quadrivalent HPV Vaccine for Males

29. HPV Epidemiology in Males Males have similar prevalence of HPV infection compared to females Burden of diseases and cancers includes genital warts, RRP, anal, penile, oral cavity and oropharyngeal cancers Transmission high between sex partners MSM - Greater burden of HPV-related outcomes –Anal cancer: 2 per 100,000 in men and 35 per 100,000 in MSM (HIV negative) RRP, recurrent respiratory papillomatosis

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. Quadrivalent HPV Vaccine Efficacy Study in Males Study population –Heterosexual men (HM) ~ 3000 –Men having sex with men (MSM) ~ 600 Primary objectives –Efficacy for HPV 6/11/16/18 ‑ related –Main study: HM + MSM External genital warts Penile/perianal/perineal precancers and cancer – Sub-study: MSM Anal precancer lesions and cancer

32. Quadrivalent Vaccine Efficacy Prevention of HPV 6/11 Related Genital Warts, Males 16-26 Years Endpoint HPV4 N Cases Placebo N Cases % Efficacy (95% CI) Genital warts1245 31244 2889 (66, 98) Interim Analysis; per-protocol efficacy population, mean follow-Up 2.2 yrs, received all three doses of vaccine; naïve to vaccine type at baseline FDA licensed for use in males 9 through 26 years for prevention of HPV 6/11 related genital warts

33. Considerations HPV vaccine for Males Vaccine efficacy Epidemiology and burden of disease Programmatic issues Cost effectiveness –Male vaccination is most cost effective when Coverage among females is low All potential health outcomes included Vaccine efficacy is high in males

34. Cost Effectiveness Ratios for Male HPV Vaccination in the US Impact of Disease Outcomes Kim and Goldie. BMJ 2009 Assumes 100% efficacy in girls Assumes 75% coverage in girls and boys

35. Estimated 1+ Dose HPV Vaccination Coverage, Females 13-17 Years National Immunization Survey 2007 and 2008 National Immunization Survey. MMWR 2008;57 National Immunization Survey. MMWR 2009;58

36. HPV Vaccine Use in Males: Discussions at October 2009 ACIP Programmatic challenges at state and local level Most of the burden of disease/cancers in females Priority should be given to vaccinating females to reduce the overall burden of disease/cancers Outstanding information for future consideration: –Efficacy for prevention of AIN –Cost effectiveness in MSM –Vaccine price

37. ACIP Guidance: Q uadrivalent HPV vaccine may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. Ideally, should be administered before potential exposure to HPV through sexual contact. Vaccines for Children (VFC): Quadrivalent HPV vaccine for males approved to be included in VFC enabling VFC providers to provide VFC HPV vaccine to eligible males, age 9 through 18 years. ACIP Guidance and VFC Resolution, October 2009 http://www.cdc.gov/vaccines/recs/provisional/default.htm#acip http://www.cdc.gov/vaccines/programs/vfc/downloads/resolutions/1009hpv-508.pdf

38. Quadrivalent HPV Vaccine Efficacy Prevention of HPV 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) Males 16-26 years Endpoint HPV N Cases Placebo N Cases % Efficacy (95% CI) Any grade AIN194 5208 2478 (40, 93) AIN 2/3194 3203 1375 (9, 95) Haupt R, ACIP Presentation, February 2010

39. HPV Vaccine for Males Further consideration of –Vaccine efficacy data –Cost effectiveness analyses with different efficacy and coverage assumptions –Programmatic issues, equity issues –Epidemiology and cost effectiveness of HPV vaccine in MSM –Feasibility of reaching MSM when they would most benefit from vaccination

40. Quadrivalent HPV vaccine for Women Older than 26 Years? Trials conducted in women age 24-45 years Relatively small impact of vaccination of adult women –Incidence of new infections decreases –% of women with previous infection increases Models show potential for high cost per QALY

41. Summary –ACIP recommendations first made in 2006 and updated in October 2009 Two vaccines available for females 9 through 26 years –Either vaccine recommended at 11 or 12 years –Catch up through age 26 years Quadrivalent HPV vaccine may be given to males ages 9 through 26 years –Further data/policy issues in next year Quadrivalent HPV vaccine in males HPV vaccine for women >age 26 years

42. Thank you