HPV Vaccines and Data Needed for Development of Recommendations in the United States Lauri E. Markowitz, MD Centers for Disease Control and Prevention National Immunization Conference March 2006

Candidate HPV VLP Vaccines HPV L1 major capsid protein of the virus is antigen used for immunization Expression of L1 protein uses recombinant technology L1 proteins self-assemble into virus-like particles (VLP) HPV VLP

Candidate HPV VLP Vaccines Manufacturer HPV Types Schedule Adjuvant Target Groups Quadrivalent Merck 6/11/16/18 0,2,6 mos Alum females & males Bivalent GSK 16/18 0,1,6 mos and MPL females

HPV Vaccine Clinical Development Programs Manufacturer Efficacy Trials* Adolescent Immunogenicity Safety Trials Quadrivalent Merck females 16-26 yrs 9-15 yrs Bivalent GSK 15-25 yrs 10-14 yrs *endpoints include CIN2/3, AIS

HPV Vaccine Clinical Development Programs Manufacturer Efficacy Older Females Long Term Follow-up Efficacy in Men Quadrivalent Merck X Bivalent GSK

Mean 17 Months of Follow-Up Quadrivalent HPV Vaccine HPV 16/18 Related Cervical Cancer Precursor Lesions Mean 17 Months of Follow-Up Endpoint Vaccine (N=5301) Placebo (N=5258) Efficacy CI HPV 16/18-related CIN 2/3 or AIS 21 100% 76%,100% HPV 16-related CIN 2/3 or AIS 16 75%,100% HPV 18-related CIN 2/3 or AIS 8 42%,100% CI = Confidence Interval (for composite endpoint, 97.5% CI; for remaining rows, 95% CI) Merck, unpublished data

Mean 20 Months of Follow-Up Quadrivalent HPV Vaccine HPV 6/11/16/18 Related External Genital Lesions Mean 20 Months of Follow-Up Endpoint Vaccine (N = 2261) Placebo (N = 2279) Efficacy CI HPV 6/11/16/18-EGL 40 100% 88%,100% HPV 6-related EGL 23 83%,100% HPV 11-related EGL 10 55%,100% HPV 16-related EGL 56%,100% HPV 18-related EGL 3 <0%,100% CI = Confidence Interval (for composite endpoint, 97.5% CI; for remaining rows, 95% CI) Merck, unpublished data

Anti-HPV 16 GMTs Through 3.5 Years Postdose 3 Month Since Enrollment 7 12 18 30 42 48 1 10 100 1000 2000 3000 Vaccination HPV 16 L1 VLP Vaccine Placebo recipients previously infected with HPV 16 Anti-HPV 16 cRIA Geometric Mean Titer (mMU/mL) Mao et al, Obstetrics and Gynecology, 2006

HPV VLP Vaccines: Other findings Bivalent and Quadrivalent HPV Vaccines Younger adolescent bridging studies >99% seroconverson rates GMTs higher than in older females Adverse reactions Mainly local injection site pain No serologic correlate of protection; duration of protection unknown

Background Information for HPV Vaccine Recommendations Vaccine and clinical trials HPV epidemiology and HPV related disease Sexual behavior Vaccine acceptability Impact and cost effectiveness Program/implementation issues

Background Information for HPV Vaccine Recommendations Vaccine and clinical trials HPV epidemiology and HPV related disease Sexual behavior Vaccine acceptability Impact and cost effectiveness Program/implementation issues

Percentage of young adults who have had vaginal sex by gender and age: NSFG 2002 90 77 80 70 70 69 60 49 62 50 Females 40 46 40 Males 26 37 30 20 25 10 15 16 17 18 19 Age Mosher et al., 2005; Vital and Health Statistics: No. 362

Vaccine Acceptability Multiple issues related to a vaccine for a sexually transmitted infection Surveys of providers and parents show generally high acceptability Education about HPV and vaccine likely to increase acceptability

Kahn J et al. Journal of Adolescent Health 2005 Pediatricians’ Intention to Recommend HPV Vaccine to Male and Female Patients, by Age Kahn J et al. Journal of Adolescent Health 2005

Family Research Council and HPV Vaccines FRC welcomes the news that vaccines are in development for preventing…HPV Media reports suggesting that FRC opposes all development or distribution of such vaccines are false. While we welcome medical advances such as an HPV vaccine, it remains clear that practicing abstinence until marriage and fidelity within marriage is the single best way of preventing the full range of STD…, Press release, 10/18/05

Background Information for HPV Vaccine Recommendations Vaccine and clinical trials HPV related disease and epidemiology Sexual behavior Vaccine acceptability Impact and cost effectiveness Programmatic/Implementation

Impact and Cost Effectiveness Models to evaluate HPV vaccine are complex Current HPV vaccines will not eliminate need for cervical cancer screening - types other than HPV 16,18 account for approximately 30% of cervical cancer Vaccine cost ? Costs used in economic analyses: $300 range for 3 dose series including administration

Markov vs Dynamic models Markov models Dynamic models Do not include HPV transmission effects, herd immunity Include HPV transmission effects, herd immunity May understate the benefits of vaccination Potentially more realistic, but introduce additional uncertainty

Models and Cost-Effectiveness of HPV vaccine in the U. S Models and Cost-Effectiveness of HPV vaccine in the U.S. Vaccination of females against HPV types 16/18 at 12 years Markov Models Cost/QALY Goldie et al. (2004) $24,300 Sanders & Taira (2003) $22,800 Kulasingam and Myers (2003) n/a Dynamic Models Taira et al. (2004) $14,600 References: Goldie SJ, et al. Journal of the National Cancer Institute 2004;96:604-15. Sanders GD, Taira AV. Emerging Infectious Diseases 2003;9:37-48. Kulasingam SL, Myers ER. JAMA 2003;290:781-89. Taira AV et al. Emerging Infectious Diseases 2004;19,1915-23

HPV Vaccine Licensure Assumptions Quadrivalent HPV 6,11,16,18 vaccine will be licensed for use in females 9-26 years of age in mid 2006 Quadrivalent HPV vaccine may be licensed for use in males at a later date Bivalent HPV 16,18 vaccine will be licensed for use in females at a later date

Issues - Quadrivalent HPV Vaccine Recommendations Should HPV vaccine be recommended for routine vaccination of females; what age? Should catch-up vaccination be recommended? Should vaccine be recommended for males?

Should HPV vaccine be recommended for routine vaccination of females Should HPV vaccine be recommended for routine vaccination of females? What age? Routine Prevalent infection, targeting ‘high risk’ groups not possible and modeling shows more impact 11-12 years Females vaccinated prior to sexual debut Implementation advantages; consistent with young adolescent health care visit Although duration of protection not known, no evidence of waning immunity; ongoing studies will monitor duration

Should “catch-up” be recommended? Vaccine likely licensed for use through 26 years of age Vaccination could be recommended for some or all ages up to 26 years Ideally vaccine should be administered before onset of sexual activity Modeling indicates impact of vaccination will be realized sooner with wider target age group

Should vaccination of males be recommended? Men play an important role in transmission to women Efficacy for prevention of infection/persistent infection in men unknown Cost effectiveness of vaccinating males for prevention of cervical cancer in women –models differ in their findings HPV vaccine could have direct benefit for men; efficacy for prevention of genital warts or HPV related cancers in males unknown

Summary Two HPV vaccines are in development; FDA approval for the quadrivalent HPV vaccine may be in mid 2006 Vaccines have high efficacy for prevention of persistent HPV infection, cervical cancer precursor lesions, external genital lesions in females Recommendations needed to take into consideration multiple factors, including epidemiology, acceptability, impact and cost effectiveness Vaccine would be most efficacious administered to young adolescents females Impact and cost effectiveness of catch-up vaccination and of vaccination of men need to be considered and recommendations developed when data are available.

Factors Associated with Intention to Recommend HPV vaccine Knowledge about HPV Number of children 10-15 years seen weekly Estimated percentage of children 10-15 sexually active Likelihood of following recommendations Lack of perceived barriers Kahn J et al. Journal of Adolescent Health 2005

Results from Phase II Trials: Vaccine HPV Type Related Persistent Infection Manufacturer Vaccine Vaccine Placebo VE (95% CI) N cases N cases Merck HPV 16 768 0 765 41 100 (90,100) GSK HPV 16/18 366 0 355 16 100 (77,100) NEJM 2002;347 Lancet 2004;364