1. 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

2. 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

3. 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

4. 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

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

6. 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Merck, unpublished data

7. 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Merck, unpublished data

8. 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

9. 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

10. 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

11. 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

12. Percentage of young adults who have had vaginal sex by gender and age: NSFG 200290 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

13. 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

14. 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

16. 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

17. 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

18. 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

19. 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

20. 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:
Sanders GD, Taira AV. Emerging Infectious Diseases 2003;9:37-48.
Kulasingam SL, Myers ER. JAMA 2003;290:
Taira AV et al. Emerging Infectious Diseases 2004;19,

21. 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

22. 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?

23. 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

24. 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

25. 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

26. 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.

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

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