2. Overview HPV and HPV Vaccines
Lauri E. Markowitz, MD
NCHHSTP
Centers for Disease Control and Prevention
National Immunization Conference
March 2007

3. The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy.

4. Overview Background HPV HPV vaccines Quadrivalent HPV vaccine
Post Licensure monitoring

5. Background - HPV >100 HPV Types Cutaneous Mucosal (~40 types)
“Common”
“high-risk”
“low-risk”
warts
types
(16,18)
types
(6,11)
(hands/feet)
HPV types differ in their disease association. Cutaneous types cause warts of the hands and feet. Mucosal types are sexually transmitted and are divided into high and low risk types based on their association with cervical cancer. Low risk types cause……
low grade cervical abnormalities
high grade abnormalities/
cancer precursors
anogenital cancers
low grade cervical abnormalities
genital warts
respiratory papillomatosis

6. Genital HPV Infection
HPV is very a prevalent sexually transmitted infection
First genital HPV infection is often acquired soon after sexual debut. Infection with multiple types not uncommon
Infection is usually transient and not associated with symptoms; 90% of infections clear within 2 years
Persistent infection with high risk types - risk factor for cervical cancer
Types 16, 18 cause ~70% of cervical cancers
Types 6, 11 cause ~90% of genital warts

7. HPV Types in Cases of Cervical Cancer
from Different Regions of the World
Types 16 18 45 31 33 52 58
Others
HPV types in cervical cancer from different regions of the world are shown in this slide. The largest % are due to HPV 16 in all areas although there is some regional variation. Together with HPV 18 shown in beige, these two types are responsible for about 70% of cervical cancers.
Clifford: Br J Cancer 2003

8. Percentage of US Adolescents Who Have Had Vaginal Sex, by Gender and Age National Survey of Family Growth (NSFG), 2002 90 77 80 70 70 69 60 49 62 50
Females 40 46 40
Males 26 37 30
To understand HPV epidemiology, one needs to understand sexual behavior. This slide shows the percentabe of US adolescneet who have had sex by gender and age from the National survey of family growth. By 15 years of age, 26% of females have had sex, increasing to 77% by age 19 20 25 10 15 16 17 18 19
Age
Mosher et al., 2005; Vital and Health Statistics: No. 362

9. Cumulative Incidence of HPV Infection among Female College Students by Time Since Sexual Debut
4 years, > 50%
These data show cumulative incidence of any HPV infection by time since sexual debut among a study of college students. Most of whom only had 1 partner. Incidence rises early after onset of sexual activity and by 4 years over 50% have had at least one hpv infection.
Winer et al. Am J Epidemiol 2003,157

10. Prevalence of Any HPV Type among Females by Age, NHANES, 2003-2004 (N=1921)
As I mentioned, HPV is a very prevalent infection. These data are from a recently published study looking at prevalence of HPV among a nationally representative sample of females in the US. Overall prevalence was 27% corresponding to 24.9 million females in this age group with infection in the US. This is prevalence infection and does not represent cummulative infection. It does not measure post infections that may have cleared. Prevalance was highest in year olds – 45%
Dunne et al. JAMA 2007: 297

11. Natural History of HPV Infection and Cervical Cancer
1 year
Up to 5 years
Decades
Persistent
infection
CIN* 2/3
Initial
HPV
infection
CANCER
CIN* 1
The schematic shows some aspects of the natural history of hpv and cervical cancer.
Because cervical cancer screening can allow detection and treatment of precancerous lesions and because of the long time for development of cervical cancer, it was neither ethical nor feasible to use CC as endpoint in clinical trials and CIN2/3 was used.
CLEARED HPV INFECTION
*cervical intraepithelial neoplasia

12. Timeline: Licensed and Candidate Prophylactic HPV Vaccines
Manufacturer
HPV Types
FDA Filing
FDA Decision
ACIP Vote
Quadrivalent
Merck
6/11/16/18
Dec 2005
June
2006
Bivalent
GSK
16/18
2007* ?
* announced

13. 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

14. Licensed and Candidate HPV 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 (ASO4)
females
Vaccine are similar but there are some differences

15. 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
16-26 yrs
9-15 yrs
Bivalent
GSK
15-25 yrs
~15-25 yrs
10-14 yrs
Clinical development programs for these two vaccines have been similar. Both companies conducted phase II efficacy trials, These smaller trials were conducted in female 16 – 23 or 15 to 25 years of age. Larger multinational efficacy trials were conducted in simlar aged women looking at clinical endpoints such as CIN/23 and then adolescent immunogenicity and safety studes were conducted in 9-15 year olds. These immunogenicity studies bridged data from the efficay studies in older women by demonstrating comparable antibody titers in the younger females.

16. HPV Vaccine Phase II Trials Prevention of Persistent Infection
Manufacturer
Vaccine Vaccine Placebo VE (95% CI)
N cases N cases
Merck
HPV % (90,100)
GSK
HPV 16/ % (77,100)
Koutsky et al. NEJM 2002, 347
Harper et al. Lancet 2004, 364
Early data from both manufacturers were very promising. As early as 2002, data suggesting these vaccines would be very effective. A monovalent HPV 16 vaccine was 100% effective in preventing persistent infection as was the bivalent vaccine.

17. Quadrivalent
HPV (types 6,11,16,18) Vaccine

18. Quadrivalent HPV Vaccine FDA Licensure – June 8, 2006
Indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, 18:
Cervical cancer
Genital warts (condyloma acuminata)
Cervical, vaginal and vulvar precancerous or dysplastic lesions

19. Quadrivalent Vaccine: Selected Studies
Phase II “Proof of Concept” Efficacy (HPV 16)
Phase II Quadrivalent Dose-Ranging and Efficacy
Phase III CIN/Warts Efficacy Study
Phase III CIN 2/3 Efficacy Study
Adolescent/Adult Bridging Study
Adolescent Immunogenicity and Safety Study

20. Quadrivalent Vaccine Prophylactic Efficacy Analysis Population
Per Protocol Population:
Naïve to relevant vaccine HPV type through month 7
Received all 3 vaccinations
No protocol deviation
Cases counted after month 7
Although women were enrolled in the efficacy trials regardless of their HPV status, the prespecified analysis populations was done in women who were naïve to the relevant vaccine hpv type through month 7…..

21. Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses
Endpoints
Baseline HPV Status
HPV 6- related
HPV 11- related
HPV 16-related
HPV 18- related
Naïve to all 4 vaccine HPV types
Yes
Positive HPV 6 or 11 Naïve 16/18
Positive HPV 16 Naïve for 6/11/18
Positive HPV 18 Naïve 6/11/16
This slides illustrates an important aspect of the way the analysis was done for the vaccine efficacy analysis.If a women was negative for all 4 vaccine types, she was included in the analysis for all types,

22. Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses
Endpoints
Baseline HPV Status
HPV 6- related
HPV 11- related
HPV 16-related
HPV 18- related
Naïve to all 4 vaccine HPV types
Yes
Positive HPV 6 or 11 Naïve 16/18
Positive HPV 16 Naïve for 6/11/18
Positive HPV 18 Naïve 6/11/16
If she was positive for HPV 16 for example, she was not included in the analysis for HPV 16 endpoints but was included in the analysis of endpoints due to 6, 11 and 18. So some women could have been excluded from the analysis of HPV 16 efficacy but included in the evaluation of efficacy for HPV 18.

23. Efficacy for Prevention of Clinical HPV Disease Due to HPV 6/11/16/18 among 16-26 year-old females*
Endpoint
Vaccine
N Cases
Placebo
Efficacy
(95% CI)
HPV 16/18
related CIN2/3 or AIS
100
(93,100)
HPV 6/11/16/18
related CIN 95
(87, 99)
related genital warts 99
(94,100)
This slide shows the efficacy data for prevention of clinical HPV disease due to vaccine HPV types from the integrated dataset, which included several studies studies. For prevention of HPV 16/18 related cervical intraepithelial neoplasia 2/3 or adenocarcinoma in situ, there were no cases among over 8000 women who received vaccine compared with 83 cases among women who received placebo -- for a 100% efficacy. For prevention of any cervical intraepithelial neoplasia, there were 4 cases among over 7000 women who received vaccine and 83 who received placebo, for an efficacy of 95%; and for prevention of genital warts, there was 1 case in the vaccine group and 91 cases in the placebo group, for an efficacy of 99%.
Package insert: Gardasil® *Integrated dataset; results in the per-protocol populations
CIN – cervical intra epithelial neoplasia; AIS – adenocarcinoma in situ

24. Prophylactic efficacy in HPV-naïve women
Classification by Sero- and PCR- Status at Baseline, Quadrivalent HPV Vaccine Trials
Seronegative
Seropositive
PCR (-)
Prophylactic efficacy in HPV-naïve women
PCR (+)
Because women were enrolled into the study regardless of their HPV status, it was possible to look at efficacy of the vaccine in women who were not naiive to the HPV vaccine types. This slide show 4 different groups of women based on their PCR or serologic status at enrollment. The prophylactic efficcacy was done in women who were pcr and seronative,which I just reviewed showing very high efficacy

25. Classification by Sero- and PCR- Status at Baseline, Quadrivalent HPV Vaccine Trials
Seronegative
Seropositive
PCR (-)
Prophylactic efficacy in HPV-naïve women
PCR (+)
No evidence of efficacy against respective type
Among women who had evidence of infection with a specific type, by pcr, there was no evidence of projection against disese due to that type.

26. Classification by Sero- and PCR- Status at Baseline, Quadrivalent HPV Vaccine Trials
Seronegative
Seropositive
PCR (-)
Prophylactic efficacy in HPV-naïve women
Low infection rate
High efficacy
PCR (+)
No evidence of efficacy against respective type
For those who were were seropostive and PCR negative, there was low recurrent but 100% efficacy

27. Analysis of all women regardless of prior exposure or current infection
27% had evidence of prior exposure or current infection with >1 of 4 vaccine types
Overall efficacy for HPV16/18 related CIN2/3 in this population was 39%
Efficacy will increase with increasing time as more participants exposed to new infections
An analysis was also done including all women regardless of prior exposure or current infection including women in all l four groups I just described. Of note, 27% had evidence of prior expsoure or current infection Because the vaccine is prophylactic and not therapeutic and because some women had infection with vaccine types at enrollment, when all women were included in the analysis the vaccine efficacy against CIN2/3 was 39% rather than 100% seen in the naïve population. Almost all of the disesae was due to infection present at the time of enrollment. Efficacy will increase with increasing time as more participants are exposured to new infections.

28. Quadrivalent HPV Vaccine Immunogenicity Data

29. Seropositivity for Months 7 and 36, Quadrivalent HPV Vaccine Phase II Study
HPV type
Month 7
Month 36
Anti-HPV 6
100%
95.7%
Anti-HPV 11
97.6%
Anti-HPV 16
99.6%
Anti-HPV 18
73.9%
The Month 7 seropositivity rate for each of the 4 vaccine HPV types was nearly 100%.
It is noted that seropositivity remained at >95% for HPV 6, 11, and 16, but fell to 73.9% by Month 24 for HPV 18. The loss of detectable antibody for HPV18 was not associated with loss of protection and efficacy in this group remained high.
Villa et al. Vaccine 2006;24

30. Anti-HPV 16 GMTs Through 5 Years
Protocol 007
10000
Quadrivalent HPV Vaccine
1000
(Log Scale)
GMT
100
This slide shows both the height and the duration of HPV 16 antibody response after vaccination. The white line represents the subset of placebo recipients who were HPV 16 seropositive at day 1 and provides a reference for the natural HPV 16 antibody over a 5 year period. In yellow, is the antibody response to vaccine. As shown, geometric mean antibody titers to HPV 16 after vaccination are much higher than those developed after natural infection. Antibody titers decline over time after the third injection, but plateau by 24 months and for HPV 16 remained higher than those after natural infection through 5 years. 10
Placebo (Sero (+) and PCR (-) * * *
Vaccination
to HPV 16 at Day 1) 7 12 18 24 30 36 54 60
Time Since Vaccination 1 (Months)
Merck, unpublished data, Presented at ACIP meeting, June 2006

31. Immunogenicity Bridge
Anti-HPV 6 Antibody Titers after 3 Doses by Age at Enrollment, Quadrivalent HPV vaccine
Immunogenicity Bridge
Efficacy Program
1600
1500
1300
1100
900
Serum GMT with 95% CI, mMU/mL
700
Immunobriding data – shown here for hpv 6 show that antibody titer were similar or higher than those in women who partcipated in the efficacy evaluation. Titers were highest at yougest ages.
500 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Age at Enrollment (Years)

32. Quadrivalent HPV Vaccine Safety Data

33. Summary: Safety Data Generally well tolerated
Minor adverse events (pain, erythema and edema) occurred more often in vaccine than placebo recipients
No increase in serious adverse or systemic adverse events in vaccine group

34. Infection Site Adverse Events 1-5 Days Post Vaccination Quadrivalent HPV Vaccine Trials
Alum Containing placebo
Saline
Placebo
Pain
84%
75%
49%
Swelling
25%
16% 7%
Erythema
18%
12%
In the vaccine trials, the vaccine was found to be safe with no serious adverse events. The most common adverse events were local injection sites reactions. Here you can see injection site pain, swelling and eyrthema in vaccinees alum containing and saline containing placebo. 84% of vaccinees had pain, 25% swelling and 25% erythema. Almost all of these were described a mild or moderate.

35. Vaccine in Pregnancy
~ 1000 women with pregnancies in vaccine and placebo groups
Of pregnancies with known outcomes
Rates of miscarriages similar in both groups
Rates of congenital anomalies similar
among women with vaccine exposure within 30 days of conception, 5 in vaccine group and 0 in placebo group. All unrelated to each other

36. Quadrivalent HPV Vaccine Summary
High efficacy in 16 to 26 year-old females who are naïve to the respective vaccine HPV types
HPV 16,18 related CIN 2/3
HPV 6,11,16,18 related CIN, external genital lesions
Most reported data from Phase III trials are from a mean of 1.5 years follow-up; Data are available up to 5 years from Phase II trial
No evidence of therapeutic efficacy
Safe; side effects mainly local reactions

37. Quadrivalent HPV Vaccine Summary
>99% seroconversion rates in 9-26 year-olds
Antibody titers decline over time after 3rd injection, but plateau by 24 months
Antibody titers substantially higher than after natural infection; highest in those vaccinated at younger ages
No serologic correlate of immunity

38. HPV Vaccines Additional Clinical Development
Manufacturer
Immunogenicity and Efficacy in
Females >26
Long Term Follow-up
Efficacy
in Men
Quadrivalent
Merck X
Bivalent
GSK

39. Monitoring HPV Vaccine
Post-licensure safety
Coverage
Impact

40. Monitoring Vaccine Safety
CDC
Vaccine Adverse Event Reporting System (VAERS)
Vaccine Safety Datalink (VSD)
Manufacturer
Vaccine in Pregnancy Registry
Follow up of vaccine cohorts (Nordic Cancer Registries)

41. Vaccine Adverse Event Reporting System (VAERS): Quadrivalent HPV Vaccine 5 most frequently reported symptoms (N = 542)
Injection site pain
18%
Dizziness
11%
Syncope
Fever 9%
Nausea (
Data through January 2007; Each report may be coded with more than one symptom
Coding system changed from COSTART to MedDRA, Jan 2007

42. Plans for Monitoring Vaccine Coverage
National Immunization Survey
National Survey of Children’s Health
National Health Interview Survey
Immunization Information System Sentinel Sites
Would be ideal to run these by Nidhi again.

43. National Immunization Survey Teen Module
Conducted Oct-Dec 2006 and may be repeated 4th Q 2007
First data available June 2007
Uses National Immunization Survey (NIS) sample frame methodology
Random digit dial telephone survey
National sample of parents of adolescents aged years (~5000 )
Provider check for verification of vaccination status

44. National Immunization Survey Adult Module
To be conducted in 2nd Q 2007
Telephone interview of adults years
Questions
HPV, other vaccines recommended
Questions being designed currently
No provider check for verification
Will help guide National Health Interview Survey 2008 questions

45. Adolescent Registry Module, Immunization Information System Sentinel Sites
Six geographically limited sites in AZ, DC, MI, MN, MT, and OR
Quarterly data: 3rd Q th Q 2007
Coverage estimates:
Individual vaccines (e.g.,Tdap)
Vaccine series recommended for adolescents
Concomitant administration of recently recommended vaccines (e.g., HPV and Tdap)

46. Monitoring Impact of HPV Vaccination in the United States
Cervical cancer
Cancer registries
HPV typing to be initiated at several sites
Type-specific HPV prevalence
NHANES - self collected vaginal swabs added in 2002
CIN 2/3
Supplemental data collection in Vaccine Safety Datalink (VSD)
Administrative databases
New sentinel projects to be initiated
Genital warts
STD clinics
Other

47. Acknowledgements Robin Curtis Deblina Datta Eileen Dunne Nidhi Jain
Laura Leidel
John Iskander
Claudia Vellozzi