1. Preventing Cervical Cancer: Human Papillomavirus (HPV) Vaccine
Laura A. Koutsky, Ph.D.
Department of Epidemiology
University of Washington

2. Financial Disclosure
The University of Washington has received funds from Merck to support HPV vaccine research conducted by Laura Koutsky

3. Who gets genital HPV infection?

4. Transmission of Genital HPV Types
Mother to infant during birth -uncommon
Fingers - uncommon
Oral sex - uncommon
Anal intercourse - common
Vaginal intercourse - common

5. Cumulative Incidence of HPV Genital Infection Associated with a First Sex Partner (n=122)
*From date of first reported vaginal intercourse with a male partner (Women were censored at reported date of a second sex partner)

6. Genital HPV Types CANCER HPV TYPE FINDINGS POTENTIAL Low (negligible)
6, 11
40, 42, 43, 44, 54, 61, 70, 71, 72, 81
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
Uncertain cancer potential: HPV 26, 34, 53, 57, 66, 83
CLINICAL
FINDINGS
genital warts,
low grade genital lesions, RRP
low grade genital lesions
low & high grade genital lesions,
cancer
CANCER
POTENTIAL
Low
(negligible)
High

7. Potential Annual Impact of HPV 6/11/16/18 Vaccine in the U. S
Potential Annual Impact of HPV 6/11/16/18 Vaccine in the U.S. (SEER, Chesson HW, Persp Repro Health 2004, Saslow D, CA Cancer 2007)
HPV- Related Disease
Estimated Annual
Morbidity Prior to HPV Vaccines
Vaccine Preventable
HPV 6-, 11-, 16-, or 18-Related Morbidity
Invasive cervical cancer
9,700
6,790 (~70%)
Vulvar, vaginal, penile, and anal cancers
5,700
2,850 (~50%)
Head and neck cancers
39,000
5,850 (~15%)
Recurrent Respiratory papillomatosis (RRP)
1,000
800 (~80%)
CIN 2/3, AIS
500,000
250,000 (~50%)
Genital warts
400,000 (~80%)

8. HPV L1 Virus-Like-Particle (VLP) Vaccine Synthesis
+ adjuvant
L1 gene of HPV DNA
Inside
HPV
empty viral capsids
(VLP)
Elicits immune response in host
Transcription
L1 gene is inserted into a plasmid, which is inserted in the nucleus of a cell
Capsid proteins
mRNA
Translation
Eukaryotic Cell

9. Randomized Clinical Trials (Phase IIb) of HPV6/11/16/18 or HPV16/18 Vaccines in Susceptible Women (~15 to 25 Yrs); 4.5 Yrs F/U Post-Vaccination
Merck GlaxoSmithKline
Gardasil™ Vaccine Cervarix™ Vaccine
HPV6/11/16/ Efficacy HPV16/ Efficacy
Vaccine Placebo (95% CI) Vaccine Placebo (95% CI)
Endpoint:
HPV 6/11/16/ %
CIN or EGW (12, 100)
HPV16/ %
CIN (42,100)
Merck Vaccine: HPV6/11/16/18 L1 VLP with injections 0, 2, 6 mo. (BJC 2006;95:1459)
GSK Vaccine: HPV16 & 18 L1 VLP with injections 0, 1, 6 mo. (Lancet 2006; 364:1757)

10. Anti- HPV-6, -11,-16, & -18 Titers after Natural Infection or after Immunization with HPV6/11/16/18 Vaccine

11. Phase III Prophylactic Quadrivalent HPV 6/11/16/18 Vaccine Program

12. Characteristics of Women from Asia, Europe, Latin America and North America in the Quadrivalent HPV6/11/16/18 Vaccine Trials
Day 1 Characteristics
Total (N=20,887)
Mean Age (Range)
20 (15-26)
Mean Age at Sexual Debut (yrs) 17
Median Lifetime Number of Sex Partners 2
LSIL or HSIL 6%
HPV 6, 11, 16, or 18 (+)
27%
Naïve to all 4 HPV types
73%

13. HPV6/11/16/18 Vaccine Efficacy
Prevention of HPV16/18-Related CIN2/3+, and HPV6/11/16/18-Related Vaginal & Vulvar Lesions in Susceptible Female Populations (16-26 years of age) HPV6, HPV11, HPV16, and/or HPV18 naïve at enrollment Mean 2.9 years follow-up post-dose 1
Endpoint
Vaccine Cases
Placebo Cases
HPV6/11/16/18 Vaccine Efficacy
(95% CI)
HPV 16/18-related CIN 2/3
or AIS
N=5,865 3
N=5,863 62
95% (85, 95)
N=2,667
N=2,684
HPV 6/11/16/18- Lesions of the
Vagina and Vulva 4 81
95% (87, 99)

14. Prevention of CIN2/3+ in General Female Population Samples (16 to 26 Years of Age)
Intention-to-Treat populations
Mean 2.9 years follow-up post-dose 1
Endpoint
Vaccine Cases
Placebo Cases
HPV6/11/16/18 Vaccine Efficacy (95% CI)
HPV 16/18-
CIN 2/3 or AIS
Any HPV type-
CIN2/3 or AIS
N=6,087 83
219
N=6,080
148
266
44% (26, 58)
18% (1, 31)

15. Integrated Detailed Safety Database: Clinical Adverse Experience Summary Day 1 to 15 Following Any Vaccination
HPV6/11/16/18 Vaccine
(N = 6,160)
Placebo (N = 4,064)
Women with Follow-up
6069
3994
Women with at Least 1 Adverse Event
90%
86%
Women with ≥ 1 Injection-Site Adverse Event
83%
73%
Women with ≥ 1 Systemic Adverse Event
35%
37%
Women with ≥ 1 Serious Adverse Event
0.6%
0.7%
Discontinued Due to an Adverse Event
0.2%
Women with a Fever (Temp 100F)
11%
10%
Women with High Fever (Temp 102F) 2% 1%

16. Pregnancy Outcomes for Women Enrolled in Merck Phase III HPV Vaccine Trials
1,244 pregnancies in vaccinees and 1,272 pregnancies in placebo recipients
Proportions with live births, difficulties with delivery, and fetal deaths were similar for the two groups
Estimated date of conception within 30 days after any vaccination:
Spontaneous abs in 19 vaccinees and 26 placebo recipients
Congenital anomalies in 5 infants born to women in vaccine group and none in infants born to women in placebo group
(Pyloric stenosis and ankyloglossia, congenital megacolon, congenital hydronephrosis, hip dysplasia, club foot)
Congenital anomalies were diverse and consistent with those generally observed in infants born to young women

17. Summary of HPV6/11/16/18 Vaccine Findings
High efficacy when administered to HPV6/11/16/18 naïve
Administer before sexual debut (11-12 year-old females)
Partial to full protection through age 26 years
Generally safe and well-tolerated
Cannot cause infection; only one viral protein (L1) from each targeted type is included
HPV L1 protein is not a human carcinogen
Safety/tolerability profile similar for those with/without vaccine-type infection
Not recommended for pregnant women
High antibody titers sustained through 5 years
The few vaccine failures not related to low antibody titers
HPV L1 VLPs appear to elicit both B cell and T cell responses
Antigen challenge with HPV6/11/16/18 vaccine at 5 years stimulated anamnestic response (hallmark of vaccine with long-lasting protection)

18. HPV Vaccine Efficacy: Future Data
How long does protection last?
Is there cross-protection for precancerous lesions due to other HPV types?
What is the extent of post-infection prophylaxis?
Does HPV vaccination prevent HPV infection among young men including MSM?
Do rates of HPV acquisition and development of incident CIN2/3 warrant vaccination of older women?
Is HPV vaccination effective in HIV+ adolescents and adults?
If HPV16 and HPV18 infections are prevented will other oncogenic infections take their place?
What is the effect of herd immunity?