Preventing Cervical Cancer: Human Papillomavirus (HPV) Vaccine Laura A. Koutsky, Ph.D. Department of Epidemiology University of Washington
Financial Disclosure The University of Washington has received funds from Merck to support HPV vaccine research conducted by Laura Koutsky
Who gets genital HPV infection?
Transmission of Genital HPV Types Mother to infant during birth -uncommon Fingers - uncommon Oral sex - uncommon Anal intercourse - common Vaginal intercourse - common
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)
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
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%)
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
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 HPV6/11/16/18 Efficacy HPV16/18 Efficacy Vaccine Placebo (95% CI) Vaccine Placebo (95% CI) 266 263 481 470 Endpoint: HPV 6/11/16/18- 0 6 100% CIN or EGW (12, 100) HPV16/18- 0 8 100% 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)
Anti- HPV-6, -11,-16, & -18 Titers after Natural Infection or after Immunization with HPV6/11/16/18 Vaccine
Phase III Prophylactic Quadrivalent HPV 6/11/16/18 Vaccine Program
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%
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)
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)
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 100F) 11% 10% Women with High Fever (Temp 102F) 2% 1%
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
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)
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?