1	Human Papillomavirus (HPV) Vaccine June 2006 Lauri Markowitz, MD DSTD/NCHHSTP Centers for Disease Control and Prevention
2	Candidate Prophylactic HPV Vaccines
3	Outline Background on HPV and cervical cancer HPV vaccine Acceptability Proposed recommendations
4	Background Human Papillomavirus Non enveloped DNA virus >100 different types ~40 types are sexually transmitted “Low-risk” types (6,11, 42, 43, 44…) “High-risk” types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58….)
5
6	Genital HPV Infection HPV is the most common sexually transmitted infection in the US First infection is usually acquired soon after sexual debut. Infection with multiple types common Infection is usually transient and not associated with symptoms – 90% of infections clear within 2 years Persistent HPV infection is cause of cervical cancer as well as other anogenital cancers
7	Natural History of HPV Infection and Cervical Cancer
8	Age-Adjusted Invasive Cancer Incidence Rates, Among Women, U. S., 2000
9	Cervical Cancer Mortality Rates U.S., 1946-1984
10	HPV-Related Disease Burden, U.S. Cervical cancer: 9,710 cases & 3,700 deaths (2006 estimate) 70% caused by types 16,18 Pap tests: 50 million; 2.8 million abnormal Genital warts: .5 to 1million 90% caused by types 6,11 Recurrent respiratory papillomatosis (rare) 90% caused by types 6,11 Other anogenital cancers: (anal, penile, vaginal, vulvar)
11	Percentage of Adolescents Who Have Had Vaginal Sex, by Gender and Age National Survey of Family Growth (NSFG), 2002
12	High Risk HPV Prevalence, by Age Sentinel Surveillance, U.S. 2003-2004 (N=5555)
13	Cumulative Incidence of HPV Infection among Female College Students, by Time Since Sexual Debut
14	HPV Prevalence Population Estimates, U.S. 20 million people are infected 15% of persons age 15-49 currently infected 6.2 million new infections each year > 50% of sexually active men & women acquire genital HPV infection
15	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)
16	Candidate HPV VLP Vaccines
17	HPV Vaccine Initial Clinical Development Programs
18	HPV Vaccine Additional Clinical Development
19	HPV Vaccine Phase II Trials Prevention of 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) Koutsky et al. NEJM 2002, 347 Harper et al. Lancet 2004, 364
20	Efficacy - Phase III Trial Quadrivalent HPV Vaccine HPV 16/18 Related Cervical Cancer Precursors
21	Efficacy - Phase III Trial Quadrivalent HPV Vaccine HPV 6/11/16/18 Related External Genital Lesions
22	Populations in Quadrivalent HPV Vaccine Phase III Clinical Trials
23	"Modified Intent to Treat-3 Population" Modified Intent to Treat-3 Population (MITT-3) Received at least one vaccination and had any follow-up visit one month after dose 1. Cases were counted from 30 days after dose 1. Subjects were included regardless of baseline HPV status.
24	Analysis of Efficacy Against HPV 16/18 Related CIN 2/3 or AIS (Protocol 015)
25
26
27	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 HPV 6,11,16,18 related external genital lesions Efficacy data available through 5 years; duration of protection and need for booster unknown No evidence of therapeutic efficacy Safe; side effects mainly local reactions
28	Quadrivalent HPV Vaccine Summary >99% seroconversion rates in 9-26 year-olds Antibody titers decline over time after 3^rd injection, but plateau by 18 months Antibody titers substantially higher than after natural infection; highest in those vaccinated at younger ages No serologic correlate of immunity
29	HPV Vaccine and Cervical Cancer Screening Even with 100% coverage, current generation HPV vaccines will not eliminate need for cervical cancer screening in the US Types other than HPV 16 and 18 cause ~30% of cervical cancers
30	Pediatricians’ Intention to Recommend HPV Vaccine for Female and Male Patients, by Age
31	Potential Unintended Consequences of HPV Vaccine Increase in sexual risk unlikely Research shows generally low levels of HPV knowledge Multiple influences on adolescent sexual behavior Fear of STD not apparent major motivation for abstinence No evidence of behavioral disinhibition in other similar fields
32	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…. www.frc.org Press release, 10/18/05
33	FDA Licensure – June 8, 2006 GARDASIL is indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18: Cervical cancer Genital warts (condyloma acuminata) and the following precancerous or dysplastic lesions: Cervical adenocarcinoma in situ (AIS) Cervical intraepithelial neoplasia (CIN) grade 2 and grade 3 Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3 Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3 Cervical intraepithelial neoplasia (CIN) grade 1
34	ACIP HPV Vaccine Workgroup Proposed Recommendations (2/06) Routine Vaccination ACIP recommends routine vaccination of females 11-12 years of age with three doses of quadrivalent HPV vaccine. The vaccination series can be started as young as 9 years of age at the discretion of the physician. Presented at February 2006 ACIP meeting
35	Rationale: Routine Vaccination of Females at 11-12 Years Routine Prevalent infection, targeting ‘high risk’ groups not possible Modeling shows more impact 11-12 years More females vaccinated prior to sexual debut than at older ages 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
36	ACIP HPV Vaccine Workgroup Proposed Recommendations Vaccination of Females 13-26 years Vaccination is also recommended for females 13-26 years of age who have not been previously vaccinated. Ideally vaccine should be administered before onset of sexual activity, but females who are sexually active should still be vaccinated.
37	Rationale: Vaccination of Females 13-26 years Older females not yet sexually active can be expected to have the full benefit of vaccination Studies evaluating type-specific prevalence in the US indicate only a small percentage of sexually active females have been infected with all HPV vaccine types Infection with one HPV type does not appear to adversely impact the protection afforded by the vaccine against other vaccine HPV types Overall vaccine effectiveness would be lower when administered to a population of females who are sexually active; most females will derive benefit from vaccination
38	Supply and Price HPV vaccine Potential doses for 11-18 year olds (first year) Estimated uptake = 25% 0.25 x 2 M x 8 cohorts x 3 doses = 12 M doses $120 per dose; $320 per series (private sector)
39	Summary Two HPV vaccines are in development; FDA licensed the quadrivalent HPV vaccine June 2006 ACIP will consider recommendations for quadrivalent vaccine at the June 29-30 meeting Vaccines have high efficacy for prevention of HPV infection, cervical cancer precursor lesions, external genital lesions in females Cervical cancer screening will need to continue Vaccine would be most efficacious administered to young adolescent females HPV vaccine will substantially increase spending in VFC