Update on HPV vaccines and recommendations - Lauri Markowitz Plans for monitoring impact of HPV vaccine - Eileen Dunne Uptake of HPV vaccine, ISS Sentinel Sites - Diana Bartlett National Immunization Conference March 2008 HPV Vaccines: New Developments and Current Assessments

Update on HPV Vaccines and Recommendations National Immunization Conference March 2008 Lauri Markowitz, MD NCHHSTP/ CDC

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention

June 2006 Advisory Committee on Immunization Practices (ACIP) Recommendations for Quadrivalent HPV Vaccine Routine vaccination Females age years Catch-up Females age years

Upcoming Issues for HPV Vaccine Recommendations Bivalent HPV vaccine HPV vaccines for females >26 yrs HPV vaccine for males

Prophylactic HPV VLP Vaccines Quadrivalent (Merck)Bivalent (GSK) Vaccine TypeHPV 6/11/16/18HPV 16/18 ManufacturingYeast - S. cerevisiaeBaculovirus Schedule0,2,6 months0,1,6 months Adjuvant Alum: 225 µg Aluminum Hydroxyphosphate Sulfate AS04: 500 µg Aluminum Hydroxide 50 µg 3-deacylated Monophosphoryl Lipid A Availability in US Licensed in June 2006 Application submitted to FDA in March 2007

HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials* Phase III Efficacy Trials** Adolescent Immunogenicity Safety Trials Quadrivalent Merck females yrs females yrs 9-15 yrs Bivalent GSK females yrs females yrs yrs *powered to detected incident and persistent infection endpoints **powered to detect CIN 2/3 or AIS endpoints

HPV Vaccines: Selected Aspects of Clinical Development Programs Vaccine/ Manufacturer Phase II Efficacy Trials* Phase III Efficacy Trials** Adolescent Immunogenicity Safety Trials Immunogenicity and efficacy in females > 25 years Quadrivalent Merck females yrs females yrs 9-15 yrs24-45 yrs Bivalent GSK females yrs females yrs yrs25-55 yrs *powered to detected incident and persistent infection endpoints **powered to detect CIN 2/3 or AIS endpoints

Quadrivalent HPV Vaccine Efficacy Phase III Trials Prevention of HPV 6,11,16,18-related outcomes Endpoint Vaccine N cases Placebo N cases Efficacy(95% CI) CIN 2/3 or AIS %(86-100) Condyloma %(92, 100) VIN or VaIN 2/ %(72-100) Per Protocol Population; mean follow-up 3 years CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ; VIN – vulvar intraepithelial neoplasia; VaIN – vaginal intraepithelial neoplasia NEJM 2007;356 NEJM 2007;356 Lancet 2007;369

Quadrivalent HPV Vaccine Intent-to-Treat Analysis HPV 6,11,16,18-related outcomes Endpoint Vaccine cases Placebo cases Efficacy(95% CI) CIN2/3 or AIS %(27, 53) VIN or VaIN 2/393171%(37, 88) Vulvar and vaginal lesions (including genital warts) %(71, 83) Barr, Presented at ACIP – February 2007; mean follow up 2.8 years No ‘therapeutic efficacy’ – therefore, efficacy lower in intent-to-treat population

Bivalent HPV Vaccine Efficacy Phase III Trial Prevention of HPV 16/18 CIN2/3 and AIS Endpoint Vaccine N cases Control N cases Efficacy(97.9%CI) CIN2/3 or AIS %(53-99) Total vaccinated population,15-25 year old females; mean follow-up 15 months CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ Lancet 2007;369

Duration of protection How long will the vaccines provide protection?

Mean Follow-up Time in Clinical Trials to Date TrialsQuadrivalentBivalent Phase III4 years15 months Phase II5 years~6 years Published or presented % efficacy found for all endpoints No evidence of waning protection against disease

Quadrivalent Vaccine HPV 16 GMTs and Response to Dose 4 Olsson, et al. Vaccine 2007

Cross Protection Do the HPV vaccines provide protection against related HPV types?

HPV Types in Cervical Cancer Worldwide Cancer cases attributed to the most frequent HPV genotypes (%) HPV genotype Vaccine types X Other % 70.7% Munoz N et al. Int J Cancer 2004; 111: 278–85.

Phylogenetic Characterization of Oncogenic HPV Types HPV 16 related HPV 18 related

Cross-protection: Bivalent Vaccine 6 month Persistent Infection HPV Type Efficacy(97.9% CI) Type 45*59.9( ) Type ( ) Type ( ) Type ( ) Type (-132 – 24.7) Paavonen, et al. Lancet 2007;369 * HPV 18 related; + HPV 16 related Significant protection against combination of (12) non-vaccine oncogenic types using 12 mos persistent infection: VE = 27%; CI: %

Cross Protection: Quadrivalent Vaccine CIN 2/3 and AIS HPV TypesEfficacy(95% CI) A9 Species (16 related) 45%(10, 68) HPV 31, 33, 35, 52, 58 A7 Species (18 related) 46%(-35, 80) HPV 39, 45, 59 Villa, et al. Presented at Eurogin 2007

Ongoing or Planned Studies QuadrivalentBivalent Follow-up phase II and III trials xx Immuno/efficacy in females >25 yrs xx Efficacy trials in men yrs x Simultaneous administration xx Comparative immunogenicity xx Safety & immunogenicity in HIV+ women (and men - Quadrivalent) xx Phase 4: long term follow-up xx

HPV Vaccine Recommendations Upcoming Issues Projected Dates for ACIP Review Issue June/Oct 2008 Quadrivalent vaccine: females yrs Bivalent vaccine: females 2009 Quadrivalent vaccine: males

Quadrivalent HPV Vaccine Efficacy in Women years Per-Protocol Efficacy Endpoint Vaccine (N=1910) Placebo (N=1907)Efficacy95% CI HPV 6/11/16/18-related persistent infection, CIN or EGL 44191%(74, 98) HPV 16/18-related persistent infection, CIN or EGL 42383%(51, 96) HPV 6/11-related persistent infection, CIN or EGL %(79, 100) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ, EGL – external genital lesions Haupt – presented at Feb 2008 ACIP meeting

Quadrivalent HPV Vaccine in women years If FDA approved, what recommendations should be made for vaccine use in women in this age group? –Efficacy in women naïve to respective vaccine type –With increasing age, the rate of new HPV infections decrease and the likelihood of prior infection increases –Cost effectiveness of vaccination decreases with increasing age

Bivalent HPV Vaccine If FDA approved, there will be two HPV vaccines on market –How should recommendations be stated for the two vaccines? –Can the vaccines be used interchangeably in the vaccination series (for protection against HPV 16/18)?

Comparison of HPV Vaccines AttributeQuadrivalentBivalent Protection against HPV 16/18 related CIN/AIS* Similar Protection against HPV 6/11 related genital lesions YesNo Cross-protection against high risk types other than HPV 16,18 ? Similar Duration of protection? Similar Safety and adverse events? Similar Cost of vaccine series~$360? * Quadrivalent vaccine - also demonstrated protection against VIN and VaIN

Quadrivalent HPV Vaccine for Men No efficacy data available – studies ongoing Considerations for recommendations include impact on reduction of disease in women, benefit to men, cost effectiveness

Summary Data on HPV vaccines continue to show high efficacy and good duration of protection New data for HPV vaccines will be available over the coming months and years Upcoming HPV vaccine recommendations to consider –Quadrivalent HPV vaccine for women >26 years –Bivalent HPV vaccine for females –Quadrivalent HPV vaccine for males

Thank you

Acknowledgments Eileen Dunne Mona Saraiya Deblina Datta Herschel Lawson Beth Unger Harrell Chesson Richard Haupt Gary Dubin

Upcoming Issues for ACIP Considerations DateIssue June 2006 Quadrivalent vaccine: females 9-26 yrs June/Oct 2008 Quadrivalent vaccine: females yrs Bivalent vaccine: females 2009 Quadrivalent vaccine: males

Immunogenicity Main basis of protection is neutralizing antibody Minimum protective antibody titer is not known Serologic tests for HPV antibody not standardized Merck - competitive Luminex immunoassay (cLIA) GSK - type specific ELISA

Quadrivalent HPV Vaccine Adolescent Bridging Immunogenicity

34 Seropositivity at Months 7 and 36 Post Vaccination Vaccine/ HPV typeMonth 7Month 36 Quadrivalent* Anti-HPV 6 100%96% Anti-HPV %98% Anti-HPV %99% Anti-HPV %74% Bivalent + Anti-HPV %99% Anti-HPV %99% * Villa, et al. Vaccine competitive Luminex immunoassay (cLIA) + Harper, et al. Lancet type specific ELISA

Efficacy Analysis Populations In phase III trials, most females were sexually active and were enrolled without regard to PCR or antibody status Per Protocol Population for Efficacy Naïve to relevant vaccine HPV type through month 7 Cases counted after dose 3 Unrestricted susceptible populations (or total vaccinated) Naïve to relevant vaccine HPV type Cases counted day one after dose 1 Intent-to-Treat Population All subjects regardless of baseline status Cases counted day one after dose 1

Bivalent HPV Vaccine Immunogenicity in Women >25 Years Immunogenicity and safety study –Designed to compare titers in women yrs and years ATP cohort, Seronegative at entry GMT (EU/ml) Month 7 HPV-16 HPV % [15-25] [26-35] [36-45] [46-55] Non-inferiority of the immune response was demonstrated for both the and years age groups

Ongoing or Planned Studies Quadrivalent HPV Vaccine Efficacy trials –Women yrs (N ~ 3800) –Men yrs (N ~ 4000) –Follow-up of adolescent trials (N~1500) Phase IV program –Long term follow-up of phase III Nordic cancer registry –Demonstrate population impact of mass vaccination programs on overall rates of disease - General population of Norway –Post marketing surveillance in US (N ~ 44,000) Alternative dosing schedules

Ongoing or Planned Studies Bivalent HPV Vaccine Efficacy trials –Women >25 yrs of age (N ~ 5700) –Women yrs Costa Rica (NCI sponsored; N~7500) –Follow-up of adolescent trials (N~1200) Phase IV program –Long term pre-cancer/cancer surveillance in Finland of phase III cohort –Community randomized trial to evaluate herd immunity (60-70,000) –Other phase IV studies under development Comparative Immunogenicity –Bivalent vs quadrivalent (N~ 1000)

HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/Analysis Vaccine N cases Control N cases Efficacy( CI ) Quadrivalent Per protocol %(86-100) Unrestricted %(85-99) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ The Future II Study Group. NEJM 2007; year old females; mean follow-up 3 years

Safety Integrated prelicensure database - Injection site events occur more often in vaccine than control recipients No significant increase in serious adverse events or new onset chronic diseases No difference in overall pregnancy outcomes in vaccine or control groups

Serious Adverse Events Vaccine Total n (%) Control Total n (%) Quadrivalent* (0.9%) (1.0%) Bivalent** (3.5%) (3.5%) *Source: / protocols 007, 013, 015, 016, 018 ** Paavonen; Lancet 2007; 369

Bivalent Vaccine Viral Clearance for HPV 16/18 Endpoint Vaccine N cleared Control N cleared Efficacy (95% CI) 6 months %(−10.1 to 13.8) 12 months %(−31.7 to 13.0) Hildesheim, et al. JAMA 2007

HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/Analysis Vaccine N cases Control N cases Efficacy( CI ) Quadrivalent Per protocol (86-100) Unrestricted (85-99) Bivalent Unrestricted (53-99) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ The Future II Study Group. NEJM 2007; year old females; mean follow-up 3 years Paavonen, et al. Lancet 2007; year old females; mean follow-up 15 months

HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/HPV type Vaccine N Cases Control N Cases Efficacy( CI ) Quadrivalent HPV 16 HPV (82-99) (74-100) Bivalent HPV 16 HPV (47-100) ( ) Unrestricted susceptible or total vaccinated populations The Future II Study Group. NEJM 2007; year old females; mean follow-up 3 years Paavonen, et al. Lancet 2007; year old females; mean follow-up 15 months

Quadrivalent Vaccine Prevention of HPV 16/18 Related CIN 2/3 or AIS by Baseline HPV Status Baseline Status Vaccine N cases Placebo N cases Efficacy(95% CI) PCR + Sero %(<0-46) PCR + Sero %(<0-100) PCR - Sero % (<0-35) The Future II Study Group. NEJM 2007;356 – supplementary appendix At baseline, 16% sero or PCR positive to HPV 16; 7% sero or PCR positive to HPV 18

HPV-Related Cancers United States, 2003 Anatomic siteTotal Cancers% due to HPV Cervix11, Anus4,18785 Vaginal/vulvar4,57740 Penis1,05940 Oral/Pharyngeal29,62715

Safety Multiple safety outcomes evaluated in clinical trials including: –Injection site reactions –Serious adverse events –New onset chronic diseases including new onset of autoimmune diseases –Pregnancy and pregnancy related outcomes

Summary: Immune Response Serum antibodies induced in all vaccinees Vaccine induced antibody levels are higher than those seen after natural infection Duration of antibody through ~5 years. Loss of detectable antibody to HPV 18 not associated with loss of protection (Quadrivalent) Challenge produces anamnestic response (Quadrivalent) Antibody titers are non inferior in young adolescents (9 or years) compared with women in efficacy trials

Summary: Efficacy High efficacy against vaccine HPV type CIN endpoints among females ~16-26 yrs naïve to the relevant vaccine type High efficacy against vaccine HPV type related genital warts, VIN and VaIN (Quadrivalent) Some cross protection against non vaccine types No evidence of therapeutic efficacy

Adolescent Bridging Immunogenicity Data Immunogenicity in adolescents non-inferior to older females in phase III efficacy trials Seropositivity similar (>99%) GMTs 2- fold higher

HPV Vaccine Efficacy Prevention of HPV 16/18-related CIN 2/3 or AIS Vaccine/Analysis Vaccine N cases Control N cases Efficacy( CI ) Quadrivalent Per protocol %(86-100) Unrestricted %(85-99) Bivalent Unrestricted %(53-99) CIN – cervical intraepithelial neoplasia; AIS – adenocarcinoma in situ The Future II Study Group. NEJM 2007; year old females; mean follow-up 3 years Paavonen, et al. Lancet 2007; year old females; mean follow-up 15 months

Time to HPV 16/18-Related CIN 2/3 or AIS Intent to treat populations – protocols 07, 013, 015

Efficacy for Prevention of HPV Disease, by Baseline Status Quadrivalent HPV Vaccine SeronegativeSeropositive PCR (-)Prophylactic efficacy Few cases 100% efficacy PCR (+) No evidence of efficacy against respective type