3  prof james bently hpv vaccination 2014
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  • 1. HPV Vaccination in 2014 IFCCP Jeddah Jan 2014 James Bentley Professor Dept. Obstetrics and Gynecology Dalhousie University Halifax, Canada
  • 2. HPV cancers - Highest burden in cervical cancer Adapted from Parkin DM, Bray F. Vaccine. 2006;24 Suppl 3:S11-25 HPV related cancer in women 527,100 cases WW/year 2 HPV related cancer in men 33,800 cases WW/year 90% of HPV cancer in women are cervical cancers 492800 16000 14300 2900 1100 13000 10500 5200 5100
  • 3. Cervical cancer burden – World Wide 3 FerlayJ, et al.GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide. IARC CancerBaseNo.10. Lyon, France. 2010 Every 2 minutes a woman dies of cervical cancer.1 Every minute a woman is diagnosed with cervical cancer.1 New cases per year: ~ 530,000 Deaths per year: ~ 275,000 NA + Europe Africa Asia Latina 29,000 53,000 31,000 159,000 77,000 80,000 68,000 312,000 80% in developing countries = 2nd cause of cancer death in women
  • 4. Active protection via vaccination is mediated by neutralizing antibodies at the cervix HPV Cervical canal Neutralizing antibodies Blood vessel Epithelial tear Basement membrane Cervical epithelium Stanley M. Vaccine 2006; 24:S16–S22; Giannini S, et al. Vaccine 2006; 24:5937–5949; Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137; Poncelet S, et al. IPvC 2007; Abstract.
  • 5. HPV causes cervical cancer • Undisputed epidemiological evidence • RR higher than for cigarettes & lung cancer1,2 • Lifetime risk of infection ~ 80%3–5 • > 70% of HPV types are oncogenic6,7 • Vast majority of infections are transient, clearance 12–18 months6 • ~ 10% infections persist beyond 2 years8 • Persistent infection is a necessary cause of pre-cancer or cancer9,10 • Development of cancer from persistent HPV infection takes 10–20 years, although rarely, it may take only 1–2 years9 1. Vineis P, et al. J Natl Cancer Inst 2004; 96:99–106; 2. Lorincz A, et al. ObstetGynecol 1992; 79:328–337; 3. Brown DR, et al. J InfectDis 2005; 191:182–192; 4. Koutsky L, et al. Am J Med 1997; 102:3–8; 5. Bosch FX, et al. J Natl Cancer Inst Monogr 2003; 31:3–13; 6. Brown DR, et al. J Infect Dis. 2005; 191:182–192; 7. Peto J, et al. BJC 2004; 91:942– 953; 8. Ho GY, et al. N Engl J Med 1998; 338:423–428; 9. Burd EM. Clin MicrobiolRev 2003; 16:1–17; 10. Solomon D, et al. JAMA 2002; 287:2114–2119.
  • 6. de Sanjosé S, et al. Lancet Oncol 2010; 11:1048–1056. Cervical cancer is caused by a variety of HPV types Cumulative relative contribution of HPV in invasive cervical cancer * 50% 60% 70% 80% 90% 100% Global Squamous cell carcinoma Adenocarcinoma 70.8 76.7 84.2 91.3 Cumulative relative contribution, % 16+18 16+18+45 16+18+45+33+31 16+18+45+33+31+52+58+35 16+18 16+18+45 16+18+45+33+31 16+18+45+33+31+52+58+35 16+18 16+18+45 16+18+45+33+31 16+18+45+33+31+52+58+35 70.0 75.4 83.5 91.0 82.3 94.2 95.2 95.7 *Focus on 8 most common types
  • 7. Papillomavirus – phylogenetics HPV18- Related 45, 39, 59, 51, 56 HPV16- Related 31, 33, 35, 52, 58
  • 8. Cervarix ® : Vaccine design Specificity of the immune response Cervarix is a registered trade mark of the GlaxoSmithKline group of companies. Cervarix® Antigen 20 µg L1 HPV 16 20 µg L1 HPV 18 + Adjuvant Substances that potentiate the immune response to antigen Through MPL, AS04 Adjuvant System utilizes natural ‘danger’ signals AS04 Adjuvant System Aluminium salt + MPL (Al(OH)3) Giannini SL, et al. Vaccine 2006; 24:5937–5949. Manufactured in insect vector
  • 9. Gardasil ® :Vaccine design Specificity of the immune response Gardasil ® Merck Gardasil ® Antigen 40 µg L1 HPV 16 + Adjuvant Substances that potentiate the immune response to antigen (Al(OH)3) Manufactured in recombinant Saccharomyces Cerevisiae (yeast) 20 µg L1 HPV 6 40 µg L1 HPV 11 20 µg L1 HPV 18
  • 10. CIN2 and CIN3 as disease endpoints for studies • There is substantial heterogeneity in the microscopic diagnosis and biologic meaning of CIN 2 lesions in particular.1 • Some non-oncogenic HPV infections are capable of producing lesions diagnosed as CIN 2.1 • CIN-3 can be reliably distinguished from recently acquired HPV infection and it is a good indicator of subsequent cancer risk.2 • CIN3 is a more reproducible and stringent diagnostic endpoint than CIN2 and frequently progresses to ICC.3,4,5 • The recent “LAST” publication from the ASCCP and CAP suggested a HSIL/ LSIL terminology with breakdown of HSIL into CIN2, CIN3 to fit with current clinical practice 6 1. Schiffman, Kjaer. JNCI Monographs 2003 ,No. 31; 2. Moscicki A, et al. Vaccine. 2006 Aug 31;24 Suppl 3:S3/42-51; 3. Carreon et al. Int J Gynecol Pathol 2007; 26: 441–46.; 4. Castle PE,et al. Obstet Gynecol 2009; 113: 18–25.; 5. Lehtinen M, et al. Lancet Oncol. 2012 Jan;13(1):89-99. 6. Darragh et al. J Low GenitTract Dis. 2012 Jul;16(3):205-242
  • 11. Prophylactic HPV Vaccines: Phase III Randomized Controlled Trials Outcomes to Date (Per Protocol Efficacy Populations) Vaccine Quadrivalent 6/11/16/18 Bivalent 16/18 Mean follow up 36 months 34.9 months Prophylactic efficacy HPV 16 CIN 2/3 100% 93% HPV 18 CIN 2/3 100% 83.3% HPV 16/18 CIN 2/3 98%* (100%)† 90%* (98%)† HPV 16/18 AIS 100% Not reported HPV 16/18 VIN 3 100% Not reported HPV 16/18 VaIN 3 100% Not reported 6/11 Anogenital disease 100% Not a target EGW, VIN1 VaIN1 99%, 100% Cross protection Demonstrated Demonstrated Tolerability Well tolerated Well tolerated Therapeutic efficacy None None *pre-specified endpoint analysis HPV 16 or 18 DNA in the lesion. †post hoc endpoint analysis HPV 16 or 18 DNA in the lesion and in preceding cytology samples. 1. Stanley M. Curr Opin Infect Dis 2010; 23(1):70-5. 2. Garland SM, et al. N Engl J Med 2007; 356(19):1928-43. 3. FUTURE II Study Group. N Engl J Med 2007; 356(19):1915-27. 4. Paavonen J, et al. Lancet 2007; 369:2161-70.
  • 12. Cervarix® demonstrated high efficacy for High Grade lesions against types included in the vaccine PATRICIA end-of-study analysis , VE against HPV-16/18; primary endpoint$ Vaccine cases n (N) Control cases n (N) Vaccine efficacy, % 95% CI $ATP cohort – primary analysis CIN3+ 2 (7338) 24 (7305) 91.7 * 66.0–99.1 CIN2+ 5 (7338) 97 (7305) 94.9 87.7–98.4 TVC-Naïve – primary analysis CIN3+ 0 (5466) 27 (5452) 100.0 85.5–100.0 CIN2+ 1 (5466) 97 (5452) 99.9 94.2–100.0 95% CIs > 0 Wheeler CM, et al. Lancet Oncol 2012; 13:100–110. * CIN3+, ATP cohort , TAA analysis: 100.0 (81.8-100.0) $ ATP cohort for efficacy: Subjects seronegative, DNA negative at baseline for the corresponding type; primary endpoint N = number of evaluable women in each group; TVC-naïve cohort: Population naïve to 14 oncogenic HPV types at baseline; N = number of evaluable women in each group; Lesions associated with HPV 16/18 vaccine types
  • 13. 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99; 2. Schiffman M, et al. Virology 2005; 337:76–84; 3. Carreon JD, et al. Int J Gynecol Pathol 2007; 26:441–446; 4. Castle PE, et al. Obstet Gynecol 2009; 113:18–25; 5. Hakama M, et al. Int J Cancer 2004; 112:1072–1074. Cervarix® demonstrated high protection against high grade lesions PATRICIA end-of-study analysis; analysis irrespective of type, TVC-naïve1 Endpoint Vaccine cases (N = 5,466) Control cases (N = 5,452) Vaccine efficacy, % 95% CI CIN3+ 3 44 93.2 78.9–98.7 CIN2+ 61 172 64.9 52.7–74.2 95% CIs > 0 CIN3+ is generally regarded as a better surrogate of ICC than CIN2+ –CIN3+ is a more severe lesion and the immediate precursor of ICC –The HPV type distribution in CIN3+ is closer to that in ICC2 –CIN3+ is a more reproducible and stringent surrogate of ICC compared with CIN2+3–5 In an analysis of CIN3+ lesions, conducted irrespective of HPV type, Cervarix® showed 93% efficacy(95% CI: 78.9–98.7)
  • 14. Long-term protection against CIN3+ lesions can be expected from vaccination with Cervarix® PATRICIA end-of-study, analysis irrespective of HPV type in ; TVC-naive Lehtinen M, et al. Lancet Oncol 2012; 13:89–99. 0 0.01 0.02 0 6 12 18 24 30 36 42 48 Cumulativeincidence Time, months Control Vaccine Cases in control group continue to accrue with no indication of plateauing at 4 years
  • 15. Cervarix® : high and sustained anti-HPV 16/18 neutralizing antibodies* up to 9.4 years PRE = pre-vaccination; * By PBNA. Combined analysis of HPV-001/007/023 in the subcohort. Naud et al. IPvC 2011. Presentation O18.04; EMA. Cervarix®. European Summary of Product Characteristics, 2012.. = Natural infection antibody levels ≥ 8-fold higher than natural infection 100 % seropositivity ≥ 4-fold higher than natural infection HPV-023HPV-007HPV-001 100% seropositivity HPV 16 GMT, ED50 HPV 18 GMT, ED50 Months after 1st vaccination
  • 16. Challenge Dose at 60 Months Post Quadrivalent HPV 6/11/16/18 Vaccine Elicits Anamnestic Response Olsson SE, Villa LL, Costa RL, et al. Vaccine 2007; 25(26):4931-9. SerumcLIAGMT.mMU/mL (Loog10Scale) HPV 6 10 100 1,000 10,000 D123 67 12 18 24 30 36 54 60 61 Time Since Vaccination 1 (Months) Vaccination **** PPI Quadrivalent Vaccine PPI Placebo Baseline Seropositive and PCR Negative Placebo SerumcLIAGMT.mMU/mL (Loog10Scale) 10 100 1,000 10,000 D123 67 12 18 24 30 36 54 6061 Time Since Vaccination 1 (Months) Vaccination **** PPI Quadrivalent Vaccine PPI Placebo Baseline Seropositive and PCR Negative Placebo SerumcLIAGMT.mMU/mL (Loog10Scale) 10 100 1,000 D123 67 12 18 24 30 36 54 60 61 Time Since Vaccination 1 (Months) Vaccination **** PPI Quadrivalent Vaccine PPI Placebo Baseline Seropositive and PCR Negative Placebo SerumcLIAGMT.mMU/mL (Loog10Scale) 10 100 1,000 10,000 D123 67 12 18 24 30 36 54 60 61 Time Since Vaccination 1 (Months) Vaccination **** PPI Quadrivalent Vaccine PPI Placebo Baseline Seropositive and PCR Negative Placebo HPV 11 HPV 16 HPV 18
  • 17. Cervarix® Protocol 008 TVC-naïve cohort (48 months of FU)2 Cervarix® Control %Efficacy (95% CI) N n N n 5466 61 5452 172 64.9 (52.7; 74.2) 5466 3 5452 44 93.2 (78.9; 98.7) Gardasil® Combined protocols Future I, Future II R-MITT-2 cohort (EOS* data)1 Lesion Gardasil® Control %Efficacy (95% CI)N n N n CIN2+, irrespective of causal HPV type 4616 77 4680 136 42.7 (23.7; 57.3) CIN3+, irrespective of causal HPV type 4616 36 4680 64 43.0 (13.0; 63.2)* Cervarixand Gardasil – Efficacy CIN2+/CIN3+ irrespective of HPV Type * The median duration of follow-up for the combined protocols (005, 007, 013, and 015) was 3.6 years after receipt of dose 1 and maximum of 4.9 years. * for Gardasil® the endpoint was CIN3 N = number of evaluable women in each group; n = number of evaluable women reporting at least one event in each group; - : not available; Bold = statistically significant. No head-head efficacy studies were carried out – those comparisons are only informative 1. Munoz et al. J Natl Cancer Inst 2010; 102:1–15; 2. HPV-008 Month 48 analysis. ※サーバリックスの日本での効能・効果は”HPV16型及び18型感染に起因する子宮頸癌及びその前駆病変(CIN2及び3)の予防”です。添付文書
  • 18. Safety of HPV Vaccines • The vaccines do not contain any living virus • More than 79 million doses of the quadrivalent vaccine have been distributed globally (3.3 million in Canada), with no serious adverse events found to be associated with the vaccine and with no greater risk of adverse events than with placebo • Approximately 7 million doses of the bivalent vaccine have been distributed worldwide (6,473 in Canada) • NACI and Health Canada recommend HPV vaccination for women who have already had HPV-related disease because it is safe and offers significant protection against HPV-related diseases related to the genotypes to which they were not exposed • There is ongoing surveillance by healthcare authorities, companies and registries GARDASIL Product Monograph. Merck Canada Inc. August 2011. CERVARIX Product Monograph. GlaxoSmithKline Inc. August 2011. Data on file, Merck Canada Inc.
  • 19. Post-licensure Safety Study of Quadrivalent HPV 6/11/16/18 Vaccine Among 189,629 Females • Favorable safety profile; NO association between vaccination with quadrivalent HPV vaccine and: – Congenital anomalies, miscarriages – 16 pre-specified autoimmune (AI) conditions – Venous thromboembolism – Death – Any other general safety events (except syncope & possibly local skin infection) • Syncope associated with quadrivalent HPV vaccine: injection-related • Local skin infection (cellulitis/abscess) possibly associated with quadrivalent HPV vaccine: could be injection site reaction • All safety conclusions were made by independent, external Safety Review Committee of 5 experts Velicer C. Presented at EUROGIN 2011.
  • 20. What about the older woman?
  • 21. Relatedcases 0 40 60 80 100 20 1. Castellagué X, et al. Br J Cancer 2011; 105(1):28-37. 2. Ferris D, et al. Presented at: EUROGIN 2010 Congress. February 17-20, 2010. Monte Carlo. Abstract SS 3-3. Per-protocol Efficacy Population, Mean Follow-up: 3.8 Years Efficacy Against Combined Incidence of HPV 6/11/16/18-related Persistent Infection, CIN (Any Grade), and EGLs: Results by Age Strata n=1,601 10 24- to 45-year-olds n=1,599 86 89% reduction 95% CI: 78.1 – 94.8 Total n=816 5 35- to 45-year-olds n=809 30 n=785 5 24- to 34-year-olds n=790 5691% reduction 95% CI: 78.4 – 97.3 84% reduction 95% CI: 57.9 – 95.1 Quadrivalent HPV vaccine Placebo
  • 22. Relatedcases 0 40 60 80 100 20 1. Castellagué X, et al. Br J Cancer 2011; 105(1):28-37. 2. Ferris D, et al. Presented at: EUROGIN 2010 Congress. February 17-20, 2010. Monte Carlo. Abstract SS 3-3. Per-protocol Efficacy Population, Mean Follow-up: 3.8 Years Efficacy Against HPV 6/11/16/18-related Persistent Infection, CIN (Any Grade), CIN 2/3 or Worse, and EGLs n=1,581 9 Persistent infection n=1,586 85 90% reduction 95% CI: 79.3 – 95.4 n=1,600 0 EGLs n=1,599 7 100% reduction 95% CI: 30.8 - 100 n=1,581 1 CIN 2/3 or worse n=1,584 6 83% reduction 95% CI: -37.6 – 99.6 n=1,581 1 CIN (any grade) n=1,584 17 94% reduction 95% CI: 62.5 – 99.9 Quadrivalent HPV vaccine Placebo
  • 23. Quadrivalent HPV Vaccine (n=1,578) Placebo (n=1,583) % Reduction 95% CI ASC-US (HR+) or worse 1 38 97% 84.5, 99.9 ASC-US HR(+) 1 13 92% 48.8, 99.8 LSIL 0 25 100% 84.1, 100 ASC-H 0 1 100% <0, 100 HSIL 0 0 – – 1. Castellagué X, et al. Br J Cancer 2011; 105(1):28-37. Per-protocol Efficacy Population, Mean Follow-up: 3.8 Years Reduction in Incidence of HPV 6/11/16/18-related Pap Diagnoses n = number of subjects who have at least 1 follow-up visit after month 7.
  • 24. Do you need 3 doses?
  • 25. • The AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine has been shown to be immunogenic, efficacious and generally well tolerated in clinical studies1–3 • The licensed administration schedule includes 3 doses to be given at Months 0, 1 and 6 • In young girls aged 10–14 years the vaccine-induced immune response is 2-fold higher as compared with subjects 15–25 years4 • Higher immunogenicity of the vaccine in adolescents could make a 2-dose schedule feasible, providing better convenience for vaccinees and health care staff, and potentially facilitate implementation of HPV vaccination
  • 26. Study design • Phase I/II study evaluating the HPV-16/18 vaccine: – According to a 2-dose schedule vs. the standard 3-dose schedule – Using the licensed vaccine formulation (20 μg of each antigen) or an alternative formulation (40 μg of each antigen) • Healthy females (N=960) were age-stratified (9–14 years, 15–19 years, 20–25 years) and randomised to the following groups: 26 * Blinded for the 2-dose schedule groups Group Month 0 Month 1 Month 2 Month 6 40/40 M0,2* 40/40 - 40/40 Placebo 40/40 M0,6* 40/40 - Placebo 40/40 20/20 M0,6* 20/20 - Placebo 20/20 20/20 M0,1,6 (control) 20/20 20/20 - 20/20
  • 27. 2 vs. 3 dose trial: Objectives • To evaluate the antibody response to 2 doses in subjects aged 9–14 years* as compared with 3 doses in subjects aged 15–25 years† – GMT ratios between the 3-dose and 2-dose schedules were calculated with 95% confidence intervals • To evaluate the safety and reactogenicity of the vaccine in all study groups 27 *Target population for HPV vaccination, †Age group in which efficacy was demonstrated
  • 28. 2 vs. 3 dose: Conclusions • 2-dose schedules of the HPV-16/18 AS04-adjuvanted vaccine were immunogenic and generally well-tolerated in girls aged 9–14 years and women aged 15–25 years, up to 3 years after the first vaccine dose • Antibody responses to a 2-dose schedule of the licensed vaccine formulation in girls aged 9–14 years administered at M0,6 appeared comparable to the standard 3-dose schedule in women aged 15–25 years • Similar results have been shown for Gardasil • Recent review showed sustained antibody levels post one dose of Cervarix 29  A 2-dose schedule may be more convenient for physicians and vaccinees, could facilitate implementation of HPV vaccination and may help optimise compliance in school-based immunisation programmes Further investigations are required to evaluate the overall protection, long term protection and cross-protection induced by a 2- dose schedule
  • 29. Effect of Gardasil on recurrence post treatment: irrespective of HPV type Joura et al. BMJ 2012;344:e1401
  • 30. Effect of Gardasil on recurrence post treatment: HPV type 6,11,16 or 18 Joura et al. BMJ 2012;344:e1401
  • 31. What have the effects of vaccination been?
  • 32. Fig 1 Proportion of Australian born women diagnosed as having genital warts at first visit, by age group, 2004-11. Ali H et al. BMJ 2013;346:bmj.f2032 ©2013 by British Medical Journal Publishing Group
  • 33. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological Study – Australian Data – All women 12-26 were offered vaccination with Gardasil – Using State based Pap Test Registers – Vaccination rates: • 71-79% in the school based program • 74% I dose, 69% 2 doses, 56% 3 doses in 18-28 year olds – Screening starts at age 18 or 2 years after sexual activity Brotherton JM et al Lancet (2011) Vol 337 June 18 2085-2091
  • 34. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: Low Grade effect by age Brotherton JM et al Lancet (2011) Vol 337 June 18 2085-2091
  • 35. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: High Grade effect by stage Brotherton JM et al Lancet (2011) Vol 337 June 18 2085-2091
  • 36. New HPV vaccines • Nonavalent vaccine (Merck)(HPV 6/11/16/18/31/33/45/52/58) • 14204 16-26 yr old women 9vHPV vs qHPV • Followed for 4.5 yrs • Similar immunological responses • Efficacy for high grade lesions with HPV 31/33/45/52/56 greater than 96% • Not inferior for HPV 16/18 Joura et al. Eurogin Nov 2013
  • 37. Conclusions • HPV vaccination is effective at preventing CIN • Vaccination is effective on the “older woman” but there is less CIN… • HPV Vaccination seems to be effective at preventing “recurrence” • Real world experience is very promising