HPV Vaccines


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HPV Vaccines

  1. 1. HPV Vaccines Dr W H LI Queen Elizabeth Hospital 5 August 2007
  2. 2. Content ♦ Introduction ♦ Basic Information for Human Papillomavirus ♦ HPV Vaccine Target Antigens ♦ Vaccine Types ♦ Phase II/III clinical trials ♦ Gardasil / Cervarix ♦ FAQ ♦ Conclusion
  3. 3. Introduction (1) ♦ Cervical cancer is one of the leading causes of cancer mortality worldwide ♦ Estimated to have 470 000 new cases and 230 000 deaths every year worldwide with 80% of the cases occurred in developing countries
  4. 4. Cervical Cancer in Hong Kong 439 (2004) 126 (2005 )
  5. 5. Introduction (2) ♦ Even though screening reduces the risk of cervical cancer, it does not prevent pre- cancerous lesions, which need careful / expensive follow-ups and intervention ♦ Although there are effective treatment for CIN lesions, recurrence still occur and management of recurrent disease maybe difficult ♦ Establishing screening programs is not the only solution to the problem
  6. 6. Introduction (3) ♦ Especially in developing / under-developed countries, limited national screening program, late presentation of disease and limited treatment facilities are the main obstacles in fighting against cervical cancer ♦ High morbidity / mortality for advanced disease ♦ New modality for prevention and treatment of cervical cancer is required
  7. 7. Introduction (4) ≥95%Cervical >70%Anal 50%Penile >50%Vulval 50%Vaginal Association with HPV Cancer Human papillomavirus is the perfect candidate to investigate for Prevention and Treatment of Anogenital Tract Cancers
  8. 8. Introduction (5) ♦ HPV infection is primarily transmitted by genital contact: ♦ Penetrative sexual intercourse ♦ Oral-genital, manual-genital, genital-genital ♦ Sharing sex toys / auto-innoculation (from your own hand to your genital tract) ♦ Non sexual route include transmission from mother to newborn baby (Caesarean section not indicated)
  9. 9. Introduction (6) ♦ Up to 70% of sexually active women will become infected with HPV during their sexual life, but the majority of these infections are transient with 70-90% spontaneously cleared within 12-30 months ♦ High-risk HPV highly associated with pre- cancerous cervical lesions and cervical cancer (up to 99.7% with highly sensitive PCR tests) ♦ Most important factor is persistent type- specific high-risk HPV infection
  10. 10. Introduction (7) ♦ Most prevalent HPV types associated with cervical cancer are: ♦ HPV 16 (54.3%) HPV 18 (12.6%) ♦ HPV 45 (4.2%) HPV 31 (4.2%) ♦ HPV 33 (4.3%) HPV 58 (3%) ♦ HPV 52 (2.5%) *Prevalence of HPV 58 in Chinese may be up to 23.8%
  11. 11. Introduction (8) ♦ HPV vaccines that protect against HPV infections theoretically prevent women from developing pre-cancerous lesions and cervical cancer (Prophylactic vaccine) ♦ HPV vaccine that control the HPV infected cells theoretically treat women with active disease or act as adjuvant agent (Therapeutic vaccine)
  12. 12. Introduction (9) ♦ HPV type 16 and 18 present in ♦ ~70% of Ca cervix cases ♦ ~50 % HGSIL cases ♦ ~14-25% LGSIL cases ♦ Provides an estimate of the potential impact of a vaccine against HPV-16 and HPV-18
  13. 13. Basic Information for Human Papillomavirus
  14. 14. Human Papillomavirus
  15. 15. Human Papillomavirus ♦ Non enveloped virions consists of 72- capsomere capsid (outer coat) containing the double stranded circular DNA genome ♦ Capsid made up of the major structural protein L1 (80%) and minor structural protein L2 (20%)
  16. 16. HPV genome ♦ 3 regions: – Long control region (LCR) without coding potential Origin of replication and regulation of HPV gene expression – Regulatory (early) proteins E1-E8 – Structural (late) proteins L1 and L2 (capsid)
  17. 17. Gene Function/HPV Proteins ♦ L1: Major capsid protein: can form virus-like particles. ♦ L2: Minor capsid protein: possible DNA packaging protein ♦ E1: DNA-dependent ATPase, ATP dependent helicase: allow unwinding of the viral genome and act as an elongation factor for DNA replication. ♦ E2: Responsible for recognition and binding of origin of replication. Exists in two forms: full length (transcriptional transactivator) and truncated (transcriptional repressor). The ratio of these found in the heterotrimeric complex formed before complexing with E1 regulates transcription of viral genome. ♦ E3: ??? ♦ E4: Late Expression: C terminal binds intermediate filament, allowing release of virus-like particles. Also involved in transformation of host cell by deregulation of host cell mitogenic signalling pathway. ♦ E5: Obstruction of growth suppression mechanisms: e.g EGF receptor; activation of mitogenic signalling pathways via transcription factors: c-Jun and c- Fos (important in ubiquitin pathway degradation of p53 complex by E6). Inactivation of p21 (p53 induced expression halts cell cycle until DNA is proof- read for mutations). ♦ E6: E6 Transformation of host cell by binding p53 tumour suppressor protein. ♦ E7: Transforming protein, binds to pRB ♦ E8-E2 fusion protein: Long distance transcription and replication repressor protein
  18. 18. HPV Proteins ♦ Structural proteins L1 and L2: ♦ Building the capsid (outer coat) ♦ Replication proteins E1 and E2 ♦ Viral replication inside the infected cells ♦ Oncoproteins E6 and E7 ♦ Inhibiting tumour suppressor genes (p53 and pRB)
  19. 19. Life Cycle ♦ After HPV infection, early (replication) proteins (E1, E2, E6 and E7) are expressed within the basal epithelial layers and viral replication occurs ♦ As infected cells reach the surface, late proteins (structural) L1 and L2 proteins are produced and allow shedding of mature virions with exfoliated cells
  20. 20. Tumourigenesis ♦ Majority of tumour showed integration of HR HPV DNA into host genome ♦ Integration disrupts the HPV virus in the E2 open reading frame. ♦ Loss of E2 increase expression of E6 and E7 leading to uncontrolled proliferation and tumour formation
  21. 21. HPV Vaccine Target Antigens ♦ Capsid proteins L1 and L2 (Viral entry) ♦ Replication proteins E1 and E2 ♦ Oncoproteins E6 and E7
  22. 22. HPV Vaccine Target Antigens (1) ♦ Capsid proteins L1 and L2 (outer coat of the HPV particles) – Interact with the surface molecules of human epithelial cells during early stages of infection to gain entry for the viral DNA – Ideal targets for prophylactic but not therapeutic vaccines since L1/L2 are not present when HPVs are integrated into tumour cells – Most candidate vaccines target L1 since L1>L2 for 30x
  23. 23. HPV Vaccine Target Antigens (2) ♦ Replication proteins E1 and E2 – Necessary for HPV to replicate within cells before the virus is integrated into host DNA – Expressed in early stage of HPV infection – Targets for therapeutic vaccines to treat early stages of disease such as low-grade dysplasia
  24. 24. HPV Vaccine Target Antigens (3) ♦ Oncoproteins E6 and E7 – Bind tumour supressor genes (p53/pRB) which are involved in malignant transformation / continue tumour growth – Expressed in the later stage of disease – Targets for therapeutic vaccines to treat later stages of disease
  25. 25. HPV Vaccines Prophylactic Vaccines – Before HPV exposure – Antibody-mediated immunity at genital mucosal surface – Inactivate HPV before the virus infects the host cells – Takes many years to make impact on the prevalence of cervical cancer Therapeutic Vaccines – Already exposed to HPV – Cell-mediate immunity at the genital mucosal surface – Adjunct to standard therapies Prevent progression of low-grade lesions Induce regression of existing lesions Control metastasis Prevent recurrence
  26. 26. Ideal HPV Vaccine ♦ Safe and effective ♦ Both prophylactic and therapeutic – Stimulating cell-mediated immunity to eliminate lesions when neutralizing antibodies fail to block all of the virus – Distributed to young women whether or not that are infected with HPV ♦ Single inoculation with long-term protection ♦ Cheap and easy to handle and administer
  27. 27. Vaccine Types ♦ Virus-like particles (VLPs) ♦ Recombinant live vector vaccine ♦ Protein and peptide vaccines ♦ “Naked” DNA vaccines ♦ Edible vaccines
  28. 28. Virus-Like Particles (VLPs) - 1 ♦ Capsid proteins L1 and L2 will self-assemble into virus-like particles (VLPs) when expressed in cells – Empty viral capsids ♦ VLPs resembles native HPV particles and include the conformational epitopes that induce virus-neutralizing antibodies ♦ The immune system perceives VLPs as infectious (indeed they are not since they do not include viral DNA) and induce the immune response
  29. 29. Virus-Like Particles (VLPs) - 2 ♦ Immune response targets the capsid proteins (at the time of viral entry), therefore ideal for prophylactic vaccine Vaccination No Vaccination
  30. 30. Selection of HPV Types in Vaccine Development ♦ HPV type 16 and 18 present in ♦ ~70% of Ca cervix cases ♦ ~50 % HGSIL cases ♦ ~14-25% LGSIL cases ♦ Provides an estimate of the potential impact of a vaccine against HPV-16 and HPV-18  Quadrivalent vaccine also include HPV 6/11 to prevent genital warts – HPV 6/11 account for 90% of genital warts – Clinically apparent in 1% of sexually active US adult population – Estimated lifetime risk of genital warts ~10%
  31. 31. Selection of Trial Endpoints Although prevention of cancer is the final endpoint for the success of a prophylactic vaccine Studies to allow patients to develop cancers as endpoint are unethical Surrogate endpoints are precancerous lesions (CIN, AIS, VAIN, VIN)
  32. 32. Multicenter Randomised Double Blind Controlled (Phase II) Trials Monovalent A Controlled Trial of a Human Papillomavirus Type 16 Vaccine (Nov 2002, NEJM) Median FU 17.4 mths Bivalent Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection with HPV Type 16 and 18 in Young Women: A Randomised Controlled Trial (Nov 2004, Lancet) Up to 27 mths Quadrivalent Prophylactic Quadrivalent HPV (Types 6,11,16 and 18) L1 Virus-Like Particle Vaccine in Young Women: A Randomised Double-Blind Placebo-Controlled Multicenter Phase II Efficacy Trial (May 2005, Lancet Oncology) 36 mths Monovalent Efficacy of Human Papillomavirus-16 Vaccine to prevent Cervical Intraepithelial Neoplasia (Jan 2006, Obstetrics & Gynecology) 48 mths Bivalent Sustained efficacy up to 4.5 years of a Bivalent L1 virus-like particle vaccine against human papillomavirus Types 16 and 18: follow-up from a randomised control trial (15 April 2006, Lancet) 4.5 years Quadrivalent High Sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up (Nov 2006, British Journal of Cancer) 5 years
  33. 33. Multicenter Randomised Double Blind Controlled (Phase III) Trials Quadrivalent (Gardasil) Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases (May 2007, NEJM) (FUTURE I Trial) N=5455 Average 3 yrs Efficacy of a quadrivalent prophylactic human papillomavirus (types 6,11,16 and 18) L1 virus-like particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of 3 randomised clinical trials (May 2007, The Lancet) N=18174 Mean FU 3 yrs Quadrivalent (Gardasil) Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade Cervical Lesions (May 2007, NEJM) (FUTURE II Trial) N=12167 Average 3 yrs Efficacy of prophylactic human papillomavirus L1 virus-like particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma in situ: a combined analysis of four randomised clinical trials (June 2007, The Lancet) N=20583 Mean FU 3 yrs Bivalent (Cervarix) Efficacy of a prophylactic adjuvanted bivalent L1 virus-like particle types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controled trial (June 2007) N=18644 Mean FU 14.8 mths FUTURE I/II Trials: Females United to Unilaterally Reduce Endo/Ectocervical Disease
  34. 34. Study Design Quadrivalent (HPV 6/11/16/18) Gardasil Bivalent (HPV 16/18) Cervarix Vaccine L1 VLP L1 VLP Dose 0 / 1 mth / 6 mth 0 / 2 mth / 6 mth Sexual Partners < = 4 < = 6 No prior abnormal pap smears HPV seronegative and HPV DNA negative in cervico-vaginal sample for the respective HPV types in the vaccine (For per-protocol and Modified Intention-To-Treat analysis) FU Schedule Mth 1, 2, 3, 6, 7, 12, 24, 36, 54,60 Every 6 months FU Protocol Pap smear, HPV DNA testing and HPV antibody Further Investigations Colposcopy and biopsy according to standard
  35. 35. Phase II / III Clinical Trials Lesions associated with Vaccine Type HPV Endpoints Per-protocol (Baseline vaccine- related HPV –ve All 3 doses) Modified ITT (Baseline vaccine- related HPV –ve) ITT (Irrespective of baseline HPV) Lesions Rregardless of Any HPV Type Future I 16 countries 6463 (16-24y) 3yrs Total Vuval/Vaginal Condyloma VAIN/VIN 1 / 2 or 3 CIN 1 / 2 or 3 or AIS 100% 100% 100% 100% 95% 96% 82%/91% 98% 73% 76% 63%/62% 55% 34% 51% 18%/26% 20% Future II 13 countries 12167 (15-26y) 3 yrs CIN 2/3/AIS 98% (CIN 3 x 1) 95% 44% 17% Combined High-grade VAIN/VIN 2/3 18174 (16-26y) 3 yrs VAIN/VIN 2/3 100% 97% 71% 49% Combined High-grade CIN2/3/AIS 20583 (16-26y) 3 yrs CIN 2/3/AIS 99% (CIN 3 x 1 ) 98% 44% 18% Bivalent Phase II 776 (15-25y) Up to 4.5 yrs CIN 2+ 100% Bivalent Phase III 18644 (15-25y) Average 14.8m CIN 2+ 90.4% (HPV 16 x 1 & HPV 18 x 1)
  36. 36. Side Effects Gardasil Cervarix Vaccine Placebo Vaccine Placebo Fever 10.3% 8.6% 12.4% 10.9% Pain 83.9% 75.4% 16.3% 4.4% Redness (All) >5cm 24.6% 18.4% 43.8% 1.2% 27.6% 0.1% Swelling (All) >5cm 25.4% 15.8% 42.0% 2.4% 19.8% 0.5% Serious Adverse Experience 0.06% Vaccine-related (Brochospasm/Asthma/Pain with impaired joint movement) 0.1% 0.1% Death No death related to vaccination No death related to vaccination
  37. 37. Two HPV Vaccines Available Gardasil (HPV 6/11/16/18) approved in many countries including HK (Oct 2006) Cervarix (HPV16/18) approved in Australia (July 2007), Indonesia, Kenya and pending approval in Europe and USA etc
  38. 38. Which is better ?  Gardasil (0/2/6m IMI)  Storage 0-8 deg C  HPV 6/11/16/18  Adjuvant contained aluminum  Age 9-26 yrs  Up to 5 years  Efficacy 99% – 1 case CIN 3: HPV 58 at baseline and 5 histology samples, HPV 16 in only 1 sample  Cervarix (0/1/6m IMI)  Storage 0-8 deg C  HPV 16/18  Adjuvant AS04 – Claimed to enhance immune response and longer duration  Age10-45yrs (Australia)  Up to 4.5 years  Efficacy 90.4% – 2 cases CIN 2+: Multiple infection with preceding cytology HPV 16/18 -ve (Efficacy 100%)  Cross-protection ? – 45 and 31 Pending results from a head-to-head trial to compare immunogenicity of Cervarix and Gardasil initiated in 2007
  39. 39. Phylogenetic Tree of HPV Family 11 6 35 31 16 33 18 45 Human Genital Papillomavirus Human Cutaneous Papillomavirus Genotypying of HPV is based on DNA sequences of the L1 genes
  40. 40. Cross-Protection for Bivalent Vaccine (Cervarix) HPV Type Incident Infection 6-mth Persistent Infection 12-mth Persistent Infection 45 94.2% 59.9% 62.3% 31 54.5% 36.1% 10.8% 33 8.6% 36.5% 45.1% 52 18.6% 31.6% 46.5% 58 14.0% -31.4% -1.1% No cross protection for other HPV types other than 16/18 has been approved
  41. 41. FAQ (For Gardasil)  When and whom to vaccinate ?  Vaccination for females <9yr and >26 yrs ?  Vaccination in sexually active females  Prior HPV testing before vaccination  Past history of abnormal pap smear / histology ?  History of genital warts  Antibody testing before vaccination  Will a booster be required ?  Vaccination in pregnancy / during lactation  Duration of protection  Interrupted schedules / Incorrectly vaccinated individuals  Simultaneous administration of other vaccines  Immunocompromised patients  Precautions / Contraindications  Any therapeutic effect ?  Role of cervical screening ?  Other ways to prevent HPV infection  Vaccination in males ?  Social acceptance
  42. 42. When and Whom to Vaccinate  Licensed for use in 9-26 yr females – Age 16-26: Based on phase II/III studies conducted among females aged 16-26 yrs – Age 9-15: Based on immunological studies Not inferior to 16-26yrs – Recommendation at age 11-12: Before sexual exposure – US: 3.7% females sexually active before age 13 – HK: 4.9% before age 15 High probability of HPV acquisition within several yrs of sexual exposure Immune system “ages” after puberty – Antibody level after vaccination 9-10y > 13-15y > 16-23y Incorporate into adolescent vaccination program
  43. 43. Vaccination for females <9yrs and > 26 yrs  Not licensed for use in these age range  Protocol 019 (FUTURE III) – In 3870 24-45yr women followed for 3 years – Primary endpoint: Persistent HPV 16/18 infection and related disease Efficacy against HPV 16/18-related CIN 2/3 and AIS  Off-label use: Counseling on limitations and based on clinical judgment  No studies are under way among children aged <9 years
  44. 44. Vaccination in Sexually Active Females  May also benefit from the vaccine – May have less benefit since they may have already been infected – Unlikely that they acquired all 4 types – Even if the patient has been infected, vaccination would provide protection against infection with HPV vaccine types not already acquired
  45. 45. Prior HPV Testing before Vaccination  No indication for prior HPV testing: 1. Specific HPV testing not performed routinely in clinical setting Although Hybrid Capture 2 is available to test for high-risk HPV (16/18/31/33/35/39/45/51/52/56/58/59/68) Does not identify specific HPV types 1. Unlikely that the women having all 4 HPV types (0.1%) Positive to >= 1 types 23.7% Positive to >= 2 types 6% Positive to >= 3 types 1.1% Positive to >= 4 types 0.1% Even if the patient has been infected, vaccination would provide protection against infection with HPV vaccine types not already acquired 1. HPV infection mostly transient in young women and a positive HC 2 test may cause confusion and unnecessary anxiety
  46. 46. Prior HPV Testing before Vaccination In the combined analysis of previous studies – Analysis of Intent-To-Treat subset: Received at least 1 dose of vaccine (Protocol violation) Any follow-up 1 month after the first dose Even if pap smear abnormal on day 1 Regardless of initial PCR or serology for HPV (Overall 27% of the study population at baseline had evidence of infection with a vaccine HPV type) i.e. Presumed HPV status unknown / no prior HPV testing before vaccination / Regardless of pap smears results (General Population) – Prevention of vaccine-related (6/11/16/18) lesions: CIN2/3/AIS – 39% - 46.4% VAIN 2/3 and VIN 2/3 – 69.1% Genital warts – 68.5%
  47. 47. Past history of Abnormal Pap Smears / Histology  No contraindication for vaccination: 1. Females with equivocal / abnormal pap smears could be infected with any HPV types (high/low- risk) Might not be infected with any of the 4 vaccine-types (6/11/16/18) Unlikely to have infected all 4 types (0.1%) Vaccination would protect them against infection with HPV vaccine types not already acquired 1. With increasing severity of pap smear (such as HGSIL) Likelihood of infection with HPV 16/18 increases Benefit of vaccine wound decrease
  48. 48. History of Genital Warts No contraindication – Most often HPV 6 or HPV 11 – But might not have infection with both types or infection with HPV 16 or HPV 18 – Vaccination would protect them against infection with HPV vaccine types not already acquired
  49. 49. Antibody Testing before Vaccination  No indication for prior antibody testing: 1. Not all naturally infected individuals have antibodies Only 54%-69% with incident HPV 6/16/18 seroconvert 1. Serological assays are only available in research settings and only being done by the manufacturer Key laboratory reagents are not standardized 1. No gold standard for setting a threshold for a positive result
  50. 50. Decision to Vaccinate should NOT be based on Pap testing, HPV DNA or HPV serologic testing
  51. 51. Booster  Not recommended at this moment 1. High efficacy for preventing anogenital lesions through 5 years follow-up 2. High seropositivity remained at 36 months: – HPV 6 94% – HPV 11 96% – HPV 16 100% – HPV 18 76% 1. No evidence of waning efficacy among seronegative individuals 2. Demonstration of immune memory when a challenge dose was given at 5 yrs HPV 6 HPV 11 HPV 16 HPV 18
  52. 52. Vaccination in Pregnancy Not recommended for use during pregnancy (Category B) – Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women / Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester Not been causally associated with adverse outcome
  53. 53. Vaccination in Pregnancy  Vaccine group 1396/10418 (13.4%) vs Placebo group 1436/9120 (15.7%) – No difference in live birth, difficulty with delivery, spontaneous abortion, late fetal deaths – No difference in congenital abnormality (vaccine 25 VS placebo 22) Vaccination within 30 days of conception Vaccination more than 30 days of conception Vaccine Placebo Vaccine Placebo Spontaneous Abortion 19/112 26/115 266/1198 283/1218 Congenital Abnormality 5 0 20 22
  54. 54. Vaccination in Pregnancy If a women is found to be pregnant after initiating the vaccination series: – The reminder of the dose(s) should be delayed until after delivery – No intervention is needed (TOP not indicated)
  55. 55. Vaccination During Lactation No contraindication – Serious adverse event: – None were considered vaccine related Vaccine Placebo 17/500 (3.4%) 9/495 (1.8%) 12 Respiratory infection 5 Gastroenteritis
  56. 56. Duration of Protection  Data available for up to 5 years and exact duration depends on on-going trials – Phase III trials up to 3 years – A subset 241 participants still demonstrated 100% efficacy up to 5 years – Women in the Nordic countries will be followed for at least 14 years and serological testing will be obtained at 5 and 10 years
  57. 57. Interrupted Schedules (0/2m/6m) Does not need to be restarted – Interrupted after 1st dose: Second dose to be given as soon as possible and the 2nd and 3rd dose be separated by at least 12 weeks – Interrupted after 2nd dose: Third dose to be given as soon as possible
  58. 58. Incorrectly Vaccinated Individuals (0/2m/6m)  Studies: – Interval between 1st and 2nd dose Ranged from 6-12 weeks – Interval between 2nd and 3rd dose Ranged from 12-23 weeks – Variation in interval did not diminish the antibody titre after vaccination  Minimum intervals: – Between 1st and 2nd dose: 4 weeks – Between 2nd and 3rd dose: 12 weeks  Inadequate doses/shorter than recommended dosing interval should be readministered
  59. 59. Simultaneous Administration of Other Vaccines No contraindication: – Can be given with other age appropriate vaccine – Not live vaccine with no components that adversely impact safety or efficacy of other vaccination
  60. 60. Immunocompromised Patients No contraindication – Non-infectious vaccine – Immune response or vaccine efficacy might be lower
  61. 61. Precautions / Contraindications  Can be given with minor illness such as diarrhoea or mild URTI  Withhold in persons with moderate or severe acute illness  Manufacturing process for GARDASIL is free of egg or egg derivatives. Therefore, GARDASIL can be used in subjects with egg allergy  Contraindicated with history of allergy to yeast or to any known vaccine component
  62. 62. Any Therapeutic Effect ?  No therapeutic effect on existing infection / precancerous lesions / genital warts demonstrated  However, among subcohort of women: – HPV 16 DNA +ve / seronegative at enrollement less likely to develop HPV 16 related CIN 2/3 than those received placebo – No such benefit if they were HPV 16 DNA +ve and seropositive at enrollment – Vaccination may have some benefit in recent infection or in the early stage of disease (Hypothesis only)  Sub-analysis in 1,565 women who were infected with HPV at the time of study enrollment – 28 percent reduction in the rate of progression to CIN 2 or worse – Not statistically significant
  63. 63. Role of Cervical Screening Program ♦ Even if an ideal vaccine is developed, reduction of cervical cancer would not become apparent for at least a decade ♦ Decline in abnormal pap smears, especially in high risk groups, may become evident within months
  64. 64. Role of Cervical Screening Program ♦ Pap smear screening programs remain vital – Millions have already been exposed to HPV Multivalent vaccine may protect them from other HPV types (immunological interference) – Unless a multivalent vaccine can prevent every type of high-risk HPV, a proportion of women will continue to develop cervical cancer – Certain cervical cancers may not be associated with HPV – Some women may not respond immunologically to the vaccine Efficacy in immunocompromised patients (HIV, organ transplant) unclear – Vaccine coverage will not be 100% especially in under-developed and developing countries
  65. 65. Role of Cervical Screening Program  Need to continue Pap smear screening even after vaccination  Screening program may evolved from cytopathology basis to DNA basis  Need modification of screening recommendations when more long term data is available – Safety and cost-effectiveness to lengthen the screening interval Providers should educate women about the importance of cervical cancer screening
  66. 66. Other Ways to Prevent HPV Infection Avoid potential cofactors involved in HPV carcinogenesis: – Stop smoking – Prevent Co-infection with other STDs (Chlamydia and Herpes) Use of Condom Decrease the number of sexual partners
  67. 67. Vaccination in Males  Immunological studies showed immune response equally well among adolescent boys and girls  Theoretically prevents Genital warts / Anal cancer in males  Important transmission vector – Protect females from HPV 16 and 18 infection by herd immunity  Not licensed for use yet  Protocol 020 to evaluate young men – 3870 men in 16-26 year old men – Endpoints: HPV 6/11/16/18 related external genital lesions – HPV 6/11/16/18 infection – HPV 16/18 AIN (anal cancer)
  68. 68. Social Acceptance  Stigmata of STD – Unwilling to discuss about sexuality / STD to children – Concern about riskier sexual behaviors after vaccination – Over 80% of respondents indicated that they would get or let their daughters get vaccinated against cervical cancer – Over 95% of respondents would like to know more about the new cervical cancer vaccine
  69. 69. Conclusion ♦ HPV Vaccines have high efficacy in preventing vaccine-related anogenital diseases ♦ On-going studies to establish its duration of protection and impact on general health / cervical cancer ♦ Pap smear screening is still the most important and useful test to prevent cervical cancer
  70. 70. Thank You