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HPV Vaccines

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HPV Vaccines HPV Vaccines Presentation Transcript

  • HPV Vaccines Dr W H LI Queen Elizabeth Hospital 5 August 2007
  • Content
    • Introduction
    • Basic Information for Human Papillomavirus
    • HPV Vaccine Target Antigens
    • Vaccine Types
    • Phase II/III clinical trials
    • Gardasil / Cervarix
    • FAQ
    • Conclusion
  • 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
    View slide
  • Cervical Cancer in Hong Kong 439 (2004) 126 (2005) View slide
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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%
  • 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)
  • 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
  • Basic Information for Human Papillomavirus
  • Human Papillomavirus
  • 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%)
  • 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)
  • 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
  • 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)
  • 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
  • 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
  • HPV Vaccine Target Antigens
    • Capsid proteins L1 and L2 (Viral entry)
    • Replication proteins E1 and E2
    • Oncoproteins E6 and E7
  • 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
  • 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
  • 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
  • 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
  • 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
  • Vaccine Types
    • Virus-like particles (VLPs)
    • Recombinant live vector vaccine
    • Protein and peptide vaccines
    • “ Naked” DNA vaccines
    • Edible vaccines
  • 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
  • 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
  • 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%
  • 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)
  • 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
  • Multicenter Randomised Double Blind Controlled (Phase III) Trials FUTURE I/II Trials: Females United to Unilaterally Reduce Endo/Ectocervical Disease 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
  • Study Design
  • Phase II / III Clinical Trials
  • Side Effects
  • 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
  • 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
  • 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
  • Cross-Protection for Bivalent Vaccine (Cervarix) No cross protection for other HPV types other than 16/18 has been approved
  • 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
  • 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
  • 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
  • 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
  • Prior HPV Testing before Vaccination
    • No indication for prior HPV testing:
      • 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
      • 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
      • HPV infection mostly transient in young women and a positive HC 2 test may cause confusion and unnecessary anxiety
  • 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%
  • Past history of Abnormal Pap Smears / Histology
    • No contraindication for vaccination:
      • 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
      • With increasing severity of pap smear (such as HGSIL)
        • Likelihood of infection with HPV 16/18 increases
        • Benefit of vaccine wound decrease
  • 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
  • Antibody Testing before Vaccination
    • No indication for prior antibody testing:
      • Not all naturally infected individuals have antibodies
        • Only 54%-69% with incident HPV 6/16/18 seroconvert
      • Serological assays are only available in research settings and only being done by the manufacturer
        • Key laboratory reagents are not standardized
      • No gold standard for setting a threshold for a positive result
  • Decision to Vaccinate should NOT be based on Pap testing, HPV DNA or HPV serologic testing
  • Booster
    • Not recommended at this moment
      • High efficacy for preventing anogenital lesions through 5 years follow-up
      • High seropositivity remained at 36 months:
            • HPV 6 94%
            • HPV 11 96%
            • HPV 16 100%
            • HPV 18 76%
      • No evidence of waning efficacy among seronegative individuals
      • Demonstration of
      • immune memory
      • when a challenge
      • dose was given
      • at 5 yrs
    HPV 6 HPV 11 HPV 16 HPV 18
  • 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
  • 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
  • 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)
  • 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
  • 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
  • Interrupted Schedules (0/2m/6m)
    • Does not need to be restarted
      • Interrupted after 1 st dose:
        • Second dose to be given as soon as possible and the 2 nd and 3 rd dose be separated by at least 12 weeks
      • Interrupted after 2 nd dose:
        • Third dose to be given as soon as possible
  • Incorrectly Vaccinated Individuals (0/2m/6m)
    • Studies:
      • Interval between 1 st and 2 nd dose
        • Ranged from 6-12 weeks
      • Interval between 2 nd and 3 rd dose
        • Ranged from 12-23 weeks
      • Variation in interval did not diminish the antibody titre after vaccination
    • Minimum intervals:
      • Between 1 st and 2 nd dose: 4 weeks
      • Between 2 nd and 3 rd dose: 12 weeks
    • Inadequate doses/shorter than recommended dosing interval should be readministered
  • 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
  • Immunocompromised Patients
    • No contraindication
      • Non-infectious vaccine
      • Immune response or vaccine efficacy might be lower
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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
  • Thank You