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Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
Harper Presentation
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Harper Presentation

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  • HPV becomes incorporated in the special Basal cells that act as stem cells.
    First HPV spreads laterally to the other basal cells.
    Second, HPV spreads up into the cellular differentiation schema.
    Infectious particles are manufactured in the stratum granulosum and released in the superficial layer in cervical and vaginal secretions.
  • HPV becomes incorporated in the special Basal cells that act as stem cells.
    First HPV spreads laterally to the other basal cells.
    Second, HPV spreads up into the cellular differentiation schema.
    Infectious particles are manufactured in the stratum granulosum and released in the superficial layer in cervical and vaginal secretions.
  • Confidence intervals with number of cases (events) occurring in the placebo group to the vaccine group (P/V).
  • No events (cases) occurred in either study’s vaccine group – all events were in the placebo group.
  • No events (cases) occurred in either study’s vaccine group – all events were in the placebo group.
  • Transcript

    • 1. Human PapillomavirusHuman Papillomavirus Infectious AgentsInfectious Agents CancerCancer Diane M. Harper, MD, MPH, MSDiane M. Harper, MD, MPH, MS Director, Gynecologic Cancer Prevention Research GroupDirector, Gynecologic Cancer Prevention Research Group Norris Cotton Cancer CenterNorris Cotton Cancer Center Dartmouth Medical SchoolDartmouth Medical School
    • 2. HPV different from STDsHPV different from STDs  HPV is common toHPV is common to ALLALL humanityhumanity  Every personEvery person has at least one HPV infectionhas at least one HPV infection  70-80%70-80% have had an anogenital infection at some time in their liveshave had an anogenital infection at some time in their lives  All agesAll ages are susceptible to infectionare susceptible to infection  HPV transmission must beHPV transmission must be skin to skin contactskin to skin contact  AnyAny rubbing, touching, chafing, wrestling provides skin to skin contactrubbing, touching, chafing, wrestling provides skin to skin contact  Penetrative intercourse isPenetrative intercourse is onlyonly one method of skin to skin contactone method of skin to skin contact  HPV type concordance between monogamous partners isHPV type concordance between monogamous partners is only 20-30%only 20-30%  Due to low viral copyDue to low viral copy  Due to inadequate sampling of partners’ genital skinDue to inadequate sampling of partners’ genital skin  Due to transmission patterns that are independent of intercourseDue to transmission patterns that are independent of intercourse  HPV can only live in the cells of theHPV can only live in the cells of the skin that coverskin that cover the whole bodythe whole body  All STD’s added together occur inAll STD’s added together occur in 5%5% of the entire populationof the entire population (CDC)(CDC)  STD’s are infections that resideSTD’s are infections that reside insideinside the body organsthe body organs  STD’s are transmitted bySTD’s are transmitted by bodily fluidsbodily fluids  HIV in the bloodHIV in the blood  HSV in the spinal columnHSV in the spinal column  Chlamydia in the fallopian tubesChlamydia in the fallopian tubes  Gonorrhea in the urethraGonorrhea in the urethra  Syphilis in multiple tissuesSyphilis in multiple tissues  Chancroid in the lymph systemChancroid in the lymph system
    • 3. Basal StemCell NORMAL SKIN
    • 4. SKIN - TO - SKINSKIN - TO - SKIN CONTACT HPV Transmission
    • 5. Three Forms of HPV InfectionThree Forms of HPV Infection  ResidentialResidential  Usually minimally six weeks from exposureUsually minimally six weeks from exposure  Can persist undetected for decadesCan persist undetected for decades  Can be LR or HR typeCan be LR or HR type  Can be prevented with vaccinationCan be prevented with vaccination  EpisomalEpisomal  Virally active HPV located in the cell nucleusVirally active HPV located in the cell nucleus  Separate from the human DNASeparate from the human DNA  Can be LR or HR typeCan be LR or HR type  Can cause abnormal Pap testsCan cause abnormal Pap tests  Can be seen colposcopicallyCan be seen colposcopically  Can be prevented with vaccinationCan be prevented with vaccination  IntegratedIntegrated  HPV DNA circle has opened and joined the human DNAHPV DNA circle has opened and joined the human DNA  Only HR typesOnly HR types  Causes abnormal Pap testsCauses abnormal Pap tests  Seen colposcopically: must be treated to prevent cancerSeen colposcopically: must be treated to prevent cancer  Can be prevented with vaccinationCan be prevented with vaccination
    • 6. ResidentialResidential
    • 7. HPV Basal StemCell 44 Week– Early gene expression E4/E5 66 Week– Early gene expression E6/E7 Viral DNA replication continues rapidly 88 Week– L1/L2 capsid proteins made indicating virion assembly at this level of cellular differentiation Releasing infectious particles EpisomalEpisomal
    • 8. EpisomalEpisomal Histology of a low-grade lesionHistology of a low-grade lesion Multiple HPVMultiple HPV virions per cellvirions per cell nucleusnucleus Not integratedNot integrated with human DNAwith human DNA
    • 9. IntegrationIntegration HPV DNA integratedHPV DNA integrated in genomein genome CIN 3CIN 3HPV DNA is circular HPV DNA opens HPV DNA inserts into the human DNA
    • 10. Episomal vs. IntegrationEpisomal vs. Integration HPVHPV Basal Stem CellBasal Stem Cell 4 Week4 Week Early gene expression E4/E5Early gene expression E4/E5 4 Week4 Week Early gene expression E4/E5Early gene expression E4/E5 6 Week6 Week Early gene expression E6/E7Early gene expression E6/E7 6 Week6 Week Early gene expression E6/E7Early gene expression E6/E7 Viral DNA replicationViral DNA replication continues rapidlycontinues rapidly Viral DNA replicationViral DNA replication continues rapidlycontinues rapidly HPV InfectionHPV Infection CIN 2/3CIN 2/3 8 week8 week L1 L2 capsid proteins madeL1 L2 capsid proteins made indicating virion assembly at thisindicating virion assembly at this level of cellular differentiationlevel of cellular differentiation 8 week8 week L1 L2 capsid proteins madeL1 L2 capsid proteins made indicating virion assembly at thisindicating virion assembly at this level of cellular differentiationlevel of cellular differentiation Releasing infectious particles intoReleasing infectious particles into the cervical and vaginal secretionsthe cervical and vaginal secretions EpisomalEpisomal HPV 16HPV 16 IntegratedIntegrated HPV 16HPV 16
    • 11. InvasiveInvasive CervicalCervical CancerCancer
    • 12. Randomized Controlled TrialsRandomized Controlled Trials Phase II - HPV VaccinesPhase II - HPV Vaccines Quadrivalent Vaccine1 Bivalent Vaccine2 Reference Villa LL et al., Lancet Oncology Online, April 7, 2005 Harper DM et al., Lancet 364:1757-1765, November 2004 Vaccine Type Quadrivalent HPV-6/11/16/ 18 VLP, L1 capsid component Bivalent HPV-16 and HPV-18 VLP , L1 capsid component Manufacturing Yeast Insect Cells (Baculovirus) Concentration 20 µg HPV 6 40 µg HPV 11 40 µg HPV 16 20 µg HPV 18 20 µg HPV 16 20 µg HPV 18 Adjuvant 225 µg Aluminum Hydroxyphosphate Sulfate 500 µg Aluminum Hydroxide with 50 µg 3-deacylated monophosphoryl lipid A (AS04) 1 Villa LL, et al. Lancet Oncol. 2005;6:271-278. 2 Harper DM, et al. Lancet. 2004;364:1757-1765.
    • 13. Quadrivalent Vaccine1 Bivalent Vaccine2 Dose and Administration 0.5 ml, intramuscular 0.5 ml, intramuscular Schedule 0, 2, 6 months 0, 1, 6 months Trial Size 277 vaccinees, 275 placebo 560 vaccinees, 553 placebo Site US, Brazil, Europe US, Canada, Brazil Age Range of Women 16-23 years 15-25 years Key Eligibility Requirements No history of cervical lesions, few sexual partners No history of cervical lesions, few sexual partners Duration Up to 35 months Up to 27 months Primary Endpoint Persistent Type-Specific HPV Persistent Type-Specific HPV 1 Villa LL, et al. Lancet Oncol. 2005;6:271-278. 2 Harper DM, et al. Lancet. 2004;364:1757-1765.
    • 14. ATP Group Quadrivalent Vaccine1 Bivalent Vaccine2 (cx/cxvag samples) Efficacy in Preventing Persistent Vaccine Specific HPV type Infections 89% (95% CI: 70-97 P/V: 47/6 events) 100% (95% CI: 77-100 P: 16 events) HPV 6 100% (95% CI: 68-100 P: 13 events) Not a Study Aim HPV 11 NS (P: 3 events) Not a Study Aim HPV 16 86%(95% CI: 54-97 P/V: 21/3 events) 100% (95% CI: 72-100 P: 13 events) HPV 18 89% (95% CI: 21-100 P/V: 9/1 events) 100% (95% CI: 7-100 P: 4 events) 1 Villa LL, et al. Lancet Oncol. 2005;6:271-278. 2 Harper DM, et al. Lancet. 2004;364:1757-1765.
    • 15. ITT Group Quadrivalent Vaccine1 Bivalent Vaccine2 (cx/cxvag samples) Efficacy in Preventing type specific associated Cytologic Abnormalities Not Reported 94% (95% CI: 70-98) Efficacy in Preventing Any type specific associated Lesions 100% (95% CI: 56-100) 10 placebo events 100% (95% CI: 16-100) 6 placebo events CIN Lesions 100% (95% CI: 32-100) (7 events) 100% (6 events) External Genital Warts 100% No CI (4 events) Not a Study Aim 1 Villa et al. Lancet Oncol. 2005;6:271-278. 2 Harper et al. Lancet. 2004;364:1757-1765.
    • 16. Efficacy of HPV Vaccines forEfficacy of HPV Vaccines for HPV 16 or 18 (+) CIN 2,3HPV 16 or 18 (+) CIN 2,3 Quadrivalent Vaccine1 Per protocol analysis P/V (n=5258/5301) 100% 95% CI: 76, 100 P/V: 21/0 Intention-to-treat P/V (n=5766/5736) 97% 95% CI: 83, 100 P/V: 36/1 Phase III TrialPhase III Trial Skjeldestad FE, et al. IDSA. San Francisco, 2005. Abstract LB-8a.
    • 17. Acceptable rate of adverse events Yes Yes Serious Adverse Events No No Seroconversion 100% 100% Specific Titers compared to Natural Infection at Month 7 10 times greater for HPV 6 10 times greater for HPV 11 100 times greater for HPV 16 20 times greater for HPV 18 200 times greater for HPV 16 100 times greater for HPV 18 Specific Titers compared to Natural Infection at follow-up 27 months 1.4 times greater for HPV 6 No greater for HPV 11 20 times greater for HPV 16 6 times greater for HPV 18 18 month 100 times greater for HPV 16 10 times greater for HPV 18 Quadrivalent Vaccine1 Bivalent Vaccine2 1 Villa et al. Lancet Oncol. 2005;6:271-278. 2 Harper et al. Lancet. 2004;364:1757-1765.
    • 18. ConclusionsConclusions  HPV VLP vaccines are well toleratedHPV VLP vaccines are well tolerated  Vaccines are highly immunogenicVaccines are highly immunogenic  Vaccines induce high antibody titersVaccines induce high antibody titers  Vaccines are highly effective in reducing:Vaccines are highly effective in reducing: Persistent HPV infectionPersistent HPV infection HPV-associated clinical diseaseHPV-associated clinical disease

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