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Overview of Cervical Cancer Vaccines

Overview of Cervical Cancer Vaccines. Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim Division of Cancer Epidemiology and Genetics National Cancer Institute. BACKGROUND. Helicobacter Pylori (5.5%) Stomach Cancer

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Overview of Cervical Cancer Vaccines

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  1. Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim Division of Cancer Epidemiology and Genetics National Cancer Institute

  2. BACKGROUND

  3. Helicobacter Pylori (5.5%) Stomach Cancer Human Papillomaviruses (5.2%) Cervix Other Ano-Genital Sites Oropharynx/Mouth Hepatitis B/C Viruses (4.9%) Liver Cancer Epstein-Barr Virus (1.0%) Burkitt’s Lymphoma Other Lymphomas (HD/NHL) Nasopharngeal Carcinoma (NPC) HIV & HHV-8 (1.0%) Kaposi’s Sarcoma B-cell NHL Leiomyosarcoma SCC of the Conjunctiva Schistosomiasis (0.3%) Bladder Cancer HTLV-I/II (0.1%) ATLL Liver Flukes (<0.1%) Cholangiocarcinoma Infectious Agents Involved in Cancer Pathogenesis

  4. % of Cancers Attributable to Infectious Agents(Based on 2002 incidence data) • 17.7% (1,900,000 cases) of worldwide incidence of cancer attributed to infection. • This figure is higher (27%) in developing nations and lower (8%) in developed nations. From Parkin, M., 2005

  5. The Most Common Cancers in Women Less developed countries More developed countries Breast Cervix Ovary Endometrium Colon/rectum Lung Stomach 600 200 400 600 400 0 200 Annual number of cases (thousands) Adapted from Parkin et al, Eur J Cancer 37:S4, 2001

  6. Pyramid of DiagnosesUnited States CA 15,000 HSIL 300,000 LSIL 1,000,000 HPV Persistence ASCUS 2,000,000

  7. HPV Genotypes • Tissue tropism • Cutaneous vs. mucosal • Cancer association • Oncogenic • Non-oncogenic • Unknown • 13 HPV types recognized to be linked to cancer • HPV-16 accounts for 50% of tumors

  8. Experimental/Animal Evidence in Support of a Causal Link Between HPV and Cervical Cancer • HPV E6/E7 proteins are capable of binding and inactivating p53 & pRb. Cancer-associated HPV types better able to do so than low-risk types. • Integration of viral genome into host in invasive tumors invariably conserves the E6/E7 coding regions (and disrupts E2). • BPV is linked to the development of alimentary tract cancers in cows. • CRPV is linked to the development of skin tumors in rabbits.

  9. HPV Infection at Baseline Predicts Subsequent Precancer and Cancer Sherman et al. (JNCI, 2003) Cumulative Incidence (%) Year of follow-up

  10. 20 HPV16+ HPV18+ HC2+ 15 HR HPV- 10 Cumulative incidence rate (%) 5 0 1 2 3 4 5 6 7 8 9 10 11 Follow-up time (years) Portland Results (Khan et al. [WS1-03])

  11. VACCINES

  12. Prophylactic Therapeutic Two Broad Classes of HPV Vaccines

  13. Prophylactic Antibody-mediated Rely on IR to structural proteins (L1/L2) Most promising candidate is the VLP-based vaccine Therapeutic Two Broad Classes of HPV Vaccines

  14. Prophylactic Antibody-mediated Rely on IR to structural proteins (L1/L2) Most promising candidate is the VLP-based vaccine Therapeutic CMI-mediated Rely on IR to proteins required for maintenance of infection & transformation (E2/E6/E7) Two Broad Classes of HPV Vaccines

  15. HPV Vaccine Development Stages • Pre-clinical/Animal Studies • Phase I/IIA Safety & Immunogenicity Trials • Phase IIB Virological Efficacy Trials (Proof-of-Principle) • Phase III Efficacy Studies (Pivotal for Licensure)

  16. HPV Vaccine Development Stages • Pre-clinical/Animal Studies

  17. Evidence that Immunization with VLPs Protects Against Infection: Canine Model % Warts Immunogen Suzich et al, PNAS, 1995

  18. HPV Vaccine Development Stages • Pre-clinical/Animal Studies • Phase I/IIA Safety & Immunogenicity Trials

  19. NCI/JHU Phase I HPV Vaccine TrialMean Symptom Incidence for All Vaccine Types and Placebo N=177 vaccine administrations, N=35 placebo administrations V V P P V V V P P P V=Vaccine P=Placebo *Excludes concurrent illness + < 5 mm excluded Harro et al, JNCI 2001

  20. NCI/JHU Phase IIA VLP Trial Results also Indicate that Cervical Anti-HPV16 VLP Antibody Levels Increase Following Vaccination Castle et al, Unpublished

  21. HPV Vaccine Development Stages • Pre-clinical/Animal Studies • Phase I/IIA Safety & Immunogenicity Trials • Phase IIB Virological Efficacy Trials (Proof-of-Principle)

  22. HPV16 L1 VLP Proof of Principle Efficacy Trial (1) • Placebo controlled trial of 2392 16-23 year old women given 3 intramuscular doses of HPV16 L1 VLP vaccine with alum adjuvant. • Analyzed 1533 women who had been fully vaccinated and who were HPV negative throughout vaccination period. • Mean duration of follow-up: 17.4 months. From Koutsky et al., New Eng J Med 347:1645, 2002

  23. HPV16 L1 VLP Proof of Principle Efficacy Trial (2) • Transient HPV16 infection: 27 cases in placebos, 6 in vaccinees. • Persistent HPV16 infection: 41 cases in placebos, none in vacinees. • Total incident infection (transient + persistent): 68 in placebos, 6 in vaccinees. • HPV16 associated cytologic abnormalities: 9 in placebo (mild or moderate), none in vacinees. From Koutsky et al., New Eng J Med 347:1645, 2002

  24. GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial Design • Placebo controlled trial of 1113 15-25 year old women given 3 intramuscular doses of HPV16/18 L1 VLP vaccine with AS04 adjuvant. • Analyzed 1113 (100%) women in an Intent-to-Treat (ITT) analysis, and 721 (65%) who had been fully vaccinated and who were HPV negative throughout vaccination period (ATP cohort). • Mean duration of follow-up: 18 months. Harper et al., The L:ancet 2004

  25. GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial ResultsITT Analysis % Efficacy * * 100% efficacy in ATP analysis Harper et al., The Lancet, 2004

  26. HPV Vaccine Development Stages • Pre-clinical/Animal Studies • Phase I/IIA Safety/Immunogenicity Trials • Phase IIB Virological Efficacy Trials (Proof-of-Principle) • Phase III Efficacy Studies (Pivotal for Licensure)

  27. Three Ongoing Efforts • Merck Pharmaceuticals – Gardasil (HPV-16/18/6/11) – Filling in US end 2005 • GlaxoSmithKline Biologicals – Cervarix (HPV-16/18) – Filling in Europe 2006 • National Cancer Institute in Costa Rica – (HPV-16/18 Cervarix)

  28. HPV Vaccine DevelopmentMany Unanswered Questions • How long will protection last?

  29. Levels of anti-HPV16 VLP antibodies in serum up to 36 months following initial vaccination Fife et al., Vaccine 22:2943, 2004

  30. 10000 v31 v35 1000 v34 v21 anti-HPV16 VLP IgG 100 v56 v71 v49 10 v34b v49b 1 0 10 -10 20 -20 Days before and after ovulation Titers of anti-HPV16 VLP IgG in cervical secretions during ovulatory cycles Nardelli et al, JNCI, 2003

  31. HPV Vaccine DevelopmentMany Unanswered Questions • How long will protection last? • Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?

  32. Induction of CMI and Humoral Responses by L1 VLP (Pinto et. al. JID, 2003)

  33. HPV Vaccine DevelopmentMany Unanswered Questions • How long will protection last? • Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit? • Will vaccination protect men or reduce transmission by men to their partners?

  34. HPV Vaccine DevelopmentMany Unanswered Questions • How long will protection last? • Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit? • Will vaccination protect men or reduce transmission by men to their partners? • Who should be vaccinated?

  35. HPV Vaccine DevelopmentMany Unanswered Questions • How long will protection last? • Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific? • Will vaccination protect men or reduce transmission by men to their partners? • Who should be vaccinated? • Should vaccine valency be increased? If so, which types should be included?

  36. Distribution of HPV Types in Cervical Cancer by Geographical Region Bosch et al, JNCI, 1995

  37. HPV Vaccine DevelopmentMany Unanswered Questions • How long will protection last? • Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific? • Will vaccination protect men or reduce transmission by men to their partners? • Who should be vaccinated? • Should vaccine valency be increased? If so, which types should be included? • How will an effective vaccine affect the need for cervical cancer screening?

  38. National Cancer Institute: Jay Berzofsky (immunology) Clayton Harro (vaccinology) Martha Hutchinson (cytology) Douglas Lowy (virology) Ligia Pinto (immunology) Mark Schiffman (epidemiology) John Schiller (virology) Mark Sherman (pathology) Diane Solomon (pathology) Sholom Wacholder (statistics) Acknowledgements • PEG Costa Rica: • Mario Alfaro (cytology) • Jose Bonilla (immunology) • Concepcion Brattit (Assist PI) • Enrique Freer (virology) • Diego Guillen (pathology) • Rolando Herrero (co-PI) • Jorge Morales (colposcopy) • Ana Cecilia Rodriguez (Assist PI) • PEG Colleagues and Staff

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