Overview of Cervical Cancer Vaccines

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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

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BACKGROUND
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Infectious Agents Involved in Cancer Pathogenesis

• 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)
• Burkitts Lymphoma
• Other Lymphomas (HD/NHL)
• Nasopharngeal Carcinoma (NPC)

• HIV HHV-8 (1.0)
• Kaposis Sarcoma
• B-cell NHL
• Leiomyosarcoma
• SCC of the Conjunctiva
• Schistosomiasis (0.3)
• Bladder Cancer
• HTLV-I/II (0.1)
• ATLL
• Liver Flukes (
• Cholangiocarcinoma

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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
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The Most Common Cancers in Women
Less developed countries
More developed countries


Breast
Cervix
Ovary
Endometrium
Colon/rectum
Lung
Stomach
600
200
400
600
0
400
200
Annual number of cases (thousands)
Adapted from Parkin et al, Eur J Cancer 37S4,
2001
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Pyramid of DiagnosesUnited States
CA 15,000
HSIL 300,000
LSIL 1,000,000
HPV Persistence
ASCUS 2,000,000
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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

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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.

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HPV Infection at Baseline Predicts Subsequent
Precancer and Cancer

• Sherman et al. (JNCI, 2003)

Cumulative Incidence ()
Year of follow-up
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Portland Results (Khan et al. WS1-03)
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VACCINES
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Two Broad Classes of HPV Vaccines

• Prophylactic

• Therapeutic

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Two Broad Classes of HPV Vaccines

• Prophylactic
• Antibody-mediated
• Rely on IR to structural proteins (L1/L2)
• Most promising candidate is the VLP-based vaccine

• Therapeutic

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Two Broad Classes of HPV Vaccines

• 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)

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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)

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HPV Vaccine Development Stages

• Pre-clinical/Animal Studies

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Evidence that Immunization with VLPs Protects
Against Infection Canine Model
Warts
Immunogen
Suzich et al, PNAS, 1995
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HPV Vaccine Development Stages

• Pre-clinical/Animal Studies
• Phase I/IIA Safety Immunogenicity Trials

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NCI/JHU Phase I HPV Vaccine TrialMean Symptom
Incidence for All Vaccine Types and Placebo
N177 vaccine administrations, N35 placebo
administrations
V
V
P
P
V
V
V
P
P
P
VVaccine PPlacebo
Excludes concurrent illness Harro et al, JNCI 2001
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NCI/JHU Phase IIA VLP Trial Results also Indicate
that Cervical Anti-HPV16 VLP Antibody Levels
Increase Following Vaccination
Castle et al, Unpublished
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HPV Vaccine Development Stages

• Pre-clinical/Animal Studies
• Phase I/IIA Safety Immunogenicity Trials
• Phase IIB Virological Efficacy Trials
  (Proof-of-Principle)

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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 3471645, 2002
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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 3471645, 2002
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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 Lancet 2004
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GSK HPV16/18 L1 VLP Proof of Principle Efficacy
Trial ResultsITT Analysis
Efficacy

100 efficacy in ATP analysis
Harper et al., The Lancet, 2004
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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)

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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)

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HPV Vaccine DevelopmentMany Unanswered Questions

• How long will protection last?

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Levels of anti-HPV16 VLP antibodies in serum up
to 36 months following initial vaccination
Fife et al., Vaccine 222943, 2004
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Titers of anti-HPV16 VLP IgG in cervical
secretions during ovulatory cycles
Nardelli et al, JNCI, 2003
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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?

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

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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?

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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?

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

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Acknowledgements

• 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)

• 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