Prophylactic HPV Vaccines Achievements

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Prophylactic HPV VaccinesAchievements
Challenges

• Henry C. Kitchener
• Lisbon
• December 2007

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Cumulative incidence of HPV infection from time
of first sexual intercourse
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(No Transcript)
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L1 L2
E2 E1 E4 E5
E6 E7
Adapted from Doorbar 2005
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Model of HPV Carcinogenesis
15 20 HPV Infection
20 25 CIN1/2
AGE
25 35 CIN3
30 Cancer
Persists
Integrates Cofactors
Clears
Genomic Damage
FREQUENCY
50
1
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Human Papillomavirus

• Small DNA Virus
• 7 early and 2 late genes
• Oncogenic and non-oncogenic types
• Non-oncotypes include 6 and 11
• genital and respiratory papillomavirus

Cervical Cancer

• Fifteen oncotypes found in 99 of cervical
  cancers
• Five oncotypes are associated with 80 of
• cancers
• Two oncotypes 16/18 are associated with 70 of
  cancers

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Prophylactic Vaccination
L1 Capsid proteins can self assemble into virus
like particles (VPLs)? VPLs are highly
immunogenic up to 100 fold level of
neutralising antibody associated with natural
infection
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Cervarix (HPV 16-18) VaccineMean Titres
Seropositivity Rates According to HPV Type Group
Harper et al, Lancet, 2006
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Rationale for Vaccination Programme

• To prevent type specific infection, thus
  ultimately preventing type specific associated
  CIN3
• Prevention of infection by 2 types could prevent
  most cancers
• Primary prevention of cervical cancer by
  vaccination could be more cost effective than
  secondary prevention
• Vaccination offers a primary prevention strategy
  for countries without effective screening
  programmes

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Definitions used in randomised trials of HPV
vaccines

• Per Protocol
• Cervix HPV ve/Sero ve/16/18 lesions
• Unrestricted Susceptible
• Cervix HPV ve/Sero ve/ all 3 doses/16/18
  lesions
• Intention to Treat
• All randomised subjects (real world)?
• All lesions

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• Quadrivalent vaccine against human papillomavirus
  to prevent high grade cervical lesions.
• The FUTURE II study Group
• NEJM (2007) 356 1915-27

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Quadrivalent HPV Vaccine to prevent Cervical
Lesions(15-26yrs)?
Future II NEJM (2007)?
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Quadrivalent HPV Vaccine to prevent Cervical
Lesions(16/18)
Future II NEJM (2007)?
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Quadrivalent Vaccine Efficacy to Prevent Cervical
Lesions (16/18)?

• Vaccine
  Efficacy()?
• Per Protocol 98
• Unrestricted susceptible 95
• ITT Population 44
• ITT (Any Type) 17

Future II NEJM (2007)?
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Prevalence rates for four of the commonest five
types and HPV 45 by cytological grade
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Impact of Quadrivalent Vaccine on Vulval
Condylomata
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Impact of quadrivalent vaccine (6, 11, 16 18)
on VAIN and VIN
Joura et al, Lancet (2007)?
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• Efficacy of a prophylactic adjuvanted bivalent L1
  virus like particle vaccine against infection
  with HPV16 and 18 in young women

An interim analysis of a phase III double blind
randomised trial. Paavonen et al, Lancet (2007)
3692161-70
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CIN2 lesions with HPV16 or HPV18 DNA
Paavonen et al, Lancet (2007)?
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Efficacy of Cervarix in Women initially
seropositive or seronegative for HPV 16/18 in a
Phase II Trial
Assignment of cases according to HPV DNA in
lesion Causality assignment considering
preceding infection in case of multiple HPV types
in lesion
1 Paavonen et al Lancet 2007 3692161-70
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Cervarix (HPV 16/18) VaccineVaccine Efficacy
Against Incident Infection with HPV 45, HPV 31,
HPV 52, HPV 33 and HPV 58 in Cervical Samples
from Intention-to-Treat Analyses
Harper et al, Lancet (2006)?
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Key Issues (1)Who to Vaccinate

• Females aged 11-13
• Sexually naive good immunogenicity
• Catch up of older adolescents
• Will be less cost effective
• Women up to 25 years
• Would be less protective
• Should boys be vaccinated?
• Will the vaccine be protective?
• Herd immunity but male HPV-related cancer is rare

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Key Issues (2)Vaccine Specific

• Duration of protection
• Follow-up of current/previous studies
• Cross protection
• Other oncotypes
• Cost effectiveness

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Key Issues (3)Implementation

• Education
• Key messages for children and parents
• Co-existence with cervical screening
• Scope for de-intensifying screening
• How to reach women in underdeveloped countries
• Expense/cold chain/acceptability

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Chronology of Vaccination Changes to Screening
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Impact of the Vaccines

• 50-60 of CIN2/3 will be prevented and perhaps
  only 20 of low grade cytological abnormalities
• The majority of VAIN and VIN may be prevented
• Prevention of genital warts (Gardasil)?
• Less lower genital tract disease will result in
  less treatment associated morbidity
• There should be an impact on other HPV associated
  cancer e.g. head and neck

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Impact of the Vaccines

• Prevention of 70 cervical cancers
• 450,000 cases per year, worldwide
• Infertility
• Suffering
• 250,000 deaths per year worldwide
• Uptake of vaccine in developing world will save
  many thousands of lives

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• The incidence of this disease might, in great
  measure, be prevented by inoculation.
• From ignorance and prejudices the parents .
  instead of inoculating their children, crowd into
  houses . when the disease is at its most
  contagious.
• Every argument is in support of inoculation,
  however conclusive, makes no impression upon
  their minds.

Small pox, 1791 Thomas Pollock