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Development of a Human Papillomavirus Vaccine

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Development of a Human Papillomavirus Vaccine Powered By Docstoc
					HPV: Lessons learned???
    Deborah Money, MD, FRCSC
    Associate Professor, Ob/Gyn,
    University of British Columbia

        Executive Director,
  Women’s Health Research Institute
    Objectives of this presentation:
   To present some issues in HPV
    disease and prevention
   To share HPV controversies and
    perspectives that may inform the
    HIV prevention paradigm
         Financial Disclosures
   Honoraria and unrestricted grant in
    aids and participation in clinical trials
    with:
   Merck
   Glaxo Smith Kline
   IDI Diagnostics
          The HPV vaccine:
        A vaccine in evolution
   1992-2006 – much hype around
    evolving information that HPV caused
    cervical cancer (2009 Nobel Prize)
   Development of VLP L1 vaccines with
    unsuspected high levels of
    immunogenicity
   THEN – data supporting amazing
    levels of efficacy in preventing
    incident and persistent HPV infection
    in women
        The medical response
   Infectious disease, vaccinology,
    gynecologic oncology physicians,
    public health – very excited!!
   Rapid development of evidence
    reviews and guidelines for use of the
    vaccine
   Summer of 2006, the quadravalent
    vaccine licenced in many jursdictions
The lessons we thought we had
           learned!
   Other vaccines against STI’s had
    been disappointing so far – HSV, HIV
   Hepatitis B vaccine – excellent
    vaccine but role out was slow – took
    10 years and many missed
    opportunities
   This was a ‘cancer’ vaccine so public
    enthusiasm was expected to mirror
    ours!
         HPV vaccine roll out
   Rapid evaluation by national
    advisory committees on
    immunization
   Burden of disease determined to be
    significant
   Secondary prevention strategies
    effective but still secondary
    prevention (pap smear programs)
   Data on safety and efficacy deemed
    to be adequate
         Disease controversies
   Is HPV disease important for
    women’s health – YES
    • Cervical cancer – 2nd most common
      cancer in women worldwide
    • Genital warts are common and carry a
      substantive health burden
    • Other less common diseases can be
      caused by HPV and have high morbidty
    • Head and neck cancers
    • Resp papillomatosis
   What about men – YES esp for MSM
The strongest statistical relations ever
  identified in cancer epidemiology




 EL Franco, Vaccine 2005; 23
      Controversies in disease
            prevention

   What is the best way to prevent HPV
    disease and cancer sequelae:
    • Primary prevention – behaviour
      modification – abstinence, condom use
    • VS Preventative vaccine
    How are we doing with disease
     prevention without vaccine?

   Worldwide – dreadful
   In high resource settings – Pap smear
    programs have worked very well
   Low resource settings – very high
    rates of invasive disease with poor
    outcomes
   ESTIMATES OF THE WORLDWIDE INCIDENCE OF CERVICAL CANCER
       AND OF THE NUMBER OF NEW CASES FOR THE YEAR 2002



                                              5,647

                                    12,744                30,897
              14,670
                                     10,641
                                       8,175                                   61,132
                                                          4,456
               23,534                   8,201                     157,759
                                                                                42,538

                         48,328         20,919        33,903
 80% die in
   DC’s                                       7,698                                      2,004




Age Standardized Incidence Rate:    < 87.3      < 32.6         < 26.2       < 16.2      < 9.3

Ferlay J, et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence
Worldwide. IARC CancerBase No. 5, Ver. 2.0, Lyon, IARC Press, 2004
Age to vaccinate affected by age of
    acquisition of genital HPV
   Mean age of sexual debut in most
    countries is 15-16 years – highly
    variable
   60% of girls will have acquired
    genital HPV at 48 months from first
    intercourse
   Point prevalence decreases with age
    from a peak of 23% at 20-24 yrs to
    a low of 4% at 45-59 yrs (HPV DNA
    detectable in genital tract)
      What about the vaccine?
   Is it safe?
   Is it well enough studied?
   What is the cost-effectiveness when
    compared to other public health
    vaccines/programs?
        Vaccine controversies
   Which vaccine to use – bivalent vs
    quadravalent?
   Importance of cross- protection?
   At what age to initiate public vaccine
    programming?
   Who should receive the vaccine –
    girls only or girls and boys?
   How many doses are needed?
   Can this vaccine be used in a setting
    of high HIV prevalence
    Impediments to vaccination
   Expense – particularly for resource
    poor settings
   Need for refrigeration – cold chain
    just not practical
   3 doses requires substantive
    resources to implement
   Expensive and labour intensive to
    follow vaccine uptake and
    relationship to
          Is the vaccine safe?
   Over 5 large scale clinical trials of
    the quadravalent vaccine with >
    30,000 doses delivered.
   No safety concerns
   Post licensure – 28 million doses in
    US
   15,000 VAERS reports
   92% non-serious
         Is the vaccine safe?
   Of the serious reports to January
    2010:
   GBS – no increase in rate of 1-
    2/100,000
   Blood clots – all in persons with
    underlying risks
   49 deaths – none related to vaccine
  Are the current vaccines
covering the right serotypes?
Worldwide HPV Type-Specific
Distribution in Cervix Cancer




                Bosch et al. J Natl Cancer Inst 87:796-802,19
                 Which vaccine to use?
                       Bivalent                Quadrivalent
                     GSK (Cerverex)             Merck (Gardisil)

                        Bivalent                  Quadrivalent
Vaccine Type     HPV-16 and HPV-18 VLP        HPV-6/11/16/18 VLP
                  L1 capsid component         L1 capsid component
Expression
                     Hi-5 Baculovirus                Yeast
system
                                                 20 µg HPV 6
                                                 40 µg HPV 11
Concentration
                      20 µg HPV 16               40 µg HPV 16
                      20 µg HPV 18               20 µg HPV 18
                          AS04 :
                                                     Alum:
                500 µg Aluminum Hydroxide
Adjuvant                                        225 µg Aluminum
                    50 µg 3-deacylated
                                            Hydroxyphosphate Sulfate
                  Monophosphoryl Lipid A
Placebo                   Alum                       Alum
         Current understanding of HPV Vaccines in Females
Attribute                             Quadrivalent                     Bivalent
Protection against HPV 16/18                  ≥98%                            ≥93%
related CIN2+*

Protection against HPV 6/11                   ~99%                             -
related genital lesions

Cross-protection against CIN2+            Some types                    Some types
due to high risk types other than   phylogenetically related to   phylogenetically related
HPV 16, 18                                  HPV 16?                 to HPV 16 and 18?

Seroconversion to vaccine types               >99%                            >99%


Geometric mean antibody titers                      bivalent > quadrivalent
Duration of protection                            Unclear if any differences
Local reactogenicity                                bivalent > quadrivalent
Cost of vaccine dose                     $130 private                  $128 private
                                      $106 CDC contract**               Unknown
Efficacy in Women with Previous or
       Current HPV Infection
   At baseline, 27% of clinical trial population had evidence of
    past or current infection with at least 1 vaccine HPV types

         Positive to one of            No clear evidence of
         the vaccine HPV            protection against that type
         types at baseline


        Positive to one of            Protection against other
        the vaccine HPV                types included in the
        types at baseline                     vaccine

          HPV types not                   Protection not
         contained in the                 demonstrated
             vaccine
       Vaccine in public health
   In most medium to high resource
    countries including Canada, vaccine
    approved, recommended and funded
    as a school based vaccine in
    September 2007
   Public health given very short
    timeline to introduce school based
    program
August 27, 2007, Canada
       Fiji Times, 2008
‘Our girls are not guinea pigs’
                    Public Attitudes
    Parental surveys in Canada
    67.8% intend to vaccinate sons
    Those that are positive associated
     with beliefs that not associated with
     permissive sexual behaviour, more
     aware of HPV, more likely to be
     positive about vaccines in general,
     more likely to vaccinate daughters

    Ogilvie et al, STI 2008
What about the vaccine in areas
 of high HIV seroprevalence?
   HPV disease much more severe in
    HIV positive women – both genital
    warts and cervical dysplasia
   Canadian trial in progress to evaluate
    safety and efficacy
    • Need to ascertain if able to achieve
      adequate immune response
    • Safety reassuring to date
                              Screening HPV DNA Types in HIV
                                   positive women (n=95)
                    12




                             Oncogenic Strain
                    10
# of participants
                    8
                    6
                    4
                    2
                    0




                         6        16        26        33        35        40        44        51        53        56        59        62        67        69        71        73        82        84
                             11        18        31        34        39        42        45        52        54        58        61        66        68        70        72        81        83        89
              Conclusions
   Complex area from many
    perspectives of clinician, public
    health policy makers, health payers,
    parents, women, girls, boys, and
    THE MEDIA
   Lessons learned – do not assume
    that a highly effective vaccine that
    prevents an STI will be generally
    accepted by all!!!
      Can we use only 2 doses
   Motivation to evaluate 2 dose
    because:
    • High degree of efficacy and
      immunogenicity seen in 3 dose trials
    • Comparison to Hep B
    • Need to reduce costs and logistic burden
        What about the boys?
   All the large scale studies of both
    vaccines have been in girls with
    surrogate endpoints of persistent
    disease but primary goal of cervical
    cancer prevention
   Data in boys shows excellent
    immunogenicity
   Efficacy data is limited
        What about the boys?
   Cost effectiveness argument
    • If cx cancer is end point most modeling
      shows modest improvement in disease
      prevention with substantive cost –
      assuming 90% coverage
    • E.g. $50,000 per QALY for girls in
      $100,000 QALY for boys
   Gender equity argument is however
    compelling

				
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