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HPV and HPV Vaccines china

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					HPV and HPV Vaccines
  In Cervical Cancer



               Jim England, 2007
               Cervical Cancer
Worldwide:
     Second most common cancer in women
     493,000 new cases each year
       80% of cases are in developing countries
       274,000 deaths each year

USA:
       3,700 deaths each year
       $ 6B Cost of screening and intervention
       ~80% reduced incidence
       Intervention considered aggressive
         Papillomavirus


    I              I




More than 100 HPV genotypes
40 HPV genotypes infect the genital tract
HPV is the most common sexually transmitted infection
   Papillomavirus Capsid




Capsomer
-------------
                L1
    HPV is the most common sexually transmitted infection
    More than 40 HPV genotypes infect the genital mucosa

     Prevalence of HPV infection:
           10.5% Worldwide
            1.4% Spain
            9.2% Europe
           14.8% Shanxi
           16.8% Shenyang
           18.4% Shenzhen
           25.6% Nigeria

 The distribution of HPV genotypes does not significantly differ
         worldwide: HPV 58 is more prevalent in China

Worldwide, cervical cancer is the second most common cancer in
            women: mostly in developing countries
Is HPV a true etiological agent
     for Cervical Cancer?


 Modified Koch’s Postulates
       Koch’s Postulates (1890)
   The organism must be found in all animals
    suffering from the disease, but not in
    healthy animals. [? carriers]
   The organism must be isolated from a
    diseased animal and grown in pure
    culture.
   The cultured organism should cause
    disease when introduced into a healthy
    animal. [? resistant hosts]
   The organism must be re-isolated from
    the experimentally infected animal.
Modified* Koch’s Postulates




                   * T.M. Rivers, 1937
HPV and Human Cancer
  5.2 % of All Cancers; 560,000/year

                                  99.7%
HPV Genotypes in Cervical Cancer


                                           [4%]
                                            [6%]
                                           8VLP




 HPV 18 is most strongly associated with
 endocervical adenocarcinoma
    Overwhelming support that HPV is
a true etiological agent in cervical cancer
      not just a harmless passenger

A drop in cervical cancer rates following
   a reduction in HPV infection rates
         [following vaccination]
      would be definitive proof that
       HPV is an etiological agent
    HPV is Necessary but not Sufficient
          to cause Cervical Cancer

         Additional steps occur over
   10 to 20 years after initial HPV infection
          to result in cervical cancer

Most high-risk HPV infections are subclinical
      only a minority produce dysplasia

    Natural history studies show that most
  HPV infections and HPV-related dysplasias
are cleared, probably by immune mechanisms
              HPV Gene Expression
                                  E6 inactivates p53
                                  E7 inactivates pRb
                       Immature   E6&E7 required for
Mature                 Cells      malignant phenotype;
Keratinized            Infected   prevent apoptosis;
Cells
                                  promote cell cycle

                                  E4 Early/Late transition

                                  L1 form pentameric
                                  capsomers that form
                                  Virus capsids or VLPs;
                                  Basis of type-specificity
                                  L2 conserved in most
                                  HPV types
   Papillomavirus Capsid




Capsomer
-------------
                L1
HPV Infection and Cervical Cancer
    Uncertain Natural History

Most cervical dysplasias do not
progress to invasive cancer
[Patient management implications]

Time Lag between HPV infection and
development of High Grade Dysplasia
and invasive cervical cancer
[Mechanism of neoplastic progression]
    Most Dysplasias Regress
Cannot distinguish the small fraction
that will progress to invasive CA
from the majority that will regress:
Results in aggressive management
of dysplasias that is the standard of
care in developed countries
Therapeutically effective but NOT
procedurally efficient or cost effective
Need More Robust Markers of
  Of Disease Progression

 Requires a More Complete
   Understanding of the
     Natural History of
       HPV Infection
Cervical Carcinogenesis by HPV
                                Immature cell infected
                                Mature cells produce virus




         Polyclonal Infection                        Monoclonal
                                                      Tumor




                                     Early/LateTransition
       Possible Additional Steps
      in Cervical Carcinogenesis
   May Link Regression and Lag time
• Somatic genetic/epigenetic (HPV-induced
      methylation) changes to cancer-related
      gene expression/function
   •Infectious agents [including other HPVs]
   •HPV DNA Episomal vs Integrated
   •Chemicals
   •Radiation
   •Intrinsic cellular/tissue mechanisms
•Cellular Targets
   HPV and Cervical Neoplasia
HPV 16 integrated forms increase
in frequency as severity of neoplasia
increases; but some invasive CA only
have episomal HPV 16 DNA

HPV 18 DNA is almost always
integrated high grade dysplasia and
invasive CA
Epithelial Adult Stem Cells: Junctional Location
                            Are adult stem cells for
                            cervical epithelium located
                            in the transformation zone
                            at the junction of the
                            exocervix and endocervix?

                            Are these cells the
                            progenitors of metaplastic
                            cells?

                            Are they the target of HPV
                            infection that leads to
                            cervical cancer?

                            Are they a low frequency
                            target? [lag?, monoclonal?]
       Cell Target Hypothesis
A large number of immature epithelial cells
     are able to be infected by HPV.

However, only a small subset of infected
   cells [? Adult Stem Cells] are capable of
   progressing to invasive carcinoma cells.

    Time lag due to low frequency target
 Few progressors due to low frequency target
   Monoclonality due to low frequency target
Vaccination
  Vaccination in infectious disease and cancer
Prophylactic (preventive) “before exposure” vaccine
       Polio, Smallpox, MMR, etc.
HBV vaccine is the first prophylactic anti-cancer vaccine
Existing HPV vaccines

Therapeutic (treatment) “after exposure” vaccine
Rabies- slow course, post-exposure vaccination is effective
Less widely employed- attractive in some cases
      HPV- slow course,
      Detection of infected people is possible,
      Spontaneous clearance presumably immune-based
      But no therapeutic HPV vaccines have shown efficacy
      Possible role for auto-infection [L1 vaccine]
      E6 & E7: current therapeutic vaccine targets
       HPV Vaccine Construction
Animal PVs (APV) and HPV induce neutralizing Abs

Formalin-inactivated APVs protect against warts (type)

Inactivated whole HPV was not considered because:
      HPV is hard to grow in human cell culture
      HPV contains 3 potent oncogenes

HPV capsid antigen (L1 or L2) vaccine was pursued
     (like HBV Recombivax)

L1 must be native to be an effective immunogen
         Vaccine Construction
Expression of L1 recombinant DNA in
mammalian, insect, yeast or bacterial cells
Generate Virus-Like Particles (VLPs)

                  Morphologically and Immunologically
                       similar to native virions

                  Contain no viral DNA

                  Cannot produce oncoproteins
           HPV VLP Vaccine Trials

  HPV 16 Vaccine




HPV 16+18 Vaccine
HPV VLP Vaccine Trials
 Two prophylactic HPV vaccines

Gardasil [Merck]: HPV 6,11,16, 18
FDA-approved on June 8, 2006 and EC for
immunization of 9-26 year old women

Cervarix [GSK]: HPV 16,18
In phase III clinical trials

Both are VLP vaccines
        Type-restricted Protection
HPV 16 completely protects against HPV 16 dysplasia
    but not better than placebo for other types

Gardasil is quadrivalent: homologous type protection

Octivalent vaccine: theoretically >90% protection

Oncogenic HPV type are constant worldwide:
    Multivalent worldwide vaccine is possible
HPV Genotypes in Cervical Cancer



                                           8VLP




 HPV 18 is most strongly associated with
 endocervical adenocarcinoma
     Some cross-protection occurs

HPV 16 closely related to HPV 31
HPV 18 closely related to HPV 45

HPV 16, 18 vaccine protects against HPV 45 (94%)
    and HPV 31 (15%) but not other types
   Immune Correlates of Protection
Protection correlates with serum neutralizing AB titers

Neutralizing AB titers correlate with ELISA titers

Transudation of ABs to genital mucosa is probably
     important: ? Role of microtrauma

Minimal protective titer and role of cell-mediated
     immunity are not defined: ?

Significant protection for 3.5 to 4.5 years [94%]
     Practical Vaccination Issues
- Optimal age of vaccination? [prior to 9 yo?]
- Unclear duration of protection:
   -Booster?
   -Breakthrough?

- Are 2 doses sufficient vs current 3 doses?
- Are alternative adjuvants beneficial ?

- No evidence that vaccination changes HPV types
- Immune escape unlikely:
   - Intra-type cross-neutralization
   - Slow rate of sequence change
     Practical Vaccination Issues
- Cost is several hundred dollars per person
- L1 VPL vaccines require refrigeration but capsomer
      [E coli] vaccine is stable at room temperature
-Inhalation and transdermal vaccination being studied
- More than 80% of cases in developing countries

- Response in immunocompromised patients needs
     to be studied [HIV+: 8X risk of cervical CA]

- Male vaccination is more important for non-cervical
      anal(90%), penile(40%), orapharyngeal(12%) CA
      than the modest herd effect for cervical CA
     Practical Vaccination Issues

- Modeling algorithms suggest that the most cost-
effective usage of HPV vaccine is:


*HPV 16 & 18 vaccine of women at age 12

*Cervical cytology screening every 3 years after age 25

*Screening combines PAP and high & low risk HPV
     DNA testing [increases certainty of negative PAP]
   Papillomavirus Capsid




Capsomer
-------------
                L1
   L2 vaccine may solve type-specific
               Problem

L2 (minor capsid protein) is highly conserved even
            in rabbit papilloma virus

L2 can be produced in transfected E. coli

L2 is weakly immunogenic: improved immunogenicity
May provide an alternative or compliment to L1 vaccines
        Post-exposure Vaccination
Vaccination of HPV infected women is not known
     to be harmful

HPV 6,11 vaccination of women with genital warts
    Decreases vertical transmission to babies
    and recurrent respiratory papillomatosis that
    can cause airway obstruction in infants

Since basal and cervical cancer/HGSIL cells do not
     express L1, L2, they not a direct target of L1, L2
     HPV immunity

Post-exposure vaccination may prevent auto-infection
     that may be important in progression of dysplasia
  Hypothesis: Autoinfection leads to
     Progression of Dysplasia
- Basal keratinocytes are targets of HPV infection
- HPV infection is likely polyclonal
- Basal cells have integrated HPV DNA and express
     Early genes [E1, E2, E5, E6, E7] but not
     Late genes [L1, L2]; do not produce virus
- More differentiated cells express E4 and viral DNA
     replicates
- Still more differentiated cells express L1, L2 and
        produce virus
-Infectious virus can autoinfect other susceptible
        cells [blocked by HPV immunity]
   Hypothesis: Autoinfection leads to
      Progression of Dysplasia
- HPV infection of cells with the capacity of self-renewal
     [“tissue stem cells”] would result in expansion of
     HPV-infected basal cells of restricted clonality

-If cervical “stem cells” are a small population that
        occupy a niche between epithelial cell types
        it could explain:
    - Initial appearance of HGSIL in transformation zone
    - Lag between initial HPV infection and development
        of HGSIL and cervical cancer [small target size]
Cervical Carcinogenesis by HPV
                                Immature cell infected
                                Mature cells produce virus




         Polyclonal Infection                        Monoclonal
                                                      Tumor




                                     Early/LateTransition
                    Reviews
   Roden, R., Wu, T.C. Wu, How will HPV
    vaccines affect cervical cancer. Nature
    Reviews-Cancer 6: 752-763(2006)

   Woodman, C.B.J., Collins, S.I., Young ,L.S.
    The natural history of cervical HPV
    infection. Nature Reviews- Cancer 7: 11-22
    (2007)

				
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