1. My professional background
Studied Biology at University of Heidelberg
PhD at German Cancer Center Heidelberg (Breast Cancer Metastasis)
Postdoc I (Cytokines/TGF-beta in Metastasis)
Reseach associate Loyola Univ. Chicago, USA (HPV Immunology)
Group leader F. Schiller University Jena (Therapeutic HPV vaccines, Habilitation)
Head of Lab Gynecology Charité Berlin 2005-present
HPV prophylactic vaccines: Immunology and Introduction,
HPV screening methods: Development and Service, Introduction feasibility studies
HPV Epidemiology: Germany, Ghana, Ethiopia, Morokko
Cancer stem cell biology: Cervical and Hand and Neck, Ovarian and Breast Ca

2. Potential conflict of interest
I received speakers bureau honoraria and travel grants to conferences
Roche, GenProbe/Hologic, SPMSD, GSK
I received research funding
GSK
I have participated in studies for validation of assays
Arbor Vita OncoE6 cervical test (Arbor Vita),
HPV array (AID/GenID)
Quantigene HPV+ (Charité)

3. Topics HPV&CxCa Biology and Epidemiology
HPV Screening (& triaging) methods
International Guidelines

4. Nobel Price for Medicine 2008 to Harald zur Hausen…
Success story of medicine
Nobel Price for Medicine 2008 to Harald zur Hausen…
…for the proof that cervical cancer is induced by Human Papillomaviruses (HPV)

5. HPV Biology and Epidemiology
Prevention of Cervical Cancer: THE ROLE OF HPV INFECTION
Vilnius,
HPV Biology and Epidemiology
Andreas M. Kaufmann, PhD
Clinic for Gynecology, Charité-Universitätsmedizin Berlin, Germany

6. The most important measure to prevent cervical cancer in future is
HPV VACCINATION

7. Human Papillomavirus (HPV)
virus family Papillomaviridae
In every vertebrate species (>250)
Co-evolution
infecting exclusively epithelial cells in epidermis and mucosae
>206 different HPV genotypes
appx. 18 associated with cancer
anogenital
Oropharyngeal
In appx. 99% of CxCa SCC
appx. 18 associated with
condylomata acuminata
Electron microscopy
55 nm HPV particle
© AMK

8. x E6/E7 upregulation correlates to integration/progression
Repressor of E6/E7 promoter,
often destroyed during integration or binding sites in p97 methylated
Oncogene expression is upregulated when the virus ACCIDENTIALLY integrates into the host genome (no preferred site). The viral DNA circle opens at some position. It never happens in E6E7 genes. There is a selection advantage if this happens in the E2 gene that is in turn inactivated. This derepresses ongogene E6E7 expression leading to transformation.
Alternatively, the E2 binding sites may be inactivated by methylation.
E6/E7 upregulation correlates
to integration/progression
L1 Vaccine antigen
in VLP
© AMK

9. HR-HPV * * * * LR-HPV * HR Status not certain

10. ! Worldwide prevalence of individual HPV genotypes in CxCa Nonavalent
vaccine
N cases:
30 848
16+18 !
0.5 AL
IARC Handbooks of Cancer Prevention, Cervix Cancer Screening, 2005
Li et al. Int J Cancer 2011; Munoz et al., Int J Cancer, 2004

11. Mean age at diagnosis of CxCa depending on HPV genotype
de Sanjose, Lancet Oncol. 2014

12. Developmen of CIN III and HPV Status
20514 women
>30 years
initial neg. cytology
10 years follow-up
Incidence CIN III
HPV %
HPV %
HR-HPV+ 1.5%
LR-HPV/- 0.5%
Same risk
<30 vs >30
HPV 16 18 HR LR
© AMK
Khan et al., JNCI 97: (2005)
© AMK

13. HPV does it differently
Efficient transmission
Latency period, long persistence
Locally restricted infection
Low profile for immune escape
Asymptomatic infection

14. Progression from Infection to Cervical Cancer
7-30 years
Infection
CIN 1
CIN 2/3
Invasive CxCa
Ca. 50%
8-18 months
Virus production
transformation
CxCa
invasion
Aus Nature Reviews Cancer: Vol. 7: (Januar 2007)
Basal cells in the cervical epithelium rest on the basement membrane, which is supported by the dermis. Human papillomavirus (HPV) is thought to access the basal cells through micro-abrasions in the cervical epithelium. Following infection, the early HPV genes E1, E2, E4, E5, E6 and E7 are expressed and the viral DNA replicates from episomal DNA (purple nuclei). In the upper layers of epithelium (the midzone and superficial zone) the viral genome is replicated further, and the late genes L1 and L2, and E4 are expressed. L1 and L2 encapsidate the viral genomes to form progeny virions in the nucleus. The shed virus can then initiate a new infection. Low-grade intraepithelial lesions support productive viral replication. An unknown number of high-risk HPV infections progress to high-grade cervical intraepithelial neoplasia (HGCIN). The progression of untreated lesions to microinvasive and invasive cancer is associated with the integration of the HPV genome into the host chromosomes (red nuclei), with associated loss or disruption of E2, and subsequent upregulation of E6 and E7 oncogene expression. LCR, long control region.
infection
© AMK

15. Transformation Zone is Main Location of Infection
high-grade Lesion
normal
Squamo-columnar junction is fagile, stemm cells are expsoed and embryonal stem cells are present!
Accessibility and Permissivity
Courtesy by Dr.Mark Schiffman 15

16. Virus Binding and Entry Heparin sulphate proteoglycans
Cyclophilin B
Furin
cleavage
Tetraspanin
CD151
Conformational
change
Heparin sulphate proteoglycans
(HSPGs)
Basal Stem Cell
Basement Membrane (ECM)

17. Function and control of gene expression of HPV
highly restricted gene expression
Virus production and cellular differentiation
Infection/
persistence
Virus assembly (koilocytes)
Passive release (desquamation)
replication
This holds also true for the different stages during cancer progression. Wheras the
LSIL still resembles the productive infection caused by papillomavirus types, in HSIL caused by HPV16, the order of HPV markers
is preserved, but the timing is disturbed. In HSIL (CIN3) a total failure to complete the papillomavirus life cycle can occur.
This means that by analysing the transcription patterns in a quantitative fashion we believe that one can better predict
The presence and type of a cervical lesions.
Middleton et al., 2003

18. Cumulative acquisition of infection
young women with onset sexual activity
33% after 2 years
60% after 5 years
© AMK
Baseman and Koutsky, J Virol:32S, 2005

19. HPV-Prevalence and Age 11.851 women in Denmark
Start of primary
HPV Screening
HPV infection is a natural consequence of sexual activity.
% tested women
Age (years)
Krüger-Kjaer, et al. 2007, Baseman and Koutsky, J Virol:32S, 2005
© AMK 19

20. HPV persistence in men of every age
HPV detection (every type) per age group Men from Brasil, Mexico and USA
HPV persistence in men of every age
guarantees the Virus transition between
generations and spread in the crowd
Do not HPV screen women before 30 years of age
Do never HPV screen men
© AMK
Giuliano et al., Vaccine 26 suppl.10 (2008) K17-K28
© AMK 20

21. Cumulative Risk for HPV New Infections (every type) in Women acc
Cumulative Risk for HPV New Infections (every type) in Women acc. Age Cohorts in Bogotá
Bosch et al., Vaccine 26 suppl.10 (2008) K1-K16
© AMK
© AMK 21 21

22. Persistent Infections by HPV and Age
<25 25 - 34 35 44 45 54 55 64 65
Age %
Persistence
Oncogenic
HPV16
Non
HPV61 0%
10%
20%
30%
40%
50%
60%
Castle et al., JID 2005

23. HPV Infection and Immunity
Age years 15 20 22
HPV Infection ( n = 100 ) 40 55
spont. regression: natural immunity
CIN
n = 80
n = 20 CA
n = 1-2 (5?)
(premalignant Lesion
Persistence, Progression)
8-18 months
Infection!
HPV Prophylaxis
CxCa Prophylaxis/Therapy
Screening
Immunoselection/Evasion
© AMK

24. Prognosis for Dysplasia Development
CIN2+ to colposcopy/therapy
Potential over-treatent 50%!

25. Prevalence of Cervical Cancer (per 100.000 / year)60 7
3-40
80-?
<4 ? 20

26. ? ? ? !

27. HPV vaccination reduces HPV prevalence significantly
Indication
HPV vaccination
-70 bis 93% (?)
-30 bis 50%
-90%
-40 bis 70%
-50%
>90% (!)
HPV vaccination reduces HPV prevalence significantly
and in turn probably cervical cancer incidence!
(letzter Zugriff 25. September 2014)

28. Baseline HPV type prevalence in Germany
Cervico-vaginal lavage
by Delphi screener
Representatively selected young women years of age (2011)

29. Cross sectional HPV prevalence
cumulative life time incidence
80% (probably 100%)
Delere et al., BMC Infect Dis. 2014
© AMK

30. Proportion of individual HPV types
in all infections (n=407, in 235 persons)
Vaccine preventable type
Prevalence in HPV positves (%)
HPV type
Delere et al., BMC Infect Dis. 2014

31. Decrease of HPV vaccine types in vaccinated population
First signal in Germany,
HPV vaccination has expected effect!
In preparation: 2nd round 2017
Same methodology
Vaccine type reduction
Replacement?
Characteristics of population (50/50)
Positivity (%)
Ist das ein Erfolg???

32. Summary HPV is ubiquitous Carcinogenicity of genotypes differs
Males and females have different epidemiology and disease burden