Lecture for BSCCP series on HPV vaccination

1. HPV VACCINATION AND
PREVENTION OF CERVICAL
CANCER
Grainne Flannelly
National Maternity Hospital

2. Setting the scene
HPV and Cervical cancer
What are the vaccines and what do we know about their use
• Facts
• Assumptions
National immunisation programmes – challenges, effectiveness,
cost, impact on screening

3. <3.9 <7.9 <14.0 <23.8 <55.6
Cancer of the cervix (mortality/100,000)
 Mortality falling developed world
 Mortality rising in developing world

4. Relative incidence of cervical cancer Ireland
versus England
0
2
4
6
8
10
12
14
16
18
ESRper100,000women
Ireland
England
NCRI, NHSCSP (Includes Wales up to 1994)

5. Human Papilloma Virus
The link with cervical cancer
Epidemiology of
cervical cancer–
sexually transmitted
agent.
Human
Papillomavirus
(HPV) is the major
infectious agent
involved .
99.7% of cervical
cancers contain high
risk HPV DNA

6. Human Papilloma virus
The virology lesson
Double
stranded, tightly
coiled, circular
virus
More than 100
types
Genetic structure
• Early Late and Upper
regulatory areas E
(1,2,6,7), L (1,2)
Infects basal cell
layers of genital
epithelium

7. HPV and cervical neoplasia –
Molecular pathway
Integration of HPV
DNA into host
nucleus
Gatekeeper gene E2
Controls Activity of
E6 and E7.
Integration damages
E2
Interferes with
“Quality control
inspectors” or tumour
supressor genes.
•E 6 “takes out” p53
•E 7 “takes out” pRB
Result - More
abnormal cells which
live longer

8. Natural History of HPV infection
•Transmission by
sex
•Lifetime risk 80% -
most within 18
months
Exposure
•Transient
•Most resolve within
18 months
Infection
•Less than 20%
persist
•No antibodies
detectable
Persistence
•Virus integrates
into host DNA
Malignant
Transformation •Loss of tumour
supressor gene E2
•Uncontrolled cells
division
CIN

9. HPV and neoplasia the problem
A large
proportion of
sexually active
women will be
infected with
HPV
A minority will
have persistent
infection with
high grade CIN
Fewer still will
evolve into
invasive cancer
There must be other factors which interfere with immunity ? Cigarette smoking

10. Which Human Papillomaviruses to target?
Low Risk 6, 11, 40, 42, 43, 44, 54, 61
Anogenital warts
High risk 16, 18 45, 31, 33, 52, 58, 35,
59, 56, 39, 51, 73, 68, 66
Anogenital neoplasia
6,11,
16,18,
90%
warts
70%
cervical
cancer

11. HPV Vaccination
• Virus Like Particle
• L1 Surface protein as
empty shell (no DNA)
• 5 years years follow up
• Immunogenic and safe

12. Current VLP Vaccines
No comparitive studies
300 Euros for three doses
Quadrivalent
Sanofi Pasteur
Gardesil
Subtypes
16/18/6/11
Bivalent
GSK Bivalent Vaccine
Ceverix
HPV 16/18
Not yet Licenced

13. Future 2 Study: Quadrivalent
Vaccine
•93% of study
population were non
virgins
•Efficacy best in group
of women who were
HPV negative at time
zero (PPE)
•Efficacy reduced in
Modified Intention to
treat group (MIT)
(NEJM, May 2007)

14. Questions efficacy in non HPV
Naive women
Target Percentage
Reduction
High Grade CIN/AIS
associated with
HPV16/18
39%
High grade CIN/AIS
associated with any
CIN
12%
Condylomata 68.5

15. HPV Vaccine – Provisional ACIP
Recommendations
• Routine vaccination of females 11 or 12 years of age
• The vaccination series can be started as young as 9 years
of age at the clinician's discretion
• Vaccination is recommended for females 13-26 years of age
who have not been previously vaccinated (Note not
Mandated)
• Ideally vaccine should be administered before onset of
sexual activity
CDC, June 2006

16. UK
• NHS
• 27th October 2007
• JVCI – Advice
• Vaccination programme
• Girls aged 12-13
• Catch up to 18 years
delivered over two years

17. Questions - Epidemiology
• What proportion of cervical cancer and other HPV
related diseases are caused by subtypes covered by
vaccines? – (70%)
• What fraction of cervical cancer overall will be
prevented by a vaccine against HPV 16 and 18? -
(Depends on uptake and durability)
• Will immunity induced by vaccines alter the
distribution of other non vaccine HPV types? –
(Unknown)
(Lowndes, 2006)

18. Questions – Cost and impact on screening
programme
• How will a vaccination programme affect current
programmes for cervical cancer screening and when
should screening change?
• What is the cost effectiveness of various strategies for
vaccination programmes?
(Lowndes, 2006)

19. Effect on screening
While 70% of cancers
are associated with
HPV 16/18 a vaccine
with 98%
effectiveness may
reduce cancers by
only 51%
Replacement with
other high risk
vaccines an issue
• Cervical Screening will
have to continue for
vaccinated women
• Potential for Targeted
screening based on
virological tests in
future

20. HPV Vaccine and Cervical Cancer
Screening
• Cervical cancer screening recommendations have NOT
changed for females who receive HPV vaccine
• 30% of cervical cancers caused by HPV types not
prevented by the quadrivalent HPV vaccine
• Vaccinated females could subsequently be infected with
non-vaccine HPV types
• Sexually active females could have been infected prior to
vaccination
CDC, June 2006

21. Cost effectiveness – comparison with other
vaccinations
• Cost 300 euro per person – most expensive vaccine yet
but… cheaper for countries than individuals
Vaccination Life expectancy increase
(days)
HPV 2.8
Measles 2.7
Mumps 3.0
Rubella 0.3
Pertussis 3.3

22. Effectiveness
Combining vaccination of 12 year old girls with screening
would reduce cancer by 90% but would cost $45,000 per
QALY gained
Inclusion of boys would produce marginal increase in
efficacy but would increase the cost per QALY gained by
a factor of 10 to $450,000

23. Modelling study Finland
British Journal of Cancer (2007) 96, 514 – 518

24. Catch up vaccination
British Journal of Cancer (2007) 96, 514 – 518

25. Acceptability of the vaccine
• Lack of awareness
Shock, Fear,
• Before education
• Acceptors 55%
• Decline 22%
• Undecided 23%
• Following education
• Accept 74%
• Decline 18%
• Undecided 8%
Journal of lower genital tract disease 2004;8(3):188-94

26. Conclusions
• Vaccination before sexual debut maximises the long term
impact of vaccination
• Catch up programmes can speed up impact and reduce
the number of cumulative cases.
• Little evidence in favour of vaccinating women who
already have had HPV