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1. HPV Vaccination in 2014
IFCCP Jeddah Jan 2014
James Bentley
Professor Dept. Obstetrics and Gynecology
Dalhousie University
Halifax, Canada

2. HPV cancers - Highest burden in cervical cancer
Adapted from Parkin DM, Bray F. Vaccine. 2006;24 Suppl 3:S11-25
HPV related cancer in women
527,100 cases WW/year
2
HPV related cancer in men
33,800 cases WW/year
90% of HPV cancer in women are
cervical cancers
492800
16000
14300
2900
1100
13000
10500
5200
5100

3. Cervical cancer burden – World Wide
3
FerlayJ, et al.GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide. IARC CancerBaseNo.10. Lyon, France. 2010
Every 2 minutes a woman dies of cervical cancer.1
Every minute a woman is diagnosed with cervical cancer.1
New cases per year: ~ 530,000
Deaths per year: ~ 275,000
NA + Europe
Africa
Asia
Latina
29,000
53,000
31,000
159,000
77,000
80,000
68,000
312,000
80% in developing countries = 2nd
cause of cancer death in women

4. Active protection via vaccination is mediated by
neutralizing antibodies at the cervix
HPV
Cervical canal
Neutralizing antibodies
Blood vessel
Epithelial tear
Basement membrane
Cervical
epithelium
Stanley M. Vaccine 2006; 24:S16–S22;
Giannini S, et al. Vaccine 2006; 24:5937–5949;
Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137;
Poncelet S, et al. IPvC 2007; Abstract.

5. HPV causes cervical cancer
• Undisputed epidemiological evidence
• RR higher than for cigarettes & lung cancer1,2
• Lifetime risk of infection ~ 80%3–5
• > 70% of HPV types are oncogenic6,7
• Vast majority of infections are transient, clearance
12–18 months6
• ~ 10% infections persist beyond 2 years8
• Persistent infection is a necessary cause of
pre-cancer or cancer9,10
• Development of cancer from persistent HPV infection takes 10–20
years, although rarely, it may take
only 1–2 years9
1. Vineis P, et al. J Natl Cancer Inst 2004; 96:99–106; 2. Lorincz A, et al. ObstetGynecol 1992; 79:328–337; 3. Brown DR, et al. J InfectDis 2005; 191:182–192; 4. Koutsky L, et
al. Am J Med 1997; 102:3–8; 5. Bosch FX, et al. J Natl Cancer Inst Monogr 2003; 31:3–13; 6. Brown DR, et al. J Infect Dis. 2005; 191:182–192; 7. Peto J, et al. BJC 2004; 91:942–
953; 8. Ho GY, et al. N Engl J Med 1998; 338:423–428; 9. Burd EM. Clin MicrobiolRev 2003; 16:1–17; 10. Solomon D, et al. JAMA 2002; 287:2114–2119.

6. de Sanjosé S, et al. Lancet Oncol 2010; 11:1048–1056.
Cervical cancer is caused by a
variety of HPV types
Cumulative relative contribution of HPV in invasive cervical cancer *
50% 60% 70% 80% 90% 100%
Global
Squamous cell carcinoma
Adenocarcinoma
70.8
76.7
84.2
91.3
Cumulative relative contribution, %
16+18
16+18+45
16+18+45+33+31
16+18+45+33+31+52+58+35
16+18
16+18+45
16+18+45+33+31
16+18+45+33+31+52+58+35
16+18
16+18+45
16+18+45+33+31
16+18+45+33+31+52+58+35
70.0
75.4
83.5
91.0
82.3
94.2
95.2
95.7
*Focus on 8 most common types

7. Papillomavirus – phylogenetics
HPV18- Related
45, 39, 59, 51, 56 HPV16- Related
31, 33, 35, 52, 58

8. Cervarix ® : Vaccine design
Specificity of the immune response
Cervarix is a registered trade mark of the GlaxoSmithKline group of companies.
Cervarix®
Antigen
20 µg
L1 HPV 16
20 µg
L1 HPV 18
+
Adjuvant
Substances that potentiate the immune
response to antigen
Through MPL, AS04 Adjuvant System utilizes
natural ‘danger’ signals
AS04 Adjuvant System
Aluminium salt + MPL
(Al(OH)3)
Giannini SL, et al. Vaccine 2006; 24:5937–5949.
Manufactured in insect
vector

9. Gardasil ® :Vaccine design
Specificity of the immune response
Gardasil ® Merck
Gardasil ®
Antigen
40 µg
L1 HPV 16
+
Adjuvant
Substances that potentiate the immune
response to antigen
(Al(OH)3)
Manufactured in recombinant
Saccharomyces Cerevisiae (yeast)
20 µg
L1 HPV 6
40 µg
L1 HPV 11
20 µg
L1 HPV 18

10. CIN2 and CIN3 as disease endpoints
for studies
• There is substantial heterogeneity in the microscopic diagnosis and
biologic meaning of CIN 2 lesions in particular.1
• Some non-oncogenic HPV infections are capable of producing lesions
diagnosed as CIN 2.1
• CIN-3 can be reliably distinguished from recently acquired HPV
infection and it is a good indicator of subsequent cancer risk.2
• CIN3 is a more reproducible and stringent diagnostic endpoint than
CIN2 and frequently progresses to ICC.3,4,5
• The recent “LAST” publication from the ASCCP and CAP suggested
a HSIL/ LSIL terminology with breakdown of HSIL into CIN2, CIN3 to
fit with current clinical practice 6
1. Schiffman, Kjaer. JNCI Monographs 2003 ,No. 31; 2. Moscicki A, et al. Vaccine. 2006 Aug 31;24 Suppl 3:S3/42-51; 3. Carreon et al. Int J Gynecol Pathol
2007; 26: 441–46.; 4. Castle PE,et al. Obstet Gynecol 2009; 113: 18–25.; 5. Lehtinen M, et al. Lancet Oncol. 2012 Jan;13(1):89-99. 6. Darragh et al. J Low
GenitTract Dis. 2012 Jul;16(3):205-242

11. Prophylactic HPV Vaccines: Phase III Randomized Controlled Trials
Outcomes to Date (Per Protocol Efficacy Populations)
Vaccine Quadrivalent 6/11/16/18 Bivalent 16/18
Mean follow up 36 months 34.9 months
Prophylactic efficacy
HPV 16 CIN 2/3 100% 93%
HPV 18 CIN 2/3 100% 83.3%
HPV 16/18 CIN 2/3 98%* (100%)† 90%* (98%)†
HPV 16/18 AIS 100% Not reported
HPV 16/18 VIN 3 100% Not reported
HPV 16/18 VaIN 3 100% Not reported
6/11 Anogenital disease 100% Not a target
EGW, VIN1 VaIN1 99%, 100%
Cross protection Demonstrated Demonstrated
Tolerability Well tolerated Well tolerated
Therapeutic efficacy None None
*pre-specified endpoint analysis HPV 16 or 18 DNA in the lesion.
†post hoc endpoint analysis HPV 16 or 18 DNA in the lesion and in preceding cytology samples.
1. Stanley M. Curr Opin Infect Dis 2010; 23(1):70-5. 2. Garland SM, et al. N Engl J Med 2007; 356(19):1928-43.
3. FUTURE II Study Group. N Engl J Med 2007; 356(19):1915-27. 4. Paavonen J, et al. Lancet 2007; 369:2161-70.

12. Cervarix® demonstrated high efficacy for High Grade lesions
against types included in the vaccine
PATRICIA end-of-study analysis , VE against HPV-16/18; primary endpoint$
Vaccine cases
n (N)
Control cases
n (N)
Vaccine
efficacy, %
95% CI
$ATP cohort – primary analysis
CIN3+ 2 (7338) 24 (7305) 91.7 * 66.0–99.1
CIN2+ 5 (7338) 97 (7305) 94.9 87.7–98.4
TVC-Naïve – primary analysis
CIN3+ 0 (5466) 27 (5452) 100.0 85.5–100.0
CIN2+ 1 (5466) 97 (5452) 99.9 94.2–100.0
95% CIs > 0
Wheeler CM, et al. Lancet Oncol 2012; 13:100–110.
* CIN3+, ATP cohort , TAA analysis: 100.0 (81.8-100.0)
$ ATP cohort for efficacy: Subjects seronegative, DNA negative at baseline for the corresponding type; primary endpoint
N = number of evaluable women in each group;
TVC-naïve cohort: Population naïve to 14 oncogenic HPV types at baseline; N = number of evaluable women in each group;
Lesions associated with HPV 16/18 vaccine types

13. 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99; 2. Schiffman M, et al. Virology 2005; 337:76–84; 3. Carreon JD, et al. Int J Gynecol Pathol 2007;
26:441–446; 4. Castle PE, et al. Obstet Gynecol 2009; 113:18–25; 5. Hakama M, et al. Int J Cancer 2004; 112:1072–1074.
Cervarix® demonstrated high protection against high grade lesions
PATRICIA end-of-study analysis; analysis irrespective of type, TVC-naïve1
Endpoint
Vaccine cases
(N = 5,466)
Control cases
(N = 5,452)
Vaccine
efficacy, %
95% CI
CIN3+ 3 44 93.2 78.9–98.7
CIN2+ 61 172 64.9 52.7–74.2
95% CIs > 0
CIN3+ is generally regarded as a better surrogate of ICC than CIN2+
–CIN3+ is a more severe lesion and the immediate precursor of ICC
–The HPV type distribution in CIN3+ is closer to that in ICC2
–CIN3+ is a more reproducible and stringent surrogate of ICC compared with
CIN2+3–5
In an analysis of CIN3+ lesions, conducted irrespective of HPV type, Cervarix® showed 93% efficacy(95% CI: 78.9–98.7)

14. Long-term protection against CIN3+ lesions can be expected from vaccination
with Cervarix®
PATRICIA end-of-study, analysis irrespective of HPV type in ; TVC-naive
Lehtinen M, et al. Lancet Oncol 2012; 13:89–99.
0
0.01
0.02
0 6 12 18 24 30 36 42 48
Cumulativeincidence
Time, months
Control
Vaccine
Cases in
control
group
continue to
accrue with
no indication
of plateauing
at 4 years

15. Cervarix® : high and sustained anti-HPV 16/18 neutralizing
antibodies* up to 9.4 years
PRE = pre-vaccination; * By PBNA. Combined analysis of HPV-001/007/023 in the subcohort.
Naud et al. IPvC 2011. Presentation O18.04; EMA. Cervarix®. European Summary of Product Characteristics, 2012..
= Natural infection
antibody levels
≥ 8-fold higher
than natural
infection
100 %
seropositivity
≥ 4-fold higher
than natural
infection
HPV-023HPV-007HPV-001
100%
seropositivity
HPV 16
GMT, ED50
HPV 18
GMT, ED50
Months after
1st vaccination

16. Challenge Dose at 60 Months Post Quadrivalent HPV
6/11/16/18 Vaccine Elicits Anamnestic Response
Olsson SE, Villa LL, Costa RL, et al. Vaccine 2007; 25(26):4931-9.
SerumcLIAGMT.mMU/mL
(Loog10Scale)
HPV 6
10
100
1,000
10,000
D123 67 12 18 24 30 36 54 60 61
Time Since Vaccination 1 (Months)
Vaccination ****
PPI Quadrivalent Vaccine
PPI Placebo
Baseline Seropositive and PCR Negative Placebo
SerumcLIAGMT.mMU/mL
(Loog10Scale)
10
100
1,000
10,000
D123 67 12 18 24 30 36 54 6061
Time Since Vaccination 1 (Months)
Vaccination ****
PPI Quadrivalent Vaccine
PPI Placebo
Baseline Seropositive and PCR Negative Placebo
SerumcLIAGMT.mMU/mL
(Loog10Scale)
10
100
1,000
D123 67 12 18 24 30 36 54 60 61
Time Since Vaccination 1 (Months)
Vaccination ****
PPI Quadrivalent Vaccine
PPI Placebo
Baseline Seropositive and PCR Negative Placebo
SerumcLIAGMT.mMU/mL
(Loog10Scale)
10
100
1,000
10,000
D123 67 12 18 24 30 36 54 60 61
Time Since Vaccination 1 (Months)
Vaccination ****
PPI Quadrivalent Vaccine
PPI Placebo
Baseline Seropositive and PCR Negative Placebo
HPV 11
HPV 16 HPV 18

17. Cervarix®
Protocol 008
TVC-naïve cohort (48 months of FU)2
Cervarix® Control %Efficacy
(95% CI)
N n N n
5466 61 5452 172
64.9
(52.7; 74.2)
5466 3 5452 44
93.2
(78.9; 98.7)
Gardasil®
Combined protocols Future I, Future II
R-MITT-2 cohort (EOS* data)1
Lesion Gardasil® Control %Efficacy
(95% CI)N n N n
CIN2+,
irrespective of
causal HPV
type
4616 77 4680 136
42.7
(23.7; 57.3)
CIN3+,
irrespective of
causal HPV
type
4616 36 4680 64
43.0
(13.0; 63.2)*
Cervarixand Gardasil – Efficacy
CIN2+/CIN3+ irrespective of HPV Type
* The median duration of follow-up for the combined protocols (005, 007, 013, and 015) was 3.6 years after receipt of dose 1 and maximum
of 4.9 years.
* for Gardasil® the endpoint was CIN3
N = number of evaluable women in each group; n = number of evaluable women reporting at least one event
in each group; - : not available; Bold = statistically significant.
No head-head efficacy studies were carried out – those comparisons are only informative
1. Munoz et al. J Natl Cancer Inst 2010; 102:1–15; 2. HPV-008 Month 48 analysis.
※サーバリックスの日本での効能・効果は”HPV16型及び18型感染に起因する子宮頸癌及びその前駆病変(CIN2及び3)の予防”です。添付文書

18. Safety of HPV Vaccines
• The vaccines do not contain any living virus
• More than 79 million doses of the quadrivalent vaccine have been
distributed globally (3.3 million in Canada), with no serious adverse
events found to be associated with the vaccine and with no greater
risk of adverse events than with placebo
• Approximately 7 million doses of the bivalent vaccine have been
distributed worldwide (6,473 in Canada)
• NACI and Health Canada recommend HPV vaccination for women
who have already had HPV-related disease because it is safe and
offers significant protection against HPV-related diseases related to
the genotypes to which they were not exposed
• There is ongoing surveillance by healthcare authorities, companies
and registries
GARDASIL Product Monograph. Merck Canada Inc. August 2011.
CERVARIX Product Monograph. GlaxoSmithKline Inc. August 2011.
Data on file, Merck Canada Inc.

19. Post-licensure Safety Study of
Quadrivalent HPV 6/11/16/18 Vaccine
Among 189,629 Females
• Favorable safety profile; NO association between vaccination with
quadrivalent HPV vaccine and:
– Congenital anomalies, miscarriages
– 16 pre-specified autoimmune (AI) conditions
– Venous thromboembolism
– Death
– Any other general safety events (except syncope & possibly local
skin infection)
• Syncope associated with quadrivalent HPV vaccine: injection-related
• Local skin infection (cellulitis/abscess) possibly associated with
quadrivalent HPV vaccine: could be injection site reaction
• All safety conclusions were made by independent, external Safety
Review Committee of 5 experts
Velicer C. Presented at EUROGIN 2011.

20. What about the older woman?

21. Relatedcases
0
40
60
80
100
20
1. Castellagué X, et al. Br J Cancer 2011; 105(1):28-37.
2. Ferris D, et al. Presented at: EUROGIN 2010 Congress. February 17-20, 2010. Monte Carlo. Abstract SS 3-3.
Per-protocol Efficacy Population, Mean Follow-up: 3.8 Years
Efficacy Against Combined Incidence of HPV
6/11/16/18-related Persistent Infection, CIN
(Any Grade), and EGLs: Results by Age Strata
n=1,601
10
24- to 45-year-olds
n=1,599
86
89%
reduction
95% CI:
78.1 – 94.8
Total
n=816
5
35- to 45-year-olds
n=809
30
n=785
5
24- to 34-year-olds
n=790
5691%
reduction
95% CI:
78.4 – 97.3
84%
reduction
95% CI:
57.9 – 95.1
Quadrivalent HPV vaccine Placebo

22. Relatedcases
0
40
60
80
100
20
1. Castellagué X, et al. Br J Cancer 2011; 105(1):28-37.
2. Ferris D, et al. Presented at: EUROGIN 2010 Congress. February 17-20, 2010. Monte Carlo. Abstract SS 3-3.
Per-protocol Efficacy Population, Mean Follow-up: 3.8 Years
Efficacy Against HPV 6/11/16/18-related
Persistent Infection, CIN (Any Grade),
CIN 2/3 or Worse, and EGLs
n=1,581
9
Persistent infection
n=1,586
85
90%
reduction
95% CI:
79.3 – 95.4
n=1,600
0
EGLs
n=1,599
7
100%
reduction
95% CI:
30.8 - 100
n=1,581
1
CIN 2/3 or worse
n=1,584
6
83%
reduction
95% CI:
-37.6 – 99.6
n=1,581
1
CIN (any grade)
n=1,584
17
94%
reduction
95% CI:
62.5 – 99.9
Quadrivalent HPV vaccine Placebo

23. Quadrivalent
HPV Vaccine
(n=1,578)
Placebo
(n=1,583) % Reduction 95% CI
ASC-US (HR+)
or worse
1 38 97% 84.5, 99.9
ASC-US HR(+) 1 13 92% 48.8, 99.8
LSIL 0 25 100% 84.1, 100
ASC-H 0 1 100% <0, 100
HSIL 0 0 – –
1. Castellagué X, et al. Br J Cancer 2011; 105(1):28-37.
Per-protocol Efficacy Population, Mean Follow-up: 3.8 Years
Reduction in Incidence of
HPV 6/11/16/18-related Pap Diagnoses
n = number of subjects who have at least 1 follow-up visit after month 7.

24. Do you need 3 doses?

25. • The AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine has been shown to be
immunogenic, efficacious and generally well tolerated in clinical studies1–3
• The licensed administration schedule includes 3 doses to be given at Months 0, 1 and 6
• In young girls aged 10–14 years the vaccine-induced immune response is 2-fold higher as compared
with subjects 15–25 years4
• Higher immunogenicity of the vaccine in adolescents could make a 2-dose schedule feasible,
providing better convenience for vaccinees and health care staff, and potentially facilitate
implementation of HPV vaccination

26. Study design
• Phase I/II study evaluating the HPV-16/18 vaccine:
– According to a 2-dose schedule vs. the standard 3-dose
schedule
– Using the licensed vaccine formulation (20 μg of each
antigen)
or an alternative formulation (40 μg of each antigen)
• Healthy females (N=960) were age-stratified (9–14 years, 15–19
years, 20–25 years) and randomised to the following groups:
26
* Blinded for the 2-dose schedule groups
Group Month 0 Month 1 Month 2 Month 6
40/40 M0,2* 40/40 - 40/40 Placebo
40/40 M0,6* 40/40 - Placebo 40/40
20/20 M0,6* 20/20 - Placebo 20/20
20/20 M0,1,6 (control) 20/20 20/20 - 20/20

27. 2 vs. 3 dose trial: Objectives
• To evaluate the antibody response to 2 doses in subjects aged 9–14 years*
as compared with 3 doses in subjects aged 15–25 years†
– GMT ratios between the 3-dose and 2-dose schedules were calculated
with 95% confidence intervals
• To evaluate the safety and reactogenicity of the vaccine in all study groups
27
*Target population for HPV vaccination, †Age group in which efficacy was demonstrated

29. 2 vs. 3 dose: Conclusions
• 2-dose schedules of the HPV-16/18 AS04-adjuvanted vaccine were
immunogenic and generally well-tolerated in girls aged 9–14 years and
women aged 15–25 years, up to 3 years after the first vaccine dose
• Antibody responses to a 2-dose schedule of the licensed vaccine
formulation in girls aged 9–14 years administered at M0,6 appeared
comparable to the standard 3-dose schedule in women aged 15–25 years
• Similar results have been shown for Gardasil
• Recent review showed sustained antibody levels post one dose of Cervarix
29
 A 2-dose schedule may be more convenient for physicians and
vaccinees, could facilitate implementation of HPV vaccination and may
help optimise compliance in school-based immunisation programmes
Further investigations are required to evaluate the overall
protection, long term protection and cross-protection induced by a 2-
dose schedule

30. Effect of Gardasil on recurrence post
treatment: irrespective of HPV type
Joura et al. BMJ 2012;344:e1401

31. Effect of Gardasil on recurrence post
treatment: HPV type 6,11,16 or 18
Joura et al. BMJ 2012;344:e1401

32. What have the effects of vaccination
been?

33. Fig 1 Proportion of Australian born women diagnosed as having genital warts at first visit, by
age group, 2004-11.
Ali H et al. BMJ 2013;346:bmj.f2032
©2013 by British Medical Journal Publishing Group

34. Early effect of the HPV vaccination programme on cervical
abnormalities in Victoria, Australia: an ecological Study
– Australian Data
– All women 12-26 were offered vaccination with Gardasil
– Using State based Pap Test Registers
– Vaccination rates:
• 71-79% in the school based program
• 74% I dose, 69% 2 doses, 56% 3 doses in 18-28 year olds
– Screening starts at age 18 or 2 years after sexual activity
Brotherton JM et al Lancet (2011) Vol 337 June
18 2085-2091

35. Early effect of the HPV vaccination programme on cervical
abnormalities in Victoria, Australia: Low Grade effect by age
Brotherton JM et al Lancet (2011) Vol 337 June
18 2085-2091

36. Early effect of the HPV vaccination programme on cervical
abnormalities in Victoria, Australia: High Grade effect by stage
Brotherton JM et al Lancet (2011) Vol 337 June
18 2085-2091

37. New HPV vaccines
• Nonavalent vaccine (Merck)(HPV
6/11/16/18/31/33/45/52/58)
• 14204 16-26 yr old women 9vHPV vs qHPV
• Followed for 4.5 yrs
• Similar immunological responses
• Efficacy for high grade lesions with HPV
31/33/45/52/56 greater than 96%
• Not inferior for HPV 16/18
Joura et al. Eurogin Nov 2013

38. Conclusions
• HPV vaccination is effective at preventing CIN
• Vaccination is effective on the “older woman”
but there is less CIN…
• HPV Vaccination seems to be effective at
preventing “recurrence”
• Real world experience is very promising