1- prof james bently - hpv and vaccine jeddah 2015

1. HPV and primary prevention of
Cervical Cancer
James Bentley
Professor Department of Obstetrics and Gynecology
Dalhousie University
Halifax, Nova Scotia

2. Disclosure of Potential for
Conflict of Interest
Facilitator’s Name: Dr James Bentley
Grants/research support: Merck, GSK, Guided Therapeutics
Speaker’s bureau/honoraria: Merck, GSK
Consulting fees: GSK

3. Mitigation of Potential for
Conflict of Interest
• Although I have been involved with HPV
vaccine companies and a new screening
modality, performing research and speaking
engagements I will be using evidence based
medicine in this presentation.

4. Cervical Cancer Incidence 2012
Every minute a woman is diagnosed with cervical cancer.1
New cases per year: ~ 530,000

5. Cervical Cancer Trends

6. Cervical Cancer

7. 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. Obstet Gynecol 1992; 79:328–337; 3. Brown DR, et al. J Infect Dis 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 Microbiol Rev 2003; 16:1–17; 10. Solomon D, et al. JAMA 2002; 287:2114–2119.

8. Natural Course of Genital HPV
Infection: Need skin to skin contact
First
Lesion
Immune
Response
CMI
Virological
clearance
DNA-ve
80% of cases
Viral
persistence
DNA+ve
LSIL/HSIL
infection
Seroconversion
Antibody to L1
DNA-ve Productive viral
infection, low grade
lesions DNA+ve
HrHPVs 12-18months
LrHPVs 4-9months
Time

9. Spectrum of Changes in Cervical Squamous
Epithelium Caused by HPV Infection1
Normal
Cervix
HPV Infection /
CIN* 1
CIN 2 / CIN 3 /
Cervical Cancer
*CIN = cervical intraepithelial neoplasia
1. Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564. Copyright © 2003 Massachusetts
Medical Society. All rights reserved. Adapted with permission.

10. 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

11. Cervical Cancer Prevention
Normal
Cervix
HPV
Infection
Cervical
Dysplasia
Cervical
Cancer
Primary
Prevention:
Vaccination
Secondary
Prevention:
Screening

12. Primary Prevention: HPV
Vaccination
• HPV Vaccination
• Vaccine like particles
• L1 capsid protein
• Introduced in 2006/2007

13. 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.

14. 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

15. 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

16. 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 Genit Tract Dis. 2012 Jul;16(3):205-242

17. 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.

18. 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

19. 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

20. 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

21. V503 – 9-Valent HPV recombinant
vaccine
• HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58
• Manufactured in Saccharomyces cerevisiae
• Proprietary aluminum adjuvant 500 μg per dose
• Each 0.5 mL injection volume contains
HPV types 6/11/16/18/31/33/45/52/58
• 0-, 2-, 6-month dosing regimen

22. AAHS
225μg
AAHS
500μg
6
20μg
11
40μg
“ ORIGINAL TYPES” “ NEW TYPES”
ADJUVANT4HPV
9HPV
16
40μg
18
20μg
6
30μg
11
40μg
16
60μg
18
40μg
31
20μg
33
20μg
45
20μg
52
20μg
58
20μg
V503 Composition: 9-Valent HPV
vaccine
ACIP meeting October 24, 2013

23. V503-001 Study design
International, multi-centered, randomized 1:1 study
Enrollment • Double Blind
• n = 14620 Women, 16 to 26 years old
• Has never had Pap testing or has only had
normal Pap test results
Vaccine
administration
Biological Comparator: GARDASIL(R) 0.5 mL
Biological Experimental: V503 0.5 mL injection
3 vaccination visits: Day 1, Month 2, Month 6
Duration September 2007 to April 2013
ACIP Oct. 24 2013 ;Clinical trial.gov. http://clinicaltrials.gov/ct2/show/record/NCT00543543?term=V503-001&rank=1

24. Immunogenicity of a novel 9-valent HPV
vaccine in 16-26 year old women
V503-001 Primary immunogenicity findings:
• Anti-HPV 6/11/16/18 response were non-
inferior to those generated by the qHPV
vaccine.
• These results support the bridging of efficacy
finding with qHPV to 9vHPV vaccine
Joura E. Abstract SS 8-4 Eurogin Florence Nov 3-6, 2013

25. Anti-HPV 6, 11, 16, 18 cLIA GMTs at Month 7
Primary Immunogenicity Objective – Per Protocol Analysis
The non-inferiority criterion was met for all 4 HPV types
9vHPV
Vaccine
qHPV
Vaccine
9vHPV/qHPV
Assay (cLIA) GMT GMT
GMT
ratio
95% CI
Anti-HPV 6 893 875 1.02 (0.99, 1.06)*
Anti-HPV 11 666 830 0.80 (0.77, 0.83)*
Anti-HPV 16 3131 3157 0.99 (0.96, 1.03)*
Anti-HPV 18 805 679 1.19 (1.14, 1.23)*
V503 Protocol 001: analysis at Month 7 (4 weeks post-dose 3)
*Non-inferiority p<0.001

26. Efficacy of a novel 9-valent HPV vaccine
in 16-26 year old women
Joura E. Abstract SS 8-4 Eurogin Florence Nov 3-6, 2013, NEJM 372;8 Feb 19 2015
Endpoint 9vHPV
vaccine
No cases/n
qHPV
Vaccine
No of cases/n
Efficacy
(95%CI)
High grade
HPV31/33/45/52/58
cervical/vulvar/vaginal
disease
1/6016 30/6017
96.7 %
(80.9-99.8)
Any grade
HPV31/33/45/52/58
cervical/vulvar/vaginal
disease
3/6016 103/6017
97.1 %
(91.8-99.2)
HPV31/33/45/52/58
6 months related
persistent infection
35/5939 810/5953
96.0 %
(94.4-97.2)
Per protocol population

27. Endpoint
9vHPV Vaccine
No. of cases/n
qHPV Vaccine
No. of cases/n
Risk Reduction
(95% CI)
Biopsy 7 / 6016 222 / 6017
96.9%
(93.6, 98.6)
External Genital
Biopsy
2 / 6009 22 / 6012
90.9%
(65.7, 98.5)
Cervical Biopsy 6 / 6012 208 / 6014
97.2%
(93.9, 98.8)
Definitive Therapy
(Cervical, Non-
ablative)
4 / 6012 32 / 6014
87.5%
(65.7, 96.0)
Anti-HPV 31/33/45/52/58 Efficacy
Per Protocol Efficacy Population
Luxembourg A. ACIP meeting Feb 27 2014

28. Girls and Women
The nonavalent vaccine is indicated in girls and women 9 through 45 years of age for the
prevention of infection caused by the Human Papillomavirus (HPV) types 6, 11, 16, 18, 31, 33,
45, 52 and 58 and the following diseases associated with the HPV types included in the vaccine:
 Cervical, vulvar, and vaginal cancer
 Genital warts (condyloma acuminata)
 Cervical adenocarcinoma in situ (AIS)
 Cervical intraepithelial neoplasia (CIN) grade 2 and grade 3
 Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
 Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
 Cervical intraepithelial neoplasia (CIN) grade 1
The nonavalent vaccine is indicated in girls and women 9 through 26 years of age for the prevention of:
 Anal cancer
 Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3
Boys and Men
The nonavalent vaccine is indicated in boys and men 9 through 26 years of age for the prevention of
infection caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58 and the following diseases
associated with the HPV types included in the vaccine:
 Anal cancer
 Genital warts
 Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3
GARDSIL 9: INDICATIONS AND CLINICAL USE
PRODUCT MONOGRAPH GARDASIL®9 January 29, 2015

29. Conclusions
• Cervical cancer is a common world wide
problem
• HPV is the proven etiological cause
• Vaccination ultimately may make screening
unnecessary