1. The journey of HPV vaccine : From Study to Real world experience

2. Burden of HPV-related
diseases

3. HPV is a widespread virus, easily acquired and transmitted even without sexual intercourse3 3

4. High HPV Disease Burden Among Males and Females Globally
Estimated annual new HPV-related disease cases in males and females globally
Male
Female
Penile cancer 1
10,500
19,960
Vulvar & vagina cancer 2
Anal cancer 1
13,000
14,300
Anal cancer 1
Head and neck cancer 2
42,000
18,000
Head and neck cancer 2
529,800
Cervical cancer 2
High-grade
8,500,000
cervical dysplasia 3
Estimated annual new HPV-related disease cases in males and females globally
Published HPV prevalence rates were applied as follows: Parkin D et al. Vaccine (penile, vulvar, anal, oropharyngeal, cervical cancers); De Vuyst H et al. Int J Cancer (vaginal cancer); Guan P et al. Int J Cancer (high- and low-grade cervical dysplasia); Greer CE et al. J Clin Microbiol (genital warts).
1. Parkin DM et al. Vaccine. 2006;24(Suppl 3):S3/11–S3/ WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in World. Summary Report World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1– World Health Organization (WHO). Executive summary: the state of world health Accessed June 7, 2012.
Low-grade
22,800,000
cervical dysplasia 3
Genital warts 4
17,600,000
14,400,000
Genital warts 4
1. Parkin DM et al. Vaccine. 2006;24(Suppl 3):S3/11–S3/ WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in World. Summary Report World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1– World Health Organization (WHO). Executive summary: the state of world health Accessed June 7, 2012. 4 4 4 4

5. Leading cancers in Thai women
# cases / yr
# deaths / yr
Breast Cancer
12,566
4,427
5,216
Cervical Cancer
9,999
In Thailand, each day 27 new cases of cervical cancer are detected and 14 women die of cervical cancer
Ferlay J, et al. GLOBOCAN 2008 Cancer Incidence and Mortality Worldwide. IARC CancerBase; Lyon, 2010. 5 5

6. How to evaluate HPV vaccine efficacy in clinical trials

7. Persistent HPV Infection No mention about antibody level !!!
Disease prevention (CIN 2, 3 & AIS) is the only accepted clinically relevant measure of efficacy
Regulatory Agency
Persistent HPV Infection
CIN 1
CIN 2/3 or AIS
USA FDA NO
YES EU
WHO
No mention about antibody level !!!
WHO guideline 2006

8. No correlation between antibody level vs efficacy seen in HPV4 clinical trial
99%
100%
100%
100%
100
Seropositivity* 80
71%
Efficacy against HPV 18-related CIN 2/3 or AIS
68%
60% 60 % 40 20
6-10 months
2 year
3 year
4 year
*Seropositivity to HPV 18 neutralising antibodies to a single neutralising epitope measured by cLIA
Joura A, et al. Vaccine. 2008;26: 8 8

9. Efficacy in women

10. HPV4 demonstrated 98% efficacy against HPV 16/18-related CIN2/3 (4 years) in women age 16-26 years
*One case was a co-infection with HPV 52, the other was a co-infection with HPV 51 and 56
Total
120
112
Gardasil
Placebo
Ferris/slide 11.
100 93
98% Reduction (94, 100)
98% Reduction (92, 100)
100% Reduction (87,100) 80
Related Cases 60
Ferris/slide 13. 40 29 20 2* 2*
HPV 16/18-Related
HPV 16-Related
HPV 18-Related
n=8493
n=8464
n=7402
n=7205
n=7382
n=7316
Ferris D; for the FUTURE I and II Study Group. Presented at: 2008 Biennial Meeting of the American Society for Colposcopy and Cervical Pathology; March 17–21, 2008; Orlando, FL. 10

11. Per-Protocol Efficacy Population
HPV4 demonstrated 99% efficacy against HPV6/11/16/18-related EGL (4 years) in women age years
Per-Protocol Efficacy Population
Haupt/Slide 5.
Total
Gardasil
Placebo
250
227
99% Reduction (97, 100)
193
200
99% Reduction (96, 100)
150
Related Cases
100% Reduction (86,100)
100% Reduction (83,100)
100 50 28 23 2 2
HPV 6/11/16/ 18-Related EGL
Genital Warts
VIN 1, VaIN 1
VIN 2/3, VaIN 2/3
n=9075
n=9075
Haupt RM. ACIP. February 27, Available at: Accessed July 11, 2008. 11

12. HPV4 demonstrated 88.7% efficacy against HPV6/11/16/18-related CIN and EGL (4 years) in women age years
1/Munoz/p.1950/col 1/¶3; p. 1951/col 2/¶1; p. 1952/col 1/¶1; p. 1955/Table 3
Per-Protocol Efficacy Populationa – Primary Endpoint
Mean Follow-Up: 3.8 Years
Total
Gardasil
Placebo 86 80 60
88.7% Reduction (78, 95)
Related Cases 56
91.3% Reduction (78.4, 97.3)
83.8% Reduction (57.9, 95.1) 40 30 20 10 5 5
n=1910
n=1907
24- to 45-Year-Olds
24- to 34-Year-Olds
35- to 45-Year-Olds
aEfficacy after 3 doses in women 24–45 years of age naïve to the relevant type at baseline.
X Castellsague et al, British Journal of Cancer (2011) 105,

13. Efficacy in men aged 16-26 years

14. HPV 16/18 among HPV positive (%)
HPV in Males
Cancer
HPV prevalence (%)
HPV 16/18 among HPV positive (%)
Cervix
100%
70%
Vulva
40%
80%
Vagina
64-91%
Anus
90%
75-90%
Penis
60%
Susanne Krüger Kjær, Presented at Eurogin 2010, Monte-Carlo:France

15. Data from 4,065 men aged 16-26 years, mean follow-up 2.9 years
HPV4 demonstrated 90% efficacy against HPV6/11/16/18-related EGL in men
Data from 4,065 men aged years, mean follow-up 2.9 years 36 40 31
83.8 Reduction (61.2, 94.4)
90.4% Reduction (69.2, 98.1) 30
Placebo
Related Cases 20
Gardasil 10 6 3
EGL related to HPV
6/11/16/18
EGL related to
any HPV type
*Efficacy after 3 doses in men 16 to 26 years of age naïve to the relevant type at baseline.
Giuliano AR, Palefsky J. ,New England Journal Feb 3,2011 15 15 15 15

16. Data from 598 MSM aged 16-26, mean follow-up 2.5 years
HPV4 demonstrated 77% efficacy against HPV6/11/16/18-related AIN in MSM
Data from 598 MSM aged 16-26, mean follow-up 2.5 years
77.5% Reduction (69, 98) 30 25
Placebo
Related Cases 20
Gardasil 10 5
HPV 6/11/16/18-related
AIN and anal cancer
*Efficacy after 3 doses in men 16 to 26 years of age naïve to the relevant type at baseline.
Giuliano AR, Palefsky J. ,New England Journal 364(5)Feb 3,2011 16 16 16 16

17. The rationale for HPV immunization in males
Immunization in males provides direct benefit to males, including prevention of genital warts and anal cancer
Immunization in males is expected to provide indirect benefit for females through herd immunity (reduced transmission of HPV) 17 17

18. Duration of Protection

19. Per-protocol efficacy population, women followed up to 9.5 years
100% efficacy against HPV-16 related CIN2/3 up to 9.5 years follow-up of monovalent HPV 16 vaccine
Per-protocol efficacy population, women followed up to 9.5 years
HPV 16 L1 VLP Vaccine (n=148)
Placebo (n=142) 25 20
100% Efficacy (43, 100)
100% Efficacy (32, 100) 15
Related
Cases (n) 10 8 7 5
HPV 16-Related CIN
HPV 16-Related CIN
1 or Worse
2 or Worse 19
CIN = cervical intraepithelial neoplasia; VLP = virus-like particles.
Rowhani-Rahbar A et al. Vaccine 2009;27:

20. Long-term protection : Mathematical model
Mathematical modeling of the kinetics of antibody decay suggests that detectable antibody (at least for yeast derived HPV 16 VLPs) could persist for
30 years.
Model-based prediction of GMTs and proportions above different thresholds following HPV-16 L1 VLP vaccination predicted from the models. GMTs predicted from the power-law(- - -) and modified power law(—) models, 20
Fracer C, Tomassini JE, Bell J et al. (2007) Modeling the long-term anyibody response of a human papillomavirus (HPV) virus-like particle tyoe 16 prophylactic vaccine, 25,

21. Evaluation of HPV4 Duration of Protection
Denmark
Norway
Iceland
Sweden
Surveillance: e.g. In the Nordic countries
Long-term follow-up study: 14 years of follow-up
Evaluation of 5500 women aged 16–23years from FUTURE II
IIKruger KjaerEUROGIN 2010, 19. Feb, 17h30-19h,SS5-2, Auditorium Prince Pierre 21

22. HPV4 demonstrated 100% effectiveness against HPV 16/18-related CIN 2 or worse (8 years)
No Breakthrough cases
of Disease through 8 years
Per Protocol Efficacy Population (N=1724)
Longest follow up: 8 years
VE:100 %
VE:100 %
VE:100 %
100 80 60
Vaccine Effectiveness* (VE) Percentage
Zero number
of cases
Zero number
of cases
Zero number
of cases 40
V501 - Human Papillomavirus (Quadrivalent)-Cervixcancer Interim Report p53 table 4-5
Vaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared to the baseline incidence rate of per 100 person-years established from the incidence rate in an unvaccinated cohort and under the assumption vaccine effectiveness is 90%.
N = Number of subjects in the indicated cohort who have received at least one vaccination and consented to effectiveness follow-up.
n = Number of subjects who have at least one follow-up visit.
AIS = Adenocarcinoma in situ; CI = Confidence interval; CIN = Cervical intraepithelial neoplasia; HPV = Human papillomavirus. 20
(N=1,080)
Vaccine
Effectiveness
(N=921)
Vaccine
Effectiveness
(N=1.032)
Vaccine
Effectiveness
HPV 16/18-Related CIN 2 or Worse
HPV 16-Related CIN 2 or Worse
HPV 18-Related CIN 2 or Worse
*Vaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared to the baseline incidence rate of per 100 person-years established from the incidence rate in an unvaccinated cohort and under the assumption vaccine efficacy is 90%.

23. Cross Protection

24. WHO position paper : Human Papillomavirus Vaccine 10 April 2009
WHO Position Paper: Cross Protection
BOTH vaccines appear to have partial efficacy against infections caused by HPV 31 and 45, which are phylogenetically related to HPV 16 and 18
Differences among the efficacy trials of the quadrivalent and bivalent vaccines in terms of choice of placebo recipients or control subjects, immunological assays and populations analysed PRECLUDE DIRECT COMPARISON of results for the 2 vaccines
WHO position paper : Human Papillomavirus Vaccine 10 April 2009 24 24

25. Gender Neutral
Vaccination

26. HPV vaccine approved for males
HPV4 is the only
HPV vaccine approved for males

27. The rationale for routine HPV immunization at 11-12 years of is twofold
Optimal vaccine efficacy is derived if the vaccine is administered before onset of sexual activity
Antibody responses are highest at age 9-15 years.

28. Remaining annual number of cancer case at steady state
Gender neutral vaccination have a potential to reduce HPV related cancers
Benefit in Female
39% Reduction
Remaining annual number of cancer case at steady state
A Preliminary health and economic analysis of vaccinating boys and girls with Q-HPV vaccine in Switzerland, Bresse X. et al, Poster presentation, 8-11 July 2012, EUROGIN 2012, Czech Republic

29. Remaining annual number of cancer case at steady state
Gender neutral vaccination have a potential to reduce HPV related cancers
Benefit in Male
62% Reduction
Remaining annual number of cancer case at steady state
A Preliminary health and economic analysis of vaccinating boys and girls with Q-HPV vaccine in Switzerland, Bresse X. et al, Poster presentation, 8-11 July 2012, EUROGIN 2012, Czech Republic

30. Update news – In a world first !
On 12 July 2012, the Minister for Health, Australian Government
announced funding for the Quadrivalent HPV Vaccine for 12 and 13 year old boys
through school-based programs under the National Immunisation Program
, start next school year
Year 9 boys will also be able to get the vaccine at school under a catch-up
Program for the next two years. 1
In April, 2007, the Australian Government initiated aprogramme to vaccinate
all girls from the age of 12 years with the Quadrivalent HPV Vaccine existing school
vaccination system and catch-up to all female Australian residents in the
community up to the age of 26 years 2
Today we can protect & against MORE
HPV- related diseases as Gender Neutral Vaccination 1.
2 Published online November 9, 2010 DOI: /S (10) , Quadrivalent human papillomavirus vaccination and trends
in genital warts in Australia: analysis of national sentinel surveillance data, . Basil Donovan

31. Quadrivalent HPV vaccine Real world experiences

32. Impact on Genital Warts in New Zealand2
The real world impact of Gardasil consistently showed rapid and significant reductions in genital warts as well as cervical lesions seen in multiple countries.
Trends in CIN2/3 or AIS in Women Aged <18 Years in Victoria, Australia, Before and After Introduction of qHPV Vaccine3
Green dots represent the number of new diagnoses within a 3-month period per 100 women tested.
Impact on Genital Warts in New Zealand2
63% reduction
% First-visit clients
with genital warts
2010a
Incidence of Genital Warts in Sweden after Gardasil vaccination
Age-specific incidence rates of genital warts, by sex and calendar year.1
1.Figure reprinted with permission from Leval A et al, Incidence of genital warts in Sweden before and after quadrivalent human papillomavirus vaccine availability, J Infect Dis, 206, 860–866, by permission of Oxford University Press.
aIn 2010, data were collected only in the first 6 months: 40,793 new clients seen between 2007 and 2010; school-based program for 11–12-year-old girls, with catch-up for adolescents up to 20 years; vaccine coverage rate for Auckland DHB by end of 2009 school year=51.7%.
2. Oliphant J et al. N Z Med J. 2011;124:51–58.
3.Reprinted from The Lancet, 377, Brotherton JM et al, Early effect of HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study, 2085–2092, Copyright (2011), with permission from Elsevier.

33. Quadrivalent HPV vaccine Worldwide recommendation

34. ****will switch to Gardasil in 2014
HPV Recommendations by National Expert Advisory Bodies on Immunization For Female: 54 Countries – For Males: 4 countries National Funding: For Females: 50 Countries – For Males: 2 countries
Europe
Austria*
Belgium
Bulgaria
Czech Republic
Denmark
Finland
France
Germany
Greece
Iceland
Ireland
Italy
Latvia
Luxemburg
Macedonia
Netherlands
Norway
Portugal
Romania
Slovenia
Spain
Sweden
Switzerland
United Kingdom 3 24
North America
USA**
Canada*
Mexico 7
Caribbean & Central America
Puerto Rico
Panama
Barbados
Bermuda
Trinidad & Tobago
Cayman Islands
St Martin (COM – part of EU) 7
South America
Argentina
Peru
Guyana
Colombia
Uruguay
Paraguay
Surinam
Cayman Is. 6 7
Middle East & Africa
Kuwait
UAE
Lesotho
Kazakhstan
Israel****
Rwanda***
Asia Pacific
Australia**
New Zealand
Malaysia
Brunei
India
Singapore
Japan
FUNDING
GARDASIL only
Bivalent Only
Both vaccines
No funding
*Male Recommendation
**Male Funding
***Through GAVI
****will switch to Gardasil in 2014
Update: April 18, 2013

35. UK switched to HPV4 in Sep 2012
The Department of Health has decided to change the vaccine it uses to protect girls against cervical cancer throughout the UK

36. ASIAN Focus: National HPV Vaccination program
Bhutan
Free HPV immunization for 12 – 18 year old girls and young women starting since (QHPV)
Malaysia
Free HPV immunization to 13 years old girls starting (BHPV) and switch to QHPV in 2012
Thailand
On process 36

37. Take home messages
HPV infection is common, leading to many diseases, such as cervical, vulvar, vaginal, anal cancers, and genital warts
Disease prevention (CIN2/3, AIS) is still the only accepted way to measure efficacy of HPV vaccines
HPV4 is the only HPV vaccine that has demonstrated high efficacy in a variety of populations (males & females)
Cross protection with HPV vaccines may exist but magnitude and duration of protection is still unknown 37

38. Take home messages
‘Gender Neutral Vaccination’ will help reduce more disease burden related to HPV infection (only HPV4 is approved in males )
Recent data have shown that HPV4 is more cost effective than bivalent vaccine
Many countries have chosen to include HPV4 into their national immunization program 38

39. Thank you

40. Back up slides

41. HPV4 demonstrated immune memory
Olsson corrected proof/p. 4/col 2/¶2,3/ p. 5/Figure 2C/Figure 2 legend
Rapid and Strong Anamnestic Response to Antigen Challenge
Minimum protective level of antibodies is defined through breakthrough cases. Through 5 years, there were no breakthrough cases due to waning immunity for GARDASIL in a phase II extension study.
7000
6000
GARDASIL
Placebo
5714
Anti-HPV 16 Response
(GMT levels)
5000
Olsson corrected proof/p. 5/col 1/¶3.
4000
3870
3000
2000
Olsson corrected proof/p. 3/col 1/¶4/ p. 5/Figure 2 A-D/Figure 2 legend
1000
108 2 3 6 7 12 18 24 30 36 54 60 61 V A
Time (months)
60+1 Week
Vaccination series for GARDASIL
Antigen challenge
Antibodies were built
up during the 3-dose
vaccination series.
Antibody levels stabilized
through at least 5 years.
When tested by antigen challenge, vaccinated subjects had a rapid and strong anamnestic response.
V = vaccination at day 0, month 2, and month 6; A = antigen challenge at month 60; GMT = geometric mean titer aSimilar response with the other 3 types of HPV within vaccine women between 16 and 23 years of age who received either quadrivalent HPV vaccine or placebo with 3 years of follow-up. A subset of 241 subjects underwent 2 further years of follow-up. 1. Olsson SE et al. Vaccine. 2007;25:4931–4939.

43. HPV vaccine recommendations
10. Wright TC. HPV Today : 8-9

44. Study cohorts Vaccine 2700 Vaccinated Placebo 2700 Placebo Cohort I
All females in
Nordic countries in
FUTURE II trial
Vaccine
2700 Vaccinated
Placebo
2700 Placebo
Cohort I
2700
Cohort II
2100
Placebo group
600
Follow up
14yrs
10yrs
14 yr
Data

45. GARDASIL® Merck’s Quadrivalent HPV L1 VLP Vaccine1
Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine
VLPs manufactured in Saccharomyces cerevisiae
Yeast-derived vaccines given to millions of children and adults.
Alum Merck ( AAHS ) adjuvant 225 μg per dose
0.5 mL injection volume
3 doses within 6 months ( 0, 2, 6 mo. )
Key Point
GARDASIL™ is Merck’s quadrivalent HPV L1 VLP vaccine. It is produced in recombinant yeast, like the hepatitis B vaccine, and adsorbed on a proprietary aluminum adjuvant, like the tetanus vaccine.
Background
Merck’s quadrivalent vaccine has the advantage that it targets 4 HPV types (6, 11, 16 and 18).1 Together, HPV Types 16 and 18 account for about 70% of cervical cancer and high-grade lesions, whereas HPV Types 6 and 11 are associated with approximately 90% of anogenital warts.1 Together, these 4 types are responsible for over 40% of low-grade cervical lesions,2 and HPV 16 and 18 account for over 50% of high-grade lesions.3
The active quadrivalent vaccine is a mixture of 4 recombinant HPV type-specific VLPs consisting of the L1 major capsid proteins of HPV 6, 11, 16, and 18 synthesized in Saccharomyces cerevisiae.1 Expression of the L1 protein in yeast generates noninfectious VLPs that resemble HPV virions.1 A similar method is used for hepatitis B vaccine.4
The 4 VLP types were purified and absorbed onto amorphous aluminum hydroxyphosphate sulfate adjuvant.1 The adjuvant dose was 225 micrograms per dose, and the vaccine injection volume was 0.5 mL, given by intramuscular injection at Day 1, Month 2, and Month 6.1
GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
References
1. Villa LL, Costa RLR, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6:271–278.
2. Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. Human papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1157–1164.
3. Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: A meta-analysis. Br J Cancer. 2003;88:63–73.
4. Recombivax HB® Hepatitis B Vaccine (Recombinant) prescribing information. Merck & Co, Inc. Whitehouse Station, NJ
GARDASIL is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
*VLP = Virus-like particle.
1. Villa LL, Costa RL, Petta CA, et al. Lancet Oncol. 2005;6:271–278.

46. This diagram summarizes how VLP-based vaccines are made
This diagram summarizes how VLP-based vaccines are made. The first step is to isolate the DNA of a naturally occurring HPV and then clone the gene or open reading frame (ORF) encoding the L1 capsid protein into a plasmid. The plasmid containing the L1 gene is then introduced into a eukaryotic cell, the L1 gene is transcribed into mRNA and the cell then translate the mRNA into L1 capsid proteins. These capsid proteins then combine together to form a viral like particle. Since no viral DNA (except for the L1 gene) has been introduced into the eukaryotic cell, there are no viral genomes available to incorporate with the viral like particles so there is no danger of producing infectious virions. The VLPs are then purified and used to elicit an immune response in the host.

47. Antibody undetectable by cLIA could be detected by other assays
100%
100 80
70% 60
% Seropositivity 40 20 0%
cLIA
PsV using purified IgG
PsV using standard dilution
Serum from subjects who were HPV 18 seronegative by cLIA at month 48 were tested by HPV 18 Pseudovirion Neutralization Assay (PsV)
Christine CR, et al. Human Vaccines & Immunotherapeutics 8:4, ; April 2012. 47 47

48. Clinical spectrum of HPV-related disease in males
Genital warts1
Recurrent respiratory papillomatosis1
Penile intraepithelial neoplasia (PIN) and carcinoma1,2
Anal intraepithelial neoplasia (AIN) and carcinoma1,3
Some oropharyngeal cancers (tongue, tonsillar, throat, and soft palate)1,4
HPV = human papillomavirus.
Top left and bottom left: Reprinted with permission from NZ DermNet ( Top right: Used with permission from Alex Ferenczy, MD; bottom right: Rosen CA, Anderson D, Murry T. Evaluating Hoarseness: Keeping Your Patient’s Voice Healthy. American Family Physician. June 1988;57(11):2775–82. Used by permission.
1. Giuliano AR et al. Vaccine. 2008;26(suppl 10):K17–K Gross G et al. Med Microbiol Immunol. 2004;193(1):35– Frisch M et al. N Engl J Med. 1997;337(19):1350– Gillison ML et al. J Natl Cancer Inst. 2000;92(9):709–720. 48
References
Giuliano AR, Tortolero-Luna G, Ferrer E, et al. Epidemiology of human papillomavirus in men, cancers other than cervical and benign conditions. Vaccine. 2008;26(suppl 10):K17–K28.
Gross G, Pfister H. Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol. 2004;193(1):35–44.
Frisch M, Glimelius B, van den Brule AJC, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med. 1997;337(19):1350–1358.
Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–720.
International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Human Papillomaviruses. Vol 90. Lyon, France: IARC, 2007.
American Cancer Society. Cancer Facts and Figures CAFFfinalsecured.pdf. Accessed February 2, 2009.
Hernandez BY, Barnholtz-Sloan J, German RR et al. Burden of invasive squamous cell carcinoma of the penis in the United States, Cancer. 2008;113(suppl 10):2883–2891 .
Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467–475.
Gissmann L, Wolnik L, Ikenberg H, Koldovsky U, Schnürch HG, zur Hausen H. Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci USA. 1983;80(2):560–563. 48

49. HPV4 showed 91% efficacy against CIN related to HPV vaccine type for which subject were naïve (3 years)
Haupt/Slide 5.
Total
Gardasil
Placebo 50 45
91% Reduction (76, 98) 40
88% Reduction (67, 97) 34 30
Related Cases
100% Reduction (64,100)
100% Reduction (55,100) 20 12 10 10 4 4
HPV 6/11/16/ 18-Related CIN
CIN 1
CIN 2
CIN 3/AIS
n=2188
n=2182
The FUTURE II study group. JID 2007; 196: 49

50. HPV4 showed 94% efficacy against EGL related to HPV vaccine type for which subject were naïve (3 years)
Total
Haupt/Slide 5. 48
Gardasil
Placebo 50 45
94% Reduction (81, 99) 40
93% Reduction (79, 99) 30
80% Reduction (<0,100)
Related Cases
100% Reduction (<0,100) 20 10 5 3 3 2 1
HPV 6/11/16/ 18-Related EGL
Condyloma
VIN 1 or VaIN 1
VIN 2/3 or
VaIN 2/3
n=2217
n=2216
The FUTURE II study group. JID 2007; 196: 50