1. Department of Pathology University of Cambridge
‘HPV vaccines: where to next?
Margaret Stanley
Department of Pathology
University of Cambridge UK

2. Disclosure Statement
Dr. Margaret Stanley has acted as a consultant and advisor for Merck Sharp & Dohme, GlaxoSmithKline, and Sanofi Pasteur Merck Sharp & Dohme. 2

3. Human papillomavirus (HPV)

4. Benign HPV-Associated Disease
The humble wart
Condylomata
acuminata
Common
warts
Laryngeal
papillomas
Libby Edwards
photo
Benign HPV-Associated Disease
Photographs courtesy of Dr Libby Edwards, Dr Renzo Barrasso
and Dr Raymond Maw.
The most common result of HPV infection is the development of a localised benign epithelial neoplasm, or common wart. These warts are most commonly associated with HPV types 1, 2, 3, 4, 7 and 10. The risk of malignant conversion is believed to be nil.1
Laryngeal papillomas are relatively uncommon and are associated with HPV types 6 and 11. Two forms occur; either in children under 5 years of age or in adults over the age of 20 years. Even though laryngeal papillomas are benign, they are associated with significant morbidity, resulting in approximately five surgical treatments per year for patients with diagnosis > 1 year.2
Ninety percent of genital warts (condylomata acuminata) are associated with HPV types 6 and 11, considered to be 'low risk' for malignant transformation.1
References
1. Phelps W, Alexander KA. Antiviral therapy for human papillomaviruses: rationale and prospects. Ann Intern Med. 1995;123:
2. Armstrong LR, Derkay CS, Reeves WC. Juvenile-onset respiratory papillomatosis (JORPP): Initial results from the National Registry data. 17th International Papillomavirus Conference, Charleston, SC, USA. Jan 10, 1999.

5. Luc Montagnier, Francoise Barre Sinoussi, Harald zur Hausen
Nobel Laureates in Medicine 2008

6. Zur Hausen and his colleagues made seminal discoveries in the 1970’s and 80’s. They cloned HPV 6 DNA from a genital wart. This DNA then allowed the partial cloning of HPV 11. The latter was a crucial step. Using the HPV 11 DNA as a probe, DNA sequences were detected in cervical cancer biopsies from Africa and the Caribbean, and HPV 16 and HPV 18 DNA were cloned and characterised from these cancers. This work was the platform upon which all subsequent studies on genital HPVs were based and eventually led to the development of HPV VLP vaccines.
HPV
Cervical cancer
1983/1984
zur Hausen group detects HPV DNA in cervical cancers
new HPVs – HPV 16 and HPV 18

7. Estimated annual global burden of HPV associated disease in men and women
Male
Female
Penile cancer1
10,500
19,960
Vulvar & vaginal cancer2
Anal cancer1
13,000
14,300
Anal cancer1
Head and neck cancer 2
42,000
18,000
Head and neck cancer 2
529,800
Cervical cancer2
Genital warts3
17,600,000
14,400,000
Genital warts3
Published HPV prevalence rates were applied as follows: Parkin D et al. Vaccine (penile, vulvar, anal, cervical cancers); WHO/ICO 2010 (head and neck cancer); De Vuyst H et al. Int J Cancer (vaginal cancer); 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 Accessed June 21, World Health Organization (WHO). Executive summary: the state of world health Accessed June 7, 2012. 7 7

8. HPV Non enveloped dsDNA virus, simple capsid of 2 proteins L1 and L2
Common virus with >100 types identified
Infects cutaneous and mucosal epithelia
30–40 infect the mucosal epithelia of women and men
2 groups
low risk types causing warts
HPV 6,11
13 high risk types causing cancer
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,68
HPV 16,18 – most important

9. RELATIVE CONTRIBUTION of HPV 16,18,45,31,33,52,58,35 & 60%
20%
40%
60%
80%
100%
HPV16
HPV18
HPV45
HPV31
HPV33
HPV52
HPV58
HPV35
HPV6
The 8 most common HPV types in CaCx
% among HPV positive cases
CERVIX
VULVA
VAGINA
PENIS
ANUS
HPV6 alone:
Cervix: 9 cases
Vulva: 2 cases
Vagina: 0 cases
Anus: 4 cases
Penis: 11 cases
Courtesy Dr X Castellsague ICO
Updated: June 1st, 2010

10. Prophylactic HPV vaccines
Efficacy
Effectiveness

11. Pentamers self-assemble Non-infectious HPV Virus Like Particles (VLP)
The Virus-Like Particles (VLPs) in HPV vaccines aim to mimic the human papillomavirus
Pentamers self-assemble
Non-infectious HPV Virus Like Particles (VLP)
5 L1 proteins
1 L1 pentamer L1
Expressed
in yeast or
baculovirus
Key point
GARDASIL® is made of virus like particles (VLPs) from the HPV L1 shell protein expressed in yeast cells.
Background
GARDASIL is a quadrivalent vaccine, containing HPV Types 6, 11, 16, and 18. Its base component, HPV-type specific L1 proteins, are synthesised in Saccharomyces cerevisiae yeast cells.1 The L1 protein monomers self-assemble in pentamers and then generate icosahedral particles virus like particles (VLPs), that closely resemble the outer shell of native human papillomavirus.2
The C-terminal arm of the L1 protein extends away from the pentamer of origin and invades an adjacent pentamer. Tight interactions between the L1 units anchor them firmly together to form the VLP.3
VLPs are noninfectious, nononcogenic and are HPV-type specific.4
References
Gardasil Summary of product characteristics. EMEA, 2007.
Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA. 1992;89:12180–12184.
Modis Y, Trus BL, Harrison SC. Atomic model of the papillomavirus capsid. The EMBO Journal. 2002;21:4754–4762.
Stanley M, Lowy DR, Frazer I. Prophylactic HPV vaccines : Underlying mechanisms. Vaccine 2006; 24 suppl 3 : S106-13
Gardasil SmPC. EMEA, Kirnbauer R, Booy F, Cheng N, et al. Proc Natl Acad Sci USA. 1992;89:12180– Modis Y, Trus BL, Harrison SC. The EMBO Journal. 2002;21:4754– Stanley M, Lowy DR, Frazer I. Vaccine 2006; 24 suppl 3 : S106-13

12. Bivalent Quadrivalent
Vaccine profiles
HPV 16/18 vaccine
Cervarix
HPV 6/11/16/18 vaccine
Gardasil
Manufacturer
GlaxoSmithKline
MSD
Volume
Per dose
0.5 mL
Adjuvant
AS04:
Al(OH)3
*MPL®
500 g
50 g
Aluminium sulphate®
225 g
Antigens
L1 HPV 16
L1 HPV 18
20 g
L1 HPV 6
L1 HPV 11
40 g
Expression system
Hi-5 Baculovirus
Yeast
Schedule
Intramuscular
0, 1, 6 mths
0, 2, 6 mths
Bivalent Quadrivalent
*MPL 3-O-deacylated-4’-monophosphoryl lipid A

13. Phase III Randomised Control Trials (RCTs)
End of Study: Per Protocol Efficacy Populations
Vaccine Quadrivalent Bivalent
WOMEN
Mean Follow up 42 months 42 months
Prophylactic Efficacy % 95%CI % 95%CI
HPV16/18 CIN (95,100) 95 (88,98)
HPV16/18 CIN (88,100) 92 (67,91)
HPV16/18 AIS (31,100) (-8,100)
HPV 16/18 VIN3/VaIN (83,100) Not reported
HPV6/11/16/18
VIN1/VaIN (86,100) Not a target
EGL (97,100) Not a target
WOMEN yrs
6/11/16/18 PI/CIN/VIN/VaIN 89 (78,95)
MEN yrs 36 months
HPV 16/18/6/11 EGL (MSW) 90 (69,98) No studies
HPV 16/18/6/11AIN (MSM) 78* (40,93) No studies
91+ (64,99)
*pre-specified +post hoc analysis
DATA FROM Kjaer etal Cancer Prev Res :868 Lehtinen Lancet Oncol :89
Dillner et al BMJ 341:3493 Guiliano 2011 NEJM364:401 Palefsky :401

14. The Australian National HPV vaccination program
Funded by federal government, delivered by States and Territories
quadrivalent HPV vaccine used.
Commenced in April/July year old females
12-13 yrs ongoing cohort catch up
School based year olds
GP/clinic based year olds
Overall coverage 70-80% 14

15. Australia: Near disappearance of genital warts after commencement of national HPV program
Women <21: %, MSW: %
Decline in nearly 90% in both men and women <21
National HPV vaccination programme
Almost 90% decline in new cases of genital warts in both men and women < 21 yrs old
1. Read et.al., Sex Transm Infect 2011; 87:544e547. doi: /sextrans 15

16. Denmark: Incidence of Genital Warts Following Introduction of qHPV Vaccine: Results and Summary1
Baandrup 2013:
p133E
Near elimination by mid-2011 of GW incidence in females 16 and 17 years old
Corresponds to catch-up cohorts, with vaccine coverage >85%
Gradual but significant decreases observed among women 18 to 29 years old
No statistically significant change observed in males of any age group
Baandrup 2013:
p132A
Baandrup 2013:
p132F,G
Baandrup 2013:
p134A
Baandrup 2013:
p133B/Figure 3
20–21 Years
Incidence Rate per 100,000
GWs in Young Females 12–21 Years Old, by Age Group
Jul 2006
Jan 2007
Jul 2007
Jan 2008
Jul 2008
Jan 2009
Jul 2009
Jan 2010
Jul 2010
Jan 2011
Jul 2011
100
200
300
400
500
600
Time (6-Month Intervals)
16–17 Years
18–19 Years
12–15 Years
36+ Years
26–29 Years
22–25 Years
30–35 Years
GWs in Adult Females 22–36+ Years Old, by Age Group
GWs=genital warts; qHPV=quadrivalent human papillomavirus.
Figures reprinted from Baandrup L et al. Significant decrease in the incidence of genital warts in young Danish women after implementation of a national human papillomavirus vaccination program. Sex Transm Dis. 2013;40:130–135, with permission of Wolters Kluwer Health.
1. Baandrup L et al. Sex Transm Dis. 2013;40:130–135.

17. HPV vaccine effectiveness for CIN outcome to end 2011
Completed 3 doses
Any vaccine dose
HPV vaccine effectiveness
for CIN outcome to end 2011
by age of vaccination in 2007
Australia
Gertig et al 2013 BMC Med Oct 22 epub

18. Differences in human papillomavirus (HPV) genoprevalence between prevaccine and postvaccine populations. *P < .05 for difference in percentages between groups.
Differences in human papillomavirus (HPV) genoprevalence between prevaccine and postvaccine populations. *P < .05 for difference in percentages between groups. Abbreviations: CI, confidence interval; excl, excluding; HR-HPV, high-risk HPV.
Tabrizi S N et al. J Infect Dis. 2012;206:
© The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please

19. efficacy of a quadrivalent HPV vaccine in women who had treatment for:
Do women with a history of cervical, vulvar, or vaginal pre-cancers or genital warts benefit from vaccination?
efficacy of a quadrivalent HPV vaccine in women who had treatment for:
cervical disease (LEEP/conization)
genital warts, VIN or VAIN
After 1:1 Randomization to Vaccine or Placebo (2 Phase 3 trials)
Joura etal BMJ April 2012 19

20. Impact of qHPV Vaccine on new HPV disease – after a pathology panel diagnosis of GW, VIN, VaIN
↓64% %
Reduction
↓46%*
95% CI
(42,79)
↓41%*
↓35%*
↓23%*
95% CI
(22, 64)
95% CI
(-15, 71)
95% CI
(14, 52)
95% CI
(-12,48
Any
disease
Any
cervical disease
CIN1+
Any
CIN2+
Any
GW, VIN
or VaIN
Any
6/11/16/18
related
disease
* Irrespective of HPV type 20

21. Current issues
Alternative immunisation schedules
Gender neutral vaccination
Next generation prophylactic
vaccines

22. Alternative dosage regimens Modified 3 dose schedules
Extended schedules
<3 dose schedules

23. Why consider a reduced dosage regimen?
Cost Reduction
adminstrative costs
vaccine costs
Difficulty of delivering 3 doses over 6 months
Immunogenicity in young adolescents

24. Quadrivalent HPV Vaccine Phase III Adolescent Immunogenicity Study Neutralizing Anti-HPV GMTs* at Month 7
Females 10–15 Years of Age Males 10–15 Years of Age Females 16–23 Years of Age
*GMT = geometric mean titers
Block SL, Nolan T, Sattler C, et al. Pediatrics. 2006:118,2135.

25. Age Specific Neutralizing HPV-6 Antibodies 1 Month Post-Vaccination1
PPE population*
Neutralizing anti-HPV 6 GMTs at month 7
Immunogenicity Bridge
Efficacy Program
1/Data on file/ VRBPAC briefing document/p. 65/fig 12
1600
1500
1300
1100
Serum cLIA GMT with 95% CI, mMU/mL
900
700
Key Point
Higher neutralizing antibody responses were observed in adolescent males and females, compared with young adult women.
Background
An evaluation of the duration of anti-HPV levels induced by GARDASIL™ in 9- to 15-year-old boys and girls is ongoing. To date it has been observed that one month after the last vaccination (month 7), GMT levels for all four types are higher in young adolescents, compared with older adolescents and young women (the age range in which the efficacy of GARDASIL was demonstrated). A similar profile is observed one year after the last vaccination dose.1
This slide presents an example at month 7 for anti-HPV 6 GMTs by age at first vaccination in the PPI population of the phase III integrated immunogenicity data set for 9- to 15-year-old boys, 9- to 17-year-old girls, and 18- to 26-year-old women (protocols 011, 012, 015, 016, 018). All GMTs in these protocols were measured using the same cLIA.1
GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Reference
1. Data on file, MSD.
500
1/Data on file/ VRBPAC briefing document/p64/¶3,5
Males + Females
Females Only 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
1/Data on file/ VRBPAC briefing document/p65/fig 12
Age at Enrollment (Years)
*Inclusive of five study protocols; all GMTs measured using cLIA
1/Data on file/ Protocol 011/ p. TBD/¶ TBD; Protocol /p. 17/¶ 5; Protocol /p. 19/¶ 3; Protocol /p. 10/¶ 5; Protocol /p. 34/¶ 6.

26. Clinical trials: immunogenicity and safety
2 dose 0, 6 months adolescent (9-14 years)
versus
3 dose 0,1 or 2,6 months adult (15-23 years)
qHPV vaccine Dobson etal 2013 JAMA 309,
bHPV vaccine Romanowski etal 2011 Human Vaccines 7,
Immunogenicity
antibody concentrations (GMTs) were non inferior
in the 2 dose group compared to 3 dose
Safety
Well tolerated

27. Unresolved issues No immune correlate
Kinetics of antibody response – limited data for 2 dose
More data on antibody affinity and avidity maturation
in natural infection and after immunisation needed
The clinical development programme of the licensed
HPV vaccines was based on clinical efficacy data
from a 3 dose regimen of prime, prime boost
The evidence from the clinical trials for 2 dose
schedules in adolescents is restricted to immunogenicity.
At the present there is no evidence from these trials
demonstrating efficacy or duration of protection.

28. Have a plan B In the absence of efficacy data and with
no immune correlate, reducing the number
of doses is a risk
Decision makers need to assess the degree
of risk and devise risk management strategies
in the event of a worst case scenario
Have a plan B

29. Gender neutral vaccination

30. HPV is a Potent Carcinogen causing Multiple Related Cancers in Men and Women
Penile Cancer
1000
3,700
Vulvar & Vaginal Cancer
1,600
2,800
Anal Cancer
Anal Cancer
H&N Cancer
11,600
2,300
H&N Cancer
23,000
Cervical Cancer
MALE
FEMALE
329,000
292,000
Genital warts
Genital warts
Annual new cancers and genital warts cases related to HPV 6,11,16 and/or 18 in Males and Females in Europe
Annual number of new cancer cases calculated based on crude incidence rates from IARC database ( ) and population estimate Eurostat 2008; estimate Globocan 2008 for cervical cancer; published HPV prevalence rates were applied (for Europe, when available) Genital warts estimates based on incidence rates in UK, HPA 2007

31. Increasing Incidence of Anal Cancer: Example of Scotland and England1
1/Brewster/p 88/col 1/¶5; p 88/col 2/¶1
0.60
0.50
0.40
Rate per 100,000
0.30
0.20
0.10
0.00
Year of Diagnosis Mid-Count of 5-Year Period
1977
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
Male
Female
Since the 1970s, the incidence of anal cancer in Scotland has more than doubled in both sexes.
Incidence rates in England from to 2003 also nearly doubled in both men and women.
1/Brewster/p 88/Figure 1
Age-standardized incidence rates of squamous cell carcinoma
of the anus by year of diagnosis (5-year moving averages) and sex; Scotland, 1975–2002.
1. Brewster DH et al. Br J Cancer. 2006;95:87–90. 31

32. Increasing incidence of 0ropharyngeal squamous cell carcinoma
in England

33. Increasing Incidence of HPV-Related Tonsillar Cancer in Sweden1
Study of all patients (N=120) diagnosed with tonsillar SCC in the County of Stockholm, Sweden, during 2003–2007
1.5
1970–1979 1
0.5
1980–1989
1990–1999
2000–2006
Calendar Years
Estimated Standardized Incidence Rate
HPV negative
HPV positive
1/Nasman/p 362/ col 2/¶3; p 365/Fig 3
1. Näsman A et al. Int J Cancer. 2009;125:362–366. 33

34. Tonsillar cancer in Sweden 1960-2003
Hammarstedt etal
Acta
Otolaryngologica
2007, 9.988
Oral cancer in Sweden

35. Increasing Incidence of Penile Cancer and High-Grade PIN in Denmark
Baldur-Felskov 2012
p275, col2, para 2
Penile cancer High grade penile pre-cancer
1.4 1
Baldur-Felskov 2012
p277, col2, para 1
Baldur-Felskov 2012
p276, fig 1
0.9
1.2
Baldur-Felskov 2012
p278, fig 3
0.8 1
0.7
Incidence per 100,000 Men–Years
0.0
Incidence per 100,000 Men–Years
0.6
0.6
0.6
0.4
0.4
0.2
0.3
2006–2008
2006–2008
Calendar Years
Calendar Years
Age-standardized incidence rates of penile cancer (all histologies),
Age-standardized incidence rates of PIN 2/3,1998–2008. 35
CI=confidence interval; PIN=penile intraepithelial neoplasia.
Baldur-Felskov B et al. Cancer Causes Control. 2012;23:273–280. 35

36. Vaccine cost per dose (excluding administrative costs)
Cost Per QALY Gained Vaccinating 12-Yr-Old Boys, All HPV Outcomes—USA CDC Model
Chesson CDC 2011 slide 15
Cost effective
$160,000 $0
$50
Cost per QALY gained
Vaccine cost per dose (excluding administrative costs)
Coverage ≈50%
Error bars show the 5th and 95th percentiles of cost per QALY estimates over hundreds of model runs when varying numerous model parameter values simultaneously
$140,000
$120,000
$100,000
$80,000
$60,000
$40,000
$20,000
$75
$116 (Base case)
$140
Coverage ≈70%
Coverage assumptions: refer to 3-dose coverage of females by age 26
Current cost per dose:
Public: $109
Private: $130
CDC=Centers for Disease Control and Prevention; QALY=quality-adjusted life year.
CDC Vaccine Price List:
Adapted from Chesson H. Presented at the Advisory Committee on Immunization Practices Meeting. February 24, 2011. 36 36

37. Global Review of Cost-Effectiveness of HPV Vaccine in Males
Jiang Value in Health 2012: pA396C
Jiang Value in Health 2012: pA396B
Jiang ISPOR Poster 2012: p2B
Cost-effectiveness varied within the same model and across different models1,2
Results were sensitive to country-specific parameters:
Vaccine price1
Vaccine characteristics1
Assumption of natural immunity of HPV1
Current HPV vaccination coverage in females1,2
Study concluded that cost-effectiveness analyses of gender-neutral vaccination should:
Be conducted on a country-by-country basis to account for local specificities1,2,a
Include all HPV-related diseases1
Jiang Value in Health 2012: pA396C
Jiang Value in Health 2012: pA396C
Jiang Value in Health 2012: pA396D
Jiang ISPOR Poster 2012: p2E
aInclude vaccine price, current vaccination and cervical screening program, coverage rate in females, and cost-effectiveness thresholds.
Nine studies (6 US and 3 European studies) were reviewed. The analysis included cost-effectiveness models of HPV vaccination that involved males (published by the end of 2011). Comparisons were made based on HPV transmission patterns, model calibration, modeling approach, diseases modeled, vaccination and screening strategies, and input parameters.1
1. Jiang Y et al. Value in Health. 2012;15:A Jiang Y et al. Presented at: 15th Annual International Society for Pharmacoeconomics and Outcomes Research (ISPOR) European Congress; 3–7 November 2012; Berlin, Germany. 37 37

38. Australia: Considerations for Gender-Neutral Recommendation and Funding
Brill 2013: p1A,E
Federally funded, school-based vaccination with qHPV vaccine for males began in February 20131
Routine vaccination: 12 and 13 years old
Catch-up vaccination: 14 and 15 years olda
Rationale favoring routine vaccination for males1,2:
Prevention of HPV-related diseases and cancers in the population
Dramatic decline in genital warts trend between 2007 and 2009b
Reasons of equity
Positive cost:benefit analysis
Includes an information campaign, adverse event monitoring, and a vaccine register2
Australia Media Release 2012: p1A
Brill 2013: p1B
Brill 2013: p1C
Australia Media Release 2012: p2A
Australia Media Release 2012: p1B
aUntil end of 2014 school year.
bIncidence of genital warts decreased by >90% in Australian-born females and >80% in heterosexual males.
1. Brill D. BMJ. 2013;346:f HPV vaccine extended to boys [media release]. Australia: Australian Government Department of Health and Ageing; July 12, 2012. 38 38

39. The burden of HPV associated disease in
men is equivalent to that in women in
industrialised countries
High vaccine coverage (>70%) in women
should give herd immunity for MSW
this makes male vaccination not cost effective
if vaccine cost per dose is high
MSM are not protected in this scenario but
targeting MSM for vaccination faces challenges
?ineffective ?stigmatising ?discriminatory
Could it threaten vaccine uptake in females?

40. Next generation vaccines
broad protection
cheap

41. Polyvalent HPV VLP vaccines
MSD Merck is conducting phase III clinical trials of an nonavalent vaccine comprising L1 VLPs of types
6, 11, 16, 18, 31, 33, 45, 52, and 58
Advantages: Proven technology; potential for decreasing Cx Ca risk by 90% vs 70% for Gardasil
Issues: cost

42. Many Other 2nd Generation Candidates
Are Being Developed
Protein:
Alternative VLP production systems: E. coli, Pichia, Hansenula, Plants
L1 pentameric subunits
L2-polypeptides – many variations
Vectored:
L1 recombinant AAV
L1 recombinant Salmonella vaccine
L1 recombinant Measles vaccine
L1 AcHERV

43. Thank you