3 prof james bently hpv vaccination 2014

HPV Vaccination in 2014

IFCCP Jeddah Jan 2014James Bentley

Professor Dept. Obstetrics and GynecologyDalhousie University

Halifax, Canada

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

Cervical cancer burden – World Wide

3FerlayJ, 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

Active protection via vaccination is mediated by neutralizing antibodies at the cervix

HPV

Cervical canal

Neutralizing antibodies

Blood vessel

Epithelial tear

Basement membrane

Cervicalepithelium

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.

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 ofpre-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.

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

Papillomavirus – phylogenetics

HPV18- Related 45, 39, 59, 51, 56 HPV16- Related

31, 33, 35, 52, 58

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

+

AdjuvantSubstances that potentiate the immune

response to antigen

Through MPL, AS04 Adjuvant System utilizes natural ‘danger’ signals

AS04 Adjuvant SystemAluminium salt + MPL

(Al(OH)3)

Giannini SL, et al. Vaccine 2006; 24:5937–5949.

Manufactured in insect vector

Gardasil ® :Vaccine design

Specificity of the immune response

Gardasil ® Merck

Gardasil ®

Antigen

40 µg

L1 HPV 16

+

AdjuvantSubstances that potentiate the immune

response to antigen

(Al(OH)3)

Manufactured in recombinant Saccharomyces Cerevisiae (yeast)

20 µg

L1 HPV 640 µg

L1 HPV 11

20 µg

L1 HPV 18

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 Pathol2007; 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

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.

Cervarix® demonstrated high efficacy for High Grade lesions

against types included in the vaccinePATRICIA 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

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 lesionsPATRICIA end-of-study analysis; analysis irrespective of type, TVC-naïve1

EndpointVaccine 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)

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

Cu

mu

lati

ve i

ncid

en

ce

Time, months

Control

Vaccine

Cases in

control

group

continue to

accrue with

no indication

of plateauing

at 4 years

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 16GMT, ED50

HPV 18GMT, ED50

Months after

1st vaccination

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.

Se

rum

cL

IA G

MT

. m

MU

/mL

(Lo

og

10

Sca

le) 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

Se

rum

cL

IA G

MT

. m

MU

/mL

(Lo

og

10

Sca

le)

10

100

1,000

10,000

D123 67 12 18 24 30 36 54 6061


Vaccination ****


PPI Placebo


Se

rum

cL

IA G

MT

. m

MU

/mL

(Lo

og

10

Sca

le)

10

100

1,000

D123 67 12 18 24 30 36 54 60 61


Vaccination ****


PPI Placebo


Se

rum

cL

IA G

MT

. m

MU

/mL

(Lo

og

10

Sca

le)

10

100

1,000

10,000

D123 67 12 18 24 30 36 54 60 61


Vaccination ****


PPI Placebo


HPV 11

HPV 16 HPV 18

Cervarix®

Protocol 008TVC-naïve cohort (48 months of FU)2

Cervarix® Control %Efficacy (95% CI)

N n N n

5466 61 5452 17264.9

(52.7; 74.2)

5466 3 5452 4493.2

(78.9; 98.7)

Gardasil®

Combined protocols Future I, Future IIR-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 13642.7

(23.7; 57.3)

CIN3+, irrespective of causal HPV type

4616 36 4680 6443.0

(13.0; 63.2)*

Cervarix and Gardasil – EfficacyCIN2+/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 CIN3N = 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

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.

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.

What about the older woman?

Rela

ted c

ases

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

Rela

ted c

ases

0

40

60

80

100

20


2. Ferris D, et al. Presented at: EUROGIN 2010 Congress. February 17-20, 2010. Monte Carlo. Abstract SS 3-3.


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

Quadrivalent

HPV Vaccine

(n=1,578)

Placebo

(n=1,583) % Reduction 95% CI

ASC-US (HR+)

or worse1 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 – –



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.

Do you need 3 doses?

• 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

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

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

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

Effect of Gardasil on recurrence post treatment: irrespective of HPV type

Joura et al. BMJ 2012;344:e1401

Effect of Gardasil on recurrence post treatment: HPV type 6,11,16 or 18

Joura et al. BMJ 2012;344:e1401

What have the effects of vaccination been?

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

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

Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: Low Grade effect by age


Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: High Grade effect by stage


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

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

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3 prof james bently hpv vaccination 2014