6. GLOBOCAN at http://www.iarc.fr/;Nganetal.J CancerEpidemiol 2011;2011:794861
Incidence and mortality rates due to
cervical cancer in AOGIN countries
Hong Kong
*per 100,000 women
7. Cervical cancer in Thailand
2004
(2547)
2008
(2551)
2010
(2553)
2015
(2558)
New cases peryear 6,243 9,999 10,465 11,526
Death per year 2,620 5,216 5,517 6,304
Death per day 7 14 15 17
7
(IARC)
19. 19
HPV infects basal cells of the epithelium
Doorbar J. Clin Sci (Lond) 2006; 110:525–541; Schiffman M, et al. Lancet 2007; 370:890–907
• No viraemia
• HPV does not induce cell death
– no inflammation
– no pro-inflammatory cytokines
– poor activation of epithelial
antigen presenting cells
• Infection occurs within a
few hours!
20. 20
การเกิดมะเร็งปากมดลูกเฉลี่ยประมาณ 10-15 ปี
Low grade squamous
intraepithelial lesion
(ASCUS/LSIL)
High grade squamous
intraepithelial lesion
(HSIL)
Invasive
Carcinoma
Pap
Screening
Treatment
Time YearsMonths
Normal
epithelium
HPV infection;
koilocytosis
CIN I CIN II CIN III
From incident to persistent HPV infection
Spontaneous regression
HPV
vaccine
34. CERVICAL CANCER PREVENTION METHODS
Normal
cervix/
Sub-clinical
HPV infection1
CIN 12
1. Image used with permission from Professor Achim Schneider; 2. Image used with permission from Professor
Muhieddine Seoud; 3. GSK Image Library
CIN 22 CIN 33 ICC3
HPV
vaccines:
Primary
prevention
Cervical screening
(VIA, Pap smear, HPV testing):
Secondary prevention
Treatment
Treatment
44. 2001 20102005 2006 2007 2008 20092002 2003 2004
HPV-001 study
(primary efficacy
study)N = 1,113
5.5 years
Follow-up3
4.5 years
Follow-up2
HPV-007 study
(extended follow-upof primary efficacy
study)N = 776
HPV-023 study (further
extended follow-upin a
subsetup to 9.5 years)
27 months
Follow-up1
1. Harper D, et al. Lancet 2004; 364:1757–1765; 2. Harper D, et al. Lancet 2006; 367:1247–1255; 3. Harper DM. Gynecol Oncol 2008;110:S11–S17;
4. GlaxoSmithKline Vaccine HPV-007 Study Group. Lancet 2009; 374:1975-1985; 5. De Carvalho ND, et al. XIX FIGO October 2009; Cape Town, South
Africa, Abstract O929; 6. Roteli-Martins CM, et al. ESPID 2010, Abstract 622;.
AS04 HPV vaccine: Phase IIb
7.3 years
Follow-up5
6.4 years
Final
Analysis4
8.4 years
Follow-up6
Cervarix™
Women aged 15-25 years old
HPV DNA - at Cervix
Sexual partner ≤ 6
45. Efficacy against CIN 2+ lesions caused by HPV 16/18, year on year
Phase IIb study vs.placebo:Data up to 9.4 years
1. Harper D, et al. Lancet 2004; 364:1757–1765; 2. Harper D, et al. Lancet 2006; 367:1247–1255; 3. Gall S, et al. AACR 2007; Abstract;
4. Harper D, et al. SGO 2008; Abstract; 5. GlaxoSmithKline Vaccine HPV-007 Study Group. Lancet 2009; 374:1975–1985;
6. Carvalho ND, et al. ESGO 2009; Abstract 1440; 7. Roteli-Martins CM, et al. ESPID 2010, Ab stract 622.
Analysis Duration
AS04 HPV
vaccine
Control Vaccine efficacy
No. cases No. cases % 95% CI
Initial efficacy study
(N = 1,113)
2.3 years1 0 3 NA* NA*
Combined analysis of
initial efficacy study
and extended follow-
up
(N = 776)
4.5 years2 0 5 100.0 -7.7–100
5.5 years3 0 7 100.0 32.7–100
6.4 years4,5 0 9 100.0 51.3–100
Brazilian cohort
(N = 436)
7.3 years6 0 10 100.0 -129.9–100
8.4 years7 0 13 100.0 <0–100
9.4 years8 0 16 100.0 -128.1, 100
* Initial efficacy study was not powered to calculate vaccine efficacy against histopathologically confirmed
CIN ITT analysis.
The longest follow-up efficacy study
reported for commercially available HPV vaccines
47. Experience with CervarixTM: PATRICIA Phase III trial
18,644 women enrolled (aged 15–25 years), double-blind,
randomized 1:1, vaccine vs control (hep A vaccine)
End of
study
analysis
Mean follow-up
43.7 months)3
Triggered event
Interim analysis
Mean follow-up 14.8 months1
Triggered event
Final analysis
Mean follow-up 39.4 months2
AS04-adjuvanted bivalent HPV vaccine
Control (hepatitis A vaccine)
Randomization
N = 18,644
0 1 6 7 12 18 24 30 36 48Month
Visit 1 2 3 4 5 6 7 8 9 10
1. Paavonen J, et al. Lancet 2007; 369:2161–2170;
2. Paavonen J, et al. Lancet 2009; 374:301–304; 3. Paavonen J, et al. IPvC 2010; Abstract.
48. • Total number of subjects: 18,644 (TVC)
• Age 15–25 (average 20.0 years)
• 1,725 dropouts (9.3%)
• 92% of subjects received 3 doses of vaccine
• ≤6 sexual partners
PATRICIA: Demographics
North
America
16.5%
N = 3,070Latin
America
14.9%
N = 2,774
Europe
34.6%
N = 6,448
Asia Pacific
34.1%
N = 6,352
1. Paavonen J, et al. Lancet 2007; 369:2161–2170; 2. Paavonen J, et al. Lancet 2009; 374:301–314.
Cervarix™
49. TVC-naïve cohort=total vaccinatedcohortof HPV-naïve women.
LehtinenM, et al. LancetOncol 2012;13:89–99
Endpoint Group N n
Vaccine efficacy (95%CI)
% LL UL p value
CIN2+HPV-16/18
Vaccine 5,466 1
99.0 94.2 100 <0.0001
Control 5,452 97
CIN3+HPV-16/18
Vaccine 5,466 0
100 85.5 100 <0.0001
Control 5,452 27
PATRICIA end of study: efficacy against CIN2+/3+
due to HPV-16/18 in the TVC-naïve cohort
51. HSIL/CIN2/3
Approx. 51% of CIN2/3
lesions are caused by
HPV 16 or HPV 18
7%
12%
44%
37%
51% attributable to HPV 16/18
63% attributable to HPV 16/18/31/45
HPV 18
54%
17%
21%
8%
Cervical cancer
More than 70% of all cervical
cancers are caused by HPV 16
or HPV 18
71% attributable to HPV 16/18
79% attributable to HPV 16/18/31/45
HPV 31/45 OtherHPV 16
HSIL = high-grade squamous
intraepithelial lesion.
Adapted from: http://www.who.int/hpvcentre/statistics (accessed February 2011);
de Sanjosé S, et al. Lancet Oncol 2010; 11:1048–1056.
What can be expected of a vaccine
against HPV 16 and HPV 18?
52. Overall vaccine efficacy results against CIN2+
and CIN3+ irrespective of HPV type in the lesion
Estimated worldwide prevalence of HPV 16/18 in
high-grade lesions (CIN2/3) is 51%1
TVC-naïve*
1. WHO/ICO Information Centre on Human papilloma Virus (HPV) and Cervical Cancer. Available at: http:www.who.int/hpvcentre/statistics (accessed March
2011) ; 2. Paavonen J, et al. IPvC 2010; Poster P-689; 3, DoF
Endpoint Vaccine
cases
N = 5,466
Control
cases
N = 5,452
Efficacy,
%
95% CI p-value
CIN2+irrespective of DNA
in the lesion † 61 172 64.9 52.7–74.2 < 0.0001
CIN3+ irrespective of DNA
in the lesion
3 44 93.2 78.9–98.7 < 0.0001
End of study analysis2
* DNA-negative for 14 oncogenic HPV types and normal cytology at baseline.
Proportion of HPV-16/18 in CIN2+ and CIN3+ lesions in the TVC-naive (control group) in the end-of-study analysis3.
For CIN2+: 35.3% to 62.8%
For CIN3+: 38.4% to 69.2%
53. TVC naïve Cohort, primary analysis
HPV-008 PATRICIA
Confirmed efficacy against HPV-31, 33 and 45 in pivotal phase III
trial (End-of-study 2, up to 4 years)
* Efficacy against CIN2+ do not correct for HPV-16/18 co-infections in the lesions
EU SPC (based on final analysis): For.HPV-31 consistent cross-protection for all
endpoints and all study cohorts. Vaccine efficacy against 6 months persistent infection
also shown for HPV-33 and HPV-45 in all study cohorts.3
Endpoint group
Final analysis1 End-of-study analyis2
N n
Efficacy%
96.1% CI
P value N n
Efficacy%
95% CI
P value
CIN 2+ HPV-31
vaccine 5449 0
100.0
(78.3; 100.0)
<0.0001
5466 3
89.4
(65.5; 97.9)
<0.0001
control 5436 20 5452 28
CIN 2+ HPV-33
vaccine 5449 5
72.3
(19.1; 92.5)
0.0065
5466 5
82.3
(53.4; 94.7)
<0.0001
control 5436 18 5452 28
CIN 2+ HPV-45
vaccine 5449 0
100.0
(-19.5; 100.0)
0.0310
5466 0
100.0
(41.7; 100.0)
0.0039
control 5436 5 5452 8
1. Paavonen J, et al. Lancet 2009; 374:301–304
2. Romanowski B. IPvC 2010; Abstract 416
3. Cervarix EU SPC 2011.
http://www.medicines.org.uk/emc/medicine/20204/SPC/Cervarix/
54. AS04 HPV Vaccine Efficacy
in ≥ 26 year-old women
S.R.Skinner, et al. IPvC 2011; Abstract.
55. Efficacy in ≥ 26 year-old women
VIVIANE Phase III trial
AS04 HPV vaccine (N=2,881)
Control (AL(OH)3) (N=2,871)
Randomizatio
n
N = 5,753
Month
Visit
S.R.Skinner, et al. IPvC 2011; Abstract.
0 1 6 7 12 18 24 30 36 42 48 54 60 66 72 78 84
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Interim analysis
56. TVC
N= 5,752
• Received ≥ 1 dose
• Case counting ≥ 1 day post-dose1
• Include women regardless of their
baseline cytological, serological or
HPV DNA status
• Include a 15% subset of women
Enrolled with prior history of HPV
Disease/ infection
ATP-E
N= 4,505
• Complied with protocol
• Received 3 doses
• Case counting ≥ 1 day post-dose3
• Normal or low grade cytological at
Month 0
• DNA negative at Month 0 and
Month 6 for the corresponding HPV
type
HPV
N = 2,881
Control
N = 2,871
HPV
N = 2,264
Control
N = 2,241
Study Cohorts
ATP-E,According-To-Protocolcohortfor Efficacy;control,subjectwho received aluminium hydroxide;
HPV, subjects who received the AS04 HPV vaccine;TVC,TotalVaccinatedCohort.
S.R.Skinner, et al. IPvC 2011; Abstract.
57. 0
20
40
60
80
100
120
140
160
TVC ATP-E
seronegative
ATP-E irrespective
of serostatus
Control AS04 HPV vaccine group
Vaccine Efficacy against 6-month PI and/or
CIN1+ lesionsassociated with HPV 16/18
43.9%
81.1%
82.8%
Cohorts TVC ATP-E seronegative
ATP-E irrespective of
serostatus
Control 158 36 51
AS04 HPV
vaccine
90 7 9
97.7% CI 23.9,59.0 52.1, 94.0 61.2, 93.5
S.R.Skinner, et al. IPvC 2011; Abstract.
60. 2001 20102005 2006 2007 2008 20092002 2003 2004
HPV-001 study
(primary efficacy
study)N = 1,113
5.5 years
Follow-up3
4.5 years
Follow-up2
HPV-007 study
(extended follow-upof primary efficacy
study)N = 776
HPV-023 study (further
extended follow-upin a
subsetup to 9.4 years)N=437
27 months
Follow-up1
1. Harper D, et al. Lancet 2004; 364:1757–1765; 2. Harper D, et al. Lancet 2006; 367:1247–1255; 3. Harper DM. Gynecol Oncol 2008;110:S11–S17;
4. GlaxoSmithKline Vaccine HPV-007 Study Group. Lancet 2009; 374:1975-1985; 5. De Carvalho ND, et al. XIX FIGO October 2009; Cape Town,
South Africa, Abstract O929; 6. Roteli-Martins CM, et al. ESPID 2010, Abstract 622; 7. Paavonen J, et al. Lancet 2007; 369:2161-2170; 8. Paavonen
J, et al. Lancet 2009; 374:301–314. 9.Paavonen J, et al. 26th IPvC, Montreal, 3-8 July 2010, abstract 689. 7. Paulo N, et al. 27th IPvC, Berlin, 17-22 Sep
2011
AS04 HPV vaccine
Phase II/ IIb: HPV001/007/023
7.3 years
Follow-up5
6.4 years
Final
Analysis4
8.4 years
Follow-up6
Phase II/IIb
Inclusion Criteria :
•15-25 years old
•HPV naïve
•Sexual partner < 6
9.4 years
Follow-up7
61. Adapted from Paolo Naud IPvC 2011; Oral presentation
AS04HPV vaccineมีการศึกษาที่ยืนยันถึงระดับภูมิคุ้มกัน
ที่ยังคงสูงอย่างต่อเนื่องยาวนานที่สุด
ภูมิสูงกว่าการติดเชื้อ
ตามธรรมชาติ
14เท่า
ภูมิสูงกว่าการติดเชื้อ
ตามธรรมชาติ
10เท่า
100%
seropositivity
100%
seropositivity
ณ ปีที่ 9.4 ระดับภูมิคุ้มกันยังคงอยู่ในระดับสูงอย่างต่อเนื่อง
และอาสาสมัครทุกราย ยังคงมีแอนติบอดีอยู่
(GMTs for anti HPV-16 and anti HPV-18 Abmeasuredby ELISA)
62. ณ ปีที่ 9.4 ประสิทธิภาพในการป้ องกัน CIN 2+ lesions
จาก HPV 16/18 ยังคง = 100%
1. Harper D, et al. Lancet 2004; 364:1757–1765; 2. Harper D, et al. Lancet 2006; 367:1247–1255; 3. Gall S, et al. AACR 2007; Abstract;
4. Harper D, et al. SGO 2008; Abstract; 5. GlaxoSmithKline Vaccine HPV-007 Study Group. Lancet 2009; 374:1975–1985;
6. Carvalho ND, et al. ESGO 2009; Abstract 1440; 7. Roteli-Martins CM, et al. ESPID 2010, Ab stract 622.
Analysis Duration
AS04 HPV
vaccine
Control Vaccine efficacy
No. cases No. cases % 95% CI
Initial efficacy study
(N = 1,113)
2.3 years1 0 3 NA* NA*
Combined analysis of
initial efficacy study
and extended follow-
up
(N = 776)
4.5 years2 0 5 100.0 -7.7–100
5.5 years3 0 7 100.0 32.7–100
6.4 years4,5 0 9 100.0 51.3–100
Brazilian cohort
(N = 436)
7.3 years6 0 10 100.0 -129.9–100
8.4 years7 0 13 100.0 <0–100
9.4 years8 0 16 100.0 -128.1, 100
* Initial efficacy study was not powered to calculate vaccine efficacy against histopathologically confirmed
CIN ITT analysis.
AS04HPV vaccineมีการศึกษาที่ยืนยันถึง
ประสิทธิภาพในการป้ องกันที่ยาวนานที่สุด
63. AS04 HPV vaccine: ระยะเวลาของภูมิคุ้มกัน
ตามการคานวณทางคณิตศาสตร์
10
100
1000
10000
0 5 10 15 20
Years since first vaccination dose
HPV-18
อย่างน้อย 20-50 ปี
10
100
1000
10000
0 5 10 15 20
Years since first vaccination dose
HPV-16
Piece-wise
Modified Power-Law
Power-Law
Natural infection level 29.8 EU/ml
Antibodytitres(EL.U/ml)
As presentedby Dr Roteli-Martins. AOGIN 2010; Session 0-6.3 Oral presentation.
Convention
al
Conservative model
Model assuming long-
term memory
64. วัคซีนที่ดีควรกระตุ้นภูมิคุ้มกันได้สูงและอยู่ได้นาน1,2
1. Stanley M, et al. Vaccine 2006; 24(Suppl 3):S106–S113; 2. WHO Department of Immunization, Vaccines and Biologicals, 2007;
3. Einstein MH, et al. Lancet Infect Dis 2009; 9:347–356; 4. Schiller JT and Lowy DR. J Infect Dis 2009; 200:166–171.
ระดับภูมิคุ้มกัน
ระยะเวลา
Vaccination
ภูมิคุ้มกันที่ต่า ไม่สามารถป้ องกันโรคได้
วัคซีนที่ดีควรกระตุ้นภูมิคุ้มกันได้สูงและอยู่ได้นาน