HPV VACCINE

CERVICAL
CANCER
Andrijono
MASALAH
 Sepuluh kanker terbanyak di Indonesia
(Data berdasarkan Patologi Anatomi, 2008)
4000

3500

3000
Breast
2500 Cervix
Ovary
2000
Thiroid

1500 Skin
Rectum
1000 Uterin corpus
Colon
500 Nasopharing
Lymphoma malignum
0
 2013

Riset Kesehatan Dasar Dalam Angka 2013. http://www.litbang.depkes.go.id/

Data
2004 - 2013
Dari Jakarta

2,47%

1.3/1000
Dari 342
Puskesmas
CERVICAL CANCER

Advanced
Stage 82,3%
Early Stage:
17.7%
 Cervical Cancer Challenge in Indonesia

• Death rate caused by cervical cancer (Globocan): 7.800 / year

Our own data, interpolation:
230 Million, 38 millions women at risk :
Cervical Cancer invasive 1 in 1000 respondent
incidence in 38 millions : 38.000 cases /year
Prediction mortality about 80% 30,400/ yr

33 cervical cancer patients

death every day
CARCINOGENEIS
 EPIDEMIOLOGY
HPV
(Human Papilloma Virus)

>100 type HPV

19 oncogenic HPV

The most common cervical cancer

Indonesia
16 (44%), 18 (39%) , 52 (14%).

Maaike C Schellekens etall. Gynecologic Oncology..2004:93(1) ; 49–53

.
 SECONDARY PREVENTION

PRIMARY
PREVENTION
 HPV
INFECTION
 HPV Genotype Distribution (Jun'11-Oct'12)

16%

14%

12%

High-Risk HPV
10%

8%
Low-Risk HPV

6%

4%

2%

0%

Kalgen Lab
 Kanker yang dapat disebabkan HPV
Kanker ~100%
Serviks1,
3

45%
Kanker Kanker ~40%
penis3 Vulva1

Kanker
mulut
12-70% tenggorok Kanker 60-90%
an3 Vagina1

~100% Genital
Kanker Female
Warts1,
3
anus1-3 80+% Both sex
Male

Percentages represent cases atrributable to HPV infection

Braaten KP et al. Rev Obstet Gynecol. 2008;1:2–10.
• Hoots BE et al. Int J Cancer. 2009;124:2375–2383.
• IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Human papillomaviruses. Vol 90. Lyon, France: IARC, 2007.
ADAKAH OBAT HPV
 VLP

VAKSIN TIDAK MENGANDUNG VIRUS

VAKSIN BERISI BAGIAN KULIT VIRUS YG DIBUAT

ATAU SINTESISNYA
 SUNTIKAN
VAKSIN YANG
MENGANDUNG
VLP-HPV

AKAN MENIMBULKAN KEKEBALAN

TERHADAP VIRUS HPV
 CARA KERJA VAKSIN HPV

HPV
VAKSIN

Tidak dapat
masuk
Merangsang tubuh
membentuk Antibodi Antibodi
(kekebalan tubuh) terhadap (terbentuk)
HPV
SERVIKS
( LEHER RAHIM )
www.cegahkankerserviks.org
 HPV vaccines generate neutralizing
antibodies which prevent infection
HPV infects target cells in the basal
layer of the cervical epithelium

Infection
 HPV vaccination focuses on
preventing HPV infection
through generation of high
Basal cell layer
of cervical

levels of ‘neutralizing’
epithelium

antibodies Neutralizing antibodies prevent HPV

from infecting basal epithelial cells

 Neutralizing antibodies bind to

HPV’s outer shell (capsid) and
prevent infection of host cells1 No infection

Neutralizing antibodies are

the likely mediator of
protection
WHO 20062 1. Stanley M, et al. Vaccine 2006; 24(Suppl 3):S106–S113;
2. WHO Expert Committee on Biological Standardization, 2006.
 Active protection via vaccination is mediated by
neutralizing antibodies at the cervix

HPV Neutralizing antibodies

Cervical canal

Cervical
epithelium

Blood vessel

Epithelial tear

Basement membrane

1. Stanley M. Vaccine 2006; 24:S16–S22;

2. Giannini S, et al. Vaccine 2006; 24:5937–5949;
3. Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137;
4. Poncelet S, et al. IPC 2007(poster).
 Composition of HPV Vaccine
Cervarix™
Antigens AS04 adjuvant

+ Aluminium
salt
(Al(OH)3)
+ MPL
Immunostimulant

HPV 16 VLPs HPV 18 VLPs

AS04-containing vaccine

QUADRIVALENT
Antigens Adjuvant

+ Aluminium salt
(amorphous aluminium
hydroxyphosphate
sulphate [AAHS])
HPV 16 VLPs HPV 18 VLPs HPV 6 VLPs HPV 11 VLPs

AAHS-containing vaccine
 Composition of MSD HPV
Vaccinesa
GARDASIL™
Human Papillomavirus
Vaccine [Types 6, 11, 16, AAHS
18] (Recombinant, 225 μg
adsorbed)1

6 11 16 18
20 μg 40 μg 40 μg 20 μg

GARDASIL™9 AAHS
Human Papillomavirus 9-valent Vaccine (Recombinant, adsorbed)2 500 μg

6 11 16 18 31 33 45 52 58
30 μg 40 μg 60 μg 40 μg 20 μg 20 μg 20 μg 20 μg 20 μg

aForthe remainder of the presentation, GARDASIL will be referred to as 4vHPV vaccine and GARDASIL 9 will be referred to as 9vHPV vaccine.
AAHS=amorphous aluminum hydroxyphosphate sulfate; HPV=human papillomavirus; MSD=Merck Sharp & Dohme Corp.
1. GARDASIL [summary of product characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2014. 2. GARDASIL 9 [summary of product
characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2015.
 Worldwide Burden of HPV Disease
 HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 are 9 of the most common types in
HPV-related cancers and diseases in males and females1–6
Estimated Type Contribution for Certain HPV-Related Cancer and Disease Cases
4 HPV types
9 HPV types cause a total of:
cause: (6, 11, 16, 18, 31, 33, 45, 52, and 58)
(6, 11, 16, and 18)

Cervical cancer cases 70%1 90%1

Vulvar cancer casesa 75%2 90%2

Vaginal cancer casesa 65%3 85%3
Anal cancer casesa 85%4 90%–95%4
High-grade cervical
50%5 80%5
precancersa,b
Low-grade cervical lesionsa 25%5 50%5

Genital warts 7cases 90% cases are2 caused by HPV. Approximately90%

aNot all cervical precancers and lesions, and vulvar, vaginal, and anal cancer 6
7
90% of6 high-grade
3
cervical precancers, 75% of low-grade cervical lesions, 30% of vulvar cancer cases, 70% to 75% of vaginal cancer cases, and 85% to
90% of anal cancer cases4 are HPV related. bHigh-grade cervical precancers defined as cervical intraepithelial neoplasia (CIN) 2/3.
1. de Sanjosé S et al. Lancet Oncol. 2010;11:1048–1056. 2. de Sanjosé S et al. Eur J Cancer. 2013;49:3450–3461. 3. Alemany L et al. Eur J Cancer.
2014;50:2846-2854. 4. Alemany L et al. Int J Cancer. 2015;136:98–107. 5. Joura EA et al. Cancer Epidemiol Biomarkers Prev. 2014;23:1997−2008.
6. Garland SM et al. J Infect Dis. 2009;199:805–814. 7. Guan P et al. Int J Cancer. 2012;131:2349–2359.
 Vaksin HPV Quadrivalent
> 227 juta dosis
di seluruh dunia,
approval
> 130 negara
HPV QUADRIVALENT VACCINE

Antigen
Viral Like Particle tanpa DNA Adjuvant
Amorphous aluminum
viral (non-infectious)
hydroxyphosphate
sulfate (AAHS)
—225 μg per dosis

*AAHS has proven Studi Kajian Terbesar “Kajian

safety profile, Keamanan Vaksin HPV Quadrivalent -
2006 sampai 2015” :
used worldwide
20 μg L1 VLP- HPV 6 for several “Vaccine with good safety profile”
40 μg L1 VLP -HPV 11 decades
40 μg L1 VLP- HPV 16 Pediatric Infectious Disease
Journal.September 2015 - Volume 34 -
20 μg L1 VLP- HPV 18 Issue 9 - p 983–991

VLPs diproduksi intraseluler

pada Saccharomyces cerevisiae
 Effectiveness terhadap HPV 16/18-terkait CIN 2
atau lebih buruk
Per Protocol Efficacy Population (N=1984)
Longest follow up: 10 years
VE:100 %
100 Tidak ada kasus
PRA-KANKER
Vaccine Effectiveness* (VE)

80
terkait HPV 16/18
10 tahun sesudah
Percentage

60
vaksinasi
Zero number
40 of cases
Vaksin qHPV tetap aman dan
ditoleransi dengan baik~10 tahun
20 setelah vaksinasi.
0
0
(N=1,984) Vaccine
Effectiveness HPV 16/18-Related
CIN 2 or Worse

LONG-TERM EFFECTIVENESS OF GARDASIL™ IN THE NORDIC COUNTRIES. Kjaer et al. Poster presented at EUROGIN 2015.
*Vaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared to the baseline incidence rate of 0.0287 per 100 person
-years established from the incidence rate in an unvaccinated cohort and under the assumption vaccine efficacy is 90%.
 Effectiveness berdasarkan Tipe Lesi
Efektifitas Population (N=1984)
Pengamatan selama : 10 years
VE:100 % VE:100 % VE:100 % VE:100 % VE:100 %
100
Vaccine Effectiveness* (VE)

80
Percentage
Percentage

60
Vaccine effectiveness

Vaccine effectiveness

Vaccine effectiveness
Vaccine effectiveness
Vaccine effectiveness
Zero number Zero number Zero number Zero number Zero number
of cases of cases of cases of cases of cases
40

20

0 0 0 0 0
0
(N=1,984) (N=1,984) (N=1,984) (N=1,984) (N=1,984)

CIN 2 CIN 3 or CIN 3 AIS CC

worse
LONG-TERM EFFECTIVENESS OF GARDASIL™ IN THE NORDIC COUNTRIES. Kjaer et al. Poster presented at EUROGIN 2015.
*Vaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared to the baseline incidence rate of 0.0287 per 100 person
-years established from the incidence rate in an unvaccinated cohort and under the assumption vaccine efficacy is 90%.
HALAL
 Fakta: Proses Pembuatan Vaksin HPV
Quadrivalent

HPV Sel Ragi

(Saccharomyces
Cerevisiae)

• Sel ragi diperintah oleh komponen virus HPV untuk membuat L1 VLP
• Tidak menggunakan enzim atau bahan dari hewan dalam proses
pembuatannya (mempunyai sertifikat kehalalan dari
IFANCA/Islamic Food and Nutrition Council of America)
 Impact of 4vHPV Vaccine in
Public Vaccination Programs
 Impact of 4vHPV Vaccine in Public
Vaccination Programs: Select
Reportsa
Genital Warts
Baandrup Ali Wilson Smith
Sex Transm Dis13 BMC Infect Dis16 Sex Transm J Infect Dis24
Infect20
Read
Sex Transm Leval
Infect8 J Infect *Blomberg Ali Chow *Droletc
Dis11 Clin Infect BMJ17 BMJ21 Lancet Infect
Dis14 Dis25
Fairley Donovan
Sex Transm Lancet
Flagg Harrison
Introduction of 4vHPV vaccine1–6 Infect7 Infect Dis9 Bauer
*Leval
Am J Public
*Petráš
JNCI3 PLoS One22 Vaccine26
Am J Health18
Public
Health12
Oliphant
Mikolajczyk Nsouli-Maktabi Liu *Dominiak-Felden
NZMJ10
Czech Republic Sex Transm MSMR19 Sex Transm PLoS One6
Dis15 Infect23

Cervical
Australia Abnormalities *Baldur-Felskov *Crowe *Smith
Cancer Causes BMJ31 Pediatrics33
*Gertig Control30
Brotherton *Powell BMC Med29
New
Canada Lancet27 Vaccine28
Zealand *Baldur-Felskov *Mahmud *Hariri *Herweijer
Sweden
JNCI4 J Clin Oncol32 Vaccine34 Int J
Cancer35
Belgium
United Denmarkb HPV Prevalence
States *Tabrizi Markowitz *Tabrizi Deleré *Dunne *Markowitz
J Infect J Infect Dis37 Lancet BMC Infect J Infect Pediatrics41
Germany Dis40
Dis36 Infect Dis38 Dis39

2006 2007 2008 2009 2011 2012 2013 2014 2015 2016
*Study links effectiveness data to vaccination statusaIncludes reports published in the peer-reviewed scientific literature, and does not encompass reports at scientific conferences. bBeginning on February 1,
2016 the childhood vaccination program includes the 2vHPV vaccine.42 cMeta-analysis of data from 20 studies in 9 countries (United States, Australia, England, Scotland, New Zealand, Sweden, Denmark,
Canada, and Germany), including both 4vHPV vaccine and 2vHPV vaccine.25
Please see corresponding slide note for references.
 Australia: Cervical Abnormalities
reduction

Australia: Population-based analysis of % reduction in cervical Australia: Population-based analysis of percentage reduction in
abnormalities among vaccinated (at least 1 dose) vs contemporaneous cervical abnormalities among vaccinated vs contemporaneous
unvaccinated screened females in Victoria unvaccinated screened females in Queensland
Garland et al; Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of
Real-world Experience: CID, 2016
 Canada & Denmark: Cervical
Abnormalities reduction

Canada: % reduction in cervical abnormalities in Denmark: %reduction in cervical abnormalities in females

vaccinated/vaccine era vs contemporaneous unvaccinated/ vaccinated with 4vHPV vaccine (≥1 dose) vs unvaccinated
prevaccine era in 3 provinces women by birth cohort
Garland et al; Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of
Real-world Experience: CID, 2016
 Sweden & USA: Cervical
Abnormalities reduction

Sweden: % reduction in CIN2+ and CIN3+ among females fully United States: % reduction in HPV 16/18-related cervical
vaccinated with 4vHPV vaccine (3 doses) vs unvaccinated abnormalities among females vaccinated with 4vHPV vaccine (at
/partially vaccinated females, by age at first dose least 1 dose) vs contemporaneous unvaccinated females
Garland et al; Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of
Real-world Experience: CID, 2016
 Significant Reductions in the Risk of
Cervical Lesions Following 4vHPV
Vaccination Program in Denmark1
• Compared to unvaccinated women, among vaccinateda women (≥1 dose):
– The risk of atypia or worse was reduced by up to 60%.
– Risks of CIN 2/3 and CIN 3 were reduced by up to 80%.

Risk of Cervical Lesions in Vaccinated Women Compared With Unvaccinated Women,

October 2006–March 2012b
Birth cohortc
† † † †
1989–1990
n=78,448
1991–1992
* ** n=74,323
** *** 1993–1994
* * n=72,544
1995–1996 d
n=71,214
1997–1999 e
n=102,715

Cytologic Outcome
Statistical significance compared to unvaccinated women: *P<0.001, **P=0.005, ***P=0.01, †not significant.
aIndividual HPV vaccination status was obtained from nationwide registries from 2006 to 2012. bError bars represent 95% confidence intervals. cTotal cohort:

N=399,244. dThere were too few events to estimate hazard ratios for CIN 2/3 or CIN 3. eThere were no events.
CIN=cervical intraepithelial neoplasia.
1. Baldur-Felskov B et al. J Natl Cancer Inst. 2014;106:djt460.
Quick Reduction of Genital Wart Incidence as Early Marker to Evaluate
Successfulness of HPV Vaccination Program

Experience from HPV Vaccination Program in Australia

Significant Decrease of Genital Wart Incidence in Women (1-4 years after HPV Quadrivalent
Vaccination Program)
*Vaccination for girls and women 12-26 years old

20 qHPV vaccine 34,900 females

introduced <21 Years (n=9,405)
Genital Wart Diagnosis (%)

18
21–30 Years (n=15,228)
16
>30 Years (n=10,246)
14 Prevaccine period Vaccination period
12

10

4 –72.6%
Ptrend <0.001
2
Ptrend <0.001 –92.6%
0
2004 2005 2006 2007 2008 2009 2010 2011

Year
qHPV=quadrivalent human papillomavirus.
Figure reproduced from BMJ, Ali H et al, 346, f2032, 2013, with permission from BMJ Publishing Group Ltd.
1. Ali H et al. BMJ. 2013;346:f2032.
 UPDATE INDIKASI DOSIS PEMBERIAN VAKSIN HPV Quadrivalent :
2 Dosis untuk usia 9-13 tahun

BPOM Indonesia approval March 2015

In individuals 9 through 13 years of
age, HPV Quadrivalent can be
administered according to a 2-dose
(0, 6 months) schedule.

Hasil Uji klinis menunjukkan bahwa respon imun pada anak perempuan berusia 9-13 tahun (n = 259) yang menerima 2
dosis Gardasil (pada 0, 6 bulan) tidak lebih rendah (non-inferior) dengan respon imun pada wanita usia 16- 26 tahun (n =
310) yang menerima 3 dosis Gardasil (pada 0, 2, 6 bulan).”
Dobson S, et al. Immunogenicity of 2 Doses of HPV Vaccine in Younger Adolescents vs 3 Doses in
Young Women. JAMA, May 1, 2013—Vol 309, No. 17: 1793-1802.
PROGRAM
VAKSINASI
Mencegah Infeksi HPV berarti Mencegah Kanker
 INJECTION SCHEDULE

Quadrivalent, 0-2-6
Bivalent, 0-1-6

9 – 13 years old : TWO DOSES

Suntikan : 0-6
 INDONESIAN HPV VACCINE GUIDELINE

PROPHYLACTIC VACCINE

IM DELTOID MUSCLE 10-55 YEARS OLD

0,1,6
0, 6
SEXUAL (-)
LACTATION
HPV VACCINE
SEXUAL (+)
NO PREGNANCY PAP SMEAR (-)

PRECANCER LESION HPV INFECTION

IN THE PAST IN THE PAST

NO HPV INFECTION NO PRECANCER LESION

VACCINATION + PAP SMEAR
POGI (HOGI)-IDAI
 Age at first marriage1 Pre-marital sex and aged of sexual
activity2
Survey taken from 63.428 respondent aged
10-24 years. 86.7% of them haven’t been
married2
Among those who haven’t been married, 3%
man and 1.1% women said they already
sexually active2

Proportion of
respondent aged
10-24 years who
haven’t been married
based on first age
sexually active 2

Percentage of women aged 10-59 years

based on age at first marriage1

1,2. Riskesdas 2010. Badan Penelitian dan Pengembangan Kesehatan,

Kemenkes RI