BIOMARKER

PADA PD3I
LAURA NAVIKA YAMANI
Departemen Epidemiologi FKM UNAIR
16 OCTOBER 2018
 Biological Markers
(BIOMARKERS)
A biological marker is a measurable indicator that can tell us
something about a person’s health or disease state, for example,
• disease (pathological) processes in the body, for example, presence of disease, disease
stage, severity, organ function examination
• biological processes in the body (heart rate, blood pressure, temperature),
 aspect of health physically
• a person’s response to a treatment or medicine, susceptible or resistant?
• or a psychological condition.
Biomarkers can be characteristic biological properties or
molecules that can be detected and measured in parts of the
body like the blood or tissue  normal or diseased processes.
Biomarkers can be specific cells, molecules, or genes, gene
products, enzymes, or hormones. Or complex organ functions or
general characteristic changes.
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 Examples of Biomarkers
• Glucose levels that are used as a biomarker in managing diabetes
(hyperglikemia).

• Brain images such as Magnetic Resonance Imaging (MRI) that can

provide information about the progression of Multiple Sclerosis.

• Biological substances such as enzymes, which may be found in the

blood or in tissue samples and are often used in cancer research.

• The presence of an Antigens or antibodies or a toxins.

• Genetic (DNA) changes.

• Medical images, or X-rays, such as CT scan.

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 Aims of Biomarker Use
1. Disease-related Biomarkers
(Diagnose of disease progression and monitor of treatment
given to individuals)
Biomarker research is helping to
• Improve how well we can predict a person’s risk of disease
• How a disease might progress once it is diagnosed
• How an individual will respond to a medicine
This will enable safer and more effective treatment decisions.
• Examples:
• Antigen or antibody is detected in persons or patients to diagnose they get infectious diseases.
• Magnetic Resonance Imaging (MRI) scans of a patient’s brain can be used to monitor the progress
of the disease in Multiple Sclerosis.
• Blood sugar levels in a patient’s blood can be used to monitor if an individual is responding to
diabetes treatment.

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Aims of Biomarker Use
2. Drug-related Biomarkers
(Improving the processes of medicines development)

• Clinical trials seek to measure patients’ responses to a

treatment.
• If it is not possible to measure the response directly,
biomarkers may provide an alternative way of measuring an
outcome - they serve as surrogate endpoints.

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• Many new biomarkers are being discovered and used
during the development of new medicines.

• “classic” biomarker in medicine is all laboratory

parameter that the doctor can use to help make decisions
in making a diagnosis and selecting a course of treatment.

• “new” biomarker have become the basis for preventive

medicine.

• Many of these use:

• genomics (analyses of changes occurring at the gene level),
• proteomics (analyses of changes on the protein level),
• and/or metabolomics (analyses of differences in chemical molecules that play an
important role in body and cell function).
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 IMUNISASI
• Setiap tahun lebih dari 1,4 juta anak di dunia meninggal karena berbagai
penyakit yang sebenarnya dapat dicegah dengan imunisasi.
• Imunisasi adalah suatu upaya untuk menimbulkan/meningkatkan kekebalan
seseorang secara aktif terhadap suatu penyakit, sehingga bila suatu saat
terpapar dengan penyakit tersebut tidak akan sakit atau hanya mengalami
sakit ringan.
• Beberapa penyakit menular yang termasuk ke dalam Penyakit yang Dapat
Dicegah dengan Imunisasi (PD3I) antara lain: TBC, Difteri, Tetanus, Hepatitis
B, Pertusis, Campak, Polio, radang selaput otak, dan radang paru-paru.
• Anak yang telah diberi imunisasi akan terlindungi dari berbagai penyakit
berbahaya tersebut, yang dapat menimbulkan kecacatan atau kematian.
• Program imunisasi merupakan salah satu upaya untuk melindungi
penduduk terhadap penyakit tertentu. Program imunisasi diberikan kepada
populasi yang dianggap rentan terjangkit penyakit menular, yaitu bayi,
balita, anak-anak, wanita usia subur, dan ibu hamil.
• setiap bayi wajib mendapatkan imunisasi dasar Lengkap yang terdiri dari : 1
dosis BCG, 3 dosis DPT-HB dan atau DPT-HB-Hib, 4 dosis polio, dan 1 dosis
campak.
 I. Pendahuluan PD3I
 Program Imunisasi di dunia di mulai akhir tahun 1960an dengan
vaksinasi Cacar dan Dunia bebas dari Cacar tahun 1970an
 EPI program di Indonesia di mulai tahun 1975
 Polio eradikasi akan mengikuti eradikasi cacar memerlukan waktu
lebih lama (1995- sekarang: exit Strategy)
 MNTE (Maternal Neonatal Tetanus Elimination) Mei 2017
 Eliminasi Campak dan kontrol Rubella pada tahun 2020
 New Vaccine Introduction (Hib-B, Rubella, Kolera, Dengue, JE, dll)
 Immunization Gap dan akibat Cakupan yang kurang (Pocket spot
area)
 Efek Samping/Adverse Event (KIPI)
 KLB Difteri di 26 Provinsi dan Campak di Papua ?
 II. Literature
Herd Immunity (Efek Individu Vs Efek Populasi)

Efek
Populasi

Efek Individu
Efek Herd Immunity

 Surveilans PD3I sangat diperlukan untuk melihat apakah terjadi penurunan tingkat
Morbiditas dan Mortalitas
 Outbreak Campak Saat Cakupan Imunisasi menurun
Association Between Vaccine Refusal and
Vaccine-Preventable Diseases in the United
States
A Review of Measles and Pertussis
Varun K. Phadke, MD, Robert A. Bednarczyk, MS, PhD, Daniel A. Salmon, MPH, PhD, and
Saad B. Omer, MBBS, MPH, PhD
EVIDENCE REVIEW
Search of PubMed through November 30, 2015, for reports of US measles outbreaks that
have occurred since measles was declared eliminated in the United States (after January 1,
2000), endemic and epidemic pertussis since the lowest point in US pertussis incidence (after
January 1, 1977), and for studies that assessed disease risk in the context of vaccine delay or
exemption.
FINDINGS
We identified 18 published measles studies (9 annual summaries and 9 outbreak reports),
which described 1416 measles cases (individual age range, 2 weeks-84 years; 178 cases
younger than 12 months) and more than half (56.8%) had no history of measles vaccination.
Of the 970 measles cases with detailed vaccination data, 574 cases were unvaccinated despite
being vaccine eligible and 405 (70.6%) of these had nonmedical exemptions (eg, exemptions
for religious or philosophical reasons, as opposed to medical contraindications; 41.8%of
total). Among 32 reports of pertussis outbreaks, which included 10 609 individuals for whom
vaccination status was reported (age range, 10 days-87 years), the 5 largest statewide
epidemics had substantial proportions (range, 24%–45%) of unvaccinated or undervaccinated
individuals. However, several pertussis outbreaks also occurred in highly vaccinated populations,
indicating waning immunity. Nine reports (describing 12 outbreaks) provided
detailed vaccination data on unimmunized cases; among 8 of these outbreaks from
59%through 93%of unvaccinated individuals were intentionally unvaccinated.
Epidemiological update: Measles - monitoring
European outbreaks, 7 July
2017
epidemiological update
7 Jul 2017
Twitter Facebook Linked In Mail
Romania has been experiencing a large outbreak of measles since February 2016. Cases continue to be reported
despite ongoing response measures implemented at national level through reinforced vaccination activities.
Between 1 January 2016 and 30 June 2017, Romania reported 7 491 measles cases, including 31 deaths. In 2016,
several other EU/EEA countries reported measles outbreaks and an increase in the number of cases continues to
be observed in 2017. Some previous and ongoing measles outbreaks in other EU/EEA countries have been
epidemiologically linked to the current outbreak in Romania. Overall, more than
14 000 cases have been reported in the EU/EEA since January 2016, including 35 deaths.
Epidemiological update: Measles -
monitoring European outbreaks, 7 July
2017
epidemiological update
7 Jul 2017
Twitter Facebook Linked In Mail
Romania has been experiencing a large outbreak of measles since February 2016. Cases continue to be reported
despite ongoing response measures implemented at national level through reinforced vaccination activities.
Between 1 January 2016 and 30 June 2017, Romania reported 7 491 measles cases, including 31 deaths. In 2016,
several other EU/EEA countries reported measles outbreaks and an increase in the number of cases continues to
be observed in 2017. Some previous and ongoing measles outbreaks in other EU/EEA countries have been
epidemiologically linked to the current outbreak in Romania. Overall, more than
14 000 cases have been reported in the EU/EEA since January 2016, including 35 deaths.
 Immunitas akibat vaksinasi

Perlu memperhatikan umur saat imunisasi, frequensi pemberian imunisasi dan dosis ulangan
untuk mempertahankan herd immunity
 UMUR (BULAN) JENIS IMUNISASI

0 Hepatitis B (< 24 jam)

1 BCG, OPV1
2 DPT/HepB/Hib1, OPV2, PCV1*
3 DPT/HepB/Hib2, OPV3, PCV2*
4 DPT/HepB/Hib3, OPV4, IPV
9 MR, JE*
12 PCV3*
18 DPT/HepB/Hib4, MR

-DT Td Td HPV* HPV*

-MR Td
* hanya di Prov/Kab/Kota
Terpilih
*MR secara nasional, 2017 di P. Jawa, 2018 di luar P. Jawa
*PCV di Lombok Barat dan Timur (2017)
*JE di Bali (2018)
*HPV di DKI, DIY dan Surabaya (2017) serta Kota Manado
dan
Makassar pada tahun 2018
1 SD 2 SD 3 SD 5 SD 6 SD

Permenkes No 12/2017
BULAN IMUNISASI ANAK SEKOLAH
 Konsep Cakupan dan Mutu pelayanan Imunisasi

Partisipasi Masyarakat Managemen dan Kualitas

pelayanan Perencanaan
Pere

Pelaksanaan
Pela
Cakupan dan Tingkat
Surveilans
Imunitas
• PD3I
• Faktor Risiko

PePemantauan
Tingkat Morbiditas dan /Evaluasi
Mortalitas PD3I
1. Kondisi Cakupan Saat ini
Routine Immunization of BCG Routine Immunization of DPT3/DPT-HB3/DPT-
Coverage in Indonesia, 2006-2017 HB-Hib3 Coverage in Indonesia, 2006-2017
 Cakupan Imunisasi Dasar Lengkap, Indonesia, 2015-2017
12
Nasional
92,04%
2017

Tidak Lapor Cakupan

<80% Cakupan 80%

-
<92%
Cakupan ≥92%

Nasional
91,6%
2016
Tidak Lapor

Cakupan <80%
Cakupan 80% - <91,5%

Nasional
86,5%
2015

Belum lapor
<80%

Source : Ditjen P2P 80%- <91%

>=91%
 Mempertahankan herd immunity Secara
berkesinambungan
Drop Out Rate Cakupan Immunisasi Anak sekolah
DTP1-D TP3 DTP1-measles

19,5
17
14,3
13
10,8
8,4
3,72,7 4,3
2 1,4
0,2

Pesel Padang Lotim Ma ta ra m HST Ba

njarmasin

Cakupan Survei dan Laporan Campak

Dosis Kedua
120
100
80
60
40
20
0
Survei Laporan Survei Laporan Survei Laporan Survei Laporan
Pidie Aceh Jaya Bantaeng Palopo

Campak I Campak II
17 Tingkat Immunitas pada Anak Balitas dengan Immunisasi Lengkap

Tingkat proteksi yang

diukur dengan Titer
Antibodi < dari studi
systematic review global

Kemungkinan
• Perlu dosis kedua utk Difteri, pertusis dan Tetanus serta HBv
• Ada penyakit atau kondisi balita yg berhubungan dgn
Imune respons (gizi, minum obat2an, dll)
Countries with highest number of unvaccinated children's
 2. Alasan Anak Tidak Diimunisasi

Takul Keluarga Pelayanan Ibu tidak

Ibu Sibuk Anak Sakit
Demam Menolak Jauh Tahu ttg
immunisasi

Source : RISKESDAS 2013 Basic Health Survey

Linking serosurveys
to immunization
coverage surveys
Serosurvey :Serologic biomarker of
vaccination for survey immunity level
• A biological indicator directly associated with the
vaccination history that could be assessed
objectively by the survey
- visual biomarkers (vaccine-induced scarring)
- Serologic biomarkers (antibody to a vaccine
component)
Considerations for use of biomarkers to
classify vaccination history
 Vaccine effectiveness (e.g. measles 85% at 9 months)
 Type of vaccine and duration of immunity
 Live-attenuated — long immunity
 Non-replicative — shorter immunity, multiple doses required
 Intervalsince vaccination (waning immunity)
 Limited ability to discriminate receipt of multiple doses
 Or RI vs. SIA doses
 Likelihood of exposure to natural infection
 Not relevant for tetanus
 Can discern hepatitis B infection from vaccination with HBsAg
 Misclassification error (sensitivity, specificity, PVP, PVN)
 Serosurvey Data
• Provide information on population immunity that is
complementary to vaccination coverage survey
data
• May be used to guide policy/strategy, from vaccine
introduction to verification of disease elimination
Vaccination coverage survey vs. serosurvey
 Vaccination coverage survey ≈ population that received
vaccine dose(s)
 Serosurvey ≈ population immunity
 When representative of population, both:
 Monitor immunization program performance if repeated
at regular intervals
 Provide complementary information useful to the
program
Pros and cons of vaccination coverage
surveys vs. serosurveys
Vaccination Coverage Serology
Pros  Relatively low cost  Objective biological measure
 Discern RI vs. SIA doses  Better marker of disease risk
 Identify missed  Useful for older children and
opportunities adults (history unreliable)

Cons  Recall bias (unless high  Can’t discern vaccination vs.

rate of documentation) natural infection (most diseases)
 Can’t measure disease  Can’t measure cell mediated
immunity immune response
 Requires high technical capacity
 Relatively high cost
Levels of tetanus antibodies among women
aged 15–39 years, Cambodia
E s ti m a te d % o f w o m e n

Long-term
100 protection
Antibody level Seroprotection
80 (IU/ml)

60 ≥1.0
0.1–0.9 No protection
40 0.01–0.09

20 <0.01
N u llip a ro u s
O v e ra ll

15–19

20–24

25–29

30–34

35–39
P a ro u s

Age (years)
Impact of Hib vaccine introduction on
invasive Hib disease in infants, Bamako,
Mali
 Invasive Hib cases/105 infants per 6-month
intervals
88%
reduction

36-month 12-month 23-month Intervention Period,

Baseline Transition 7-06 to 5-08
Period, Period,
7-02 7-05 to 6-06
to 6-05 S Sow et al 2009
Prevalence of serum Hib PRP antibodies in Malian
infants 6-7 months of age before and 18 & 30
months after the introduction of Hib conjugate
into the EPI for Malian infants
100.00% Serum
90.00% antibody
80.00% levels:
70.00%
60.00%
0.15 mcg/ml
50.00%
1.00 mcg/ml
40.00%
30.00%
20.00%
10.00%
0.00%
Baseline 18 mos. 30 mos.
S Sow et al,
N=200 N=201 N=200 AJTMH 2009
 Serum PRN measles antibody titers in Malian infants of
different ages, demonstrating the “window of vulnerability”
and the response to measles vaccine

M Tapia et al. AmJTMH 2005

 Some explanations for “immunization
failures” & other discrepancies
• Defective cold chain
• Immunogenicity of the vaccine
• Even in industrialized countries, ~ 2-3% of
children who receive their 1st measles
vaccination do not develop PRN antibodies
• Residual maternal antibodies interfere with
infant immune response (measles)
• Child responds immunologically but titer is
below the protective “cut-off”
• Transcriptional errors
5. Manajemen Efektivitas Vaksin
Provinsi
NATIONAL
STORAGE (n=17)

Vaccine arrival (E1) : Hanya dinilai pada level

Nasional

Manajemen Efektivitas Vaksin di tingkat Nasional hampir sempurna di tingkat provinsi masih
kurang
 5. Manajemen Efektivitas Vaksin

KABUPATEN Puskesmas
(n=26)

Vaccine arrival (E1) : Hanya dinilai pada level

Nasional Vaccine arrival (E1) : Hanya dinilai pada level
Nasional

Manajemen Efektivitas Vaksin di tingkat kabupaten dan Puskesmas masih kurang

 Serosurveys linked to immunization coverage surveys in
3 districts (woredas) in Ethiopia
Sample
Number
Age size in Tetanus Measles Hib PRP
of
group each Antitoxin Antibody Antibody
woredas
woreda

12-23 300
months
3
children Yes Yes -

6-8* 100
months
3
children Yes
* This age group has not historically been used to assess immunization
coverage.
CVD has shown the utility of documenting high titers of Hib antibodies as
evidence of receipt of pentavalent vaccine.
3 collaborating teams: JSI (coverage survey); Ethiopian Public Health Institute
(serosurvey) CVD, U of Maryland (serosurvey and reference laboratory)
Hintalo Wajerate: pentavalent vaccine doses and tetanus
antitoxin in toddlers 12-23 mos. of age

Toddlers with Coverage GMT, No. (%) of toddlers

with tetanus
Survey record of tetanus
pentavalent vaccine@ antitoxin antitoxin titers
> 0.15 IU/ml
3 doses (217 toddlers)  0.95 IU/ml 209/217 (96%)
2 doses (16 toddlers) 0.85 IU/ml 14/16 (88%)
1 dose (5 toddlers)  0.75 IU/ml 4/5 (80%)
238 toddlers total   227/238 (95%)
@
”Coverage Survey record” indicates documentation of vaccination
by immunization card or EPI register.
Assaieta: pentavalent vaccine doses and tetanus antitoxin
in toddlers 12-23 months of age

Toddlers with Coverage GMT, No. (%) of toddlers

Survey record of tetanus with tetanus
pentavalent vaccine@ antitoxin antitoxin titers
> 0.15 IU/ml
3 doses (57 toddlers)  0.89 IU/ml 52/57 (91%)
2 doses (9 toddlers) 0.22 IU/ml 6/9 (67%)
1 dose (15 toddlers)  0.04 IU/ml 6/15 (40%)
81 toddlers total   64/81 (79%)
@
”Coverage Survey record” indicates documentation of
vaccination by immunization card or EPI register.
Pentavalent vaccine-3 in toddlers 12-23 mos. of age:
administrative coverage, coverage survey & serosurvey

Estimate Hintalo Arbegona Assaieta

Administrative (2013) 90% 86% 65%

JSI Coverage Survey: 229/263 103/251 72/215

(Vacc. Card+ EPI Register (87%) (41%) (35%)
+ Maternal Recall)

Serosurvey: 244/263 151/251 114/215

Number (%) with tetanus (93%) (54%) (46%)
antitoxin > 0.15 IU/ml
Hintalo Wajerate: pentavalent vaccine doses and PRP &
tetanus antibodies in infants age 6-8 mos.

Coverage Survey record of No. (%) of infants with:

Penta vaccine@ PRP titers
> 1.0 mcg/ml
3 doses (43 infants)  38/43 (88%)
2 doses (15 infants) 8/15 (53%)
1 dose (12 infants)  3/12 (25%)

70 infants total 49/70 (70%)

@
”Coverage survey record” indicates documentation of
vaccination by either immunization card or EPI register.
Dried Blood Spots (DBS) in serosurveys
Good spots Poor quality spots
Correlation between tetanus antitoxin titers in DBS
eluates vs. serum from toddlers age 12-23 months

r=0.91
Correlation between measles IgG antibody titers in DBS eluates
vs. serum from the same 60 adult subjects
Measuring antibody
in oral (crevicular)
fluid
Correlation of tetanus antitoxin titers measured in serum
and oral fluid of 212 Malian subjects by IgG-ELISA

r=0.90

Tapia et al. Pediatr. Infect. Dis. J. 2006

Correlation of measles antibody titers in serum
measured by PRN and in oral fluid by IgG-ELISA

r=0.88

Vertical line = protection level 120 mIU; n=212

 Correlation of measles antibodies measured by
IgG-ELISA in serum and in oral fluid (US adults)
Oral Fluid Measles Titer (mIU/ml)

10000

1000

100

10 r = 0.9281
P < 0.0001
n = 60
1
10 100 1000 10000 100000
Serum Measles Titer (mIU/ml)
Correlation of measles antibodies in serum and in
oral fluid measured by IgG-ELISA (children)

r=0.92

Vertical line = protection level 120 mIU; n=212

 BD Veritor™ System: Serosurvey Kit

BD Veritor™ System Serosurvey Tool

30 Test Kit
For Use with Oral (Gum) Swab Specimens

• Unitized Tubes with Dispense Tips

Pre-filled with assay diluent

• Pur-Wrap foam swabs – 30 each individually wrapped

Swab Sample Processing :

Swab gums
Remove cap from unitized tube

Insert swab, swirl, remove swab

Attach dispense tip
Dispense three drops to sample well
Tetanus Antitoxin Kits used in field trials
in West Africa Read in 10 minutes
Using round filter papers

 Commercially available
 Each small circle collects 10 µl blood
 Easy to use in field (easy drying) and lab
 Prevents cross-contamination from sequential punching of filters without
proper washing
Thank You