Curriculum Vitae

Prof Dr dr Sri Rezeki S Hadinegoro Sp.A(K)

Staf pengajar
Departemen Ilmu Kes Anak FKUI/RSCM
Jakarta
• Pendidikan
– Dokter umum – FK.UNPAD 1972
– Spesialis anak – FK.UI 1983
– Doktor – FK.UI 1996
– Guru Besar – FK.UI 2000

• Organisasi
– Ketua Indonesian Technical Advisory Group on Immunization (ITAGI)
– Anggota Satuan Tugas Imunisasi IDAI
– Anggota KOMNAS PP KIPI – KEMKES
– Board member of Asian Society of Pediatric Infectious Disease (ASPID)
– Member of Asia-Pacific Dengue Prevention Board (APDPB)
– Member of Asia Dengue Vaccine Advocacy (ADVA)
– President Elect of International Society of Tropical Pediatrics (ISTP)
 Dengue Vaccine
benefits and risks

Sri Rezeki Hadinegoro

• Department of Child Health FKUI-RSCM Jakarta
• UKK Infeksi & Pediatri Tropis IDAI
• Indonesian Technical Advisory on Immunization (ITAGI)

Simposium & Pelatihan Infeksi,UKK IPT & IDAI Jateng, Semarang 8 Januari 2017
 Outlines
• Introduction of new vaccine
• Burden of disease
• Dengue vaccine clinical trial
• How to introduce dengue vaccine
application in Indonesia
• Conclusion
 Introduction of New Vaccine

IR, CFR,
age, Burden of Global
WHO, SAGE
PH impact diseases concern

Clinical trial Vaccine Vaccine

safety & availability
data efficacy

National Support to
Cost Health MOH
System policy
WHO SEARO, 2010
 Dengue: burden of disease

Indonesia, 2015
• Incidence 129.650 dengue cases
• IR 50.75/100.000 population; attack 84.8% district
• CFR 1.071 (0,83%)

Indonesia is the 2nd highest

dengue prevalence

Data: Diir Arbovirus Ditjen CDC-MOH 2016

WHO, 2013
ITAGI September 2016
Dengue: burden of disease
70
60
50

DHF incidence (%)

40
30
20
10
0

19
1993
1994
1995
1996
1997
1998
2099
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
12
Year

Pola dengue
Pola serotipe dengue pada KLB sesuai dengan curah hujan
 Dengue age specific seroprevalence:
nearly all children infected by age 18
n = 3,198, 1-18 year of age
in 30 districts

• At 1 year old, >25% of children infected at least once, at 5 years old > 50% infected
• Dengue seroprevalence: 95% in the 18 years old children
Ref. Ari Prayitno et al. Dengue seroprevalence and force of primary infection in urban
dwelling Indonesian children: a nationally-representative study. Presented at ICID Hyderabad Feb 2016
 Study of Cost of illness
• Site of study: Jakarta and Yogyakarta
• Government hospital
• Private hospital
• Health center

• Result: cost of illness per dengue case

• Outpatient
• Health center Rp 422.366 - 812.608
• Hospital Rp 329.535,73 - 1.181.991,40
• Inpatient
• Rp 3.735.54,21 - 8.387.476,06

Mardiati et al. Cost of illness dengue cases in Indonesia. Presented at ACPID Nov 2016, Bangkok
 VACCINATION IS ONE OF THE PILLARS OF THE WHO
STRATEGY TOWARDS EFFECTIVELY FIGHTING DENGUE1
WHO OBJECTIVES

Reduce Reduce Estimate

mortality morbidity true burden
by ≥50% by ≥25% of disease
by 2020* by 2020* by 2015

TECHNICAL ELEMENTS

Integrated Basic operational

Diagnosis and case surveillance and Sustainable vector vaccine and
management outbreak control implementation 2 implementational
preparedness research

Baseline data in year of 2010

*The baseline year is 2010. 1. WHO, 2012, Global Strategy for Dengue Prevention and Control.
WHO=World Health Organization. 2. Summary of the April 2016 meeting of the Strategic Advisory Group of Experts on
immunization (SAGE).
 Strategy Alliance Group of Expert
(SAGE)
Recommendation, Geneva, April 2016
• Vaksin dengue (Dengvaxia @) mempunyai efikasi
yang baik pada umur ≥9 tahun dengan jadwal 0-
6-12 bln
• Terbukti mengurangi dengue simtomatik,
dengue berat, dan perawatan
• Indikasi pemberian vaksin dengue di daerah
endemik dengue ≥70% (ditentukan oleh masing-
masing negara)
• Harus terintegrasi dengan strategi pengendalian
dengue
• Analisis cost benefit perlu dilakukan sebagai
 The target age for routine
vaccination should be defined
by each country based on an
assessment of dengue
endemicity and programmatic
feasibility of targeting
particular age groups. For the
most highly endemic settings
(e.g. seroprevalence at 9
years of age of approximately
>90%), 9 years of age is
projected to maximize impact.
In settings with
seroprevalence at 9 years
below 90% (but above 50%),
11–14 years of age may be
preferable.
Chimeric Yellow fever-tetravalent dengue vaccine
(CYD-TDV)
• 4-serotype, recombinant, live, attenuated Dengue
Dengue 17D yellow
17D fever
Yellow fever

vaccine.1,2
– Four genetic constructs: 1 for each serotype.
– Genes encoding prM/E structural proteins from each
dengue serotype combined with genes encoding
capsid (C) and nonstructural (NS) proteins from YFV
17D vaccine strain.

• Combination into a single vaccine.3

– Freeze-dried. Chimeric Virus
Recombinant virus

– Without adjuvant or preservatives.

*Vaccine referred to in the literature as Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine (CYD-TDV). 1. Guirakhoo, 2001, J Virol.
DENV=dengue virus; E=envelope; prM=precursor membrane; YFV 17D=yellow fever vaccine 17D. 2. Guirakhoo, 2000, J Virol.
3. Guy, 2011, Vaccine.
 OVERVIEW OF SANOFI PASTEUR’S CLINICAL
DEVELOPMENT PROGRAM CLINICAL DATABASE
§ 25 clinical studies, in 15 countries, completed (20) or ongoing (5).1
§ More than 40,000 subjects included in clinical studies.1
§ Nearly 29,000 individuals children, adolescent and adults received the vaccine.2

5 phase I trials3
in 3 countries
(USA, Mexico, Philippines)
N=400 CYD vaccinees
Ages: 2–45 years

14 phase II trials4
in 14 countries
(USA, Australia, Latin America, Asia)
N=5400 CYD vaccinees
Ages: 12 months–45 years

6 phase III trials 4

in 12 countries
(Australia, Latin America, Asia)
N=23,000 CYD vaccinees
Ages: 9 months–60 years

SP=Sanofi Pasteur. 1. sanofi pasteur, 2015, Dengue fact sheet.

2. Monath, 2015, Vaccine.
3. Guy, 2011, Vaccine.
4. ClinicalTrials.gov. Accessed February 10, 2016.
TWO PHASE III LARGE-SCALE RANDOMIZED EFFICACY STUDIES AND ONE PHASE
IIb PROOF OF CONCEPT EFFICACY STUDY OF THE DENGUE VACCINE INCLUDED
>35,000 PARTICIPANTS IN ENDEMIC COUNTRIES
• 2009: first proof-of-concept phase IIb efficacy study; results published in 2012. 1
• 2011: 2 large-scale efficacy studies in Asia-Pacific and Latin America; results published in 2014. 2,3

Phase IIb Efficacy Asia-Pacific (CYD23/57*)

Proof-of-concept study1,4
• Country: Thailand
• Age group: 4–11 years
• Sample size: 4002
• Long-term follow-up: 5 years postdose 3

Phase III Efficacy Asia-Pacific (CYD14)3

• Countries: Thailand, Indonesia, Malaysia, Vietnam,
Philippines
• Age group: 2–14 years
• Sample size: 10,275
• Long-term follow-up: 5 years postdose 3

Phase III Efficacy Latin America (CYD15)2

• Countries: Colombia, Mexico, Honduras,
Puerto Rico, Brazil
• Age group: 9–16 years
*CYD57 is the long-term follow–up of CYD23.
• Sample size: 20,869
1. Sabchareon, 2012, Lancet.
2. Villar, 2015, N Engl J Med. • Long-term follow-up: 5 years postdose 3
3. Capeding, 2014, Lancet.
4. Hadinegoro, 2015, N Engl J Med.
 PHASE IIb AND PHASE III STUDIES: SIMILAR STUDY DESIGN WITH A 25-
MONTH EFFICACY SURVEILLANCE PHASE AND A 4-YEAR LONG-TERM
SAFETY FOLLOW-UP PHASE1
CYD-TDV group
or
Control (placebo) group
(2:1)

VE PP 2017
VE ITT

Months 0 6 12 13 18 25 Year 6

ACTIVE PHASE FOR EFFICACY LONG-TERM FOLLOW-UP

2 PHASE FOR SAFETY
– VCD of any severity, due to any and each Surveillance of hospitalized fever/dengue
serotype (PP & ITT).
– VCD by baseline dengue serostatus (ITT).
– VE by age strata and country.
– Severe dengue (ITT).
– Surveillance of hospitalized and nonhospitalized
fever/dengue.
– Safety and reactogenicity.

ITT=intent to treat; PP=per protocol; VCD=virologically confirmed dengue; VE=vaccine efficacy.

1. Hadinegoro, 2015, N Engl J Med.

PHASE III EFFICACY TRIALS ARE EPIDEMIOLOGICAL SETTINGS AND
PREVALENCE BY AGE GROUP IN DENGUE-ENDEMIC AREAS
CYD14 Indonesia Malaysia Philippines Thailand Vietnam
2–5 y
Age group by
6–11 y
country
12–14 y

Sero+
Baseline
dengue status Sero−

Serotype ST1 ST3

distribution ST2 ST4

CYD15 Brazil Colombia Honduras Mexico Puerto Rico

Age group by 9–11 y

country 12–16 y

Sero+
Baseline
dengue status Sero−

Serotype ST1 ST3

distribution* ST2 ST4
 SUMMARY OF CYD14 (ASIA) COUNTRY-SPECIFIC
EFFICACY DURING THE ACTIVE PHASE
Vaccine Dengue Baseline Incidence Density ST Distribution
Efficacy, % Status % Control Group % Control Group %
Chart Title
Indonesia 53,3
CYD n=40 28,0–71,0
Control n=43

79,0
Malaysia
52,3–91,5
CYD n=9
Control n=21

Philippines 53,9
CYD n=143 41,7–63,6
Control n=150

Thailand 51,8
CYD n=44 25,3–68,9
Control n=45

Vietnam 51,1
CYD n=50 26,1–67,6
Control n=50

n=1983 n=3424 ST1 ST3

ST2 ST4
 SUMMARY OF CYD15 (LATIN AMERICA) COUNTRY-
SPECIFIC EFFICACY DURING THE ACTIVE PHASE
Vaccine Dengue Baseline Incidence Density ST Distribution
Efficacy, % Status % Control Group % Control Group %

77.5
Brazil 66.5–85.1 74
(n=3548)

67.5
Colombia 58.3–74.1 92
(n=9743)

71.1
Honduras 57.0–80.7 86
(n=2799)

31.3
Mexico 1.3–51.9 53
(n=3464)

57.6
Puerto Rico -2.5–82.8 56
(n=1315)

n=1944 n=6940 ST1 ST3

ST2 ST4
Seropositive (≥10 1/dil. PRNT50)
SECONDARY OBJECTIVE: SEROTYPE-SPECIFIC VACCINE
EFFICACY WAS OBSERVED
• Over the 25 month of the active phase, each of the 4 serotypes contributed to the overall
vaccine efficacy

*>28 days after injection 3 in all participants who had received 3 injections, irrespective of protocol deviations.
†>day 0 in all participants who received ≥1 injection.

CI=confidence interval; ITT=intent-to-treat.

Capeding, 2014, Lancet.

| 19
 OVERVIEW OF EFFICACY RESULTS AGAINST SEVERE AND
HOSPITALIZED Virological Confirmed Dengue (VCD)
Intent-to-treat analysis (follow-up from months 0–25)
STUDY (n episodes) EFFICACY and 95% CI

35.7 86.6
CYD14 (n=32)
VE in severe
1
dengue cases CYD15 (n=12) 68.8 99.9

52.7 92.4
VE in DHF CYD14 (n=28)
2
dengue cases 64.9 99.9
CYD15 (n=11)

50.3 78.6
VE* in CYD14 (n=101)
3 hospitalized
64.7 89.5
dengue cases CYD15 (n=60)

*The relative risk (RR) of hospital admissions for virologically confirmed dengue was calculated as
the ratio of annual incidence in the vaccine group and control groups, and presented here as
vaccine efficacy (ie, 1−RR).

| 20
 HIGHER VACCINE EFFICACY WITH AGE AND POSITIVE BASELINE
SEROSTATUS DURING THE 25-MONTH OF THE LARGE-SCALE PHASE
III EFFICACY STUDIES
VE Results by Age VE Results by Baseline Serostatus
Baseline serostatus VE and 95% CI
CYD141
CYD141* 74.3%
VE, % (95% CI)

100 74.4 DENV+ 35.7 86.6

80 59.5
60 33.7 DENV– 35.5%
-26.8 66.7
40
20
0
2–5 yo 6–11 yo 12–14 yo
CYD152
80 67.6
VE, % (95% CI)

61.7
CYD152†
60 83.7%
DENV+ 62.2 93.7
40
20 DENV– 43.2%
-61.5 80.0
0
9–11 yo 12–16 yo -80 -60 -40 -20 0 20 40 60 80 100
*Comparison made on ITT. RR=relative risk: incidence of VC dengue cases in CYD group vs control group.
†Dengue+: baseline titer for at least 1 DENV serotype is ≥10 1/dil.

DENV=dengue virus; ITT=intent to treat; VCD=virologically confirmed dengue; VE=vaccine efficacy; yo=years old.
1. Capeding, 2014, Lancet
2. Villar, 2015, N Engl J Med.
OBJECTIVE OF THE PUBLICATION: GLOBAL VIEW OF CLINICAL
PROFILE OF SANOFI PASTEUR VACCINE CANDIDATE BASED ON
EFFICACY AND LTFU INTERIM ANALYSES DATA
CYD14 efficacy study CYD15 efficacy study
in Asia1 in Latin America and the Caribbean2
2–14 years (N=10,275) 9–16 years (N=20,869)

http://www.nejm.org/doi/full/10.1056/NEJMoa1411037
http://linkinghub.elsevier.com/retrieve/pii/S0140673614610606

www.nejm.org/doi/full/10.1056/NEJMoa1506223
Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease3
LTFU=long-term follow-up.

1. Capeding, 2014, Lancet.

2. Villar, 2015, N Engl J Med
3. Hadinegoro, 2015, N Engl J Med.
 POOLED ANALYSIS OF THE 25-MONTH EFFICACY PHASE OF CYD14 AND CYD15
CONFIRMS CONSISTENT VE AGAINST VCD (ANY AND EACH SEROTYPE, ANY SEVERITY,
INDEPENDENT OF PRIOR DENGUE EXPOSURE) IN SUBJECTS 9–16 YEARS OF AGE1
Pooled results (CYD14 and CYD15; ITT) VE (%) and 95% CI
65.6
Any serotype 60.7 69.9

58.4
DENV-1 47.7 66.9

47.1
DENV-2 31.3 59.2

73.6
DENV-3 64.4 80.4

83.2
DENV-4 76.2 88.2

93.2
Severe dengue 77.3 98.0
92.9
DHF (WHO) 76.1 97.9
80.8
Hospitalized cases 70.1 87.7

81.9
In dengue-seropositive subjects 67.2 90.0

52.5
In dengue-seronegative subjects 5.9 76.1

0 20 40 60 80 100
DENV=dengue virus; DHF=dengue hemorrhagic fever; ITT=intent to treat; VE=vaccine efficacy; WHO=World
Health Organization.

1. Hadinegoro, 2015, N Engl J Med.

 ASIA CYD14 (YEAR 3): HOSPITALIZED VCD (ANY SEVERITY) IN
SUBJECTS 2 TO 14 YEARS OF AGE, BY AGE AT INCLUSION1*

Hospitalized VCD (any severity)

1.8 Year 3 - CYD14
1.6
Annual Incidence Rate (%)

1.4
1.2
1
1.0
0.8
0.6
0.6 0.5
0.4 0.4
0.4 0.3
0.2 0.1 0.1
0.0
2–5 years 6–11 years 12–14 years All ages

RR (%) 7.45 0.63 0.25 1.04

(95% CI) (1.15–313.80) (0.22–1.83) (0.02–1.74) (0.52–2.19)

Vaccine Group Control Group

*Since data were collected for 11 months during year 3 (from month 25 to month 36), the annual incidence was calculated as the number of cases divided by the total number of
participants divided by 11 times 12.
CI=confidence interval; RR=relative risk; VCD=virologically confirmed dengue.

1. Hadinegoro, 2015, N Engl J Med.

 ASIA CYD14 (YEAR 4): HOSPITALIZED VCD (ANY SEVERITY) IN
SUBJECTS 2 TO 14 YEARS OF AGE, BY AGE AT INCLUSION1

2.0
1.8
1.6
Annual Incidence Rate (%)

1.4
1.2
1.2 1.1
1.0 0.9 0.9 0.9
0.8 0.8
0.8
0.6
0.6
0.4
0.2
0.0
2–5 years < 9< years
9 years ≥ ≥99years
years All ages

RR (%) 1.42 1.19 0.73 0.98

(95% CI) (0.58, 3.99) (0.65, 2.28) (0.34, 1.61) (0.62, 1.59)

Vaccine Group Control Group

Annual incidence=cases among M * 100 converted to annual rate; cases=number of participants with at least 1 hospitalized symptomatic VCD episode.
RR=relative risk; VCD=virologically confirmed dengue.

|
1. 5th Pan American Dengue Research, Panama City, April 20 - 23, 2016
25
 ASIA CYD14:OVERALL RESULTS BY STUDY YEAR - HOSPITALIZED VCD (ANY
SEVERITY) IN SUBJECTS 2–14 YEARS OF AGE & BY AGE GROUPS: < 9 and ≥ 9 YOA

25-Month Active Phase + Year 31 + Year 4

Subjects <9 Years of Age Subjects ≥9 Years of Age
2.0 2.0
1.8 1.8
1.6 1.6
Annual Incidence Rate (%)

1.4 1.4
1.2 1.1 1.2 1.1
1
1.0 0.9 1.0
0.8 0.8 0.8
0.8 0.8 0.7
0.6 0.6 0.6
0.6 0.6 0.5 0.5
0.4 0.4 0.4
0.4 0.4 0.3 0.3
0.2 <0.1
0.2 0.2
0.0 0.0
Year 1 Year 2 Year 3 Year 4 Cumulative Year 1 Year 2 Year 3 Year 4 Cumulative
Results Results
Efficacy Surveillance Efficacy Surveillance
Phase† Phase†

RR (%) 0.36 0.53 1.58 1.19 0.79 0.39 0.08 0.57 0.73 0.39
(95% CI) (0.16, 0.78) (0.25, 1.12) (0.61, 4.83) (0.65, 2.28) (0.56, 1.13) (0.12, 1.17) (0.01, 0.25) (0.18, 1.86) (0.34, 1.61) (0.24, 0.60)

Vaccine Group Control Group

*CYD14 was conducted in Asia-Pacific in subjects 2–14 years of age.
†Efficacy surveillance phase year 1=day 0 to dose 3; year 2=dose 3 to month 25; cumulative results=day 0 to year 4.

RR=relative risk; VCD=virologically confirmed dengue.

|
1. Hadinegoro SR et al. N Engl J Med. 2015 26
 THAILAND CYD23/57 (YEARS 3 AND 4): HOSPITALIZED VCD (ANY
SEVERITY) IN SUBJECTS 4 TO 11 YEARS OF AGE, BY AGE AT
INCLUSION1*
Hospitalized VCD (any severity) Hospitalized VCD (any severity)
5.0 Year 3 - CYD23/57 Year 4 - CYD23/57
5.0
4.5 4.5
4.0 4.0
Annual Incidence Rate (%)

3.5 3.5

Annual Incidence Rate (%)

3.0 3.0
2.5 2.5
2.0 2.0
1.6 1.6 1.6
1.5 1.4 1.5 1.3
1.1 1.2 1.1 1.1
1.0 1.0 0.8
0.6 0.6
0.5 0.5
0.0 0.0
4–5 years 6–11 years All ages 4–5 years 6–11 years All ages
RR (%) 2.44 0.86 1.01 0.81 0.40 0.47
(95% CI) (0.27–115.54) (0.37–2.10) (0.47–2.30) (0.16–5.24) (0.16–0.94) (0.22–1.00)

Vaccine Group Control Group

*Since data were collected for 11 months during year 3 (from month 25 to month 36), the annual incidence was calculated as the number of cases divided by the total number of
participants divided by 11 time 12.
CI=confidence interval; RR=relative risk; VCD=virologically confirmed dengue.

1. Hadinegoro, 2015, N Engl J Med.

 LATAM CYD15 (YEAR 3): HOSPITALIZED VCD (ANY SEVERITY) IN
SUBJECTS 9 TO 16 YEARS OF AGE, BY AGE AT INCLUSION1*

Hospitalized VCD (any severity)

1.0
Year 3 - CYD15

0.8
Annual Incidence Rate (%)

0.6

0.4
0.3
0.2 0.2 0.2
0.2
<0.1 0.1

0.0
9–11 years 12–16 years All

RR (%) 0.55 0.50 0.53

(95% CI) (0.20–1.54) (0.13–1.87) (0.25–1.16)

Vaccine Group Control Group

*Since data were collected for 11 months during year 3 (from month 25 to month 36), the annual incidence was calculated as the number of cases divided by the total number of
participants divided by 11 time 12.
CI=confidence interval; LTFU=long-term follow-up; RR=relative risk; VCD=virologically confirmed dengue.

1. Hadinegoro, 2015, N Engl J Med.

 REDUCTION IN HOSPITALIZED VCD (ANY SEVERITY) IN SUBJECTS ≥9
YEARS OF AGE IN POOLED DATA FOR CYD14, CYD15, AND CYD23/57,
AT YEAR 31
Pooled analysis of RR for hospitalized VCD in Year 3 of CYD14, CYD15, and CYD23/57 in
subjects ≥9 years of age
Age Group RR (%) and 95% CI

0.84
All ages 0.56 1.24

1.58
<9 years of age 0.83 3.02

0.50
≥9 years of age 0.29 0.86

-1 0 1 2 3 4

RR=relative risk; VCD=virologically confirmed dengue.

1. Hadinegoro, 2015, N Engl J Med.

 CLINICAL PRESENTATION INSIGHTS
NO IMPORTANT DIFFERENCE IN CLINICAL SIGNS & SYMPTOMS DURING ONGOING
LTFU VERSUS EFFICACY PHASE & PLACEBO GROUP IN SUBJECTS 2–16 YEARS OF
AGE1

LENGTH DURATION OF FEVER FREQUENCIES OF SIGNS

OF HOSPITALIZATION
Similar for both the 25-month
efficacy phase and the ongoing LTFU
phase in CYD14, CYD15, and
CYD23/57.
AND CLINICAL SYMPTOMS
Similar for both the 25-month
efficacy phase and the ongoing LTFU
phase in CYD14, CYD15, and
CYD23/57.
AND SYMPTOMS
No clinically important differences
observed for the frequencies of
various signs and symptoms during
the 25-month efficacy phase and the
ongoing LTFU phase in CYD14,
CYD15, and CYD23/57.

VIREMIA AND CYTOKINE PATTERN

• Similar levels of viremia observed in vaccine vs control groups
(CYD14 and CYD15).
• No cytokine pattern associated with increased disease enhancement
in vaccinees vs placebo.

LTFU=long-term follow-up.

1. Hadinegoro, 2015, N Engl J Med. SPGLB.DENG.14.12.0107a

 OVERVIEW OF SAFETY: SOLICITED INJECTION SITE
REACTIONS1 (SUBJECTS 9–60 YEARS OF AGE)
INTEGRATED SAFETY ANALYSIS*
%, 95% CI
46.9
Adults 18–60 years of age 44.3 49.4
Solicited injection
site reaction 51.0
Subjects 9–17 years of age 49.2 52.8
0.7
Grade 3 solicited Adults 18–60 years of age 0.4 1.3
injection site
1.5
reaction Subjects 9–17 years of age 1.1 2.0

45.2
Adults 18–60 years of age 42.7 47.7
Pain
49.2
Subjects 9–17 years of age
47.5 51.0
7.9
Adults 18–60 years of age
6.6 9.3
Erythema
8.4
Subjects 9–17 years of age
7.4 9.4
2.4
Adults 18–60 years of age 1.7 3.3
Swelling
6.9
Subjects 9–17 years of age 6.0 7.8
-5 15 35 55

*Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51).

1. Chuenkitmongkol, 2015, JITMM.

 OVERVIEW OF SAFETY: SOLICITED SYSTEMIC
REACTIONS1 (SUBJECTS 9–60 YEARS OF AGE)
INTEGRATED SAFETY ANALYSIS*
%, 95% CI
65.6
Solicited Adults 18–60 years of age 63.1 67.9
systemic
67.0
reaction Subjects 9–17 years of age 65.3 68.7
10.8
Adults 18–60 years of age 9.2 12.4
Grade 3 11.1
Subjects 9–17 years of age 10.0 12.2
4.9
Adults 18–60 years of age 3.9 6.1
Fever 16.4
Subjects 9–17 years of age 15.1 17.8
51.4
Adults 18–60 years of age 48.9 54.0
Headache 54.1
Subjects 9–17 years of age 52.3 55.9
44.3
Adults 18–60 years of age 41.8 46.8
Malaise 40.9
Subjects 9–17 years of age 39.2 42.7
42.2
Adults 18–60 years of age 39.7 44.7
Myalgia 42.0
Subjects 9–17 years of age 40.2 43.8
28.3
Adults 18–60 years of age 26.1 30.7
Asthenia 34.2
Subjects 9–17 years of age 32.5 35.9

0 20 40 60
*Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51).
AE=adverse event.

1. Chuenkitmongkol, 2015, JITMM.

 SAFETY OVERVIEW AFTER ANY DENGUE VACCINE
OR PLACEBO DOSE – SUBJECTS 9–60 YEARS OF AGE1
INTEGRATED SAFETY ANALYSIS*
Placebo (n=1780)
Unsolicited non-serious 39
CYD vaccine (n=4615)
AE 44.3

Solicited systemic 59
reaction 66.5

Solicited injection site 36.5

reaction 49.6

Solicited AR 64.1
74

Immediate unsolicited AR 0
0.2

0 20 40 60 80 100

Percentage of subjects presenting with at least 1 reaction or event

*Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51).
AE=adverse event; AR=adverse reaction.

1. Chuenkitmongkol, 2015, JITMM.

 IMMUNOLOGICAL EXTRAPOLATION SUPPORTS
REGISTRATION IN ADULTS UP TO 45 YEARS OF AGE IN
ENDEMIC AREAS
§ Immunogenicity data from phase II studies suggest that subjects 18 years of age and above in
endemic areas respond well to the vaccine. 1,2
§ GMTs after the third injection were generally higher than those seen in CYD14 and CYD15, where
efficacy was demonstrated.1-4
§ It is anticipated that adults up to age 45 years living in endemic areas will have similar levels of
protection compared with those observed in the CYD14 and CYD15 studies.

GMTs in CYD14, CYD15, CYD22, and CYD471-4

1000

100 Serotype 1
GMTs

Serotype 2

10 Serotype 3
Serotype 4

1
CYD14 CYD15 CYD22* CYD47*
N=1323 N=1301 N=20 N=126
(2–14 y) (9–16 y) (18–45 y) (18–45 y)
*CYD22: Vietnam; CYD47: India.
GMT=geometric mean titer; y=years.
1. Tran, 2012, J Vaccines Vaccin.
2. Dubey, 2015, Hum Vaccin Immunother.
3. Capeding, 2014, Lancet.
4. Villar, 2015, N Engl J Med. SPGLB.DENG.14.12.0107a
 PHASE II AND III TRIALS DEMONSTRATED IMMUNOGENICITY
AGAINST ALL 4 SEROTYPES POST-DOSE 3

Trial CYD12 CYD13 CYD22 CYD24 CYD28 CYD30 CYD47 CYD32

Phase II II II II II II II III
Colombia,
Honduras,
Country USA Vietnam Peru Singapore Brazil India Malaysia
Mexico,
Puerto Rico
Ages 18–45 y 9–16 y 2–45 y 2–11 y 2–45 y 9–16 y 18 – 45 y 2–11 y
FV Immune FV non- DENV+/- DENV+/- DENV+/- DENV+/- DENV+/- DENV+/-
DENV+/-
status immune YF+/- JE+/- YF+/- YF+/- JE +/- JE+/-

N 101 600 120 186 835 150 189 250

FV=flavivirus; GMT=geometric mean titre; JE=Japanese encephalitis; PRNT50=50% plaque reduction neutralization test; YF=yellow fever.

Villar, 2013, Ped Infect Dis J. Dayan, 2013, Vaccine.

Tran, 2012, J Vaccines Vaccin. Dayan, 2013, Am J Trop Med Hyg.
Lanata, 2012, Vaccine. HSS, 2013, Vaccine.
Leo, 2012, Hum Vaccines & Immunother. | 35
BASELINE AND POSTDOSE 3 GMTs INCREASE ACCORDING TO AGE
IN ENDEMIC AREAS IN THE 2 PIVOTAL EFFICACY STUDIES,
CYD14 AND CYD151
§ Predose 1 and postdose 3 GMTs against each serotype according to age.
GMT by age in CYD14 and CYD15 - Serotype 1
GMT by age in CYD14 and CYD15 – Serotype 2 1000
100

1000
100

GM (1/dil)
100
50
CYD14 pre
CYD15 pre
CYD14 post-dose 3
CYD15 post-dose 3
100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Age at inclusion

1000
100
GMT by age in CYD14 and CYD15 - Serotype 3

CYD14 pre
GM (1/dil)

100 100

GM (1/dil)
CYD15 pre
50 50 CYD14 post-dose 3
CYD15 post-dose 3

100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Age at inclusion
CYD14pre
CYD14 pre

CYD15pre
CYD15 pre
1000
100
GMT by age in CYD14 and CYD15 - Serotype 4
CYD14
CYD14post-dose
pose-dose33

CYD15post-dose
CYD15 post-dose33
100

GM (1/dil)
0
10 50
CYD14 pre
CYD15 pre
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 CYD14 post-dose 3
CYD15 post-dose 3

Age at inclusion 10 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Age at inclusion

GMT=geometric mean titers.

1. Sanofi pasteur, 2015, CTD module 2.7.3, Section 2.

 ANTICIPATED SIMILAR PROTECTION LEVEL IN ADULTS
18–45 YEARS OF AGE IN ENDEMIC AREAS VS PROTECTION
IN CHILDREN 9–16 YEARS OF AGE FROM CYD14 & CYD151
17–45 YEARS OF AGE IN ENDEMIC AREAS COMPARED TO POPULATION IN PIVOTAL EFFICACY

SEROTYPE 2
SEROTYPE 1 100
100
Endemic Asia Pacific, CYD22
Endemic Asia Pacific, CYD22 80
80 Endemic Asia Pacific, CYD47
Endemic Asia Pacific, CYD47
Endemic Asia Pacific, CYD14
Percent

Percent
Endemic Asia Pacific, CYD14 60
60 Endemic Latin America, CYD15
Endemic Latin America, CYD15

40 40

20 20

0 0
10 100 1/dil 1000 10000 10
1 100 1000 10000
1 1/dil

100
SEROTYPE 3 SEROTYPE 4
100
80 Endemic Asia Pacific, CYD22
80 Endemic Asia Pacific, CYD22
Endemic Asia Pacific, CYD47
Percent

Percent
60 Endemic Asia Pacific, CYD14 Endemic Asia Pacific, CYD47
60
Endemic Asia Pacific, CYD14
Endemic Latin America, CYD15
40 Endemic Latin America, CYD15
40

20 20

0 0
10
1 100 1000 10000 10
1 100 1000 10000
1/dil
1/dil

1. sanofi pasteur, 2015, CTD module 2.7.3, Section 2.

 IMMUNOGENICITY PROFILE IN SUBJECTS 46–60 YEARS OF AGE
IS EXPECTED TO BE SIMILAR TO SUBJECTS 18–45 YEARS OF AGE, SUPPORTING A
REGISTRATION DOSSIER FOR INDIVIDUALS UP TO 60 YEARS OF AGE

• Immunogenicity data from Australian adults 46–60 years of age (N=241)

and 18–60 years of age (N=655) in CYD17 at baseline and 28 days postdose 3.
1E+29
1E+26
1E+23
1E+20
1E+17
100000000000000
100000000000
GMTs (1/dil)

Serotype 1
100000000
100000 Serotype 2
100 Serotype 3
0.1 83.3 144 18 45.3 74.9 111
17.7 54.2
0.0001 Serotype 4
1E-07
1E-10
1E-13
1E-16
1E-19
Pre-inj 1 46-60 yo Post-inj 3 46-60 yo Pre-inj 1 18-60 yo Post-inj 3 18-60

Assuming that adults 46–60 years of age, living in dengue-endemic areas,

are similar to adults 18–45 years of age, for whom immunogenicity data
have been generated, the immunogenicity profiles are expected to be similar.
GMT=geometric mean titer.

1. sanofi pasteur, 2015, data on file.

New Vaccine Introduction into EPI program
• Global concern
Burden of • Regional related data
disease • Local : incidence, prevalence, death rate,age

Guideline or • Guideline : SAGE & WHO position paper

• Pilot project (in certain areas)
Recommendation • ITAGI recommendations

• Registered to BPOM (NRA)

Vaccine • Cost benefit analysis
availability • Vaccine sustainability

• Policy from Ministry of Health

• Socialization & training
Planning • Operational cost from local government
• AEFI surveillance
Benefits
No difference between vaccine group &
placebo group in subjects 2–16 years of
age
– Length of hospitalization*
– Duration fever and clinical symptoms*
– Frequency of signs and symptoms*
– Levels of viraemia**
– Cytokine pattern associated with increased
disease enhancement
* In CYD14, CYD15, CYD 23/57; ** in CYD14 and CYD15
 Benefits
• Dengue vaccine CYD-TDV (Dengvaxia@)
– Vaccine efficacy for all serotype 65.6% (95% CI:
60.7–69.9)
– Prevent severe dengue 92.9% (95% CI:76.1–
97.9),
– Prevent hospitalization 80.8% (95% CI:70.1–
87.7).
– Minimal side effects and well tolerated

• Approval/registration to BPOM
– Administration: 3 doses with 6 months interval,
effective for prevent dengue infection in children 9
-16 years of age
 WHO recommendation
The target age for routine vaccination should be
defined by each country based on an assessment
of dengue endemicity and programmatic feasibility
of targeting particular age groups. For the most
highly endemic settings (e.g. seroprevalence at 9
years of age of approximately >90%), 9 years of
age is projected to maximize impact. In settings
with seroprevalence at 9 years below 90% (but
above 50%), 11–14 years of age may be preferable
 Risks
CYD-TDV dengue vaccine did not
recommended for children < 9 years of
age
• Inconsistency result in subjects <9 years of
age
– RR hospitalization of confirmed dengue virus
increased in longtern follow up at year-3 and 4
– Longer follow up is needed
• Vaccine efficacy is higher in positive
dengue seroprevalence than negative
seroprevalence
• Children <9 years of age have more
negative seroprevalence (WHO
 Evidence based data of
immunological extrapolation to support
registration in adult up to 45 years of
age in endemic areas
• Vaccine efficacy is higher in positive dengue
seroprevalence than negative seroprevalence
– Percentage positive dengue seroprevalence is
higher in older age group
– Older than18 years of age group have high
GMT dengue antibody & protective level at
post third dose vaccination
• This evidence of immunogenicity bridging
supported for extrapolation to adult population.
 Conclusions
The overall benefit : risk of dengue
vaccine supports registration for use in
individuals aged 9 to 45 years of age
living in dengue-endemic areas
 Indonesia

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