Kanal Pengetahuan | Seminar Nasional : “Tantangan baru pengendalian penyakit arbovirus di Indonesia: Dengue, Chikungunya atau Zika”

(1)

•

Education

–

General physician– FK.UNPAD 1972

–

Pediatrician– FKUI 1983

–

PhD medical sciences– FKUI 1996

–

Professor of Pediatric Infectious Diseases– FKUI 2000

•

Organization

–

Chairman of Indonesian Technical Advisory Group on

Immunization (ITAGI)

–

Member of National AEFI Committee Indonesia MOH

(KOMNAS PP KIPI)

–

Chairman of Dengue Expert Committee of Indonesia MOH

–

Member of Immunization Task Force IPS (IDAI)

–

Board member of Asian Society of Pediatric Infectious

Disease (ASPID)

–

Member of Asia Dengue Vaccine Advocacy (ADVA)

–

President Elect of International Society of Tropical Pediatrics

(ISTP)

Prof Dr dr Sri Rezeki S

Hadinegoro Sp.A(K)

Department of

Child Health FKUI/

RSCM Jakarta

(2)

A New Hope: Dengue Vaccine

Sri Rezeki S Hadinegoro

Department of Child Health

(3)

Outlines

•

Dengue: burden of disease

•

Introduction of new vaccine

•

Global concern

–

SAGE recommendation and

–

WHO position paper

•

Dengue vaccine clinical trial

(4)

Global Strategy for Dengue

!

Prevention and Control

1.

To reduce dengue deaths by

at least 50% by

2020

*

2.

To reduce dengue morbidity

by at least 25% by

2020

*

3.

To better ascertain the true

burden of the disease by

2015

(5)

Regions with dengue risk

§

Incidence has increased 30-fold over the last 50 years.

§

There are more than 100 endemic countries.

§

There are 2.5 billion people living in endemic regions.

§

The spread of dengue parallels the expanding range of the mosquito vector.

DENGUE IS A MAJOR PUBLIC HEALTH

CONCERN, AND ITS INCIDENCE IS INCREASING

WHO, 2012, Global Strategy for Dengue PrevenSon and Control.

WHO, 2009, Dengue Guidelines for Diagnosis, Treatment, PrevenSon, and Control. Gubler, 1998, Clin Microbiol Rev.

Halstead, 1992, World Heath Stat Q. Simmons, 2012, N Engl J Med.

1960

1990

2012

|

5

(6)

|

6

WHO, 2014, dengue fact sheet.

2.5 billion people

live in dengue-endemic countries

(nearly half of the world’s populaSon)

50 to 100 million symptomaSc

dengue infecSons

occur worldwide each year

500,000 people

with severe

dengue

require hospitalizaSon

each year

2.5%

of people

with severe

dengue

die

SPGLB.DENG.14.10.0090

(7)

Global Incidence of Dengue Infection

Indonesia is the 2

nd

highest

dengue prevalence

(8)

Indonesia, 2015

•

Incidence 129.650 dengue cases

•

IR 50.75/100.000 population; attack 84.8% district

•

CFR 1.071 (0,83%)

Data: Subdit Arbovirus Ditjen CDC-MOH 2016

ITAGI September 2016

Morbidity & Mortality

!

Dengue Infection

(9)

(10)

Dengue Incidence by Age Group

!

Indonesia, 1993-2012

0

10

20

30

40

50

60

70

D

H

F

i

n

c

id

e

n

c

e

(%

)

Year

Age group

(year)

≥

15

5-14

1-4

<1

(11)

(12)

Dengue sero-prevalence (DNG26) Study

Division of Infection & Tropical Pediatric, Child Health Department, FKUI-RSCM Jakarta,

Sept 2014-July 2015

Multi-stage, population-based, cross-sectional study

•

Divide urban Indonesia into 30 zones and select one Puskesmas in each

•

Select 5 RT per sub-district and visit houses until 107 children enrolled (n=3210)

•

Test every sample for dengue IgG, JEV; Sub-sample for serotyping (n = 780)

DNG26 sites (red dots)

(13)

•

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

Dengue age speciﬁc seroprevalence

!

in 30 districts in Indonesia, 2014-2015

n = 3,198, 1-18 year of age

in 30 districts

Ref. Ari Prayitno et al. Dengue seroprevalence and force of primary infection in urban

(14)

Dengue Cost of Illness

•

Site of study: Jakarta and Yogyakarta

•

Government & private hospital

•

Health centers

•

Result: cost of illness per dengue case (IDR)

•

Outpatient

•

Health center 422.366 - 812.608

•

Hospital 329.535,73 - 1.181.991,40

•

Inpatient

•

3.735.54,21 - 8.387.476,06

(15)

VACCINATION IS ONE OF THE PILLARS OF THE WHO

STRATEGY TOWARDS EFFECTIVELY FIGHTING DENGUE

1

*The baseline year is 2010. WHO=World Health OrganizaSon.

1.  WHO, 2012, Global Strategy for Dengue PrevenSon and Control.

2.  Summary of the April 2016 meeSng of the Strategic Advisory Group of Experts on immunizaSon (SAGE).

Reduce

mortality

by ≥50%

by 2020*

Reduce

morbidity

by ≥25%

by 2020*

EsDmate

true burden

of disease

by 2015

World Health Organization OBJECTIVES

TECHNICAL ELEMENTS

Diagnosis and case

management

Integrated

surveillance and

outbreak

preparedness

Sustainable vector

control

vaccine

implementaSon

2

Basic operaSonal

and

implementaSonal

research

(16)

Strategy Alliance Group of Expert

(SAGE) Recommendation

,

!

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 pertimbangan introduksi

vaksin dengue

(17)

Global

concern

WHO, SAGE

Vaccine

safety &

eﬃcacy

Clinical trial

data

NaSonal

Health

System

Support to

MOH

policy

Burden of

diseases

Cost

Vaccine

availability

IR, CFR,

age,

PH impact

Introduction of New Vaccine

(18)

GeneSc recombinaSon applied to ﬂavivirus vaccine

‘

Cut and paste

’

18

C

E

prM

NS

Yellow fever 17D genome

C

E

prM

NS

Flavivirus of interest genome

C

NS

YF 17D backbone

E

prM

Cut out E and PrM genes of

Yellow Fever 17D vaccine,

resulSng in YF17D backbone

Cut our E and prM genes of

ﬂavivirus of interest to

paste them into YF17D

backbone

C

E

prM

NS

YF 17D based recombinant construct

(19)

Chimeric Yellow fever-tetravalent dengue vaccine

(CYD-TDV)

•

4-serotype, recombinant, live, aZenuated

vaccine

.

1,2

–

Four geneSc 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.

•

CombinaDon into a single vaccine

.

3

–

Freeze-dried.

–

Without adjuvant or preservaSves.

17D Yellow fever Dengue

Chimeric Virus

17D yellow fever Dengue

Recombinant virus

1. Guirakhoo, 2001, J Virol.

2.  Guirakhoo, 2000, J Virol.

3.  Guy, 2011, Vaccine.

(20)

OVERVIEW OF SANOFI PASTEUR’S CLINICAL

DEVELOPMENT PROGRAM CLINICAL DATABASE

5

phase I trials

3

in 3 countries

(USA, Mexico, Philippines)

N=400 CYD vaccinees

Ages: 2–45 years

14 phase II trials

4

in 14 countries

(USA, Australia, LaDn America, Asia)

N=5400 CYD vaccinees

Ages: 12 months–45 years

6 phase III trials

4

in 12 countries

(Australia, LaDn America, Asia)

N=23,000 CYD vaccinees

Ages: 9 months–60 years

§

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

SP=Sanoﬁ Pasteur. 1.  sanoﬁ pasteur, 2015, Dengue fact sheet. 2.  Monath, 2015, Vaccine.

3.  Guy, 2011, Vaccine.

(21)

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 LaSn America; results published in 2014.

2,3

1.  Sabchareon, 2012, Lancet. 2.  Villar, 2015, N Engl J Med. 3.  Capeding, 2014, Lancet. 4.  Hadinegoro, 2015, N Engl J Med.

Phase III Eﬃcacy LaDn America (CYD15)

2

•

Countries: Colombia, Mexico, Honduras,

Puerto Rico, Brazil

•

Age group: 9–16 years

•

Sample size: 20,869

•

Long-term follow-up: 5 years postdose 3

Phase III Eﬃcacy Asia-Paciﬁc (CYD14)

3

•

Countries: Thailand, Indonesia, Malaysia, Vietnam,

Philippines

•

Sample size: 10,275

•

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

Proof-of-concept study

1,4

•

Country: Thailand

•

Sample size: 4002

•

(22)

Indonesian Study Site

!

Jakarta, Bandung, and Denpasar

Total subject: 1870

Age 2-14 year of age

(23)

EFFICACY AND SAFETY WERE EVALUATED IN THE

25-MONTH ACTIVE PHASE

0

6

12 13

18

Months

CYD-TDV group

or

Control (placebo) group

(2:1)

VE PP

VE ITT

ITT=intent to treat; PP=per protocol; VCD=virologically confirmed dengue; VE=vaccine efficacy. *Data from Year 1 of LTFU of CYD14 and CYD15 and Years 1 and 2 of LTFU of CYD23 were also part of the submission file.

1.  1. Hadinegoro, 2015, N Engl J Med; 2. Villar, 2015, N Engl J Med, study protocol.

25-MONTH ACTIVE PHASE

EFFICACY

–

VCD of any severity, due to any and each

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

25

COMPLETE

EFFICACY

•

Primary endpoint:

Assess eﬃcacy of

the vaccine against symptomaSc VCD,

irrespecSve of serotype or severity

SAFETY

•

Secondary endpoint:

Describe the

occurrence of serious AEs, including

AEs of special interest*, in all study

parScipants

•

In a subset of parScipants, the

reactogenicity subset, all AEs (both

solicited and unsolicited) were

recorded

(24)

THE FIRST PHASE OF THE PHASE III EFFICACY STUDIES,

THE 25-MONTH ACTIVE PHASE, IS NOW COMPLETE

0

6

12 13

18

Months

CYD-TDV group

or

(2:1)

VE PP

VE ITT

ITT=intent to treat; PP=per protocol; VCD=virologically confirmed dengue; VE=vaccine efficacy. *Data from Year 1 of LTFU of CYD14 and CYD15 and Years 1 and 2 of LTFU of CYD23 were also part of the submission file.

1. Hadinegoro, 2015, N Engl J Med; 2. Sanoﬁ Pasteur press release. Available at:

hsp://www.sanoﬁpasteur.com/es/Documents/PDF/PR-locaux/Sanoﬁ_Pasteur_s_Dengue_Vaccine_Approved_in_Indonesia_2016_09_13.pdf. Accessed February 2017.

25-MONTH ACTIVE PHASE

EFFICACY

–

fever/dengue.

25

COMPLETE

The 25-month acSve phase

is now complete

Eﬃcacy and safety data from this

phase* have been evaluated by the

Indonesian authoriSes

At the end of these phase III

clinical trials, the Indonesian authoriSes

approved the

(25)

THE LONG-TERM FOLLOW-UP PHASE IS ONGOING TO

ASSESS LONG-TERM SAFETY AND EFFICACY OF THE

VACCINE

0

6

12 13

18

Months

CYD-TDV group

or

(2:1)

VE PP

VE ITT

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

1.  Hadinegoro, 2015, N Engl J Med.

Year 6

Documentation of dengue cases

to assess long-term protection

25-MONTH ACTIVE PHASE

EFFICACY

–

fever/dengue.

LONG-TERM FOLLOW-UP PHASE FOR SAFETY

EXPANSION OF EFFICACY PHASE

25

COMPLETE

ONGOING

(26)

Phase III dengue vaccine efﬁcacy studies

in 5 Asian countries

| 26

Thailand

Vietnam

Malaysia

Indonesia

Philippines

Mexico

Puerto Rico

Honduras

Colombia

Brazil

CYD14

eﬃcacy study in Asia

N=10,275

CYD15

eﬃcacy study in LaDn

America and the Caribbean

(27)

Phase III dengue vaccine efﬁcacy studies in 5

Latin America countries

| 27

Thailand

Vietnam

Malaysia

Indonesia

Philippines

Mexico

Puerto Rico

Honduras

Colombia

Brazil

CYD14

eﬃcacy study in Asia

N=10,275

CYD15

eﬃcacy study in LaDn

America and the Caribbean

(28)

OBJECTIVE OF THE PUBLICATION: GLOBAL VIEW OF CLINICAL

PROFILE OF SANOFI PASTEUR VACCINE CANDIDATE BASED ON

EFFICACY AND LTFU INTERIM ANALYSES DATA

1.  Capeding, 2014, Lancet. 2.  Villar, 2015, N Engl J Med 3.  Hadinegoro, 2015, N Engl J Med.

CYD14

eﬃcacy study

in Asia

1

2–14 years (N=10,275)

CYD15 eﬃcacy study

in LaDn America and the Caribbean

2

9–16 years (N=20,869)

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

Eﬃcacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease

3

LTFU=long-term follow-up.

(29)

14 27 31 25 21 65 48 42 50 65 21 25 27 25 14 0 50 100

Age group by

country

Baseline

dengue status

Indonesia

Malaysia

Philippines

Thailand

Vietnam

55 68 79 48 81 45 32 21 52 19 0 50 100

2–5 y

12–14 y

6–11 y

Sero−

Sero+

ST1

ST3

ST4

ST2

Serotype

distribuDon

CYD14

36 46 49 45 45 64 54 51 55 55 0 50 100

Age group by

country

Baseline

dengue status

Brazil

Colombia

Honduras

Mexico

Puerto Rico

56 53 86 92 74 44 47 14 8 26 0 50 100

12–16 y

9–11 y

Sero−

Sero+

Serotype

distribuDon*

CYD15

PHASE III EFFICACY TRIALS ARE EPIDEMIOLOGICAL SETTINGS AND

PREVALENCE BY AGE GROUP IN DENGUE-ENDEMIC AREAS

ST1

ST3

(30)

HIGHER VACCINE EFFICACY WITH AGE DURING THE

25-MONTH OF THE LARGE-SCALE PHASE III EFFICACY STUDIES

*Comparison made on ITT. RR=relaSve risk: incidence of VC dengue cases in CYD group vs control group.

†_{Dengue+: baseline Ster 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.

33.7

59.5

74.4

0

10

20

30

40

50

60

70

80

90

2–5 yo

6–11 yo

12–14 yo

V

E

,

%

(

9

5

%

C

I)

VE Results by Age

CYD14

1

61.7

67.6

0

10

20

30

40

50

60

70

80

9–11 yo

12–16 yo

V

E

,

%

(

9

5

%

C

I)

CYD15

2

(31)

VE and 95% CI

CYD14

1

*

DENV+

DENV–

CYD15

2†

DENV+

DENV–

74.3%

35.5%

83.7%

43.2%

-80

-60

-40

-20

0

20

40

60

80

100

HIGHER VACCINE EFFICACY in POSITIVE BASELINE

SEROSTATUS DURING 25-MONTH OF THE LARGE-SCALE

PHASE III EFFICACY STUDIES

35.7

86.6

-26.8

66.7

62.2

93.7

-61.5

80.0

*Comparison made on ITT. RR=relaSve risk: incidence of VC dengue cases in CYD group vs control group.

†_{Dengue+: baseline Ster 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.

Baseline serostatus

(32)

*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 parScipants divided by 11 Smes 12.

CI=conﬁdence interval; RR=relaSve risk; VCD=virologically conﬁrmed dengue.

1

0.3

0.1

0.4

0.1

0.5

0.6

0.4

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2–5 years

6–11 years

12–14 years

All ages

A

n

u

al

I

n

ci

d

e

n

ce

Rat

e

(

%

)

ASIA CYD14 (YEAR 3): HOSPITALIZED VCD (ANY SEVERITY) IN

SUBJECTS 2 TO 14 YEARS OF AGE, BY AGE AT INCLUSION

1

*

RR (%)

(95% CI)

Vaccine Group

Control Group

7.45

(1.15–313.80)

0.63

(0.22–1.83)

0.25

(0.02–1.74)

1.04

(0.52–2.19)

(33)

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

1.2

1.1

0.6

0.8

0.9

0.8

0.9

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2–5 years

< 9 years

≥ 9 years

All ages

A

n

u

al

I

n

ci

d

e

n

ce

Rat

e

(

%

)

< 9 years

≥ 9 years

ASIA CYD14 (YEAR 4): HOSPITALIZED VCD (ANY SEVERITY) IN

1

RR (%)

(95% CI)

Vaccine Group

Control Group

1.42

(0.58, 3.99)

1.19

(0.65, 2.28)

0.73

(0.34, 1.61)

0.98

(0.62, 1.59)

|

33

(34)

LATAM CYD15 (YEAR 3): HOSPITALIZED VCD (ANY SEVERITY) IN

1

*

0.2

<0.1

0.1

0.3

0.2

0.0

0.2

0.4

0.6

0.8

1.0

9–11 years

12–16 years

All

An

n

u

a

l

In

ci

d

e

n

ce

Ra

te

(

%)

RR (%)

(95% CI)

0.55

(0.20–1.54)

0.53

(0.25–1.16)

0.50

(0.13–1.87)

Hospitalized VCD (any severity)

Year 3 - CYD15

*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 parScipants divided by 11 Sme 12.

CI=conﬁdence interval; LTFU=long-term follow-up; RR=relaSve risk; VCD=virologically conﬁrmed dengue.

(35)

Pooled results (CYD14+CYD15; ITT)

VE (%) and 95% CI

Any serotype

DENV-1

DENV-2

DENV-3

DENV-4

Severe dengue

DHF (WHO)

Hospitalized cases

In dengue-seroposiDve

subjects

In dengue-seronegaDve

subjects

SUMMARY OF POOLED EFFICACY: EFFICACY WAS CONSISTENTLY

DEMONSTRATED FOR THE CANDIDATE DENGUE VACCINE IN SUBJECTS AGED

9–16 YEARS IN THE 25-MONTH ACTIVE PHASE

1

DENV=dengue virus; DHF=dengue hemorrhagic fever; ITT=intent to treat; VE=vaccine eﬃcacy; WHO=World Health OrganizaSon.

65.6

58.4

47.1

73.6

83.2

93.2

92.9

80.8

81.9

52.5

0

20

40

60

80

100

60.7 69.9

47.7 66.9

31.3 59.2

64.4 80.4

76.2 88.2

77.3 98.0

76.1 97.9

70.1 87.7

67.2 90.0

5.9 76.1

(36)

Reduction in

symptomatic dengue

65.6%

(95% CI: 60.7–69.9)

Reduction in

hospitalized dengue

80.8%

(95% CI: 70.1–87.7)

CONSISTENT EFFICACY PROFILE IN SUBJECTS 9–16

YEARS OF AGE DURING THE EFFICACY PHASE

Key Efﬁcacy Results

25-month acDve phase* Pooled eﬃcacy analyses

‡1

*Data come from the 2 pivotal, phase III, large-scale efficacy trials CYD14 and CYD15, which were designed to fully assess efficacy; postdose 1; 1_{Full Analysis Set for Efficacy (FASE): all}_subjects who received at least one injecSon. †_{dengue hemorrhagic fever, World Health OrganizaSon 1997 criteria. CI=confidence interval; DENV=dengue virus.}

Reduction in

severe dengue

†

92.9%

(95% CI: 76.1–97.9)

For each serotype:

§

DENV-1: 58.4%

(95% CI: 47.7–66.9)

§

DENV-2: 47.1%

(95% CI: 31.3–59.2)

§

DENV-3: 73.6%

(95% CI: 64.4–80.4)

§

DENV-4: 83.2%

(95% CI: 76.2–88.2)

By dengue serostatus:

§

SeroposiSve: 81.9%

(95% CI: 67.2–90.0)

§

SeronegaSve: 52.5%

(95% CI: 5.9–76.1)

(37)

EFFICACY STUDIES IN ASIA AND LATIN AMERICA

DEMONSTRATED A CONSISTENT EFFICACY AND SAFETY

PROFILE DURING THE 25 MONTH ACTIVE PHASE

37

(1)  World Health OrganizaSon, 2014, Dengue fact sheet (2)  Capeding, 2014, Lancet

(3)  Villar and al., 2014, NEJM

(4)  Per protocol, 12m post dose 3 (5)  DHF, WHO 1997 criteria, intent to treat (6)  Intent To Treat, 25m post dose 1

*95% CI: 52.7-92.4 †95% CI: 64.9-99.9 ‡95% CI: 50.3-78.6 §95% CI: 64.7-89.5

Both Studies Met their Primary Eﬃcacy Endpoints and Showed Consistent

Safety Proﬁle for the Observed AcSve Phase

(2,3)

CYD 14, Asia

(2)

Key Study Results

CYD 15, LatAm

(3)

56.5%

ReducSon in symptomaSc

dengue

(4)

60.8%

ReducSon in symptomaSc

dengue

(4)

67.2%

‡

ReducSon in hospitalized

cases

(6)

80.0%*

ReducSon in severe

disease

(5)

80.3%

§

ReducSon in hospitalized

cases

(6)

95.0%

†

ReducSon in severe

disease

(5)

2.5 billion people

live in dengue-endemic countries (over 40% of the world’s populaSon)(1)

50-100 million

dengue infecDons

occur worldwide each year(1)

500,000 people

with severe

dengue

require hospitalizaSon each year(1)

2.5%

of people with severe

dengue

(38)

VIREMIA AND CYTOKINE PATTERN

•

Similar levels of viremia observed in vaccine vs control groups

(CYD14 and CYD15).

•

No cytokine pasern associated with increased disease enhancement

in vaccinees vs placebo.

CLINICAL PRESENTATION INSIGHTS

:

NO IMPORTANT DIFFERENCE IN CLINICAL SIGNS & SYMPTOMS DURING

ONGOING LTFU VERSUS EFFICACY PHASE & PLACEBO GROUP IN SUBJECTS

2–16 YEARS OF AGE

1

LTFU=long-term follow-up.

LENGTH

OF HOSPITALIZATION

Similar for both the 25-month

eﬃcacy phase and the ongoing LTFU

phase in CYD14, CYD15, and

CYD23/57.

FREQUENCIES OF SIGNS

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.

DURATION OF FEVER

AND CLINICAL SYMPTOMS

Similar for both the 25-month

eﬃcacy phase and the ongoing LTFU

phase in CYD14, CYD15, and

CYD23/57.

(39)

%, 95% CI

Solicited injecDon

site reacDon

Adults 18–60 years of age

Subjects 9–17 years of age

Grade 3 solicited

injecDon site

reacDon

Pain

Erythema

Swelling

OVERVIEW OF SAFETY: SOLICITED INJECTION SITE

REACTIONS

1

(SUBJECTS 9–60 YEARS OF AGE)

!

INTEGRATED SAFETY ANALYSIS*

1.  Chuenkitmongkol, 2015, JITMM.

46.9

51.0

0.7

1.5

45.2

49.2

7.9

8.4

2.4

6.9

-5

15

35

55

44.3

49.4

49.2

52.8

0.4

1.3

1.1

2.0

42.7

47.7

47.5

51.0

6.6

9.3

7.4

9.4

1.7

3.3

6.0

7.8

(40)

OVERVIEW OF SAFETY: SOLICITED SYSTEMIC

REACTIONS

1

(SUBJECTS 9–60 YEARS OF AGE)

!

INTEGRATED SAFETY ANALYSIS*

%, 95% CI

Solicited

systemic

reacSon

Grade 3

Fever

Headache

Malaise

Myalgia

Asthenia

Subjects 9–17 years of age

65.6

67.0

10.8

11.1

4.9

16.4

51.4

54.1

44.3

40.9

42.2

42.0

28.3

34.2

0

20

40

60

63.1 67.9

65.3 68.7

9.2 12.4

10.0 12.2

3.9 6.1

15.1 17.8

48.9 54.0

52.3 55.9

41.8 46.8

39.2 42.7

39.7 44.7

40.2 43.8

26.1 30.7

32.5 35.9

(41)

0.2

74

49.6

66.5

44.3

0

64.1

36.5

59

39

0

10

20

30

40

50

60

70

80

90

100

Immediate unsolicited AR

Solicited AR

Solicited injecSon site reacSon

Solicited systemic reacSon

Unsolicited non-serious AE

Placebo (n=1780)

CYD vaccine (n=4615)

Percentage of subjects presenDng with at least 1 reacDon or event

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

SAFETY OVERVIEW AFTER ANY DENGUE VACCINE

!

OR PLACEBO DOSE – SUBJECTS 9–60 YEARS OF AGE

1

!

(42)

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 ater the third injecDon were generally higher than those seen in CYD14 and CYD15, where eﬃcacy

was demonstrated.

1-4

§

It is anScipated that adults up to age 45 years living in endemic areas will have similar levels of

protecSon compared with those observed in the CYD14 and CYD15 studies.

1

10

100

1000

G

MT

s

Serotype 1

Serotype 2

Serotype 3

Serotype 4

CYD22*

N=20

(

18–45 y)

CYD47*

N=126

(

18–45 y

)

CYD14

N=1323

(2–14 y)

CYD15

N=1301

(9–16 y)

1.  Tran, 2012, J Vaccines Vaccin.

2.  Dubey, 2015, Hum Vaccin Immunother. 3.  Capeding, 2014, Lancet.

4.  Villar, 2015, N Engl J Med.

GMTs in CYD14, CYD15, CYD22, and CYD47

1-4

*CYD22: Vietnam; CYD47: India. GMT=geometric mean Ster; y=years.

(43)

PHASE II AND III TRIALS DEMONSTRATED IMMUNOGENICITY

AGAINST ALL 4 SEROTYPES POST-DOSE 3

FV=flavivirus; GMT=geometric mean titre; JE=Japanese encephalitis; PRNT

50

=50% plaque reduction neutralization test; YF=yellow fever.

Villar, 2013, Ped Infect Dis J. Tran, 2012, J Vaccines Vaccin. Lanata, 2012, Vaccine.

Leo, 2012, Hum Vaccines & Immunother.

Dayan, 2013, Vaccine.

Dayan, 2013, Am J Trop Med Hyg. HSS, 2013, Vaccine.

|

43

Trial

CYD12

CYD13

CYD22

CYD24

CYD28

CYD30

CYD47

CYD32

Phase

II

III

Country

USA

Colombia,

Honduras,

Mexico,

Puerto Rico

Vietnam

Peru

Singapore

Brazil

India

Malaysia

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

status

FV

non-immune

DENV+/-

YF+/-

DENV+/-

JE+/-

DENV+/-

YF+/-

DENV+/-

YF+/-

DENV+/-

JE +/-

DENV+/-

JE+/-

N

101

600

120

186

835

150

189

250

1

10

100

1000

10000

CYD12

CYD13

CYD22

CYD24

CYD28

CYD30

CYD47

CYD32

DENV-1

DENV-2

DENV-3

(44)

BASELINE AND POSTDOSE 3 GMTs INCREASE ACCORDING TO

AGE IN ENDEMIC AREAS IN THE 2 PIVOTAL EFFICACY STUDIES,

CYD14 AND CYD15

1

§ 

Predose 1 and postdose 3 GMTs against each serotype according to age.

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

GMT=geometric mean Sters.

1000 100 10 0 50 100

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

G M ( 1 /d il )

Age at inclusion

GMT by age in CYD14 and CYD15 - Serotype 1

CYD14 pre CYD15 pre CYD14 post-dose 3 CYD15 post-dose 3

1000 100 10 0 50 100

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

G M ( 1 /d il )

Age at inclusion

1000 100 10 0 50 100

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

G M ( 1 /d il )

Age at inclusion

1000 100 10

0

50

100

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17

G

M

(1

/d

il

)

Age at inclusion

GMT by age in CYD14 and CYD15

–

Serotype 2

(45)

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 & CYD15

1

17–45 YEARS OF AGE IN ENDEMIC AREAS COMPARED TO POPULATION IN PIVOTAL EFFICACY

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

0 20 40 60 80 100

1

1/dil

SEROTYPE 1

Endemic Asia Pacific, CYD22 Endemic Asia Pacific, CYD47 Endemic Asia Pacific, CYD14 Endemic LaSn America, CYD15

10 100 1000 10000

0 20 40 60 80 100

1

1/dil

SEROTYPE 2

10 100 1000 10000

0 20 40 60 80 100

1

1/dil

SEROTYPE 3

10 100 1000 10000 0

20 40 60 80 100 1

1/dil

SEROTYPE 4

10 100 1000 10000

(46)

•

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.

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

17.7

18

54.2

45.3

83.3

74.9

144

111

1

10

100

1000

Pre-inj 1 46-60 yo

Post-inj 3 46-60 yo

Pre-inj 1 18-60 yo

Post-inj 3 18-60

Serotype 1

Serotype 2

Serotype 3

Serotype 4

G

MT

s

(1

/d

il

)

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 Ster.

(47)

WHO Guidelines for introduction of

dengue vaccine

Decision for a vaccine

introduction

•

The public health and priority

•

Disease burden, including costs

•

Efﬁcacy of other disease prevention &

control measures

•

Proﬁle of available vaccine(s),

potential impact (modeling)

•

Vaccine supply

•

Economic and ﬁnancial issues

•

Strength of health system

(48)

•

Global concern

•

Regional related data

•

Local data: incidence, prevalence, death rate, age

vulnerable group, sequelae

Burden of disease

•

Guideline : SAGE & WHO position paper

•

Pilot project (in certain areas)

•

Technical Advisory Groups on Immunization

(ITAGI) recommendations

Guideline

Recommendation

•

Release/ registered to National Regulatory

Authority (NRA)

•

Cost beneﬁt analysis

•

Vaccine sustainability

Vaccine availability

•

Ministry of Health’s policy

•

Socialization /training

•

Operational cost from local government

•

AEFI surveillance

Planning

(49)

Conclusion (1)

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*

(50)

Conclusions (2)

•

Dengue vaccine CYD-TDV (Dengvaxia

@

) for

9-16 years of age

–

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,

(51)

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

(52)

Conclusions (3)

•

With 3-dose regimen administered 6 months

apart, the CYD-TDV dengue vaccine is efﬁcacious

in the prevention of dengue disease in subjects

aged 9–16 years.

•

Efﬁcacy has been demonstrated against each of the

4 serotypes.

•

High efﬁcacy was demonstrated against severe

(53)

•

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.

Note.

Evidence based data of immunological

(54)

h

ey are