DENGUE: PREVENTION & CONTROL Professor Usa Thisyakorn, M.D. Chulalongkorn University Bangkok, Thailand
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DENGUE: PREVENTION & CONTROL
Professor Usa Thisyakorn, M.D. Chulalongkorn University
Bangkok, Thailand
Global strategy for dengue prevention & control, 2012-2020
DENGUE
• Most common global vector-borne viral infection
• Increasing global burden driven by
- population growth
- urbanization
- globalization
- ecological changes
• An integrated approach to dengue prevention
and control is crucial
DENGUE VIRUS
RECEPTORS AND TARGET CELL OF DENGUE
RECEPTORS TARGET CELLS
Heparin sulfate Liver cells; VERO; BHK21; C636
Hsp 70/90 Monocyte derived Macrophage;
human; Neuroblastoma cells
GRP78/BiP Liver cells
37/67 Kda high affinity Liver cells
Lamina receptor
CD14 Monocyte derived Macrophage
DC-SIGN Dendritic cells, Langerhans cells
L-SIGN Liver cell; LN; Spleen
PATHOGENESIS OF DENGUE DISEASES
• Dengue NS1 protein
• Dengue virus genome
• Antibody-Dependent Enhancement
• T cell
• Endothelial cell
• Dendritic cell
Fever, headache, retro-orbital pain, myalgias, arthralgias
+/- Haemorrhagic manifestations
Thrombocytopenia Haemoconcentration
Spontaneous bleeding
Pulse Pressure 20 mmHg Hypotension, cold clammy
skin, restlessness
Profound shock Undetectable blood
pressure & pulse
Classic Dengue Fever
Grade I DHF
Grade II DHF
Grade III DHF
Grade IV DHF
DSS
1997 WHO dengue classification
5
Dengue Guidelines for diagnosis, treatment, prevention and control, New edn. Geneva: WHO; 2009
2009 WHO revised dengue classification by severity
7
DENGUE: PITFALLS IN DIAGNOSIS AND MANAGEMENT
• Communications to parents and caregivers
• Diagnostic tests
• Medications
• DDx with other acute febrile illnesses
• Fluid therapy
• Bleeding tendency
• Organopathy
Thisyakorn & Thisyakorn. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1): 112-6.
Age distribution of dengue patients in King Chulalongkorn Memorial Hospital between 1987- 2007
Thisyakorn & Thisyakorn. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1): 106-11.
0
20
40
60
80
100
120
1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Nu
mb
er o
f ca
ses
Year
0-1 years
2-5 years
6-9 years
10-15 years
Seasonal distribution of dengue patients in King Chulalongkorn Memorial Hospital between 1987- 2007
Thisyakorn & Thisyakorn. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1): 106-11.
0
50
100
150
200
250
NU
MB
ER O
F C
ASE
S
MONTH
Dengue in Bangkok 2015
DENGUE AT THAMMASAT UNIVERSITY 2006 - 2015
Tangsathapornpong A, et al. Southeast Asian J Trop Med Public Health 2017; 48 (Suppl1): 39-46.
294
498
748
985 962
562
395
303
235 181
151 116
203
0
200
400
600
800
1000
1200
0-4 yrs 5-9 yrs 10 -14 yrs 15 - 19 yrs 20 - 24 yrs 25 - 29 yrs 30 - 34 yrs 35 - 39 yrs 40 - 44 yrs 45 - 49 yrs 50-54 yrs 55-59 yrs >60 yrs
Nu
mb
er
of
case
s
Age group
DENGUE AT VACHIRA PHUKET HOSPITAL 2009 - 2015
Lawtongkum W, et al. Southeast Asian J Trop Med Public Health 2017; 48 (Suppl1): 47-51.
0
50
100
150
200
250
300
350
400
450
2009 2010 2011 2012 2013 2014 2015
Nu
mb
er o
f ca
ses
Year
0 – 4
5 – 9
10 – 14
15 - 24
25 - 34
≥ 35
Thailand, number of dengue cases per age group from 2010 to 2015
Bureau of Epidemiology, D. o. D. C., MoPH, Thailand (2016). "Bureau of Epidemiology, Department of
Disease Control." Annual Epidemiology Surveillance Report (2010 to 2014), Report 506 (2015),
Retrieved 12/02/2016, 2016, from http://203.157.15.110/boe/home.php.
Changing epidemiology of dengue in South-East Asia
Shift in affected age groups
and
expansion to rural areas
are evident
WHO South-East Asia Journal of Public Health | January-March 2013 | 2(1)
DENGUE IN BANGKOK
• First outbreak: 1958
• Rate of patients: 27.99-292.24 per 100,000 population
• Case fatality rate: 0-0.21%
• Serotype: all 4 serotypes circulate continuously with predominant serotype emerging as the cause of each epidemic
• Changing epidemiology: a trend towards higher ages
Liulak W, et al. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1): 33-8.
Age distribution VS dengue severity in Bangkok 2015-2016
Liulak W, et al. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1):33-8.
0
20
40
60
80
100
120
140
0-1 years 2-5 years 6-8 years 9-15 years 16-30 years 31-60 years >60 years
Nu
mb
er o
f ca
ses
Age (years)
UFI
DF
DHF
DSS
Age distribution VS DEN serotype in Bangkok 2015-2016
Liulak W, et al. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1): 33-8.
0
10
20
30
40
50
60
70
80
90
100
0-1 years 2-5 years 6-8 years 9-15 years 16-30 years 31-60 years >60 years
Nu
mb
er o
f ca
ses
Age (years)
DEN1
DEN2
DEN3
DEN4
Combined
Dengue serotype VS dengue severity in Bangkok 2015-2016
Liulak W, et al. Southeast Asian J Trop Med Public Health2017; 48 (Supplement 1): 33-8.
0
20
40
60
80
100
120
140
160
DEN1 DEN2 DEN3 DEN4 Combined
Nu
mb
er o
f ca
ses
Serotype
UFI
DF
DHF
DSS
Dengue serotype VS dengue severity in Bangkok 2015-2016
Liulak W, et al. Southeast Asian J Trop Med Public Health2017; 48 (Supplement 1): 33-8.
0
20
40
60
80
100
120
140
160
UFI DF DHF DSS
Nu
mb
er o
f ca
ses
Severity
DEN1
DEN2
DEN3
DEN4
Combined
Dengue serotype in Bangkok 2015-2016
Liulak W, et al. Southeast Asian J Trop Med Public Health 2017; 48 (Supplement 1): 33-8.
[CATEGORY NAME]
[PERCENTAGE]
[CATEGORY NAME]
[PERCENTAGE]
[CATEGORY NAME] [PERCENTAGE]
[CATEGORY NAME]
[PERCENTAGE]
[CATEGORY NAME]
[PERCENTAGE]
D1
D2
D3
D4
Combined
Dengue serotype in Thailand from 2000-2016
Source: NIH, MOPH, 2000-2016
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
20
15
20
16
DENV-1 DENV-2 DENV-3 DENV-4
The King’s announcement about the prioritization of dengue in 1999
• Major impact on the surveillance for dengue and increased in number of DF reports seen from 2003 to 2011, after the electronic system was in place.
• In 1999, MOPH initiated
a dengue prevention and control program
• Aim is to reduce incidence of dengue to < 50 cases per 100,000 population
• A. aegypti larval source reduction through an integrated, community-based approach
INTEGRATED VECTOR MANAGEMENT
• Advocacy, social mobilization and legislation
• Collaboration within the health sector and with other sectors
• Integrated approach to disease control
• Evidence-based decision-making
• Capacity-building
WHO. Dengue: guidelines for diagnosis, treatment, prevention and control.
Accessible at http://apps.who.int/tdr/svc/publications/training-guideline
publications/dengue-diagnosis-treatment; 2009 [accessed 04.07.11].
DENGUE VECTOR CONTROL: ASSESSING WHAT WORKS?
• Vector control can be effective, implementation remains an issue
• Single interventions are probably not useful, efficacy varies, with little sustainability
• Combinations of interventions have mixed results
• Interventions are often applied in outbreaks with questionable effectiveness
• Key elements for more effective vector control: timely alerts of outbreaks followed by immediate vector control and health promotional campaigns
• Careful implementation may be most important
Horstick O, et al. Southeast Asian J Trop Med Public Health2017; 48 (Supplement 1): 181-95.
*The baseline year is 2010.
WHO=World Health Organization. 1. WHO, 2012, Global Strategy for Dengue Prevention and Control.
The candidates dengue vaccine could help
meet WHO objectives of decreasing dengue-related
mortality by ≥50% and morbidity by ≥25% by 2020.1
| 36
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 Asia1
2–14 years (N=10,275)
CYD15 efficacy study in Latin America and the Caribbean2
9–16 years (N=20,869)
http://linkinghub.elsevier.com/retrieve/pii/S0140673614610606 http://www.nejm.org/doi/full/10.1056/NEJMoa1411037
Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease3
LTFU=long-term follow-up.
www.nejm.org/doi/full/10.1056/NEJMoa1506223
KEY RESULTS OF CYD14 & CYD15
• Variable efficacy for all serotypes
• Increased efficacy in people with prior dengue infection
• High efficacy in protecting against severe dengue
• Good efficacy in decreasing hospitalization
• Prevented asymptomatic dengue infection
• Safe
SAGE & DENGUE VACCINE
• The WHO SAGE recommends countries consider introduction of CYD-TDV in geographic settings where dengue is highly prevalent.
• Integrated vaccination strategy with a communication strategy, vector control, clinical care, surveillance.
• Introduction requires careful assessment by each country.
15 April 2016
| 39
DENGUE VACCINE:
WHO POSITION PAPER
• Countries should consider introduction of CYD-TDV in geographic settings where dengue is high burden.
• A combination of seroprevalence data, and programmatic
factors should define the target population.
• Integrated vaccination strategy with vector control, clinical care, surveillance, communication strategy.
• Introduction requires careful assessment by each country. 29 July 2016
| 41
WHO estimates1
1. WHO, 2015, Dengue Fact Sheet. 2. WHO, 2012, Global Strategy for Dengue Prevention and Control.
ABOUT 400 MILLION PEOPLE INFECTED PER YEAR 300 MILLION OF ASYMPTOMATIC = RESERVOIR FOR DENGUE TRANSMISSION
3.9 billion people live in dengue-endemic countries (about half of the world’s population).
390 million people are infected per year.
96 million symptomatic infections per year.
500,000 people with severe dengue require
hospitalization each year.
2.5% of people with severe
dengue die.
WHO=World Health Organization.
SILENT INFECTION: 300M/Year
SYMPTOMATIC
INFECTION: 96M/Year
Symptomatic : Asymptomatic 1 : 4
| 42
Studies That Assessed Relative Incidence of Asymptomatic Dengue Virus Infection
JID 2016:214 (1 October) • Olivera-Botello et al
| 43
| 44
New Supplementary Analysis by Anti-Dengue NS1 Lab
Sanofi Press Release on November 29, 2017 Sanofi updates information on dengue vaccine
http://mediaroom.sanofi.com/sanofi-updates-information-on-dengue-vaccine/ (retrieved on 6 December 2017)
| 46
Measuring dengue exposure status: NS1 study initiative All subjects provided M13 samples – Possible surrogate of baseline for post M13 outcomes*
Safety Outcomes (Hospitalized/Severe Dengue)
Efficacy Outcomes NS1 Suppl.
Analysis
* Conditional to applying an assay not meaningfully affected by vaccination
Surrogate of baseline (M13)
True baseline PRNT50 (M0)
|
46
1.Hadinegoro, 2015, N Engl J Med.
1. The results are preliminary and were made
by retrospective analysis of blood samples
taken a month after the third dose of the
vaccine in the original CYD 14 (in Asia)
and CYD 15 (in Latin America) studies.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (I)
2. The test performed is new and had been
validated using PRNT as the reference. It
indicates past-infection with wild dengue
virus only, and excludes vaccine-induced
immunity.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (II)
3. The results showed that seropositive
(previously infected) individuals benefited
from the vaccine. As many parts of Asia
and areas in our own countries have high
seropositive rates, the vaccine will have
potential benefits across populations in
Asia.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (III)
4. Seronegative subjects (no previous
dengue infection) tend to have higher
hospitalization rates–Specifically, an
additional 5 hospitalisations per 1000
vaccines in five years.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (IV)
5. Seronegative subjects were also observed
to have more DHF Grades I and II,
speficically two extra cases per 1000
vaccinees in five years. There was no
shock, bleeding nor mortality in this group.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (V)
6. Serological pretesting is required, although not
practical, but we need to have an appropriate,
cheap, readily- and universally- available test.
The gold-standard PRNT test is costly and not
readily available while the test used by the
manufacturer is currently only used on a
research basis.
To avoid confusion, a practical approach using the
most reliable laboratory testing has to be discussed
and implemented.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (VI)
Summary
This outcome should not cause undue panic
among individuals who have already received
the dengue vaccine. The severe dengue that
occurred in initially seronegative vaccinees were
in DHF Grades I and II and did not lead to shock,
any bleeding or mortality.
The report also reinforces the fact that
seropositive individuals would benefit from receiving the vaccine.
Asian Dengue Vaccination Advocacy ADVA statement regarding the CYD-TDV (VII)
Conclusion
• Dengue is one disease entity with different clinical manifestations, often with unpredictable clinical evolutions and outcomes
• The human and economic cost of dengue are significant and likely to be even higher than estimated
• Disease prevention is a key to public health
35
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