1 | 1 Dengue: About the Disease and Emerging Vaccines Gustavo Dayan, MD Vaccine Preventable Diseases: Policy, Practices, Preparedness New York City, NY July 23, 2012 | 2 Overview ● Dengue ● Virus ● Disease ● Public health burden ● Vaccines in development ● Live virus ● Inactivated ● Subunit ● DNA/vector ● Sanofi Pasteur dengue vaccine ● Clinical development ● Safety ● Immunogenicity | 3 • Flavivirus (YF, JE, TBE, WN) • Positive sense single stranded RNA (~11kb) that codes for 3 structural proteins & 7 non-structural proteins • Four closely related, but antigenically distinct serotypes (DEN 1-4) - Immunity: serotype specific and prolonged - Cross protection: little and short duration - Some variants more virulent and with greater epidemic potential ’’’’NS3 C E NS1 NS2A NS2B NS4A NS4B NS5 Structural Proteins 5’ NC 3’NC prM Non Structural Proteins Zhang et al., 2003, Dengue Virus Source: Zhang Structure of Dengue Virus Cell, 2002;(108):717–725. | 4 Dengue – Clinical Stages ● Asymptomatic Dengue Virus Infection ● Non-specific Febrile Illness ● Dengue Fever (DF) ● High fever for 5-7 days, with headache, myalgia ● Usually followed by 2-3 weeks of debilitating fatigue ● Dengue Hemorrhagic Fever (DHF) ● DF with vascular permeability, ● Primarily in children, with a peak around 5-9 years old ● In outbreak situations, DHF is seen in all ages ● Case fatality rate • 20% without treatment • <1% with treatment ● Dengue Shock Syndrome (DSS) DSS DHF Dengue Fever Undifferentiated Fever Asymptomatic | 5 Courtesy Dr. S. Kalayanarooj Adolescent diagnosed with dengue fever. Dengue Unit Ratchaburi Hospital, Thailand – Feb 2011 | 6 Dengue – Public Health Burden ● Mosquito borne disease ● Aedes aegypti main vector ● Arthropod-borne viral disease with highest morbidity and mortality ● 2.5 billion people at risk in over 100 countries ● >50 million people infected annually ● 2 million, mostly children, develop a severe form of the disease Source: CDC - Outbreak Notice - Update: Dengue in Tropical and Subtropical Regions available on: http://wwwnc.cdc.gov/travel/notices/outbreak-notice/dengue-tropical-sub-tropical.htm WHO - Dengue and dengue haemorrhagic fever, Fact sheet n 117, March 2009, available on: http://www.who.int/mediacentre/factsheets/fs117/en
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Dengue: About the Disease and Emerging Vaccines · Dengue: About the Disease and Emerging Vaccines Gustavo Dayan, MD ... DENV-1 WT PUO359 prM E DENV-2 WT PUO218 DENV-3 WT PaH881/88
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codes for 3 structural proteins & 7 non-structural
proteins
• Four closely related, but
antigenically distinct serotypes (DEN 1-4)
- Immunity: serotype specific and prolonged - Cross protection: little and short duration - Some variants more virulent and with greater epidemic potential
Prot é ines de structure 5 ’ Non
Codant 3 ’ Non
Codant
Prot é ines non stucturales NS Prot é ines de structure 5 ’ Non
Codant 3 ’ Non
Codant
Prot é ines non stucturales NS
NS3 C E NS1 NS2A NS2B NS4A NS4B NS5
Structural
Proteins
5’ NC 3 ’ NC
prM
Non Structural Proteins Zhang et al., 2003,
Dengue Virus
Source: Zhang Structure of Dengue Virus Cell, 2002;(108):717–725.
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Dengue – Clinical Stages
● Asymptomatic Dengue Virus Infection
● Non-specific Febrile Illness
● Dengue Fever (DF) ● High fever for 5-7 days, with headache,
myalgia
● Usually followed by 2-3 weeks of debilitating fatigue
● Dengue Hemorrhagic Fever (DHF) ● DF with vascular permeability,
● Primarily in children, with a peak around 5-9 years old
● In outbreak situations, DHF is seen in all ages
● Case fatality rate
• 20% without treatment
• <1% with treatment
● Dengue Shock Syndrome (DSS)
DSS
DHF
Dengue Fever
Undifferentiated Fever
Asymptomatic
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Courtesy Dr. S. Kalayanarooj
Adolescent diagnosed with dengue fever. Dengue Unit
Ratchaburi Hospital, Thailand – Feb 2011
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Dengue – Public Health Burden
● Mosquito borne disease
● Aedes aegypti main vector
● Arthropod-borne viral disease with highest morbidity
and mortality
● 2.5 billion people at risk in over 100 countries
● >50 million people infected annually
● 2 million, mostly children, develop a severe form of the
disease
Source:
CDC - Outbreak Notice - Update: Dengue in Tropical and Subtropical Regions available on: http://wwwnc.cdc.gov/travel/notices/outbreak-notice/dengue-tropical-sub-tropical.htm
WHO - Dengue and dengue haemorrhagic fever, Fact sheet n
117, March 2009, available on: http://www.who.int/mediacentre/factsheets/fs117/en
2
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Global Dengue Risk
Source: Simmons CP, et al. N Engl J Med. 2012;366-1423-32
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Dengue in the Americas, 1980-2010
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
1,800,000
19
80
19
82
19
84
19
86
19
88
19
90
19
92
19
94
19
96
19
98
20
00
20
02
20
04
20
06
20
08
20
10
Y E AR
NU
MB
ER
OF
CA
SE
S
YEAR 1981 CUBA 344,203
YEAR 2002 HONDURAS 32.269 COLOMBIA 76,996 VENEZUELA 37,676 BRAZIL 780,644
YEAR 2009 ARGENTINA 26,612 BOLIVIA 84,047 MEXICO 249,763 COLOMBIA 51,543 VENEZUELA 65,869 BRAZIL 528,883
YEAR 2010 COLOMBIA 157,152 VENEZUELA 123,967 BRAZIL 1,004,392 HONDURAS 66,814 GUADELOUPE 41,100 PUERTO RICO 21,298
YEAR 1998 MEXICO 23,639 COLOMBIA 63,182 VENEZUELA 37,586 BRAZIL 535,388
Source:
Pan American Health Organization (PAHO). Number of reported cases of dengue & dengue haemorrhagic fever (DHF), Region of the Americas
Available at URL: http://new.paho.org/hq/index.php?option=com_content&task=view&id=264&Itemid=363&lang=en
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Dengue Incidence in the Americas, 1980-2010
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Dengue - Public Health Challenge
● WHO Neglected Tropical Diseases Group (WHA,
Geneva - May 2012)
● Targets and milestones for control of neglected tropical
diseases, 2015-2020
● To reduce dengue deaths by 50% by 2020
● To reduce dengue morbidity by at least 25% by 2020
Source: Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases - a roadmap for Implementation (WHO, May 2012)
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Dengue Prevention
● Prevention relies on vector control and personal protection measures ● Difficult to enforce and maintain, expensive
● Development of a dengue vaccine is viewed as a public health priority
II Inviragen Tetravalent Attenuated chimeric: DENV prME in attenuated DENV2 backbone
prM, E SC
I NIH (NIAID) Tetravalent DENV-4 30NT en 3’UTR deletion and chimerization
prM, E SC
I Merck Tetravalent Subunidad + Adyuvante Iscomatrix® E, NS1 IM
I NMRC Monovalent DNA (D1ME100) prM, E IM
I WRAIR Monovalent Inactivated DENV-1 Whole Virus IM
www.clinicaltrials.gov
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0
2
4
6
8
10
12
14
16
18
20
Phase I Phase II Phase III
NIAID Sanofi Pasteur GSK Inviragen
AMR&MC Merck H. Biotech WRAIR
Dengue: Clinical Trials Published/ in ClinicalTrials.gov
Mainly monovalent formulations
www.clinicaltrials.gov. Ultimo acceso: Abril 2012 Guirakhoo et al. Human vaccines 2006;2(2):60-67 Morrison et al JID 2010;201:370-7 Poo et al PIDJ 2011;30(1):e9-e17 Capeding et al Vaccine 2011;29:3863-72
AMR&MC Merck H. Biotech WRAIRwww.clinicaltrials.gov. accessed: Abril 2012 Guirakhoo et al. Human vaccines 2006;2(2):60-67 Morrison et al JID 2010;201:370-7 Poo et al PIDJ 2011;30(1):e9-e17 Capeding et al Vaccine 2011;29:3863-72
Dengue: Clinical Trials Published/ in ClinicalTrials.gov
| 20
0
2
4
6
8
10
12
14
16
18
20
Phase I Phase II Phase III
NIAID Sanofi Pasteur GSK Inviragen
AMR&MC Merck H. Biotech WRAIRwww.clinicaltrials.gov. Ultimo acceso: Abril 2012 Guirakhoo et al. Human vaccines 2006;2(2):60-67 Morrison et al JID 2010;201:370-7 Poo et al PIDJ 2011;30(1):e9-e17 Capeding et al Vaccine 2011;29:3863-72
Dengue: Clinical Trials Published/ in ClinicalTrials.gov
| 21
non- st ruct ural genes C 5’ 3’
DEN
E prM
Sanofi Pasteur New Generation Dengue Vaccine
17D YF genome cl oned as cDNA
non- st ruct ural genes C E prM 3’ 5’
YF NS genes C E prM 3’ 5’
non- st ruct ural genes C 3’ 5’
E prM E prM
Dengue vi rus genome
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non- st ruct ural genes C E prM 3’ 5’
Construction of CYD Dengue Vaccine
Ful l l engt h recombi nant cDNA RNA ( t ranscri pt i on)
RNA t ransf ect i on
Vero cel l s cul t ure
17 D YF replication “engine”
DEN envel ope prot ei ns
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3’ 5’
3’ 5’
3’ 5’
3’ 5’
3’ 5’
17D YF virus
DNA 17 D YF vaccine virus
prM E DENV-1
WT PUO359
prM E DENV-2
WT PUO218
prM E DENV-3
WT PaH881/88
prM E DENV-4
WT 1228
Construction of CYD Dengue Vaccine
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● Composition
● Live attenuated virus, tetravalent (4 vaccinal strains cultured in serum free Vero cells) 5
1 log10 CCID50 of each serotype
● Stabilizer without preservatives antibiotics or adjuvants
● Route of administration/Schedule
● Subcutaneous
● 3 injections 0 - 6 - 12 months
● Pharmaceutical form
● Powder and solvent for suspension for injection (0.5 ml)
● Indications
● Prevention of symptomatic dengue disease (from Dengue Fever to severe Dengue disease) due to serotypes 1, 2, 3 or 4
● Children and adults living in endemic areas, people working in (traveling to) endemic areas
● Priority: Endemic countries (Asia/Pacific, Latin America, Caribbean)