Dengue: About the Disease and Emerging Vaccines -...
Transcript of Dengue: About the Disease and Emerging Vaccines -...
1
Dengue: About the Disease and Emerging Vaccines
| 1
Gustavo Dayan, MDVaccine Preventable Diseases: Policy, Practices, PreparednessNew York City, NYJuly 23, 2012
Overview
● Dengue● Virus● Disease● Public health burden
● Vaccines in development● Live virus
| 2
e us● Inactivated● Subunit● DNA/vector
● Sanofi Pasteur dengue vaccine● Clinical development ● Safety● Immunogenicity
•Flavivirus (YF, JE, TBE, WN) •Positive sense single stranded RNA (~11kb) that codes for 3 structural proteins & 7 non-structural proteins
Protéines de structure5’Non Codant
3’Non Codant
Protéines non stucturalesNSProtéines de structure5’Non Codant
3’Non Codant
Protéines non stucturalesNSStructural Proteins
5’NC 3’NCNon Structural Proteins Zhang et al., 2003,
Dengue Virus
| 3
• 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
NS3C E NS1 NS2A NS2B NS4A NS4B NS5prM
Source: Zhang Structure of Dengue Virus Cell, 2002;(108):717–725.
2
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)
DSS
DHF
DSS
DHF
| 4
● 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)
Dengue Fever
Undifferentiated Fever
Asymptomatic
Dengue Fever
Undifferentiated Fever
Asymptomatic
| 5
Courtesy Dr. S. Kalayanarooj
Adolescent diagnosed with dengue fever. Dengue Unit
Ratchaburi Hospital, Thailand – Feb 2011
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
| 6
● 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.htmWHO - Dengue and dengue haemorrhagic fever, Fact sheet n 117, March 2009, available on: http://www.who.int/mediacentre/factsheets/fs117/en
3
Global Dengue Risk
| 7
Source: Simmons CP, et al. N Engl J Med. 2012;366-1423-32
Dengue in the Americas, 1980-2010
1,00 0,000
1,20 0,000
1,40 0,000
1,60 0,000
1,80 0,000
R O
F C
AS
YEAR 2002 HONDURAS 32.269 COLOMBIA 76,996 VENEZUELA 37,676 BRAZIL 780,644
YEAR 2010 COLOMBIA 157,152 VENEZUELA 123,967 BRAZIL 1,004,392 HONDURAS 66,814 GUADELOUPE 41,100 PUERTO RICO 21,298
YEAR1998
| 8
0
20 0,000
40 0,000
60 0,000
80 0,000
1980
1982
198 4
198 6
198 8
199 0
1992
1994
1996
1998
2000
2 002
2 004
2006
2008
201 0
Y EAR
NU
MB
E
YEAR 1981 CUBA 344,203
YEAR 2009 ARGENTINA 26,612 BOLIVIA 84,047 MEXICO 249,763 COLOMBIA 51,543 VENEZUELA 65,869 BRAZIL 528,883
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 AmericasAvailable at URL: http://new.paho.org/hq/index.php?option=com_content&task=view&id=264&Itemid=363&lang=en
Dengue Incidence in the Americas, 1980-2010
| 9
4
Dengue - Public Health Challenge
● WHO Neglected Tropical Diseases Group (WHA, Geneva - May 2012)
● Targets and milestones for control of neglected tropical
| 10
● 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)
Dengue Prevention
● Prevention relies on vector control and personal protection measures● Difficult to enforce and maintain, expensive
| 11
● Development of a dengue vaccine is viewed as a public health priority
Virus isolation(Hotta & Kimura)
Sabin & Schelsinger2W. Hammon3
US Army/Univ. Hawaii/Univ MahidolThailand
Attenuation of DEN viruses
LAV DEN1-4(1st generation)
Blanc & Caminopetros1
Killed & Attenuated DEN vaccines
Construction of chimericDEN4/DEN2(2nd generation)
Bray M. et al19915
Constructionof chimeric
YF/DEN2
Guirakhoo et al20006 Construction
of chimericYF/DEN1,3,4
Guirakhoo et al20017
Virus isolation and identification of serotypes
Dengue Vaccines
DEN3&4ManilaDEN1 Hawaii
DEN N. Guinea
Monovalent
Killed DEN vaccines
Simmons et al1
Virus isolation(Hotta & Kimura)
Sabin & Schelsinger2W. Hammon3
US Army/Univ. Hawaii/Univ MahidolThailand
Attenuation of DEN viruses
LAV DEN1-4(1st generation)
Blanc & Caminopetros1
Killed & Attenuated DEN vaccines
Construction of chimericDEN4/DEN2(2nd generation)
Bray M. et al19915
Constructionof chimeric
YF/DEN2
Guirakhoo et al20006 Construction
of chimericYF/DEN1,3,4
Guirakhoo et al20017
Virus isolation and identification of serotypes
Dengue Vaccines
DEN3&4ManilaDEN1 Hawaii
DEN N. Guinea
Monovalent
Killed DEN vaccines
Simmons et al1
History of Dengue Vaccines
| 12
19441943 19561944-45 1970 -’80
Sabin, Schelsinger2
/Univ MahidolThailand/Fund. Rockefeller4
1928-1930
Caminopetros1
1990 - 2000BZ 2009
1: AJTMH 1931;77:77-102 2: Science 1945;101(2634):640-642 3: Science 1960;131:1102-3 4: AJTMH 2003;69(Suppl 6):5-115: J Virol 1996;70:4162-6 6: J Virol 2000;74:3020-8 7: J Virol 2001;75:7290-7304
LAV DEN1
19441943 19561944-45 1970 -’80
Sabin, Schelsinger2
/Univ MahidolThailand/Fund. Rockefeller4
1928-1930
Caminopetros1
1990 - 2000BZ 2009
1: AJTMH 1931;77:77-102 2: Science 1945;101(2634):640-642 3: Science 1960;131:1102-3 4: AJTMH 2003;69(Suppl 6):5-115: J Virol 1996;70:4162-6 6: J Virol 2000;74:3020-8 7: J Virol 2001;75:7290-7304
LAV DEN1
5
Challenges for Dengue Vaccine Development
● 4 different serotypes● Technical difficulties● Inter-serotype competition● Need for balanced protection against all four serotypes
● There is no animal model for the disease
| 13
● Theoretical risk of immunoenhancement after sequential infections (antibody-dependent enhancement - ADE): need for a combined tetravalent vaccine
● No established correlates of protection – efficacy trials are needed
Dengue Vaccines in Development
● Live virus vaccinesTraditional attenuationRecombinant
● Inactivated vaccines
| 14
Inactivated vaccines● Subunit vaccines● DNA vaccines● Vector vaccines
Candidate Vaccines I -- Live Virus Vaccines
● Traditional attenuation● Cell culture passages
• PDK, PRhL cells - WRAIR/GSKSun et al Hum Vaccin. 2009;5(1):33-40
● Recombinant● Molecular attenuation through selective mutations and chimerization
• E.g., rDENV4- Δ30 - NIH/ University of Maryland• Blaney et al Curr Top Microbiol Immunol 2010;338:145 58
| 15
• Blaney et al Curr Top Microbiol Immunol 2010;338:145-58
● Insertion of dengue structural genes (prM/E) in a traditionally attenuated dengue virus
• DENV2 16681 PDK-53 vaccine strain - CDC/Inviragen• Huang et al. J Virol 2003;77(21):11436-47
● Insertion of dengue structural genes (prM/E) in the yellow fever vaccine virus• Yellow fever vaccine virus strain YF17D - Acambis/Sanofi Pasteur
Capeding et al Vaccine 2011;29(22):3863-72
6
Candidate Vaccines II
● Inactivated vaccines - WRAIR/GSKPutnak et al. Vaccine 2005;23:4442-52
● Subunit vaccines● Envelope + NS1 Ag- Hawaii Biotech/Merck
Clements et al. Vaccine 2010;28(15):2705-15 ● Protein DEN E Structural Subunits – Genetic and Biotecnology Center
Cuba
| 16
Valdes et al. Clin Vaccine Immunol. 2011;18(3):455-9
● DNA and vector vaccines● DNA – NMRC/WRAIR
Raviprakash et al. Virology 2006;353:166-73● Vector adenovirus - NMRC/WRAIR
Raviprakash et al. J Virol 2008;82(14):6927-34
Main Candidate Vaccines in Clinical Development
Phase Developer # of serotypes
Method Antigen Admin. route
III Sanofi Pasteur
Tetravalent Atenuated, chimeric: DENV prME in YF vaccine virus 17D backbone
prM, E SC
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 prM E SC
| 17
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
8
10
12
14
16
18
20
Dengue: Clinical Trials Published/ in ClinicalTrials.gov
Mainly monovalent formulations
| 18
0
2
4
6
Phase I Phase II Phase III
NIAID Sanofi Pasteur GSK Inviragen
AMR&MC Merck H. Biotech WRAIRwww.clinicaltrials.gov. Ultimo acceso: Abril 2012Guirakhoo et al. Human vaccines 2006;2(2):60‐67Morrison et al JID 2010;201:370‐7Poo et al PIDJ 2011;30(1):e9‐e17Capeding et al Vaccine 2011;29:3863‐72
7
8
10
12
14
16
18
20
Dengue: Clinical Trials Published/ in ClinicalTrials.gov
| 19
0
2
4
6
Phase I Phase II Phase III
NIAID Sanofi Pasteur GSK Inviragen
AMR&MC Merck H. Biotech WRAIRwww.clinicaltrials.gov. accessed: Abril 2012Guirakhoo et al. Human vaccines 2006;2(2):60‐67Morrison et al JID 2010;201:370‐7Poo et al PIDJ 2011;30(1):e9‐e17Capeding et al Vaccine 2011;29:3863‐72
8
10
12
14
16
18
20
Dengue: Clinical Trials Published/ in ClinicalTrials.gov
| 20
0
2
4
6
Phase I Phase II Phase III
NIAID Sanofi Pasteur GSK Inviragen
AMR&MC Merck H. Biotech WRAIRwww.clinicaltrials.gov. Ultimo acceso: Abril 2012Guirakhoo et al. Human vaccines 2006;2(2):60‐67Morrison et al JID 2010;201:370‐7Poo et al PIDJ 2011;30(1):e9‐e17Capeding et al Vaccine 2011;29:3863‐72
non-structural genesC5’ 3’EprM
Sanofi Pasteur New Generation Dengue Vaccine
17D YF genome cloned as cDNA
YF NS genesC EprM 3’5’
Dengue virus genome
| 21
DEN
non-structural genesC EprM 3’5’
non-structural genesC 3’5’
EprMEprM
8
non-structural genesC EprM 3’5’
Construction of CYD Dengue VaccineConstruction of CYD Dengue Vaccine
Full length recombinant cDNA RNA (transcription)
RNA transfection
DEN envelope proteins
| 22
Vero cells culture
17 D YF replication “engine”
3’5’
3’5’
17D YF virus
prM E DENV‐1
WT PUO359
prM E DENV‐2
WT PUO218
Construction of CYD Dengue Vaccine
| 23
3’5’
3’5’
3’5’
DNA 17 D YF vaccine virus
prM E DENV‐3
WT PaH881/88
prM E DENV‐4
WT 1228
● 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
CYD Vaccine Characteristics
| 24
● 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)
9
CYD Vaccine Clinical Development
Phase I studies5 completed S&I studies in USA, Mexico, Philippines
Phase II studies• 6 completed and 2 ongoing S&I studies in USA, Australia, Latin America, Asia • 1 ongoing PoC efficacy trial in Asia• 1 ongoing PoC co-ad. in Asia
| 25
Phase III studies• 1 ongoing Lot-to-lot consistency in Australia• 1 ongoing S&I study in Asia• 2 ongoing S&I studies in Latin America• 2 ongoing efficacy studies in Asia and Latin America• 2 ongoing co-ad. studies in Latin America
Safety Database
● Safety status as of March 28th 2012● Approximate Nbr of subjects who received at least one CYD dose
Phase Toddlers Children Adolescents Adults Total
Phase I 0 140 71 185 396Phase II 179 3368 474 893 4914
| 26
Over 28,000 individuals have already received at least one dose of CYD Dengue vaccine
Phase III 839 10558 10411 1020 22828Total 1018 14066 10956 2098 28138
● Reactogenicity profile similar to control vaccines
● No increase in reactogenicity
● In Flavivirus (FV)-immune subjects in comparison to FV naïve subjects
● After a 2nd or a 3rd dose
● In younger subjects (youngest group 2-11 years)
Summary of Safety Data so far
| 27
● No mild dengue-like syndrome observed
● Low vaccine viremia
● Similar rate of AEs and SAEs reported in Dengue vaccine group and control
● No evidence to suggest a safety concern with the vaccine
10
Immunogenicity Database
● Immuno status as of March 28th
● Nbr of subjects immuno post dose 3 with unblind data available
Phase Toddlers Children Adolescents Adults Total
Phase I 0 83 48 45 176Phase II 0 576 437 245 1258
| 28
Over 2,800 individuals have immune unblinded data after three doses of CYD Dengue vaccine
Phase II 0 576 437 245 1258Phase III 0 659 485 290 1434
Total 0 1318 970 580 2868
Key Phase II Immunogenicity ResultsPost-Dose 3
GMTs
1
10
100
1000
GM
T
●USA●Population
FV non inmune Adultss 18‐45 y
● 101 subjects
CYD12●Peru●Population
DEN+/‐ y YF+Children 2‐11 y
● 196 subjects
CYD24
| 2929
1CYD12 CYD22 CYD24 CYD28
CYD12 CYD22 CYD24 CYD28
● Vietnam●Population
DEN+/‐ y JE+/‐Chldren/adults 2‐45y
● 120 subjects
CYD22●Singapore●Population
DEN+/‐Children/adults 2‐45y
431 subjects
CYD28
% seropositive subjects
0
10
20
30
40
50
60
70
80
90
100
CYD12 CYD22 CYD24 CYD28
Tasa
de
sero
posi
tivid
ad (>
= 1
0l/d
il)
Seropositiviy ≥ 10
Serotype 1 Serotype 2 Serotype 3 Serotype 4
Summary of Immunogenicity Data so far
● Balanced immune response against all 4 serotypes after 3
doses of tetravalent Dengue vaccine
● Stepwise increase of seropositivity rates against each
serotype
| 30
● Higher immune responses observed in children
● Higher titers in subjects with previous flavivirus vaccination
● Higher titers in subjects previously exposed to wild type
dengue
11
Efficacy Clinical Trials
CYD15 Expanded Efficacy StudyCYD15 Expanded Efficacy StudyLatin AmericaLatin America• Countries: Colombia, Mexico, Honduras,
Puerto Rico, and Brazil• Age group: 9-16 years• N subjects: ~20,000
CYD14 Expanded Efficacy StudyCYD14 Expanded Efficacy StudyAsiaAsia• Countries: Thailand, Indonesia, Malaysia,
Viet Nam, Philippines• Age group: 2-14 years• N subjects: ~10,000
| 31
CYD23 First Efficacy StudyCYD23 First Efficacy Study• Country: Thailand• Age group: 4-11 years• N subjects ~4,000
Conclusions
● Dengue disease burden increasing globally
● Several dengue vaccines in development. Sanofi Pasteur CYD vaccine the most advanced
● > 20 clinical trials completed or ongoing
| 32
20 clinical trials completed or ongoing● > 28,000 subjects received > 1 dose of CYD vaccine● Favorable safety profile in children adolescents and adults● Balanced neutralizing antibody response against 4 serotypes
● First efficacy trial in Thailand – Results available later in 2012 and 2 major efficacy trials (in Asia and Latin America) ongoing
Thank you!
| 33
y