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Development - update
KONIKA XV Conference
Ikatan Dokter Anak Indonesia
Manado, Sulawezi 13 July, 2011
Alain Bouckenooghe, MD, MPH
Presentation Content
Introduction
Dengue Vaccine Development challenges
Sp Tetravalent Dengue Vaccine
Completed Phase I Clinical Trials
Summary of safety data
Summary of vaccine viremia data
Summary of immunogenicity data
Conclusion
Introduction
Adolescent diagnosed with dengue fever. Dengue Unit, Ratchaburi Hospital, Thailand Feb 2011
Malaria
Dengue
Population at risk
3 billion
3.6 billion
Endemic countries
108
125
Infections/year
243 million
70500 million
Severe cases/year
3.15 million
2.1 million
Deaths/year
863,000
21,000
Source: http://www.who.int/csr/disease/dengue/impact/en/
6
505714
Thailand
502207
Viet Nam
445140
131603
Philippines
126438
Malaysia
80522
Myanmar
57460
Sri Lanka
36570
Lao
India
33775
Cambodia
32166
Singapore
Bangladesh
Maldives
23905
18782
6822
Bhutan
2574
China
2325
Australia
2024
Timor-Leste
Japan
Nepal
Indonesia,
Thailand, Vietnam, Philippines and Malaysia are the first 5 countries
0
300000
400000
with highest
number of100000
reported cases200000
In Asia, most of the reported cases are severe cases*
*Severe cases: dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)
500
Monovalent
LAV DEN1
Sabin,
Schelsinger1
1st generation
Attenuation
of DEN viruses
LAV DEN1-4
US Army/Univ.
Hawaii
/Univ
MahidolThailand
/Fund.
Rockefeller2
Partnership
University
of Mahidol
Thailand
Proof of
concept
1st
generation
2nd
Generation
LAV
Proof of
concept
1994
2001
2004
2007
First
Pediatric
clinical
efficacy
study
First phase
III clinical
study
Dr Albert Sabin
1944-45
1970 -80
1 Science 1945;101(2634):640-642
2 AJTMH 2003;69(Suppl 6):5-11
2009
2010-11
4 different serotypes
Technical difficulties
Inter-serotype competition
Need for balanced protection against all four
serotypes
Technology
Phase I
Phase II
Chimeric YF17D
attenuated virus
Whole virion attenuated
virus
Chimeric Deng 4
attenuated virus
Merck/HB
Recombinant E subunit
Inviragen
Chimeric Deng 2
attenuated virus
GSK
Inactivated virus
Other Candidates
11
Pre-clinical
Phase III
12
13
*Farshad Guirakhoo et al. Live Attenuated Chimeric Yellow Fever Dengue Type 2 (ChimeriVax-DEN2) vaccine: Phase I Clinical
Trial for Safety and Immunogenicity. Human Vaccines. 2006 2(2): 60-67
**Dennis Morrison et al. A novel tetravalent Dengue vaccine is well tolerated and immunogenici against all 4
serotypes in Flavivirus-Naive adults. Journal of Infectious Diseases. 2010 201: 370-7
14
Dengue vaccine
Population
Country
Status
CYD01
Monovalent D2
(3&5 log10 PFU)
US
Completed
Tetravalent
(4 log10 CCID50/
serotype)
Tetravalent
(5 log10 CCID50/
serotype)
US
Tetravalent
(5 log10 CCID50/
serotype)
phase I
CYD02
Phase I
CYD04*
Phase I
CYD05
Phase I
CYD06
Phase I
Tetravalent
(5 log10 CCID50/
serotype)
Completed
Completed
US
Philippines
Mexico
Completed
*Dennis Morrison et al. A novel tetravalent Dengue vaccine is well tolerated and immunogenici against all 4
serotypes in Flavivirus-Naive adults. Journal of Infectious Diseases. 2010 201: 370-7
** Bruno Guy et al. Development of Sanofi Pasteur Tetravalent Dengue Vaccine. Hum Vaccines 2010; 6-9: 697-705
16
17
In Endemic Populations
Booster effect in people previously exposed to wild type dengue
Stepwise increase of seropositivity rates against each serotype with 3
dose (0, 3-4 and 12 month schedule)
Two doses with a longer interval (0/8 months) induced a similar
response
18
Serotype 2
100
100
60
90
40
79.3
53
58.5
67.9
87.2
64.1
51.2
20
% Subjects
% Subjects
80
80
60
40
56 64.3
20
58.5
76.5 71.8
93.8 89.7
0
Pre-Vacc 1
Post-Vacc 1
Post-Vacc 2
Post-Vacc 3
Pre-Vacc 1
Serotype 3
100
80
80
60
40
58.5
67.5
70.7
95
84.1
61.9
Post-Vacc 1
Post-Vacc 2
Post-Vacc 3
92.7
96.3 92.3
Serotype 4
100
97.4
66.7
20
% Subjects
% Subjects
70.7
60
40
73.5
57.1 56.1
82.1
58.5
20
0
Pre-Vacc 1
Post-Vacc 1
Post-Vacc 2
Post-Vacc 3
Pre-Vacc 1
Post-Vacc 1
Post-Vacc 2
Post-Vacc 3
20
Code
Populations
Country
Status
CYD08
Philippines
On-going
CYD10
Australia
CYD11
Adults , n=150
Mexico
Completed
CYD12
Adults, n=250
US
Completed
CYD13
Mexico,
Puerto Rico, Honduras
Colombia
Ongoing
CYD22
Vietnam
Ongoing
CYD23
Thailand
Ongoing
CYD24
Peru
Ongoing
CYD28
Singapore
Ongoing
CYD30
Brazil
Preparation phase
Completed
Immunogenicity
Balanced immune response against all 4 serotypes after 3 doses
of tetravalent Dengue vaccine
Higher immune responses observed in children
Previous flavivirus vaccination has a priming potential
Booster effect in people previously exposed to wild type dengue
Stepwise increase of seropositivity rates against each serotype
with 3 dose
21
CYD12
S&I
Adults
FV naive
US
CYD11
S&I
Adults
FV naive
Mexico
CYD13 /CYD30
S&I
Adolescents
Den+/Latin Am
CYD24
S&I
Children
YF+, Den+/Peru
CYD23
POC -Efficacy
Children
JE+/-, Den+/Thailand
CYD32
S&I
Children
JE+/-,Den+/Malaysia
22
Co-administration
Efficacy trials
CYD14- CYD15
Large Ph 3 efficacy
CYD17
LtoL
Adults
Nave
Australia
Encouraging results
May 2011: more than 6,000 people have received
at least one dose of Sanofi Pasteurs dengue
vaccine
Well tolerated with a similar safety profile after
each dose
A balanced immune response against all four
serotypes after 3-dose of the vaccine
End of 2012: results of first efficacy study Thailand
23
24
Study vaccine
Number of subjects
Group 1
6,852
Group 2
3,426
Total
10,278
Malaysia
(National
Coordinator)
Philippines
Viet Nam
Thailand
Dr. Tawee
Chotpitayasunondh
(Principal Investigator)
(Coordinating
Investigator)
(Coordinating
Investigator)
Dr Luong Chan
Quang
(PI - Jakarta)
(Country Coordinator)
Prof. Dewa
Nyoman Wirawan
(PI Bali)
Dr. Kusnandi
Rusmil Rusli
(PI Bandung)
25
Dr. Revathy
Nallusamy
(PI Penang)
(PI Cebu)
Dr. Punnee
Pitisuttithum
(Co-Investigator My
Tho)
Conclusion
The first clinical efficacy trial started in
February 2009 in Thailand
Objective: assess the vaccine efficacy in children
Key step in the development of the live
attenuated tetravalent dengue vaccine candidate
26
Conclusion
A safe and efficacious vaccine would be the best disease control
measure for endemic countries
Thank you
Merci
Terima
Kasih
Thank you
Salamat
m n
Maraming Salamat
Terima Kasih
Merci
Cm n
28