sanofi pasteur Dengue Vaccine

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

Expanded Phase II/III Clinical Program

Summary of safety data
Summary of immunogenicity data

Conclusion

Introduction

A global public health

Challenge
2.5 billion people at risk in over 100
countries
220 million people infected annually

2 million, mostly children, develop a

severe form of the disease

Adolescent diagnosed with dengue fever. Dengue Unit, Ratchaburi Hospital, Thailand Feb 2011

1 PDVI Newsletter N 7, April 2010 available on: http://www.pdvi.org/PDVI_newsletter/newsletter.asp

2 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
3 WHO - Dengue and dengue haemorrhagic fever, Fact sheet n 117, March 2009, available on:
4http://www.who.int/mediacentre/factsheets/fs117/en

Dengue An Emerging Concern and Public Health

Priority
Second most important tropical disease after malaria

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: Global Malaria Report 2009 http://www.pdvi.org/anout_dengue/GBD.aspc

Global Distribution of Dengue

Source: http://www.who.int/csr/disease/dengue/impact/en/
6

DengueNet Total Dengue Cases reported 1998

2006
Indonesia

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

Dengue Vaccine Development challenges

From early scientific

discoveries

Monovalent
LAV DEN1
Sabin,
Schelsinger1

1st generation
Attenuation
of DEN viruses
LAV DEN1-4
US Army/Univ.
Hawaii
/Univ
MahidolThailand
/Fund.
Rockefeller2

To the leading candidate dengue vaccine from Sanofi Pasteur

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

Challenges for Dengue Vaccine R & D:

why has it been so difficult?

4 different serotypes
Technical difficulties
Inter-serotype competition
Need for balanced protection against all four
serotypes

There is no animal model for the disease

Theoretical risk of immunopotentiation after
sequential infections (antibody-dependent
enhancement - ADE) : need for a combined tetravalent
vaccine
10

Most Advanced Dengue Vaccine Strategies

Leading Dengue Vaccine Candidates:
Advanced candidates based on classic approaches
Current candidates largely based on molecular biology
Developer
Sanofi pasteur*
GSK/WRAIR
NIH

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

* Sanofi pasteur was in phase I adult TV in 2003

11

Pre-clinical

Phase III

Sp Approach to Vaccine Development

Live attenuated vaccine technology to optimise
protection
Finding the right balance between attenuation
(safety) and immunogenicity (efficacy)
No demonstrated correlate of human protection
Large efficacy and safety trials
Industrialization of the production process of vaccine
and consistent large-scale manufacturing

12

Sanofi Pasteur Dengue Vaccine Development

13

Sanofi Pasteur Tetravalent Dengue Vaccine Candidate

Sanofi pasteur is developing a dengue vaccine based a molecular
biology- based technology (ChimerivaxTM ) licensed-in from former
Acambis, Cambridge, USA in 1998*
Four live attenuated Dengue-YF17D viruses with genes encoding for
envelope protein of dengue (Pr-M and E) and the non structural and
capsid protein of the 17D Yellow Fever vaccine strain.
Each dose contains: 5log10 CCID50 of each dengue vaccine
serotype (1,2,3,4)
A good immunogenicity/safety balance and high seroconversion
rates against all 4 serotypes were established in 2007**

*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 Candidates Current Company Target

Product Profile
Description: Live attenuated virus, tetravalent (4 vaccinal strains cultured
in serum free Vero cells)
Pharmaceutical form: Powder and solvent for suspension for injection (0.5
ml)
Route of administration: Sub-cutaneous
Schedule: 3 injections 0 - 6 - 12 months
Dosage: 5 1 log10 CCID50 of each serotype for one dose
Storage: +5 C
Indication: Prevention of symptomatic dengue disease i.e. covering the
spectrum from Dengue Fever to severe Dengue cases due to serotypes 1,
2, 3 or 4.
Populations: Children as of 9 months of age and adults living in endemic
areas, people working in (traveling to) endemic areas
Priority: Endemic countries (Asia/Pacific, Latin America, Caribbean)

Completed Phase I Clinical Studies**

Code

Dengue vaccine

Population

Country

Status

CYD01

Monovalent D2
(3&5 log10 PFU)

Adults (18-40 yo)

n=56

US

Completed

Tetravalent
(4 log10 CCID50/
serotype)
Tetravalent
(5 log10 CCID50/
serotype)

Adults (18-40 yo)

n=99

US

Tetravalent
(5 log10 CCID50/
serotype)

Adults (18-45 yo)

Adolescents (12-17 yo),
Children (2-11 yo)
n=126
Adults (18-45 yo)
Adolescents (12-17 yo),
Children (2-11 yo)
n=126

phase I

CYD02
Phase I

CYD04*
Phase I

CYD05
Phase I

CYD06
Phase I

Tetravalent
(5 log10 CCID50/
serotype)

Adults (18-45 yo)

n=66

Completed
Completed

US

Philippines

Mexico

Long-term followup on-going

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

Summary of Safety from Phase I Clinical Studies

Reactogenicity profile (clinical & biological) comparable to
control vaccines
No increase in reactogenicity
In Flavivirus (FV)-immune subjects (Dengue or yellow
fever) in comparison to FV nave subjects
When moving to younger subjects (youngest group 2-11
years)
After a 2nd or a 3rd dose
No Serious Adverse Events related to vaccination

17

Conclusions on Ph 1 Immunogenicity Data

Humoral immune response
In Non-endemic Populations
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

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

Overall, these data support the use of a schedule 0, 6 and 12 months

in further efficacy trials

18

Philippines - 2 to 45y - Seropositivity (PRNT50 > 10 [1/dil]) After

Each Dose
Serotype 1

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

Group 1 TDV > TDV > TDV

Group 2 TYP
YFV > TDV > TDV

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

A two dose schedule at 0-8/9 months apart induced similar seropositivity

and GMT as a three doses schedule at 0-3/4-12 months
19

Expanded Phase II Clinical Program (Endemic

Population)

20

Code

Populations

Country

Status

CYD08

Toddlers (12-15 mos)

n=210

Philippines

On-going

CYD10

Adults (18-40 yo), (DIV12 Trial subjects, VDV1,

VDV2 or YF primed), n=48

Australia

CYD11

Adults , n=150

Mexico

Completed

CYD12

Adults, n=250

US

Completed

CYD13

Children Adolescents (9-16 yo), n=600

Mexico,
Puerto Rico, Honduras
Colombia

Ongoing

CYD22

Adults (18-45 yo) Adolescents (12-17 yo)

Children (2-11 yo) ,n=180

Vietnam

Ongoing

CYD23

Children 4-11 yrs, n=4002

Thailand

Ongoing

CYD24

Children (2-5 yo) Children (6-11 yo) , n=300

Peru

Ongoing

CYD28

Adults (18-45 yo) Adolescents (12-17 yo)

Children 2-11 yo), n=1200

Singapore

Ongoing

CYD30

Children Adolescents (9-16 yo), n=150

Brazil

Preparation phase

*With 0, 6, 12 month schedule

Completed

Phase 2 experience: largely confirming ph 1 findings

Safety
Reactogenicity profile comparable to control vaccines
Ongoing Phase II studies, including CYD 23 and CYD 28: >5,000
subjects have received 1 dose (half 2-11 years in endemic
countries) and > 3,000 subjects have received 2nd dose.

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

From phase II trials to phase III trials

Phase II trials safety and immunogenicity (S&I)
CYD22
CYD47
CYD08
CYD28
S&I
S&I
S&I
S&I
Adults-ado
Child-Ado-Adults Toddlers/MMR Child-Ado-Adults
Children
Den+/Den+/Den+/JE+/-, Den+/India
Philippines
Singapore
Vietnam

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

Phase III trials

Large Scale S&I

CYD32
S&I
Children
JE+/-,Den+/Malaysia
22

Co-administration

Efficacy trials

CYD14- CYD15
Large Ph 3 efficacy

Lot to lot consistency

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

Participant dengue vaccine clinical study in Ratchaburi, Thailand Feb 2011

5 country efficacy trial: Study Design

Efficacy and Safety of a Novel Tetravalent Dengue Vaccine in
Healthy Children Aged 2 to 14 years in Asia
10,278 subjects will receive 3 vaccinations
at 0, 6 and 12months

A subset of 2,000 subjects will be evaluated for reactogenicity and

immunogenicity
Phase III, multi-center, observer-blind, randomized, placebo-controlled

24

Study vaccine

Number of subjects

Group 1

CYD dengue vaccine

6,852

Group 2

Placebo (NaCl 0.9%)

3,426

Total

10,278

Investigators and Study Centers

Indonesia

Malaysia

Prof. Sri Rezeki

Dato' Dr Hasan
Harun Hadinegoro Bin Abdul Rahman
(Coordinating
Investigator)

(National
Coordinator)

Philippines

Viet Nam

Thailand

Dr. Maria Rosario

Capeding

Dr. Tran Ngoc Huu

Dr. Tawee
Chotpitayasunondh

(Principal Investigator)

(Coordinating
Investigator)

(Coordinating
Investigator)

Prof. Sri Rezeki

Harun Hadinegoro

Dr. Hussain Imah

Hj. Muhammad

Dr. Maria Rosario

Capeding

Dr Luong Chan
Quang

(PI - Jakarta)

(PI Kuala Lumpur)

(PI San Pablo)

(Country Coordinator)

Prof. Dewa
Nyoman Wirawan
(PI Bali)

Dr. Kusnandi
Rusmil Rusli
(PI Bandung)

25

Dr. Revathy
Nallusamy

Dr. Mary Noreen

Chua

(PI Penang)

(PI Cebu)

Dr. Usa Thisyakorn

(PI Rachaburi)

Dr. Nyuyen Thi Nhu

Mai

Dr. Punnee
Pitisuttithum

(Co-Investigator My
Tho)

(PI Kamphaeng Phet)

Dr Phan Kim Hoang

(Co-Investigator Lung
Xuyen)

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

Next Step is phase 3 efficacy multi-country

study in Asia

26

Conclusion
A safe and efficacious vaccine would be the best disease control
measure for endemic countries

Clinical Development: Pase III

High seroconversion rate against all 4 sero-types
Good safety profile
Phase IIb study ongoing in Thailand
Other ongoing trials in endemic regions in all age groups
Availability of the vaccine
foreseen in next 3 to 5 years

New production facility

100m + dose capacity

Bulk facility planned to be

on line by 2014
27

Dengue Facility Under Construction

in Neuville, France

Thank you
Merci
Terima
Kasih
Thank you
Salamat
m n
Maraming Salamat
Terima Kasih
Merci
Cm n

28