Dengue Vaccine

sanofi pasteur Dengue Vaccine Development - update

KONIKA XV Conference

Ikatan Dokter Anak Indonesia

Manado, Sulawezi 13 July, 2011Alain Bouckenooghe, MD, MPH

2

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

3

Introduction

4

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

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: http://www.who.int/mediacentre/factsheets/fs117/en

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

5

Dengue An Emerging Concern and Public Health Priority

Second most important tropical disease after malaria

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

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

6

Global Distribution of Dengue

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

7

DengueNet Total Dengue Cases reported 19982006

Indonesia, Thailand, Vietnam, Philippines and Malaysia are the first 5 countries with highest number of reported cases

In Asia, most of the reported cases are severe cases*

2024

2325

2574

6822

18782

23905

32166

33775

36570

57460

80522

126438

131603

445140

502207

505714

0 100000 200000 300000 400000 500000 600000

Nepal

Japan

Timor-Leste

Australia

China

Bhutan

Maldives

Bangladesh

Singapore

Cambodia

India

Lao

Sri Lanka

Myanmar

Malaysia

Philippines

Viet Nam

Thailand

Indonesia

*Severe cases: dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)

8

Dengue Vaccine Development challenges

9

Partnership

University

of Mahidol

Thailand

Proof of

concept

1st

generation

2nd

Generation

LAV

Proof of

concept

First

Pediatric

clinical

efficacy

study

First phase

III clinical

study

From early scientific discoveries

Monovalent

LAV DEN1

Sabin,

Schelsinger1

1st generation

Attenuation

of DEN viruses

LAV DEN1-4US Army/Univ.

Hawaii

/Univ

MahidolThailand

/Fund.

Rockefeller2

To the leading candidate dengue vaccine from Sanofi Pasteur

20041994 2007 2009 2010-111944-45 1970 -80 2001

1 Science 1945;101(2634):640-642

2 AJTMH 2003;69(Suppl 6):5-11

Dr Albert Sabin

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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

11

Developer Technology Pre-clinical Phase I Phase II Phase III

Sanofi pasteur* Chimeric YF17D attenuated virus

GSK/WRAIR Whole virion attenuated virus

NIH Chimeric Deng 4 attenuated virus

Merck/HB Recombinant E subunit

Inviragen Chimeric Deng 2 attenuated virus

GSK Inactivated virus

Other Candidates

X

* Sanofi pasteur was in phase I adult TV in 2003

Most Advanced Dengue Vaccine StrategiesLeading Dengue Vaccine Candidates:

Advanced candidates based on classic approaches

Current candidates largely based on molecular biology

12

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

13

Sanofi Pasteur Dengue Vaccine Development

14

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

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)

Dengue Vaccine Candidates Current Company Target Product Profile

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Code Dengue vaccine Population Country Status

CYD01phase I

Monovalent D2

(3&5 log10 PFU)

Adults (18-40 yo)

n=56US Completed

CYD02Phase I

Tetravalent(4 log10 CCID50/

serotype)

Adults (18-40 yo)

n=99US

Completed

CYD04*Phase I

Tetravalent

(5 log10 CCID50/ serotype)

Adults (18-45 yo)n=66

USCompleted

CYD05Phase I

Tetravalent


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

Children (2-11 yo)n=126

PhilippinesLong-term follow-

up on-going

CYD06Phase I

Tetravalent


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

Children (2-11 yo)n=126

MexicoCompleted

Completed Phase I Clinical Studies**

*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

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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

Summary of Safety from Phase I Clinical Studies

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Humoral immune response

In Non-endemic PopulationsBalanced immune response against all 4 serotypes after 3 doses of tetravalent Dengue vaccineHigher immune responses observed in childrenPrevious flavivirus vaccination has a priming potential

In Endemic PopulationsBooster effect in people previously exposed to wild type dengueStepwise 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

Conclusions on Ph 1 Immunogenicity Data

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

in further efficacy trials

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

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

Serotype 1

53

67.979.3

90

58.551.2

87.2

64.1

0

20

40

60

80

100

Pre-Vacc 1 Post-Vacc 1 Post-Vacc 2 Post-Vacc 3

% S

ub

jects

Serotype 2

64.3 58.5

89.793.876.570.7

5671.8

0

20

40

60

80

100


% S

ubje

cts

Group 1 TDV > TDV > TDV

Group 2 YFV > TDV > TDV

Group 1 TDV > TDV > TDV

Group 2 YFV > TDV > TDVSerotype 3

58.570.7

84.195

67.5 61.9

97.4

66.7

0

20

40

60

80

100


% S

ub

jects

Serotype 4

57.173.5

92.7 96.3

56.1 58.5

92.382.1

0

20

40

60

80

100


% S

ub

jects

TYP

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Code Populations Country Status

CYD08Toddlers (12-15 mos)

n=210Philippines On-going

CYD10Adults (18-40 yo), (DIV12 Trial subjects, VDV1,

VDV2 or YF primed), n=48Australia

Completed

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

CYD28Adults (18-45 yo) Adolescents (12-17 yo)

Children 2-11 yo), n=1200Singapore Ongoing

CYD30 Children Adolescents (9-16 yo), n=150 Brazil Preparation phase

Expanded Phase II Clinical Program (Endemic Population)

*With 0, 6, 12 month schedule

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Phase 2 experience: largely confirming ph 1 findings

SafetyReactogenicity 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.

ImmunogenicityBalanced 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

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From phase II trials to phase III trials

CYD22

S&I

Adults-ado

Children

JE+/-, Den+/-

Vietnam

CYD23

POC -Efficacy

Children

JE+/-, Den+/-

Thailand

CYD28

S&I

Child-Ado-Adults

Den+/-

Singapore

CYD24

S&I

Children

YF+, Den+/-

Peru

CYD12

S&I

Adults

FV naive

US

CYD13 /CYD30

S&I

Adolescents

Den+/-

Latin Am

Phase II trials safety and immunogenicity (S&I)

Phase III trials

Large Scale S&I Lot to lot consistencyCo-administration Efficacy trials

CYD11

S&I

Adults

FV naive

Mexico

CYD08

S&I

Toddlers/MMR

Den+/-

Philippines

CYD47

S&I

Child-Ado-Adults

Den+/-

India

CYD32

S&I

Children

JE+/-,Den+/-

Malaysia

CYD17

LtoL

Adults

Nave

Australia

CYD14- CYD15

Large Ph 3 efficacy

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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

Participant dengue vaccine clinical study in Ratchaburi, Thailand Feb 2011

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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

Study vaccine Number of subjects

Group 1 CYD dengue vaccine 6,852

Group 2 Placebo (NaCl 0.9%) 3,426

Total 10,278

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Indonesia Malaysia Philippines Viet Nam Thailand

Prof. Sri Rezeki Harun Hadinegoro

(Coordinating Investigator)

Dato' Dr Hasan Bin Abdul Rahman

(National Coordinator)

Dr. Maria Rosario Capeding


Dr. Tran Ngoc Huu

(Principal Investigator)

Dr. Tawee Chotpitayasunondh


Prof. Sri Rezeki Harun Hadinegoro

(PI - Jakarta)

Prof. Dewa Nyoman Wirawan

(PI Bali)

Dr. Kusnandi Rusmil Rusli

(PI Bandung)

Dr. Hussain Imah Hj. Muhammad

(PI Kuala Lumpur)

Dr. Revathy Nallusamy

(PI Penang)

Dr. Maria Rosario Capeding

(PI San Pablo)

Dr. Mary Noreen Chua

(PI Cebu)

Dr Luong Chan Quang

(Country Coordinator)

Dr. Nyuyen Thi Nhu Mai

(Co-Investigator My Tho)

Dr Phan Kim Hoang

(Co-Investigator Lung Xuyen)

Dr. Usa Thisyakorn

(PI Rachaburi)

Dr. Punnee Pitisuttithum

(PI Kamphaeng Phet)

Investigators and Study Centers

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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

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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

Dengue Facility Under Construction

in Neuville, France

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

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Terima Kasih

Thank you

Salamat

m n

Merci

Thank you

Merci

Maraming Salamat Terima Kasih

Cm n

Documents

Dengue Vaccine