Dengue Hemorrhagic Fever:A Model for International

CollaborationPrida Malasit, MD., FRCP

Medical Molecular Biology UnitSiriraj Hospital, Faculty of Medicine,

Mahidol University, Thailand

Dengue Hemorrhagic Fever DHF

• Caused by dengue viruses – flavivirus• Four serotypes exist in endemic areas• Endemicity in SE Asia, starting in 1950’s• Aedes aegypti as vector• Sudden onset of shock, leakage and hemorrhage

(skin and GI tract) mainly in children• Association of DHF with secondary infection

Problems – Public Health

Gubler D Emerging Infectious Diseases 1 55 1995

MOPH Statistics

1997-2001 SE Asian countries reported 1.2 million cases of DF/DHF

Gubler D. Adv Virus Res 1999;(53):35

Calculated average annual dengue infection rate

530 m

26 m/y

6.3 m/y

3000

380,000

Southeast Asia

Vaccine most cost effectiveBut will not be available

within few years

Clinical Manifestation

Days of illness

403938373635

°C

2 4 6 8 10 12

120100

8060

BPmm Hg

50

46

42

38

%Hct

240,000 245,000

25,000

Tourniquet +ve.Petichae +ve

Pleural EffusionAscites

Hypoproteinemia

platelets

Temp.

HCT

Narrow pulse pressureor shock

PlasmaDNAPBMC

SerologyPCRVirus isolationHLA

Challenge Questions for Research• Mechanisms of shock and leakage?

• What are they?• Any pharmacological agent assist the treatment?• Preventable – any agent to abort?• Why hemorrhage?

• Public health• Efficient Surveillance - Prediction of outbreak?• Vector control

• Vaccine Development

Dengue Research in Thailand – Key Factors• Continual research and clinical activities (since 1960):

• Children hospital – Bangkok and AFRIMS• Ministry of Public Health – country surveillance system and

laboratory services• Center for vaccine development – Mahidol University• Continual interest in basic/clinical research:

Existing graduate programs, BSc., PhD/MD• Internal granting system – the T2 Program• The Dengue research map – commissioned by T2

Key Areas from the Research Map

• Clinical database for bio-medical research• Vaccine development; vaccine trial site• Diagnostic development• Genomic/Genetic research• Clinical trials• National surveillance system - Cohort

High Quality Clinical Database and Specimen Collection for Dengue Bio-

Medical ResearchNetwork linking two clinical sites with a

University LaboratoryLinked to International Collaboration Sites

Reference LaboratorySpecimen repository

Serological & Virological

Clinical Management Scheme

Database

Pyrexia <3 days

Admission Criteria

Pyrexia >3 days

Admission

Consent

Treatment/Monitor

PCR

Follow-Up

Specimens

Clinical Study – Record and Specimens

Days of illness

403938373635

°C

2 4 6 8 10 12

120100

8060

BPmm Hg

50

46

42

38

%Hct

240,000 245,000

25,000

Tourniquet +ve.Petichae +ve

Pleural EffusionAscites

Hypoproteinemia

platelets

Temp.

HCT

Narrow pulse pressureor shock

PlasmaDNAPBMC

SerologyPCRVirus isolationHLA

BIOTECMedical

Biotechnology Unit

Overall Structure of the Units

SirirajMedical Molecular

Biology Unit, Office for Research & Development

Chiang MaiDpt. Microbiology, Fac. Of MedicineDpt. Immunology,

Fac. of Assoc. Med. Sciences

ParisPasteur

CNG

Imperial College London

Wash U.U.S.A.

Dengue Clinical

UnitsKhon Kaen

Songkla

Mainz Germany

Center of Center of ExcellenceExcellence

Cluster

Local EnvironmentGroup of Excellence

Collaborations

International Environment

Bring Local Problem into International Arena

Den-1

Den

-2

NYA Den-2 specific T cells

IFN-γ

19%

NYA Den-1 specific T cells

IFN-γ

29%

NYA Den-1/Den-2 specific T cells

IFN-γ

52%

4920

1417

256

2940

22 25

2825

IFN-γ+and/orTNF-α+

CD107a+

CD107a+

(IFN-γ+and/orTNF-α+)

No-response

Network with Mainz University

Potential diagnostic tool for early diagnosis of dengue hemorrhagic fever using circulating levels of NS1 protein with the host’s SC5b-9 complement complex

Academic Contributions 2543-6 (2000-3)• PhD new recruits 6

• RGJ program 2• PhD/MD Mahidol 4

• Master Degree 19• Graduated: master 10 • Current students:

• PhD 12• Master 21

• Post Doctoral 2

Key Local Factors• Set of highly-focused basic research targets• Establishment of essential technology and reagents

shared between partners• Competent personnel – handling necessary

techniques with quality• Adequate supports from local grants• High quality clinical database and specimens

Key International Factors• Willingness to share intellectual property rights - TRUST• Efficient management – communication, progress monitoring• Investment in “brain storming sessions” for project

developments (preferably co-funding)• Transparency and just sharing of resources, technology,

personnel, funding• Partnership in research funding• Partnership in research personnel development• Partnership in infrastructure developments• Long-term commitment from both partners