1. Dengue Virus and Its Risk to the U.S. Blood Supply
Blood Products Advisory Committee
December 14, 2010
Deborah R. Taylor, Ph.D.
Division of Emerging Transfusion Transmitted Diseases
Center for Biologics Evaluation and Research

2. Issue FDA is seeking the advice of the Blood Products
Advisory Committee on:
an appropriate strategy, including donor deferral, to mitigate the risk of dengue virus infection in recipients of blood and blood components for transfusion.
the potential utility of donor screening either by a nucleic acid-based test (NAT), an antibody test, and/or an antigen test, given the current technological limitations.

3. Flaviviridae Family Genus Flavivirus WNV, Dengue, Yellow Fever, TBE
Pestivirus Bovine Viral Diarrhea Viruses
Hepacivirus Hepatitis C

4. Dengue Viruses

5. Dengue Viruses Structural Proteins Nonstructural (NS) Proteins C E NS1
prM E
NS1 A B
NS3 A B
NS5
NS2
NS4
Core
Pre-Membrane
Envelope

6. Dengue Virus (DENV): Most common vector-borne virus
Threatens 2.5 billion people worldwide
More than 50 million infections occur each year
More than 24,000 deaths per year

7. DENV has expanded its range and increased worldwide
Urbanization
Population migration
Population growth
Global travel
Climate change
Ineffective mosquito control

8. Autochthonous DENV in the U.S.
Puerto Rico and the U.S. Virgin Islands
Pacific Islands

9. Both important mosquito vectors occur in the U.S.
Aedes aegypti
Aedes albopictus
2006

10. Primary DENV infection: Immune response
The incubation period can be 15 days with
an unknown level and duration of viremia.
50-80% of infections are asymptomatic.
Viral RNA

11. Primary DENV infection: Immune response
 The incubation period can be 15 days with
an unknown level and duration of viremia.
50-80% of infections are asymptomatic.
 The viral NS1 protein is secreted early in
infection and usually correlates with
symptom onset/severity.
NS1

12. Primary DENV infection: Immune response
The incubation period can be 15 days with
an unknown level and duration of viremia.
50-80% of infections are asymptomatic.
 The viral NS1 protein is secreted early in
infection and usually correlates with
symptom onset/severity.
 IgM is usually detectable at 3-5 days
after infection and declines at 2 weeks.
IgM
NS1

13. Primary DENV infection: Immune response
 The incubation period can be 15 days with
an unknown level and duration of viremia.
50-80% of infections are asymptomatic.
 The viral NS1 protein is secreted early in
infection and usually correlates with
symptom onset/severity.
 IgM is usually detectable at 3-5 days
after infection and declines at 2 weeks.
 IgG increases after 10 days and is lifelong.
IgG
IgM
NS1

14. Secondary DENV infection: Immune response
Rapid increase in IgG to higher
levels within 2 weeks.
IgG
IgM
NS1

15. Secondary DENV infection: Immune response
Rapid increase in IgG to higher
levels within 2 weeks.
Lower or absent IgM
IgG
IgM
NS1

16. Secondary DENV infection: Immune response
Rapid increase in IgG to higher
levels within 2 weeks.
Lower or absent IgM
Persons can acquire a second dengue infection with a different serotype,
and secondary infections place them at greater risk for severe dengue.
IgG
IgM
NS1

17. Transfusion-related Transmission
Transfusion transmitted DENV has been reported
involving all blood components:
Fresh Frozen Plasma (FFP)  Red Blood Cells (RBC)  Platelets
5 reported transmissions from 3 donations

18. The rate of transmissibility by transfusion may be inaccurate due to:
The high proportion of asymptomatic infections
The high incidence during outbreaks
The unknown duration of viremia
Lack of a licensed test
Lack of recognition by clinicians
Lack of surveillance and reporting

19. Potential Screening Methods:
Currently, there are no FDA approved or licensed tests for diagnosis or screening for DENV.
DENV can be detected by viral isolation, antigen, and nucleic acid tests.
Antibody tests may detect a past or present infection.

20. Potential Screening Methods:
Nucleic Acid Tests
RT-PCR and TMA assays are highly sensitive for detecting viral
RNA from all 4 serotypes early in infection.
Dengue NS1 antigen ELISA
NS1 antigen assay may be useful for the detection of the
virus early in infection to identify asymptomatic infected people.
Immunoglobulin IgM or IgG ELISA
May not reflect an active infection but may confirm a past or present
infection.

21. Risk of Dengue Virus Infection: Presentations
K. Tomashek DENV Epidemiology in the U.S. and territories
L. Petersen Risk Model to Define Rate of Infectious Units During
DENV Outbreaks: Endemic vs Nonendemic Areas
M. Rios Dengue Virus Panel Development
M. Busch Overview of Data on Blood Donor Testing and
Transfusion Transmission of Dengue Virus
H. Margolis Experience with Dengue Virus Antigen Tests
S. Stramer Recent Experience in Testing Blood Donors in
Puerto Rico and Key West, FL

22. Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of Dengue viruses in the US?
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic / non-outbreak areas who have traveled to an outbreak and/or endemic area? If so, what deferral period should FDA consider?
Please discuss what interventions, if any, would be appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
Please comment on the potential utility of Dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.

23. Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of Dengue viruses in the US?
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic / non-outbreak areas who have traveled to an outbreak and/or endemic area? If so, what deferral period should FDA consider?
3. Please discuss what interventions, if any, would be
appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
4. Please comment on the potential utility of Dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.

24. Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of Dengue viruses in the US?
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic / non-outbreak areas who have traveled to an outbreak and/or endemic area? If so, what deferral period should FDA consider?
Please discuss what interventions, if any, would be appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
Please comment on the potential utility of Dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.

25. Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of Dengue viruses in the US?
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic / non-outbreak areas who have traveled to an outbreak and/or endemic area? If so, what deferral period should FDA consider?
Please discuss what interventions, if any, would be appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
Please comment on the potential utility of Dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.

26. Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of Dengue viruses in the US?
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic / non-outbreak areas who have traveled to an outbreak and/or endemic area? If so, what deferral period should FDA consider?
Please discuss what interventions, if any, would be appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
Please comment on the potential utility of Dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.

27. Questions for the Committee:
Are safety interventions warranted to address the risk of transfusion transmission of Dengue viruses in the US?
Do the available scientific data support a temporary deferral for donors living in U.S. non-endemic / non-outbreak areas who have traveled to an outbreak and/or endemic area? If so, what deferral period should FDA consider?
Please discuss what interventions, if any, would be appropriate for donors who are residents of endemic or outbreak regions within the U.S. and its territories.
Please comment on the potential utility of Dengue virus tests (nucleic acid, antibody and antigen tests) in donor screening.

28. Potential Interventions
Testing with or without confirmatory test
Import restrictions from endemic areas to nonendemic areas
New questions for donor questionaire
-Deferral for travel
-Deferral for residents of outbreak region
-Deferral for residents of endemic region

29. Dengue occurs in many of the same areas as malaria