Dengue Virus and Its Risk to the U.S. Blood Supply

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

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.

Flaviviridae Family Genus Flavivirus WNV, Dengue, Yellow Fever, TBE PestivirusBovine Viral Diarrhea Viruses Hepacivirus Hepatitis C

Dengue Viruses

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

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 Dengue

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

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

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

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

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

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

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

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

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

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

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

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

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.

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.

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

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.

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.

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.

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

Dengue occurs in many of the same areas as malaria Dengue Malaria

Dengue Virus and Its Risk to the U.S. Blood Supply