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WNV has a positive strand RNA genome of about 11 kb that encodes several proteins
Primarily infects birds, occasionally also infects humans and horses
About 80% of infected persons remain asymptomatic, rest 20% develop mild febrile illness
(flu-like illness)
Approximately 1 in 150 infections results in meningitis or encephalitis
Advanced age is by far the most significant risk factor for severe neurologic disease
Viremic period can occur up to 2 weeks prior to symptoms and last up to a month from the
initiation of the infection
Background Information
Blood transmission of WNV has been confirmed in the recent US outbreak. However the
magnitude of the risk of WNV from transfusion is unknown.
Virus titer in blood is low compared to other transmissible viruses (~1-5x103
copies/ml) and the viremia is transient.
Viremia in encephalitis patients can be as high as 2.5x106 copies/ml
Viremia resolves rapidly after seroconversion to IgM
IgM can persist for a long time in some cases up to a year
WNV infection does not become chronic
West Nile Virus and Blood Safety: FDA’s Actions to Date
Alert notices posted on FDA’s website:
August 17, 2002: Vigilance in excluding symptomatic donors urged prior to any
actual report of transmission
October 3, 2002: FDA states its interest in facilitating development of donor
screening & supplemental tests
Cooperation with CDC, State Public Health Departments, Blood Organizations and Health
Resources and Services Administration (HRSA)
Epidemiological investigation of all possible cases of transfusion transmitted WNV
Advice provided on deferral of donors and withdrawal of in-date products collected from
suspect donors
West Nile Virus and Blood Safety: FDA’s Actions to Date,
continued…….
Timely and ongoing communication with blood community, health professionals, media,
congress & consumers
Stimulate case reporting
Balanced message on risk of WNV
Risk of WNV higher from mosquito bites
Risks and benefits of transfusion, transplantation
Uncertainty of current knowledge base
Congressional hearings on September 10 & 24, and October 3, 2002
West Nile Virus and Blood Safety: Current FDA Initiatives
FDA Guidance on donor and product management
Facilitate development of screening and supplemental tests
Cooperation with CDC, NHLBI and Blood Organizations on rapid surveys of WNV incidence in
donors
Unlinked study by CDC
Linked study by industry coordinated through REDS
Identify needs for additional research
WNV inactivation by storage
WNV removal and inactivation during plasma fractionation
Serosurveys in frequent blood product recipients
Goals of the WNV workshop held in NOV ‘02
Current status of WNV pathogenicity and epidemiology in the US
Review of methodologies that are suitable for blood/tissue donor screening
Industry perspective on the development of WNV screening assays that are suitable for
large scale screening
Strategies aimed at inactivation of WNV
Review of proposed studies on prevalence in donors
FDA’s expectations for licensure of WNV test
Issues relevant to implementation of WNV test
Current status of WNV pathogenicity and epidemiology in the US
In year 2002 total number of WNV cases reported were 3829 out which 225 deaths.
Practically whole of USA ( 44 states including DC) is endemic for WNV
Estimated risk of 1.8-2.7 infections per 10,000 donations nation wide but can be high in
highly endemic regions (16/10,000 with a mean of 6-8/10,000)
During Aug 28, 2002-Jan 3, 2003, 57 possible Transfusion-Transmitted cases reported
14 are confirmed (6 male and 8 female with a median age of 40 years), 19 are not
transfusion related, 24 are under investigation
WNV transmission is at its peak between late Aug- late Sept ( June to Nov in southern
states and July to Oct in northern states)
Review of methodologies suitable for blood/tissue donor screening
Serological (detection of WNV IgM antibodies):
Use of recombinant antigen, microsphere immunobead assay
Cross-reactivity with SLE, DEN, JE
High through put, low specimen volume (10 µl for serum and 30 µl for CSF),
Multiplexed, short turn around, and can be adapted to other platforms
Nucleic acid based tests (NAT):
Std PCR, Taqman RT-PCR, SYBER green RT-PCR, NASBA
High through put; 80- 300 samples can be extracted and analyzed
Detection limits 15 PFU/ml to 15,000 PFU/ml
Caveats: average human viremia is 18 PFU/ml
Minipool NAT detection rate is 50%, need to adopt smaller pools or ID-NAT.
Industry perspective on the development of WNV screening assays
Industry representatives presented plans with little data
NGI:- WNV NAT sensitivity is ~100 copies/ml (10- 200 copies/ml)
Asymptomatic donors prevalence rate is 1:8,000 in samples collected during Aug-Sept.
Some donations with high titers can be detected in pools of 64 or 512
GenProbe:-Validation data of TMA assay using synthetic RNA ( 7.6 copies/ml) and can
detect in viral lysate at 2x10-6 dilution
Roche: TaqMan PCR with sensitivity performance ~ 30-50 copies/ml, which is equivalent to
0.1 PFU/ml (1 PFU/ml= ~500 copies/ml)
Development of test will be under IND/BLA mechanism
Planning to have the validated test ready by Beginning of 2003 and testing under IND by
middle of 2003.
Strategies aimed at inactivation of WNV
Several manufacturers using methods such as solvent detergent, Psorlin, Riboflavin,
Inactine treatment for viral inactivation of plasma, platelets, RBC also showed
inactivation of WNV by such methods WNV ( > 4 log reduction ).
WNV survives in RBC at 4°C and in blood bank conditions as well as in leukocytes.
No need to demonstrate WNV specific inactivation
Need to show WNV specific inactivation similar to HIV and HCV, adds a layer of safety
Caveats:
Adverse events due to treatment of blood products
Immunological reactivity including anaphylaxis
Increased sensitivity of blood cells to other drugs
Specificity of the inactivation methods (pathogen vs host)
Studies needed to assess the risk
Review of proposed studies on prevalence in donors
Objective:
Develop analytical sensitivity panels
Compare WNV RNA and IgM assays
Prevalence of viremia (viral load, IgM antibody, virus culture status)
Compare MP vs ID- NAT
Confirm donor viremia by IgM and RNA testing of donor follow up sample
Assess disease outcome in Viremic donations, routine "call back" information
Establish back ground community-acquired WNV exposure rates
WNV incidence and transfusion-transmission rates
Exposure rates in recipients by testing autologous donations for IgM reactivity
Status of proposed studies on prevalence in donors
Planned studies underway:
Linked study (ARC , ~85,000 samples including high and low risk areas)
Research Study ( REDS/TRIPS small number of samples, serological testing)
Linked study ( ARC and CDC small number of samples, ~6000)
Linked study ( Roche, ~100,000 samples including high and low risk areas)
Time lines for these studies:
Phase I, assess performance of candidate WNV RNA assays validation ( < 50 GEq/ml at
50% detection limit) bench mark against CDC NAT test (completion first quarter of 2003)
Phase II, test up to 200, 000 samples which includes > 50, 000 high risk samples (
completion by summer of 2003)
CBER/FDA’s efforts towards the development of WNV screening tests
Development of Reference Panels for lot release testing
Panels to be tested by several laboratories in a collaborative study
Development of in-house TaqMan PCR and IgM test for WNV
Using in-house primers and comparing with CDC tests
Objective:
Study viral dynamics and infectious dose
Distribution in the blood components
Viral tropism
Correlation between viral strain and infectious outcomes
Regulatory Pathways for Assay Development
Donor screening and supplemental tests will be reviewed as biologic products under the
PHS Act
IND Applications are needed
Biological License Applications filed pre-market
The instrument and software portion of the application requires a separate 510(k)
submission. (See: CDRH Guidance for the Content of Pre-market Submissions for Software
Contained in Medical Devices.)
A licensed test used for screening blood donors has been determined to be a "major
level of concern."
Even if NAT tests alone are selected for donor screening, during clinical trials,
specific antibody assays will be needed, for follow-up testing of investigational NAT +
donors to validate the NAT + test results.
Different types of NAT assay also will be useful to validate the results of
investigational NAT
Use of different primers and probes
Cross-over testing with different assay technologies
Commercially available antibody tests for clinical diagnosis also will be needed.
Screening of Tissue and Organ Donors
Screening of tissue donors will come under FDA regulation after publication of a final
rule on donor eligibility.
As proposed, FDA’s rule would require use of approved donor screening tests.
A need exists to assess effectiveness of WNV screening tests for use with cadveric blood
samples.
Solid organs and bone marrow are regulated by HRSA, however, FDA approval is needed for
commercially available screening and diagnostic tests.
West Nile Virus and Blood Safety:
FDA’s Current Thinking on Management of Donors and Products
Donors with a medical diagnosis of WNV infection should be deferred until
14 days after the condition is resolved and at least 28 days from onset of symptoms or
diagnosis, whichever is the later date. An IgM positive antibody test result alone should
not be grounds for deferral.
Donors who report an otherwise unexplained post-donation febrile illness
suggestive of WNV infection in the setting of active WNV transmission in the community
should be deferred for 28 days from the onset of illness or 14 days after the condition is
considered to be resolved, whichever is the later date.
West Nile Virus and Blood Safety:
FDA’s Current Thinking on Management of Donors and Products
In-date components should be quarantined and retrieved if a donor later
reports a medical diagnosis of WNV.
Product quarantine and retrieval should cover a time period dating back to 14 days prior
to the onset of illness and 28 days subsequent to the onset of illness.
In the absence of symptoms, an IgM positive antibody test result should not be grounds
for product quarantine and retrieval.
Medical directors should exercise judgment when an otherwise unexplained post-donation
febrile illness occurs in the setting of active WNV transmission in the community.
West Nile Virus and Blood Safety:
FDA’s Current Thinking on Management of Donors and Products
Donors are considered to be potentially associated with transmission
of WNV if the infected recipient received the donor’s blood components within the 28
days before the onset of symptoms in the recipient.
For each associated donor, product quarantine and retrieval should be applied to
in-date components that were collected in the period from 28 days prior to the suspect
donation to 28 days after the suspect donation.
West Nile Virus and Blood Safety:
FDA’s Current Thinking on Management of Donors and Products
When a blood establishment receives information that a donor has a medical diagnosis of
WNV, blood establishments should consider notifying transfusion services to permit
"lookback" recipient tracing and notification.
If a post-donation illness is not diagnosed as WNV infection, actions to identify prior
recipients are not appropriate.
When an epidemiological investigation suggests that a specific donor is the likely
source of transmission of WNV to a transfusion recipient, "lookback"
notification of other recipients is appropriate.
Issues relevant to implementation of WNV test
Logistic issues for implementation of NAT tests
SOP modification, Process Qualification, Space, Biomedical information systems
Impact on the schedule release of other tests and testing strategies
Testing
Seasonal vs Year round
Geographical vs National
Need for testing related viruses
ID NAT vs minipool NAT
Past experiences from SLE epidemic
Apply estimated risks to determine the need for donor screening
FDA’s current thinking for licensure of WNV test
Summary
FDA’s current thinking is to recommend routine use of licensed donor screening
tests to detect acute donor infections
Possible use of donor screening tests under IND
Build on existing test platforms
Validation in donor screening environment
Adequate sensitivity to detect low level viremia
Possible need for individual unit NAT
Use of technologies ( virus concentration procedures) which will amplify the viral load
in samples
Development of reference panels to standardize different tests
General Conclusions
Close cooperation between FDA, PHS, Device manufacturers, blood organization in
developing tests (NAT/serological) for screening WNV in blood donors
Testing could start under IND by the next WNV epidemic
Meanwhile the safety of the blood supply can be ensured
In place procedures in blood banking practices
FDA guidance on " Current thinking on management of donors and products"
