1. Maria Rios, Ph.D. CBER/FDA Blood Products Advisory Committee May 1st, 2008 2007 WNV Epidemiology & FDA’s Recommendations on the Use of NAT to Reduce the Risk of Transmission of WNV in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)

2. Outline  Update on the 2007 season Human cases Animal cases including sentinel chickens Mosquito pools Geographical distribution  Draft Guidance on Blood Donor Screening for Infection with WNV Screening test platform MP-NAT ID-NAT Additional Testing Donor Counseling

3. WNV Update for 2007 47 states, DC & PR 43 states  USGS and/or State Dept report as WNV positive: 3,628 animal cases 8,625 mosquito pools  CDC: 3,623 human cases: 1,213 (33%) WNV ND 2,347 (65%) WNF (milder) 63 (2%) unspecified with a total of 124 deaths 2007 Activity in 47 states, DC & PR Human cases in 43 states

4. WNV in the U.S. Human cases from 1999 to 2007

5. WNV Activity in the US April 2008 4 Human cases TN (1 in Jan), AZ (1 Mar), MS (2 Mar, Apr) 1 horse (AL) 12 Dead Birds CA (11), SC (1) 10 Mosquito Pools CA (9), FL (1) 4 Sentinel Chickens FL (2), CA (2) WNV infection is Notifiable to the CDC Endemic ( peak spring/fall ) Since 2002 yearly: >1,000 WNV ND ≥ 100 fatalities Since 2005, onset of WNV clinical cases have been reported to the CDC from Jan to Dec

6. WNV Blood Screening in the U.S. From 2003 to 2007 resulted in:  Interdiction of ~2,600 WNV NAT-reactive units  Prevention of ~2,600 to 7,800 potential transmissions by transfusion *All seronegative for WNV; + Lack of f/up, sample, recipient loss ‡ Negative in MP-NAT and positive on ID-NAT (low viremia) Transmission by Transfusion Year200220032004200520062007 NAT-Reactive Units N/A>1,000224417441511 TT Confirmed* (n=32) 236 ‡1 ‡02 ‡0 TT Inconclusive+ (n= 26) 1961000

7. Current Testing Algorithm Test individually each specimen included in the pool If suitable: Released for transfusion MP-NAT NAT NR NAT R Unit (s) discard; Donor deferred for 120 days Additional tests performed for counseling purposes ID-NAT NR ID-NAT R Repeat NAT using same or alternate NAT assay of ≥ sensitivity Ab to WNV Note: Ab cross-reactivity among Flaviviruses PPV 98% Sensitivity 98%

8. Algorithm for Additional Testing of Index Donation Specimen Prior to Donor Counseling ID-NAT Reactive Repeat NAT using same or alternate NAT assay of ≥ sensitivity Ab to WNV Rep ID-NAT R Positive Present Positive Rep ID-NAT NR Absent False Positive or TN 2% TP on Follow up ≤ 10% of IR Rep NAT NR TP on Ab

9. Issues Regarding Testing 2003: 6 cases of TT-WNV after MP-NAT MP-NAT detects 75% of WNV infected units (25% undetected) 2004: ID-NAT used in high WNV activity regions ID-NAT implementation criteria: 1 in 1000 donations reactive or 2 MP-NAT positives in a week, whichever comes first Since selective ID-NAT: Three (3) confirmed cases of WNV transmission by transfusion (1 in 2004 and 2 in 2006)

10. Issues Regarding Testing In April 2007, the following considerations were presented to the BPAC Uniform criteria to initiate ID-NAT is desirable Fully automated NAT system licensed Paucity of data to define uniform criteria AABB voluntary recommendation: Bulletin #07-02  whether blood establishments should define and validate criteria to trigger ID-NAT and to revert back to MP-NAT

11. 2007 ARC studies on suitability of ID-NAT implementation criteria (SL Stramer, 2008) Results showed that ID-NAT was required to detect: 148/540 (27%) in 2003-2004 44/154 (29%) in 2005 76/212 (36%) in 2006 (in some cases early implementation based on 2 ID-PVD) 65/147 (44%) 2007 ARC evaluated criteria for ID-NAT implementation

12. ID-NAT Detected 42 Confirmed WNV Positive Donations in Validation Studies (SL Stramer, 2008) Trigger criteria 1 PVD** 2 PVD 2 PVD & 1:1000 Yield Incremental Yield 42*31 5 1126 37 **12 /42 (29%) were IgG only 20Yield minus IgG (FP?) Incremental Yield 10 15 25 30  New data show that the previous criteria for ID-NAT implementation are inadequate 6.2-fold increase 8.4-fold increase 4-fold increase 6-fold increase *Presumed viremic donor defined as ID-NAT with S/CO ≥ 17 or repeat reactive ID-NAT 5 (100%)(74%) (12%) (88%) (100%) (18%) (83%) (67%)

13. Draft WNV NAT Guidance for Industry Draft Guidance published on April 28, 2008 for comment purposes only 90-day comment period closing in July 27, 2008

14. Recommendations on Testing  Screen for WNV should be performed year-round using a licensed NAT on donor samples of whole blood and blood components intended for transfusion.  Either MP-NAT or ID-NAT may be used for WNV screening.  ID-NAT should replace MP-NAT during high WNV activity in your region (using a previously defined geographic area).

15. Screening Algorithm for Blood Donations ID-NAT reactive unit (s) If suitable, release unit for transfusion If suitable, release unit(s) for transfusion Using a licensed MP-NAT for WNV Using a licensed ID-NAT for WNV ID-NAT non-reactive MP-NAT non-reactive MP-NAT reactive ID-NAT non-reactive unit (s) Test each specimen in the pool by ID-NAT Discard unit (s). Defer donor (s) for 120 days. Retrieve in-date products from prior collections dating back 120 days. Initiate WNV ID-NAT for that region

16. Algorithm for ID-NAT Implementation ONE ID-NAT reactive unit MP-NAT reactive Test each specimen in the pool by ID-NAT Discard unit (s); Defer donor (s); Retrieve in-date products Initiate ID-NAT for all collections from that region in 24 hours If >24 hours of collection: consider performing retrospective ID-NAT testing of retention samples from collections within that time period If blood establishments wish to revert back to MP-NAT, they may do so when the high WNV activity in the defined geographic area has subsided (e.g., minimum of 7 days has passed without a single WNV ID-NAT reactive donation)

17. * If NAT for all JE viruses used, we encourage WNV discriminatory prior to counseling ª Cross-reactivity among different Flaviviruses. ID-NAT reactive unit (s) Perform additional testing on index donation specimen as follows: 1. Repeat ID-NAT using the same assay or an alternate NAT* of ≥ sensitivity 2. Test for WNV-antibodies (WNV-Ab) using a cleared Ab assay ID-NAT reactive & WNV-Ab either Pos or Neg ID-NAT non-reactive & WNV-Ab Positiveª ID-NAT non-reactive & WNV-Ab Negative Notify of deferral & counsel the donor as testing Positive for WNV infection Notify of deferral & counsel the donor as inconclusive for WNV infection. Encourage donor return after 30 days for follow-up testing by ID-NAT and WNV-Ab. Additional Testing Algorithm

18. Recommendations Regarding Labeling  Container label and instruction circular to reflect results of WNV NAT, consistent with labeling for other infectious disease markers “A Licensed Nucleic Acid Test (NAT) for West Nile Virus (WNV) RNA has been performed and found to be non-reactive.”  WNV reactive unit not to be shipped or used except as provided in FDA approved programs and/or research or autologous use only, and such units be labeled with appropriate warnings