Presentation

Safety issues for factor concentratesUpdate 2007

Albert Farrugia

WFH Blood Safety Advisor

Issues covered

• Assessments for vCJD risk through pd CFCs

• Prion filters

• (Prion tests)

• NAT for HBV et al

• Emerging infectious agents – H5N1

Impact of TSE clearance on mean potential vCJD risk/person/year (pdFVIII risk assessment table 5.3.A.)

Treatment interval + estimated UK vCJD prevalence

7-9 * 4-6 * 2-3

Episodic, no inhibitor, UK vCJD prevalence 1.8/106

1 in 3.2

billion

1 in 9.4 million

1 in 21,500

Episodic, no inhibitor, UK vCJD prevalence 1:4,225

1 in 100 million

1 in 105,000

1 in 159

Log10 TSE Clearance

* Available data suggests that all U.S.-licensed products are likely to have TSE clearance of > 4 log10

Risk Characterization (cont’d)Importance Analysis

Efficiency of Donor Deferral Policy

Yield of FVIII from plasma (IU/L plasma)

Quantity Infectivity in Blood (ID50/ml)

Efficiency of i.c. versus i.v. route

Prevalence UK vCJD (cases/million)

FVIII used per yr (IU/yr, person)

Log Manufacture Reduction vCJD Agent

Fig 2.A. Importance Analysis ranking influential factors for predicted vCJD exposure (yr) using prevalence estimates from 0.7 to 700 cases per million

+_

Prion Capture Filter (P-CaptTM)

• Dockable filter for leucodepleted (< 5 x 106) red cell concentrates suspended in additive solution or plasma

• Wet filter (40ml SAG-M)

MacoPharma P-CAPTTM Filter

Flow

Flow

PRDT Affinity Resin

Prion-depletedRCC

Flow

Prion CapturePrion

Red Cell Ligand

Principle of the P-Capt filter

PrPC

Incubation

Growing of units

Incubation

Growing of units

+

Protein Misfolding Cyclic Amplification (PMCA)

PrPSc

Soto et al. (2002) Trends Neurosci. 25:390-394

Sonication

Multiplication of units

Sonication

Multiplication of units

Pre-symptomatic detection of PrPSc in blood

Blood taken during incubation periodInfection Clinical disease

14 days

0/5

20 days 40 days 60 days 70 days 80 days Symptomatic

3/6 6/10 2/5 1/5 0/5 8/10Time, days Controls

Total/positives Infected

Total/positives Sensitivity/ specificity

14 5/0 5/0 0% / 100%

20 4/0 6/3 50% / 100%

40 5/0 10/6 60% / 100%

60 4/0 5/2 40% / 100%

70 5/0 5/1 20% / 100%

80 5/0 5/0 0% / 100%

Symptomatic 10/0 10/8 80% / 100%

Science 313:92-94

15B3 antibody15B3 antibody

PrPPrPScSc

Anti-IgM antibodyAnti-IgM antibody

Anti-PrP antibodyAnti-PrP antibody

ASSAY FORMAT: ELISAAnte mortem TSE Diagnostics

15B3 ELISA Diagnostic TestSheep with scrapie

Clinical Pre-Clinical

Cut off

Clinical impact of transfusion transmitted HBV

• 50% of recipients do not survive past 3 yrs.• Estimate of 5% chronic carrier rate in adults; may be lower with

low-dose inocula, or in setting of HBV vaccination• 15-25% of chronic carriers develop significant clinical disease

after decades• 0.25% of transfusion transmissions (1 in 40) will result in chronic

carrier state and 1 in 200 in long term disease• Severe disease impact in immuno-compromised transfusion

recipients may be greater than the natural history data suggest• HBV often persists in the liver in the absence of the chronic

carrier state; unknown significance• Potential for secondary transmission

Acute HBV Infection Profile

00

1010

2020

3030

4040HBV DNA Copies/mLHBV DNA Copies/mL

DaysDays

S/COS/CO

00 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 110110 120120 130130100100

1,0001,000

10,00010,000

100,000100,000

1,000,0001,000,000

HBV DNAHBV DNA HBsAgHBsAg Anti-HBcAnti-HBc Anti-HBsAnti-HBs

Cost-effectiveness of adding NAT to serologic testing to detect WP donations

Strategy Cost-effectiveness [range based on cost ranges]

MP-NAT for HIV/HCV, discontinue HIV p24 Ag

$4.3 million/QALY [2.7-5.8]

SD-NAT for HIV/HCV, discontinue HIV p24 Ag


MP-NAT for HIV/HCV/HBV, discontinue HIV p24 and anti-HBc.


SD-NAT for HIV/HCV/HBV, discontinue HIV p24 and anti-HBc.


Incremental CE of ID over MP-NAT: $15 million/QALY without HBV

$12 million/QALY with HBV

Jackson, Busch, Stramer, AuBuchon. Transfusion, July 03

• Historically: pandemics of significant impact

– 1918 Spanish flu, H1N1– 1957 Asian flu, H2N2– 1968 Hong Kong flu, H3N2– ... – 2006 new: H5N1 (?)

Pandemic influenza

Picture: Univ. South Carolina Medical School, Microbiology and Immunology Online

• Viremia in Asian influenza• ED Stanley et al., Trans Ass Am Phys [1966] 79: 376

• Human influenza with proved viremia: case report• K Naficy, NEJM [1963] 269: 964

• Viremia in influenza: a report of two cases• NI Lehmann & ID Gust, Med J Aust [1971] 2: 1166

• Proved viremia in Asian ... incubation period (!)• M Khakpour et al., Br Med J [1969] 4: 208

Influenza: viremia “… uncommon …” (?)

• Viremia in Asian influenza• ED Stanley et al., Trans Ass Am Phys [1966] 79: 376

– 4 / 15 nasal infections viremia detected

– starting @ day 1 after infection• preceding symptoms and nasopharyngeal virus shedding.

i.e. asymptomatic phase after infection

– viremia detectable for up to three days after nasal challenge

– 1 / 4 challenged individuals remained asymptomatic

Influenza: viremia “… uncommon …” (?)

• Vapor heating - FEIBA 10h / 60°C + 1h / 80°C, @ 7-8% residual moisture

Influenza H5N1 inactivation

virusmoisture content [%] 7.0 8.0 7.0 8.0 7.0 8.0 7.0 8.0 7.0 8.0

virus stock 7.4 7.2 7.0 6.7 8.0 7.7 8.8 8.9 6.3 6.5spiked material 6.2 6.1 6.0 5.5 7.1 7.0 7.7 7.6 5.3 5.0

after lyo 4.6 4.8 3.2 3.5 4.8 4.6 7.0 6.9 4.4 4.4at 59°C 3.5 3.2 2.7 2.6 1.1 1.4 6.0 5.7 4.2 4.2

180 min at 60°C 1.9 2.0 1.1 0.9 1.8 <1.1 4.2 3.5 2.9 2.7360 min at 60°C 1.7 1.8 <1.1 <0.6 <1.1 <1.1 <0.1 <0.1 2.0 <0.6505 min at 60°C 1.9 1.4 <1.1 <0.6 <1.1 <1.1 <0.1 <0.1 <0.6 <0.6

at 79°C 0.6 0.6 <1.1 <0.6 <1.1 <1.1 <0.1 <0.1 <0.6 <0.630 min at 80°C <0.6 <0.6 <1.1 <0.6 <1.1 <1.1 <0.1 <0.1 <0.6 <0.655 min at 80°C <0.6 <0.6 <1.1 <0.6 <1.1 <1.1 <0.1 <0.1 <0.6 <0.6

cumulative negatives <0.3 <0.3 <0.4 <(-0.1) <04. <0.3 <(-0.5) <(-0.5) <0.0 <(-0.1)

reduction factor (RF) >5.9 >5.8 >5.6 >5.6 >6.7 >6.6 >8.2 >8.0 >5.3 >5.1

H5N1HIV BVDV PRV WNV

• Solvent-detergent (SD) - Gammagard liquid 0.3% TNBP + 1% TX-100 + 1% T-80, 1h @ 18°C


virusconditions 50%, pH 5.2 5%, pH 5.2 50%, pH 5.2 5%, pH 5.2 50%, pH 5.2 5%, pH 5.2 nd 5%, pH 5.2 50%, pH 5.2 5%, pH 5.2 5%, pH 7.2virus stock 7.9 7.9 8.3 8.1 8.0 7.7 nd 8.7 7.2 7.4 7.3

spiked material 7.6 7.6 8.6 8.2 7.8 8.4 nd 7.8 7.1 7.1 7.12 minutes 4.5 5.0 <3.7 <3.7 <4.0 7.0 nd 5.7 <5.7 <3.7 6.2

10 minutes <4.5 4.9 <3.7 <3.7 <4.0 6.4 nd 5.0 <5.2 <3.7 5.720 minutes <4.5 4.5 <3.7 <3.7 <4.0 6.0 nd 4.5 <5.2 <3.7 5.730 minutes <4.5 3.7 <3.7 <3.7 <4.0 6.1 nd 4.5 <4.7 <3.7 5.9

30 minutes, bulk <3.6 - <2.8 <2.8 <3.1 - nd - <3.8 <2.8 -60 minutes <4.5 <3.7 <3.7 <3.7 <4.0 5.7 nd 3.7 <4.7 <3.7 5.2

60 minutes, bulk <3.6 - <2.8 <2.8 <3.1 - nd - <3.8 <2.8 -hold control 7.6 7.6 8.2 8.4 7.9 7.8 nd 6.9 3.8 2.7 6.4

cumulative negatives <3.2 - <2.4 <2.4 <2.7 - nd - <3.4 <2.4 -

reduction factor (RF) >4.5 >3.9 >6.2 >5.8 >5.1 2.8 - 4.1 >3.7 >4.7 1.9

H5N1HIV BVDV PRV WNV

• Pasteurization – Human Serum Albumin (HSA) 60°C / 10h, liquid


virusHSA concentration [%] 5 25 5 25 5 25 5 25 3.5 25

virus stock 8.0 8.0 7.1 7.1 7.4 7.4 8.6 8.8 7.3 7.3spiked material 6.9 7.0 6.0 5.8 6.7 6.6 7.8 7.4 6.6 6.5

at 59°C 5.4 4.8 4.5 4.2 1.6 0.9 3.1 2.2 2.9 3.030 min at 60°C <0.1 <0.6 1.8 0.6 <0.1 <0.6 0.9 <1.1 <0.1 <0.660 min at 60°C <0.1 <0.6 0.6 0.6 <0.1 <0.6 0.6 <1.1 <0.1 <0.6

120 min at 60°C <0.1 <0.6 <0.6 <0.6 <0.1 <0.6 <1.1 <0.6 <0.1 <0.6360 min at 60°C <0.1 <0.6 <0.6 <0.6 <0.1 <0.6 <0.6 <1.1 <0.1 <0.6600 min at 60°C <0.1 <0.6 <0.6 <0.6 <0.1 <0.6 <0.6 <1.1 <0.1 <0.6

600 min at 60°C, bulk <(-0.8) <(-0.3) <(-0.3) <(-0.3) <(-0.8) <(-0.3) <(-0.3) n.a. <0.1 <0.6cumulatively negative samples <(-1.0) <(-0.5) <(-0.4) <(-0.5) <(-1.0) <(-0.5) - - <(-1.0) <(-0.5)

hold control 7.2 7.1 6.0 6.0 6.5 6.4 8.3 8.0 5.9 6.2

reduction factor (RF) >8.0 >7.5 >6.4 >6.2 >7.7 >7.2 >8.1 >6.3 >7.6 >7.0

HIV BVDV PRV WNV H5N1

• Low pH / elevated temperatur - Gammagard liquid pH 4.2 – 4.8, 21d @ 30°C

• All samples spiked into IGIV intermediate: immediately negative !! as expected: optimal fusion activity @ pH<4.9

• E. Leikina et al, EMBO J [2002] 21: 5701


• Vapor heating• Solvent-detergent• Pasteurization• low pH @ elevated temperature

• inactivate H5N1 influenza, similar to other lipid-enveloped viruses tested

• re-assurance of safety margins for (manufactured) plasma-derivatives

Investigation with H5N1 results

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