Transcript Control

Pathogen inactivation
New progress
Antonio Piga
Hemoglobinopathies Centre
Department of Clinical and Biological Sciences
University of Torino, Italy
[email protected]
Mechanism of action of pathogen
inactivation
Requirements for pathogen inactivation
1. Effective to eliminate pathogens
2. Maintaining the quality of blood products for
transfusion
3. Safe
4. Simple and cost-effective to implement in the
preparation of blood components
Declining Risks of major TTVs linked to interventions, BUT accelerating
rate of Emerging Infectious Diseases (EIDs) of concern to blood safety
Risk per Unit
XMRV
CHIKV
DENV
Leishmania
H1N1 influenza
Monkey Pox
SARS
WNV
SFV
PTLVs
HBV
T cruzi
1:1000
ICL
HCV
1:100
vCJD
Emerging Infectious Disease Threats
1:10,000
HIV
1:100,000
1:1,000,000
<1984 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Revised Donor
Deferral
Criteria
HBsAg
Screening
HIV Ab
Screening
HCV Ab
Screening
NANB Hepatitis Surrogate Testing
p24 Ag
Testing
HCV and
HIV NAT
WNV NAT
T cruzi Ab
Screening
HBV NAT
vCJD Deferral Criteria
Adapted from Busch MP, TRANSFUSION 2006;46:1624-1640
Why do infections emerge?
Source
Contributing Factors
 New agent (vCJD)
 Behavioral change among humans
 Species jump (HIV, SARS)
 Environmental change
(Dengue virus)
 Failure of control-
drug/vaccine resistance
and mutations (HBV
mutants)
(HIV)
 Inactivation resistant agents (B19,
HAV, prions)
 Intensive modern farming
practices (vCJD)
 Susceptible hosts (CMV)
 Transport of agents, reservoirs,
vectors (WNV)
 Population movement (T.cruzi,
chikungunya)
Movement of Hosts and Vectors
courtesy of MP Busch
Be a virus, see the world
Daily airline traffic patterns
Spatial epidemiology and evolution of WNV across N. America
derived from phylogenetic analysis of viremic blood donations
Pybus OG, PNAS, 2012
West Nile virus (WNV) Clinical Activity
reported to CDC,United States, 2012
(Sept. 18, 2012; N of Human Cases = 3,142)
West Nile Virus Cases in EU and Neighbouring, 2011
Source: ECDC
Rizzo C, Eurosurveillance, 2012
Dengue Viruses
•
•
•
•
Members of the genus Flavivirus
Transmitted by the Aedes mosquito; mosquito => human cycle
4 viruses: DENV1, 2, 3, and 4
Over 2.5 billion people live in risk areas for dengue infection
Dengue Risk in Puerto Rico Blood Donors 1995 - 2010
Peterson and Biggerstaff Transfusion 2012
Dengue Virus, August-October 2012 activity
Usutu Virus in Europe
Culex pipiens pipiens
Flaviviruses (similar to WNV)
Enveloped, icosahedral
nucleocapsid
Ss + RNA strand, 11kb
40-60 nm size
Mosquito transmitted
Infects birds & horses
The icons signify cases of
detection of the virus per species
ENIVD: European Network for
Diagnosis of Imported Viral Diseases
15
Vazquez et al. Euro Surveill. 201116(31) 19935
The discovery curve for human virus species
Rapid pace of viral discovery is
providing many “orphan viruses” as
candidate pathogens
Woolhouse M E et al. Proc. R. Soc. B 2008;275:2111-2115
Vazquez et al. Euro Surveill. 2011, 16(31) 19935
Vazquez et al. Euro Surveill. 201116(31) 19935
EID agent priority matrix
Stramer SL, 2009
Transfusion-transmitted Babesiosis in
the US
Herwaldt BH, 2011
Ann Int Med
21
162 cases from 1979-2009 with a 19% fatality rate
US Babesiosis – 10 new cases
22
Earliest known representation of
limb atrophy presumed due to
poliomyelitis.
Egypt, 1403–1365 BC.
from Ny Carlsberg Glyptotek.
http://www.aabb.org/Content/About_Blood/Emerging_Infectious_Disease_Agents/appendix2.htm
EUFRAT: risk model scheme
(Donor) population
infectivity
Donations
Released
components
End products
Recipients
Population
Whole
blood
RBC
RBC: 1/1
Plasma recovered
FFP: 1/1
Platelets pooled
Platelets: 5/1
Plasma-pheresis
FFP: 1/2
Platelet-pheresis
Platelets: 1/1
R
E
C
I
P
I
E
N
T
S
γ1
Donors
Infected
γ2
Plasma
pheresis
γ3
Platelet
pheresis
DHQ
Prevalence
Prevalence of
of infection
infection
in
(donor)
population
in (donor) population
STEP 1
Blood processes
and interventions
Testing
Number
Number of
of
infected
donations
infected donations
STEP 2
Number
Number of
of infected
infected
released
components
released components
STEP 3
Number
Number of
of infected
infected
end
products
end products
Risk
Risk of
of infection
infection
in
recipients
in recipients
STEP 4
STEP 5
Testing for TTDs
Summary
 Expanding the testing for known pathogens has kept
the blood safer over time
 Each new test adds safety at exponentially
increasing costs
 Emerging pathogens keep testing invariably on delay
and incomplete
 Effective and safe pathogen inactivation is the
answer
Pathogen Inactivation Technologies (PIT)
- for platelets
- for plasma
- for red cells
Pathogen Inactivation Technologies (PIT) for platelets
Solheim BG, Transfusion and Apheresis Science, 2008
Current INTERCEPT Platelet and
Plasma Use
Routine use at over 100 centers in 18
countries
More than 1,000,000 doses transfused
: Routine Customers
Chile
Réunion
Canary
Islands
Martinique
Guadeloupe
French
Polynesia
BE SURE.
29
French National Hemovigilance:
Platelet Transfusion 2006 to June 2012
PC Transfused
Transfusion-related
sepsis cases (deaths)
Conventional PC
1, 601,478
37 (7)
INTERCEPT PC
115,648
0
Agence Francaise de Securite Sanitaire des Produits de Sante (2006-2011).
Rapport Hemovigilance 2006. Paris, Afssaps.
P=0.07
D Kientz et al. 13th International Haemovigilance Seminar, Amsterdam, The Netherlands
February 9 - 11th, 2011
L Corash et al. 14th International Haemovigilance Seminar, Montreal, Canada, April 25-27 2012
BE SURE.
Pathogen Reduction Technologies (PIT) for plasma
Solheim BG, Transfusion and Apheresis Science, 2008
Pathogen Reduction Technologies (PIT) for plasma
Solheim BG, Transfusion and Apheresis Science, 2008
Pathogen Reduction Technologies (PIT) for red cells
Solheim BG, Transfusion and Apheresis Science, 2008
Pathogen Inactivation for all 3 Blood
Components:
S-303 Treated Red Blood Cells:
William Reed, MD
Director, Clinical Research and Medical Affairs
Torino and Cagliari
September, 2012
BE SURE.
INTERCEPT RBC: Mechanism of Action
S-303 is a nucleic acid-targeted alkylator that quickly diffuses into
viruses, bacteria, parasites and blood cells and is designed to
react quickly and decompose
Glutathione (GSH) is used to quench side reactions of the effector
with other biological materials
BE SURE.
Second Generation INTERCEPT RBC
Clinical Process
BE SURE.
Pathogen Inactivation Efficacy Evaluations
Pathogen
Mean Log
Reduction*
First generation system
Plasmodium
falciparum
>6.8
Babesia microti,
>4.9
Trypanosoma
cruzi
>5.3
West Nile virus
>6
Second generation system – tube
study
XMRV
>4
*n=1-3 RBC units or tubes
Pathogen
Mean Log
Reduction**
S. aureus
5.1  0.3
S. marcescens
5.1  0.1
Y. enterocolitica
≥6.8  0.2
E. coli
≥6.7  0.1
HIV
>5.9  0.1
Bovine viral
diarrhea virus
>4.8  0.1
Blue Tongue
≥5.0  0.4
Adenovirus Type 5
>7.4  0.2
**Second generation process, n=4 full RBC units BE SURE.
Henschler R, Transfus Med Hemother, 2011
Pathogen Inactivation Process Optimization:
Reduce interaction of S-303 with RBCs and
improve process flexibility
First Generation
Process
• 0.2 mM S-303
• 2 mM GSH (acidic)
• Compound adsorption
device to remove
residual S-303
• Erythrosol storage
solution
Second Generation
Process
0.2 mM S-303
20 mM GSH (Na salt)
Diluent solution for PI
Removal of treatment
solution and
replacement with
storage solution
• Approved RBC storage
solutions
•
•
•
•
BE SURE.
NEW Phase 1 Clinical, Second Generation: 24Hour Recovery meets FDA Requirements (n=27)
S-303
Control
88.0 ± 8.5
90.1 ± 6.9
1
1
Median Lifespan (T50, days)
32.8**
39.5
AUC (% of cells surviving)
22.0*
23.9
24-hour Recovery (%, Dual
Label, Cr-51 and Tc-99m)
Subjects with Dual Label
Recovery < 75%
* p<0.05, ** p<0.001
The 24-hour recovery was similar between groups and met FDA criteria
The median lifespan,T50, of Test RBC was within the reference range
of 32 to 37 days using 51Cr label
BE SURE.
Cancellas et al. Transfusion 2011
NEW Phase 1 Study, Second Generation: In
Vitro RBC Characteristics-- Day 35 (n=27)
Attribute
S-303
Control
Total Hemoglobin (g/unit)1
52.7 ± 3.6
Not measured
Hemolysis (%)2
0.24 ± 0.11
0.22 ± 0.13
Spun Hematocrit (%)2
59.7 ± 2.4*
62.4 ± 3.6
ATP concentration (mmol/g Hb)2
3.34 ± 0.80*
3.59 ± 0.81
6.404 ± 0.039*
6.483 ± 0.122
39.5 ± 3.6*
52.7 ± 6.5
pH (at 37oC)2
Extracellular Potassium (mM)2
1
2
Measured prior to storage
Measured after 35-days of storage
* p-value <0.05
The total hemoglobin, hemolysis and hematocrit meet the requirements for
leukoreduced RBC in additive solution
The ATP concentration is well over the critical threshold of
2.0 mmol/g Hb (Hess JR, Greenwalt TG. Transf Med Rev., 16 (4), 283-295 (2002))
BE SURE.
North A, Transfusion, 2011
Clinical Studies
Europe: Acute and chronic anemia separately
•
•
Chronic anemia – thalassemia major
Acute anemia – cardiac surgery
US: thalassemia and sickle cell anemia
•
•
Chronic transfusion
Final design will require Hgb increment data from Europe
and US
BE SURE.
Italian Thalassemia Study
Phase 3 study of efficacy and safety
of S-303 treated RBC components
Investigators:
A Piga - Torino
R Galanello – Cagliari
43
Design
Randomized, controlled, double-blind,
crossover study to evaluate both efficacy
and safety of S-303 treated RBC
components in 70 subjects
4 transfusion cycles for Test and 4 for Control
2 additional wash-n cycles for each period
Statistical hypothesis of non-inferiority
Non-inferiority margin of 15%
44
Italian Thalassemia Study
•Transfusion-dependent thalassemia major patients (n = 70)
• Randomized, controlled, double-blind, crossover study
• Statistical hypothesis of non-inferiority
•1° efficacy endpoint = Hemoglobin usage
•1° safety endpoint = Immunogenicity with repeat exposure
n=35
Screen,
randomize
n=35
INTERCEPT
Control
2
txns*
4 txns
2
txns*
4 txns
2
txns*
4 txns
2
txns*
4 txns
Control
INTERCEPT
Each patient is on study ~9-12 months
* Patients receive 2 wash-in transfusions
followed by 4 transfusions of INTERCEPT or control.
45
Secondary Efficacy Endpoints
Hb percent decline per day
Hb increment 1-h post-Tx
(Adjusted for mass of Hb transfused and
body weight)
46
Data and Safety Monitoring Board
A Cohen - thalassemia (Philadelphia)
L Pierelli – transfusion medicine (Rome)
T Peyrard - immunohematology (Paris)
47
Proposed U.S. Phase III – chronic RBC transfusion
Group A – Efficacy & Safety Assessment (n=82, cross-over)
1° efficacy endpoint = Hemoglobin usage
INTERCEPT
Control
2
txns*
6 txns
2
txns*
6 txns
2
n=41 txns*
6 txns
2
txns*
6 txns
n=41
Screen,
randomize
Control
INTERCEPT
Group B – Safety Assessment Only (n=291, 3:1 ratio)
n=218
INTERCEPT
3 txns
Screen,
randomize
n=73
Safety Assessment:
Groups A & B
(n=373)
1° safety endpoint
= % patients with S303 Abs with
clinically significant
hemolysis
3 txns
Control
* Group A patients receive 2 wash-in transfusions followed by 6 transfusions evaluated for efficacy.
New RBC Biologic Component for
Chronic Tranfusion?
• Pathogen inactivated
• WBC inactivated
(without gamma damage)
• Phenotyped/genotyped
• Very low plasma content
• Defined hemoglobin (gms)
• Defined Fe (mg)
• Diminished HLA and/or RBC
alloimmunization potential?
BE SURE.
Acknowledgements
William Reed
Nina Mufti
Anne North
Cerus Corporation
Concord, California USA
Renzo Galanello
University of Cagliari
Cagliari, Italy
Richard Benjamin
American Red Cross
Washington, DC, USA
Michael P Busch
Blood Systems Research Institute
University of California, San Francisco, USA
Filomena Longo
Alessandro Sandri
Simona Roggero
Marianna Genisio
Hemoglobinopathies Center,
University of Torino
Torino, Italy