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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