, Volume 19, Issue 2, pp 79–96 | Cite as

Ensuring the Biologic Safety of Plasma-Derived Therapeutic Proteins

Detection, Inactivation, and Removal of Pathogens
  • Kang Cai
  • Todd M. Gierman
  • JoAnn Hotta
  • Christopher J. Stenland
  • Douglas C. Lee
  • Dominique Y. Pifat
  • Steve R. PettewayJr
Safety of Biologics


Human plasma-derived proteins, such as immunoglobulins, coagulation factors, α1-antitrypsin, fibrin sealants, and albumin, are widely used as therapeutics for many serious and life-threatening medical conditions. The human origin of these proteins ensures excellent efficacy and compatibility but may also introduce the risk of unintentional disease transmission. Historically, only viruses, particularly hepatitis and HIV, have posed serious threats to the safety of these therapeutics. Fortunately, between 1970 and 1990, the molecular biology of each of the major viruses was elucidated. These advances led to the development and implementation of effective donor screening tests, mainly based on immunoassays and nucleic acid testing, which resulted in a significant reduction of disease transmission risk. In addition, viral inactivation and removal steps were implemented and validated by manufacturers, further reducing the risk associated with known, as well as unidentified, viruses. Since the late 1990s, a different class of transmissible agent, referred to as prions, has been identified as a new risk for disease transmission. However, prion diseases are very rare, and prion transmission through plasma-derived proteins has not been reported to date. The prion-related risk is minimized by deferring donors with certain key risk factors, and by the manufacturing processes that are capable of removing prions. Advances in science and pathogen safety-related technology, compliance with good manufacturing practices by manufacturers, and increasingly stringent regulatory oversight, has meant that plasma-derived proteins have been developed into today’s highly effective therapeutics with very low risk of disease transmission.


  1. 1.
    Cohn EJ, Strong LE, Hughes WL, et al. Preparation and properties of serum and plasma proteins: IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946; 68: 459–75PubMedCrossRefGoogle Scholar
  2. 2.
    Campbell GL, Martin AA, Lanciotti RS, et al. West Nile virus. Lancet Infect Dis 2002; 2(9): 519–29PubMedCrossRefGoogle Scholar
  3. 3.
    Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1967–76PubMedCrossRefGoogle Scholar
  4. 4.
    Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1953–66PubMedCrossRefGoogle Scholar
  5. 5.
    Wagner SJ, Friedman LI, Dodd RY. Transfusion-associated bacterial sepsis. Clin Microbiol Rev 1994; 7(3): 290–302PubMedGoogle Scholar
  6. 6.
    Nordenfelt E, Kjellen L. Presence and persistence of Australian antigen in a Swedish hepatitis series. Acta Pathol Microbiol Scand 1969; 77(3): 489–94PubMedCrossRefGoogle Scholar
  7. 7.
    Alter HJ, Blumberg BS. Further studies on a ‘new’ human isoprecipitin system (Australia antigen). Blood 1966; 27(3): 297–309PubMedGoogle Scholar
  8. 8.
    Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244(4902): 359–62PubMedCrossRefGoogle Scholar
  9. 9.
    Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989; 321(22): 1494–500PubMedCrossRefGoogle Scholar
  10. 10.
    Leveton LB, Sox Jr HC, Stoto MA, editors. HIV and the blood supply: an analysis of crisis decision making. Washington, DC: National Academy Press, 1995 [online]. Available from URL: [Accessed 2005 Feb 22]Google Scholar
  11. 11.
    Kleinman S, Busch MP, Korelitz JJ, et al. The incidence/window period model and its use to assess the risk of transfusion-transmitted human immunodeficiency virus and hepatitis C virus infection. Transfus Med Rev 1997; 11(3): 155–72PubMedCrossRefGoogle Scholar
  12. 12.
    US Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Licensed/approved HIV, HTLV and hepatitis tests [online]. Available from URL: [Accessed 2005 Feb 22]
  13. 13.
    Urba WJ, Longo DL. Clinical spectrum of human retroviral-induced diseases. Cancer Res 1985; 45(9 Suppl.): 4637s–43sPubMedGoogle Scholar
  14. 14.
    Cooper DA, Imrie AA, Penny R. Antibody response to human immunodeficiency virus after primary infection. J Infect Dis 1987; 155(6): 1113–8PubMedCrossRefGoogle Scholar
  15. 15.
    Pantaleo G, Fauci AS. Immunopathogenesis of HIV infection. Annu Rev Microbiol 1996; 50: 825–54PubMedCrossRefGoogle Scholar
  16. 16.
    Busch MP, Kleinman SH, Nemo GJ. Current and emerging infectious risks of blood transfusions. JAMA 2003; 289(8): 959–62PubMedCrossRefGoogle Scholar
  17. 17.
    Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244(4902): 362–4PubMedCrossRefGoogle Scholar
  18. 18.
    Hosein B, Fang CT, Popovsky MA, et al. Improved serodiagnosis of hepatitis C virus infection with synthetic peptide antigen from capsid protein. Proc Natl Acad sci U S A 1991; 88(9): 3647–51PubMedCrossRefGoogle Scholar
  19. 19.
    Vrielink H, Reesink HW, van den Burg PJ, et al. Performance of three generations of anti-hepatitis C virus enzyme-linked immunosorbent assays in donors and patients. Transfusion 1997; 37(8): 845–9PubMedCrossRefGoogle Scholar
  20. 20.
    Schreiber GB, Busch MP, Kleinman SH, et al. The risk of transfusion-transmitted viral infections: the Retrovirus Epidemiology Donor Study. N Engl J Med 1996; 334(26): 1685–90PubMedCrossRefGoogle Scholar
  21. 21.
    Nubling CM, Scitz R, Lower J. Application of nucleic acid amplification techniques for blood donation screening. Infusionsther Transfusionsmed 1998; 25: 86–90Google Scholar
  22. 22.
    Walsh JH, Yalow R, Berson SA. Detection of Australia antigen and antibody by means of radioimmunoassay techniques. J Infect Dis 1970; 121(5): 550–4PubMedCrossRefGoogle Scholar
  23. 23.
    Cossart YE, Field AM. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis [letter]. Lancet 1970; I(7651): 848CrossRefGoogle Scholar
  24. 24.
    Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet 1970; I(7649): 695–8CrossRefGoogle Scholar
  25. 25.
    Schroeder DD, Mozen MM. Australia antigen: distribution during Cohn ethanol fractionation of human plasma. Science 1970; 168(938): 1462–4PubMedCrossRefGoogle Scholar
  26. 26.
    Andrassy K, Ritz E, Sanwald R. Australia antigen in various plasma fractions. Vox Sang 1970; 19(3): 357–8PubMedCrossRefGoogle Scholar
  27. 27.
    Blumberg BS, London WT, Sutnick AI. Practical applications of the Australia antigen test. Postgrad Med 1971; 50(6): 70–6PubMedGoogle Scholar
  28. 28.
    Hollinger FB, Vorndam V, Dreesman GR. Assay of Australia antigen and antibody employing double-antibody and solid-phase radioimmunoassay techniques and comparison with the passive hemagglutination methods. J Immunol 1971; 107(4): 1099–111PubMedGoogle Scholar
  29. 29.
    Kliman A. Australia antigen in volunteer and paid blood donors [letter]. N Engl J Med 1971; 284(2): 109PubMedGoogle Scholar
  30. 30.
    Palmer DR, Perry KR, Mortimer PP, et al. Variation in the sensitivity of HBsAg screening kits. Transfus Med 1996; 6(4): 311–7PubMedCrossRefGoogle Scholar
  31. 31.
    Biswas R, Tabor E, Hsia CC, et al. Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection. Transfusion 2003; 43(6): 788–98PubMedCrossRefGoogle Scholar
  32. 32.
    AuBuchon JP, Birkmeyer JD, Busch MP. Cost-effectiveness of expanded human immunodeficiency virus-testing protocols for donated blood. Transfusion 1997; 37(1): 45–51PubMedCrossRefGoogle Scholar
  33. 33.
    Busch MP, Taylor PE, Lenes BA, et al. Screening of selected male blood donors for p24 antigen of human immunodeficiency virus type 1: the Transfusion Safety Study Group. N Engl J Med 1990; 323(19): 1308–12PubMedCrossRefGoogle Scholar
  34. 34.
    Alter HJ, Epstein JS, Swenson SG, et al. Prevalence of human immunodeficiency virus type 1 p24 antigen in US blood donors: an assessment of the efficacy of testing in donor screening. The HIV-Antigen Study Group. N Engl J Med 1990; 323(19): 1312–7PubMedCrossRefGoogle Scholar
  35. 35.
    US Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Recommendations for donor screening with a licensed test for HIV-1 antigen [online]. Available from URL: [Accessed 2005 Feb 22]
  36. 36.
    US Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Product approval information, Licenses #1582, #1592, #1636 [online]. Available from URL: [Accessed 2005 Feb 22]
  37. 37.
    US Food and Drug Administration, Center for Biologies Evaluation and Research (CBER). Criteria for discontinuation of HIV-1 p24 antigen screening of source plasma: current thinking, 1999 [online]. Available from URL: [Accessed 2005 Feb 22]
  38. 38.
    Lanciotti RS, Kerst AJ. Nucleic acid sequence-based amplification assays for rapid detection of West Nile and St Louis encephalitis viruses. J Clin Microbiol 2001; 39(12): 4506–13PubMedCrossRefGoogle Scholar
  39. 39.
    Murakawa GJ, Zaia JA, Spallone PA, et al. Direct detection of HIV-1 RNA from AIDS and ARC patient samples. DNA 1988; 7(4): 287–95PubMedCrossRefGoogle Scholar
  40. 40.
    Kubo Y, Takeuchi K, Boonmar S, et al. A cDNA fragment of hepatitis C virus isolated from an implicated donor of post-transfusion non-A, non-B hepatitis in Japan. Nucleic Acids Res 1989; 17(24): 10367–72PubMedCrossRefGoogle Scholar
  41. 41.
    Giachetti C, Linnen JM, Kolk DP, et al. Highly sensitive multiplex assay for detection of human immunodeficiency virus type 1 and hepatitis C virus RNA. J Clin Microbiol 2002; 40(7): 2408–19PubMedCrossRefGoogle Scholar
  42. 42.
    Kievits T, van Gemen B, van Strijp D, et al. NASBA isothermal enzymatic in vitro nucleic acid amplification optimized for the diagnosis of HIV-1 infection. J Virol Methods 1991; 35(3): 273–86PubMedCrossRefGoogle Scholar
  43. 43.
    Ichiyama S, Ito Y, Sugiura F, et al. Diagnostic value of the strand displacement amplification method compared to those of Roche Amplicor PCR and culture for detecting mycobacteria in sputum samples. J Clin Microbiol 1997; 35(12): 3082–5PubMedGoogle Scholar
  44. 44.
    Marshall RL, Laffler TG, Cerney MB, et al. Detection of HCV RNA by the asymmetric gap ligase chain reaction. PCR Methods Appl 1994; 4(2): 80–4PubMedCrossRefGoogle Scholar
  45. 45.
    Terrault NA, Dailey PJ, Ferrell L, et al. Hepatitis C virus: quantitation and distribution in liver. J Med Virol 1997; 51(3): 217–24PubMedCrossRefGoogle Scholar
  46. 46.
    Robertson JS. International standardization of gene amplification technology. Biologicals 1998; 26(2): 111–3PubMedCrossRefGoogle Scholar
  47. 47.
    Holmes H, Davis C, Heath A, et al. An international collaborative study to establish the 1st international standard for HIV-1 RNA for use in nucleic acid-based techniques. J Virol Methods 2001; 92(2): 141–50PubMedCrossRefGoogle Scholar
  48. 48.
    Davis C, Heath A, Best S, et al. Calibration of HIV-1 working reagents for nucleic acid amplification techniques against the 1st international standard for HIV-1 RNA. J Virol Methods 2003; 107(1): 37–44PubMedCrossRefGoogle Scholar
  49. 49.
    Saldanha J, Gerlich W, Lelie N, et al. An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques. Vox Sang 2001; 80(1): 63–71PubMedCrossRefGoogle Scholar
  50. 50.
    Saldanha J, Lelie N, Heath A. Establishment of the first international standard for nucleic acid amplification technology (NAT) assays for HCV RNA: WHO Collaborative Study Group. Vox Sang 1999; 76(3): 149–58PubMedCrossRefGoogle Scholar
  51. 51.
    Saldanha J, Heath A, Lelie N, et al. Calibration of HCV working reagents for NAT assays against the HCV international standard: the Collaborative Study Group. Vox Sang 2000; 78(4): 217–24PubMedCrossRefGoogle Scholar
  52. 52.
    Saldanha J, Heath A, Lelie N, et al. A World Health Organisation (WHO) international standard for hepatitis A virus (HAV) RNA nucleic acid amplification technology (NAT) assays. Vox Sang. In press 2005Google Scholar
  53. 53.
    Saldanha J, Lelie N, Yu MW, et al. Establishment of the first World Health Organization International Standard for human parvovirus B19 DNA nucleic acid amplification techniques. Vox Sang 2002; 82(1): 24–31PubMedCrossRefGoogle Scholar
  54. 54.
    European Agency for the Evaluation of Medicinal Products/Committee for Proprietory Medical Products. The introduction of nucleic acid amplification technology (NAT) for the detection of hepatitis C virus RNA in plasma pools (CPMP/BWP/390/97): addendum to Note for guidance on plasma derived medicinal products, (CPMP/BWP/269/95) [online]. Available from URL: [Accessed 2005 Feb 22]
  55. 55.
    US Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Guidance for industry: use of nucleic acid tests on pooled samples from source plasma donors to adequately and appropriately reduce the risk of transmission of HIV-1 and HCV, 2001 [online]. Available from URL: [Accessed 2005 Feb 22]
  56. 56.
    Busch MP, Lee LL, Satten GA, et al. Time course of detection of viral and serologic markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening of blood and tissue donors. Transfusion 1995; 35(2): 91–7PubMedCrossRefGoogle Scholar
  57. 57.
    Piatak Jr M, Saag MS, Yang LC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993; 259(5102): 1749–54PubMedCrossRefGoogle Scholar
  58. 58.
    Morandi PA, Schockmel GA, Yerly S, et al. Detection of human immunodeficiency virus type 1 (HIV-1) RNA in pools of sera negative for antibodies to HIV-1 and HIV-2. J Clin Microbiol 1998; 36(6): 1534–8PubMedGoogle Scholar
  59. 59.
    European Agency for the Evaluation of Medicinal Products/Committee for Proprietory Medical Products. Note for guidance on virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses [online]. Available from URL: [Accessed 2005 Feb 22]
  60. 60.
    Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1. Transfusion 1999; 39(11–12): 1160–8PubMedCrossRefGoogle Scholar
  61. 61.
    Internal viral clearance reports. Research Triangle Park (NC): Bayer Biological Products, 2003. (Data on file)Google Scholar
  62. 62.
    Scheiblauer H, Nubling M, Willkommen H, et al. Prevalence of hepatitis C virus in plasma pools and the effectiveness of cold ethanol fractionation. Clin Ther 1996; 18Suppl. B: 59–70PubMedCrossRefGoogle Scholar
  63. 63.
    Steinbuch M, Audran R. Isolation of IgG immunoglobulin from human plasma using caprylic acid [in French]. Rev Fr Etud Clin Biol 1969; 14(10): 1054–8PubMedGoogle Scholar
  64. 64.
    Habeeb AF, Francis RD. Preparation of human immunoglobulin by caprylic acid precipitation. Prep Biochem 1984; 14(1): 1–17PubMedGoogle Scholar
  65. 65.
    Stephan W, Dichtelmuller H, Schedel I. Properties and efficacy of a human immunoglobulin M preparation for intravenous administration [in German]. Arzneimittel Forschung 1985; 35(6): 933–6PubMedGoogle Scholar
  66. 66.
    Lebing W, Remington KM, Schreiner C, et al. Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sang 2003; 84(3): 193–201PubMedCrossRefGoogle Scholar
  67. 67.
    Horowitz B, Piet MP, Prince AM, et al. Inactivation of lipid-enveloped viruses in labile blood derivatives by unsaturated fatty acids. Vox Sang 1988; 54(1): 14–20PubMedCrossRefGoogle Scholar
  68. 68.
    Lundblad JL, Seng RL. Inactivation of lipid-enveloped viruses in proteins by caprylate. Vox Sang 1991; 60(2): 75–81PubMedCrossRefGoogle Scholar
  69. 69.
    Dichtelmuller H, Rudnick D, Kloft M. Inactivation of lipid enveloped viruses by octanoic acid treatment of immunoglobulin solution. Biologicals 2002; 30(2): 135–42PubMedCrossRefGoogle Scholar
  70. 70.
    Trejo SR, Hotta JA, Lebing W, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 2003; 84(3): 176–87PubMedCrossRefGoogle Scholar
  71. 71.
    Burnouf T, Radosevich M. Affinity chromatography in the industrial purification of plasma proteins for therapeutic use. J Biochem Biophys Methods 2001; 49(1-3): 575–86PubMedCrossRefGoogle Scholar
  72. 72.
    Chandra S, Groener A, Feldman F. Effectiveness of alternative treatments for reducing potential viral contaminants from plasma-derived products. Thromb Res 2002; 105(5): 391–400PubMedCrossRefGoogle Scholar
  73. 73.
    Burnouf T, Radosevich M. Nanofiltration of plasma-derived biopharmaceutical products. Haemophilia 2003; 9(1): 24–37PubMedCrossRefGoogle Scholar
  74. 74.
    Barrowcliffe TW. Viral inactivation vs biological activity. Dev Biol Stand 1993; 81: 125–35PubMedGoogle Scholar
  75. 75.
    Mannucci PM. Viral safety of coagulation factor concentrates. In: Brown F, editor. Virological safety aspects of plasma derivative. Basel: Karger, 1993: 253–9Google Scholar
  76. 76.
    Burnouf T, Radosevich M. Reducing the risk of infection from plasma products: specific preventative strategies. Blood Rev 2000; 14(2): 94–110PubMedCrossRefGoogle Scholar
  77. 77.
    Korneyeva M, Hotta J, Lebing W, et al. Enveloped virus inactivation by caprylate: a robust alternative to solvent-detergent treatment in plasma derived intermediates. Biologicals 2002; 30(2): 153–62PubMedCrossRefGoogle Scholar
  78. 78.
    Edsall JT. Stabilization of serum albumin to heat, and inactivation of the hepatitis virus. Vox Sang 1984; 46(5): 338–40PubMedCrossRefGoogle Scholar
  79. 79.
    European Agency for the Evaluation of Medicinal Products/Committee for Proprietory Medical Products. Note for guidance on plasma-derived medicinal products [online]. Available from URL: [Accessed 2005 Feb 22]
  80. 80.
    Blumel J, Schmidt I, Willkommen H, et al. Inactivation of parvovirus B19 during pasteurization of human serum albumin. Transfusion 2002; 42(8): 1011–8PubMedCrossRefGoogle Scholar
  81. 81.
    Hayakawa F, Imada K, Towatari M, et al. Life-threatening human parvovirus B19 infection transmitted by intravenous immune globulin. Br J Haematol 2002; 118(4): 1187–9PubMedCrossRefGoogle Scholar
  82. 82.
    Horwith G, Revie DR. Efficacy of viral clearance methods used in the manufacture of activated prothrombin complex concentrates: focus on AUTOPLEX T. Haemophilia 1999; 5Suppl. 3: 19–23PubMedCrossRefGoogle Scholar
  83. 83.
    Mannucci PM, Schimpf K, Abe T, et al. Low risk of viral infection after administration of vapor-heated factor VIII concentrate: International Investigator Group. Transfusion 1992; 32(2): 134–8PubMedCrossRefGoogle Scholar
  84. 84.
    Barrett PN, Meyer H, Wachtel I, et al. Inactivation of hepatitis A virus in plasma products by vapor heating. Transfusion 1997; 37(2): 215–20PubMedCrossRefGoogle Scholar
  85. 85.
    Blumel J, Schmidt I, Effenberger W, et al. Parvovirus B19 transmission by heat-treated clotting factor concentrates. Transfusion 2002; 42(11): 1473–81PubMedCrossRefGoogle Scholar
  86. 86.
    Savage M, Torres J, Franks L, et al. Determination of adequate moisture content for efficient dry-heat viral inactivation in lyophilized factor VIII by loss on drying and by near infrared spectroscopy. Biologicals 1998; 26(2): 119–24PubMedCrossRefGoogle Scholar
  87. 87.
    World Health Organization. Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products. Geneva: Expert Committee on Biological Standardization, 2001: 40–44Google Scholar
  88. 88.
    Ways JP, Preston MS, Baker D, et al. Good manufacturing practice (GMP) compliance in the biologics sector: plasma fractionation. Biotechnol Appl Biochem 1999; 30 (Pt 3): 257–65PubMedGoogle Scholar
  89. 89.
    US General Accounting Office. Blood plasma safety: plasma product risks are low if good manufacturing practices are followed. Report to the Chairman, Subcommittee on Human Resources, Committee on Government Reform and Oversight, House of Representatives, Sep 1998 [online]. Available from URL: [Accessed 2005 Feb 22]
  90. 90.
    Aguzzi A, Weissmann C. Prion diseases. Haemophilia 1998; 4(4): 619–27PubMedCrossRefGoogle Scholar
  91. 91.
    Prusiner SB. Prions. Proc Natl Acad sci U S A 1998; 95(23): 13363–83CrossRefGoogle Scholar
  92. 92.
    Chesebro B. Prion protein and the transmissible spongiform encephalopathy diseases. Neuron 1999; 24(3): 503–6PubMedCrossRefGoogle Scholar
  93. 93.
    Goldfarb LG, Brown P. The transmissible spongiform encephalopathies. Annu Rev Med 1995; 46: 57–65PubMedCrossRefGoogle Scholar
  94. 94.
    Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes vCJD and BSE. Nature 1997; 389(6650): 448–50, 526PubMedCrossRefGoogle Scholar
  95. 95.
    Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 1997; 389(6650): 498–501PubMedCrossRefGoogle Scholar
  96. 96.
    Scott MR, Will R, Ironside J, et al. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad sci U S A 1999; 96(26): 15137–42PubMedCrossRefGoogle Scholar
  97. 97.
    Glatzel M, Aguzzi A. Peripheral pathogenesis of prion diseases. Microbes Infect 2000; 2(6): 613–9PubMedCrossRefGoogle Scholar
  98. 98.
    Ramasamy I, Law M, Collins S, et al. Organ distribution of prion proteins in variant Creutzfeldt-Jakob disease. Lancet Infect Dis 2003; 3(4): 214–22PubMedCrossRefGoogle Scholar
  99. 99.
    Holman RC, Khan AS, Kent J, et al. Epidemiology of Creutzfeldt-Jakob disease in the United States, 1979-1990: analysis of national mortality data. Neuroepidemiology 1995; 14(4): 174–81PubMedCrossRefGoogle Scholar
  100. 100.
    Gibbons RV, Holman RC, Belay ED, et al. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA 2000; 284(18): 2322–3PubMedCrossRefGoogle Scholar
  101. 101.
    Evatt B, Austin H, Barnhart E, et al. Surveillance for Creutzfeldt-Jakob disease among persons with hemophilia. Transfusion 1998; 38(9): 817–20PubMedCrossRefGoogle Scholar
  102. 102.
    Lee CA, Ironside JW, Bell JE, et al. Retrospective neuropathological review of prion disease in UK haemophilic patients. Thromb Haemost 1998; 80(6): 909–11PubMedGoogle Scholar
  103. 103.
    National Blood Data Resource Center. Creutzfeldt-Jakob Disease investigational lookback study [online]. Available from URL: [Accessed 2005 Feb 22]
  104. 104.
    Heye N, Hensen S, Muller N. Creutzfeldt-Jakob disease and blood transfusion. Lancet 1994; 343(8892): 298–9PubMedCrossRefGoogle Scholar
  105. 105.
    National CJD Surveillance Unit, Western General Hospital. Creutzfeldt-Jakob disease surveillance in the UK: twelfth annual report [online]. Available from URL: [Accessed 2005 Feb 22]
  106. 106.
    Llewelyn CA, Hewitt PE, Knight RS, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417–21PubMedCrossRefGoogle Scholar
  107. 107.
    Peden AH, Head MW, Ritchie DL, et al. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527–9PubMedCrossRefGoogle Scholar
  108. 108.
    Brown P, Cervenakova L, Diringer H. Blood infectivity and the prospects for a diagnostic screening test in Creutzfeldt-Jakob disease. J Lab Clin Med 2001; 137(1): 5–13PubMedCrossRefGoogle Scholar
  109. 109.
    Brown P, Gibbs Jr CJ, Rodgers-Johnson P, et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994; 35(5): 513–29PubMedCrossRefGoogle Scholar
  110. 110.
    Bruce ME, McConnell I, Will RG, et al. Detection of variant Creutzfeldt-Jakob disease infectivity in extraneural tissues. Lancet 2001; 358(9277): 208–9PubMedCrossRefGoogle Scholar
  111. 111.
    Houston F, Foster JD, Chong A, et al. Transmission of BSE by blood transfusion in sheep. Lancet 2000; 356(9234): 999–1000PubMedCrossRefGoogle Scholar
  112. 112.
    Hunter N, Foster J, Chong A, et al. Transmission of prion diseases by blood transfusion. J Gen Virol 2002; 83 (Pt 11): 2897–905PubMedGoogle Scholar
  113. 113.
    Kuroda Y, Gibbs Jr CJ, Amyx HL, et al. Creutzfeldt-Jakob disease in mice: persistent viremia and preferential replication of virus in low-density lymphocytes. Infect Immun 1983; 41(1): 154–61PubMedGoogle Scholar
  114. 114.
    Brown P, Rohwer RG, Dunstan BC, et al. The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion 1998; 38(9): 810–6PubMedCrossRefGoogle Scholar
  115. 115.
    Brown P, Cervenakova L, McShane LM, et al. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39(11–12): 1169–78PubMedCrossRefGoogle Scholar
  116. 116.
    Holada K, Vostal JG, Theisen PW, et al. Scrapie infectivity in hamster blood is not associated with platelets. J Virol 2002; 76(9): 4649–50PubMedCrossRefGoogle Scholar
  117. 117.
    US Food and Drug Administration, Center for Biologies Evaluation and Research (CBER). Guidance for industry: revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jakob Disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products, 2002 [online]. Available from URL: httpV/ [Accessed 2005 Feb 22]
  118. 118.
    Saborio GP, Permanne B, Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 2001; 411(6839): 810–3PubMedCrossRefGoogle Scholar
  119. 119.
    Schmitt J, Beekes M, Brauer A, et al. Identification of scrapie infection from blood serum by Fourier transform infrared spectroscopy. Anal Chem 2002; 74(15): 3865–8PubMedCrossRefGoogle Scholar
  120. 120.
    Safar J, Wille H, Itri V, et al. Eight prion strains have PrP (Sc) molecules with different conformations. Nat Med 1998; 4(10): 1157–65PubMedCrossRefGoogle Scholar
  121. 121.
    Bieschke J, Giese A, Schulz-Schaeffer W, et al. Ultrasensitive detection of pathological prion protein aggregates by dual-color scanning for intensely fluorescent targets. Proc Natl Acad sci U S A 2000; 97(10): 5468–73PubMedCrossRefGoogle Scholar
  122. 122.
    Miele G, Manson J, Clinton M. A novel erythroid-specific marker of transmissible spongiform encephalopathies. Nat Med 2001; 7(3): 361–4PubMedCrossRefGoogle Scholar
  123. 123.
    European Commission. The evaluation of tests for the diagnosis of transmissible spongiform encephalophathy in bovines: Jul 1999 [online]. Available from URL: [Accessed 2005 Feb 22]
  124. 124.
    European Commission. The evaluation of five rapid tests for the diagnosis of transmissible spongiform encephalophathy in bovines: 2nd study [online]. Available from URL: [Accessed 2005 Feb 22]
  125. 125.
    European Medicines Agency. CPMP position statement on Creutzfeldt-Jakob disease and plasma-derived and urine-derived medicinal products [online]. Available from URL: [Accessed 2005 Feb 22]
  126. 126.
    Taylor DM. Inactivation of transmissible degenerative encephalopathy agents: a review. Vet J 2000; 159(1): 10–7PubMedCrossRefGoogle Scholar
  127. 127.
    Lee DC, Stenland CJ, Hartwell RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000; 84(1): 77–89PubMedCrossRefGoogle Scholar
  128. 128.
    Rapid method of determining clearance of prion protein. US Patent 6605445. 2003Google Scholar
  129. 129.
    Lee DC, Stenland CJ, Miller JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001; 41(4): 449–55PubMedCrossRefGoogle Scholar
  130. 130.
    Bellon A, Seyfert-Brandt W, Lang W, et al. Improved conformation-dependent immunoassay: suitability for human prion detection with enhanced sensitivity. J Gen Virol 2003; 84 (Pt 7): 1921–5PubMedCrossRefGoogle Scholar
  131. 131.
    Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002; 1597(1): 28–35PubMedCrossRefGoogle Scholar
  132. 132.
    Foster PR, Welch AG, McLean C, et al. Studies on the removal of abnormal prion protein by processes used in the manufacture of human plasma products. Vox Sang 2000; 78(2): 86–95PubMedCrossRefGoogle Scholar
  133. 133.
    Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002; 42(11): 1497–500PubMedCrossRefGoogle Scholar
  134. 134.
    Vey M, Baron H, Weimer T, et al. Purity of spiking agent affects partitioning of prions in plasma protein purification. Biologicals 2002; 30(3): 187–96PubMedCrossRefGoogle Scholar
  135. 135.
    Tateishi J, Kitamoto T, Mohri S, et al. Scrapie removal using planova virus removal filters. Biologicals 2001; 29(1): 17–25PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Kang Cai
    • 1
  • Todd M. Gierman
    • 1
  • JoAnn Hotta
    • 1
  • Christopher J. Stenland
    • 1
  • Douglas C. Lee
    • 1
  • Dominique Y. Pifat
    • 1
  • Steve R. PettewayJr
    • 1
  1. 1.Department of Preclinical Research and Pathogen SafetyBayer HealthCare LLCResearch Triangle ParkUSA

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