Removal of small nonenveloped viruses by antibody-enhanced nanofiltration during the manufacture of plasma derivatives

Thomas R Kreil, Andreas Wieser, Andreas Berting, Martin Spruth, Christian Medek, Gerhard Pölsler, Theodor Gaida, Thomas Hämmerle, Wolfgang Teschner, Hans Peter Schwarz, P Noel Barrett
Transfusion 2006, 46 (7): 1143-51

BACKGROUND: Filters with nominal pore sizes in the nanometer range are well-established tools for enhancing the virus safety margins of plasma-derived products, yet intrinsically less successful for smaller viruses such as hepatitis A virus (HAV) and human parvovirus B19 (B19V). The formation of virus-antibody complexes increases the effective size of these smaller viruses and would thus improve their removal by nanofiltration. While the principle of virus removal by antibody-dependent nanofiltration has been demonstrated with animal antisera and viruses spiked into human plasma product intermediates, the significance of these results remains unclear due to the potential contributions of xenoanti-bodies and/or heteroagglutination in such heterologous systems.

STUDY DESIGN AND METHODS: The current study investigated antibody-dependent virus removal by nanofiltration in a heterologous animal parvovirus system to establish the concentration dependence of the effect. In addition, the phenomenon was investigated in a homologous system with custom-made HAV and B19V antibody-free and -containing human immunoglobulin intermediates. Viruses were analyzed with infectivity assays and fully validated polymerase chain reaction assays that also circumvent the obscuring effects of neutralizing antibodies with infectivity assays.

RESULTS: By use of the heterologous mice minute virus and the homologous HAV and B19V systems, viruses passed the 35-nm (Planova 35N) filter in the absence of specific antibodies. Beyond a threshold virus antibody concentration, nanofiltration resulted in effective virus removal of viruses smaller than the nominal pore size of the filter used.

CONCLUSION: HAV and B19V are effectively removed by antibody-dependent 35N nanofiltration, already at intermediate antibody concentrations well below those comparable to human plasma pools for fractionation.

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