Hepatitis E virus and the safety of plasma products: investigations into the reduction capacity of manufacturing processes

Farcet, Maria R.; Lackner, Cornelia; Antoine, Gerhard; Rabel, Philip O.; Wieser, Andreas; Flicker, Andreas; Unger, U; Modrof, Jens; Kreil, Thomas R.

doi:10.1111/trf.13343

Cited by 33 publications

(44 citation statements)

References 36 publications

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“…Inactivation of HEV, a reemerging virus of concern, is currently under evaluation in a wide variety of stabilized product intermediates (to be published separately). Based on data presented or published, HEV appears to have similar inactivation kinetics to those of HAV. Pasteurization of HEV in stabilized VWF/FVIII intermediate using an in vivo assay (inoculation of piglets) demonstrated effective inactivation…”

Section: Discussionmentioning

confidence: 99%

Effective inactivation of a wide range of viruses by pasteurization

et al. 2017

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BACKGROUND Careful selection and testing of plasma reduces the risk of blood‐borne viruses in the starting material for plasma‐derived products. Furthermore, effective measures such as pasteurization at 60°C for 10 hours have been implemented in the manufacturing process of therapeutic plasma proteins such as human albumin, coagulation factors, immunoglobulins, and enzyme inhibitors to inactivate blood‐borne viruses of concern. A comprehensive compilation of the virus reduction capacity of pasteurization is presented including the effect of stabilizers used to protect the therapeutic protein from modifications during heat treatment. STUDY DESIGN AND METHODS The virus inactivation kinetics of pasteurization for a broad range of viruses were evaluated in the relevant intermediates from more than 15 different plasma manufacturing processes. Studies were carried out under the routine manufacturing target variables, such as temperature and product‐specific stabilizer composition. Additional studies were also performed under robustness conditions, that is, outside production specifications. RESULTS The data demonstrate that pasteurization inactivates a wide range of enveloped and nonenveloped viruses of diverse physicochemical characteristics. After a maximum of 6 hours' incubation, no residual infectivity could be detected for the majority of enveloped viruses. Effective inactivation of a range of nonenveloped viruses, with the exception of nonhuman parvoviruses, was documented. CONCLUSION Pasteurization is a very robust and reliable virus inactivation method with a broad effectiveness against known blood‐borne pathogens and emerging or potentially emerging viruses. Pasteurization has proven itself to be a highly effective step, in combination with other complementary safety measures, toward assuring the virus safety of final product.

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Section: Discussionmentioning

confidence: 99%

Effective inactivation of a wide range of viruses by pasteurization

et al. 2017

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“…Secondary antibody conjugated to Alexa Fluor 594 (Thermo Fisher Scientific) in PBTG buffer (1:1,000) was added and incubated at room temperature for 1 hour, followed by several washes with PBS. For the determination of production of infectious particles in JEG‐3 and HepG2 cells, cells were transfected as described and treated in accordance to a reported protocol 28. Briefly, cells were electroporated as described above, incubated 6‐7 days in Eagle's MEM with ultra‐low immunoglobulin G FCS, and cell growth was stopped by adding hydroxyurea where necessary.…”

Section: Methodsmentioning

confidence: 99%

Hepatitis E virus replication and interferon responses in human placental cells

Knegendorf

Drave

Thi

et al. 2018

Hepatology Communications

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Hepatitis E virus (HEV) is a member of the genus Orthohepevirus in the family Hepeviridae and the causative agent of hepatitis E in humans. HEV is a major health problem in developing countries, causing mortality rates up to 25% in pregnant women. However, these cases are mainly reported for HEV genotype (gt)1, while gt3 infections are usually associated with subclinical courses of disease. The pathogenic mechanisms of adverse maternal and fetal outcome during pregnancy in HEV‐infected pregnant women remain elusive. In this study, we observed that HEV is capable of completing the full viral life cycle in placental‐derived cells (JEG‐3). Following transfection of JEG‐3 cells, HEV replication of both HEV gts could be observed. Furthermore, determination of extracellular and intracellular viral capsid levels, infectivity, and biophysical properties revealed production of HEV infectious particles with similar characteristics as in liver‐derived cells. Viral entry was analyzed by infection of target cells and detection of either viral RNA or staining for viral capsid protein by immunofluorescence. HEV gt1 and gt3 were efficiently inhibited by ribavirin in placental as well as in human hepatoma cells. In contrast, interferon‐α sensitivity was lower in the placental cells compared to liver cells for gt1 but not gt3 HEV. Simultaneous determination of interferon‐stimulated gene expression levels demonstrated an efficient HEV‐dependent restriction in JEG‐3. Conclusion: We showed differential tissue‐specific host responses to HEV genotypes, adding to our understanding of the mechanisms contributing to fatal outcomes of HEV infections during pregnancy. Using this cell‐culture system, new therapeutic options for HEV during pregnancy can be identified and evaluated. (Hepatology Communications 2018;2:173–187)

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“…Recombinant products are therefore subject to at least one pathogen inactivation procedure. Processes such as chromatography, filtration/nanofiltration, solvent-detergent (SD) and dry heat treatment are regularly used in the manufacture of recombinant products and contribute to inactivation of pathogens that might be present [52, 54, 57]. …”

Section: Separation Of Blood Into Components For Treatment Of Bleedinmentioning

confidence: 99%

Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients?

et al. 2017

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Patients with blood disorders (including leukaemia, platelet function disorders and coagulation factor deficiencies) or acute bleeding receive blood-derived products, such as red blood cells, platelet concentrates and plasma-derived products. Although the risk of pathogen contamination of blood products has fallen considerably over the past three decades, contamination is still a topic of concern. In order to counsel patients and obtain informed consent before transfusion, physicians are required to keep up to date with current knowledge on residual risk of pathogen transmission and methods of pathogen removal/inactivation. Here, we describe pathogens relevant to transfusion of blood products and discuss contemporary pathogen removal/inactivation procedures, as well as the potential risks associated with these products: the risk of contamination by infectious agents varies according to blood product/region, and there is a fine line between adequate inactivation and functional impairment of the product. The cost implications of implementing pathogen inactivation technology are also considered.

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Hepatitis E virus and the safety of plasma products: investigations into the reduction capacity of manufacturing processes

Abstract: Substantial HEV reduction during processes commonly used in the manufacturing of plasma products was demonstrated, similar to that previously demonstrated for HAV.

Cited by 33 publications

References 36 publications

Effective inactivation of a wide range of viruses by pasteurization

Effective inactivation of a wide range of viruses by pasteurization

Hepatitis E virus replication and interferon responses in human placental cells

Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients?

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