Global Pathogen Safety

Vienna, Austria

Global Pathogen Safety

Vienna, Austria
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Kapsch A.-M.,Global Pathogen Safety | Farcet M.R.,Global Pathogen Safety | Antoine G.,Global Pathogen Safety | Kreil T.R.,Global Pathogen Safety
Transfusion | Year: 2017

BACKGROUND: Recently, a quasi-lipid-enveloped (LE) form of the traditionally nonlipid-enveloped (NLE) hepatitis A virus (HAV) was described in human serum and cell culture-derived HAV stocks. This discovery challenges the understanding of HAV reduction in virus clearance studies of plasma products, which were performed under the premise of an NLE nature of this virus. Here, the presence of LE particles in HAV stocks used for reduction studies was verified, and the hypothesis that LE and NLE particles might contribute to the differential heat sensitivity of HAV variants during heat treatment of human serum albumin was evaluated. STUDY DESIGN AND METHODS: Cell culture lysates and supernatants of two cytopathic HAV variants, HM175/18f and HM175/24a, were characterized for their LE and NLE particle content by isopycnic gradient centrifugation. The obtained fractions were characterized for relative infectivity and then subjected to heat treatment (58.0±1.0°C for 590±10 minutes) in 12.5% human serum albumin to investigate their respective heat sensitivity. RESULTS: Preparations of the two HAV variants contained either LE particles (HM175/24a) or LE and NLE particles (HM175/18f) with equivalent specific infectivity. For HM175/18f, heat sensitivity of LE and NLE fractions did not differ significantly, and inactivation of the whole virus stock was identical to the NLE particle inactivation profile, whereas the HM175/24a variant was more heat sensitive. CONCLUSION: The results indicate that, in heat-treatment studies, the LE or NLE HAV phenotype is less important than the choice of HAV variant, and the most heat-resistant HM175/18f should be used. © 2017 AABB.

Farcet M.R.,Global Pathogen Safety | Planitzer C.B.,Global Pathogen Safety | Stein O.,Global Pathogen Safety | Modrof J.,Global Pathogen Safety | Kreil T.R.,Global Pathogen Safety
Journal of Allergy and Clinical Immunology | Year: 2010

Background: Persons with primary immune deficiency receive intravenous immunoglobulin (IVIG) as antibody replacement therapy. These patients depend on the presence of protective antibody levels against circulating pathogens in IVIG. Objectives: The incidence of hepatitis A virus (HAV) infections has been decreasing globally. We investigated whether this decrease in HAV incidence is reflected in human plasma pools and evaluated whether HAV antibody titers in IVIG preparations are still adequate for antibody replacement. Methods: By using ELISA, the HAV antibody titer of 3,953 plasma pools sourced from March 2003 through September 2008 in the European Union (EU) or United States (US) and of 169 IVIG lots manufactured from 2005 through 2007 was determined. The functionality of the HAV antibodies contained in IVIG was assessed by using a microneutralization assay. Results: The results confirm a decrease in HAV antibody titers in EU (-28%) and US (-41%) plasma. Furthermore, the mean HAV antibody content in EU (1.70 ± 0.12 IU/mL) and US (0.82 ± 0.09 IU/mL [mean ± SEM]) plasma was significantly different (P = .0001). A significant difference (P < .0001) was also evident in the IVIG preparations KIOVIG (22.91 ± 0.68 IU/mL) and Gammagard Liquid (14.60 ± 0.48 IU/mL), respectively, made from EU or US plasma. In accordance with the ELISA results, there was a significant difference (P < .0001) in HAV neutralization titer 50% (NT50) values between IVIG produced from EU-sourced (2,477 ± 265 NT50 [1:X]) or US-sourced (844 ± 82 NT50 [1:X]) plasma. Conclusion: Although HAV antibody seroprevalence continues to decrease in Europe and the US, HAV antibody titers in IVIG lots appear to remain adequate for antibody replacement therapy. © 2010 American Academy of Allergy, Asthma & Immunology.

Planitzer C.B.,Global Pathogen Safety | Farcet M.R.,Global Pathogen Safety | Schiff R.I.,Clinical Affairs | Ochs H.D.,University of Washington | Kreil T.R.,Global Pathogen Safety
Journal of Medical Virology | Year: 2011

Replacement therapy using intravenous immunoglobulin (IVIG) preparations in people with antibody deficiencies is effective in preventing the majority of common bacterial and viral infections, yet echovirus break-through infections have occurred. Currently, only limited information on neutralization capacity variability of individual IVIG lots against the different echovirus serotypes is available. Infectivity assays were established for the most prevalent echovirus serotypes (E 9, E 11, E 13, and E 30) circulating in the United States (US) and the European Union (EU). The echovirus serotype-specific neutralization titers of 41 IVIG lots manufactured from either whole blood (Recovered) or collected by apheresis (Source) and from either the US or EU, were determined. Significantly higher (P < 0.0001) neutralization titers against E 11 and E 30 were found in IVIG lots manufactured from US Source plasma compared to US Recovered plasma. Geographically, IVIG lots made from US plasma contained significantly (P < 0.0001) higher neutralization titers against E 9 and E 11 than lots manufactured from EU plasma, whereas lots made from EU plasma showed significantly higher neutralization of E 30. To conclude, IVIG lots differ in their neutralizing antibody content against different echovirus serotypes, depending on plasma collection practices and geographic origin. Based on these results, an informed choice in selecting IVIG lots with the highest available neutralization titer against the specific echovirus serotype would seem to be beneficial during treatment of break-through infections. © 2010 Wiley-Liss, Inc.

Berting A.,Global Pathogen Safety | Farcet M.R.,Global Pathogen Safety | Kreil T.R.,Global Pathogen Safety
Biotechnology and Bioengineering | Year: 2010

Biopharmaceuticals are of increasing importance in the treatment of a variety of diseases. A remaining concern associated with their production is the potential introduction of adventitious agents into their manufacturing process, which may compromise the pathogen safety of a product and potentially cause stock-out situations for important medical supplies. To ensure the safety of biological therapeutics, regulatory guidance requires adventitious agent testing (AAT) of the bulk harvest. AAT is a deliberately promiscuous assay procedure which has been developed to indicate, ideally, the presence of any viral contaminant. One of the most important cell lines used in the production of biopharmaceuticals is Chinese hamster ovary (CHO) cells and while viral infections of CHO cells have occurred, a systematic screen of their virus susceptibility has never been published. We investigated the susceptibility of CHO cells to infection by 14 different viruses, including members of 12 families and representatives or the very species that were implicated in previously reported production cell infections. Based on our results, four different infection outcomes were distinguished, based on the possible combinations of the two factors (i) the induction, or not, of a cytopathic effect and (ii) the ability, or not, to replicate in CHO cells. Our results demonstrate that the current AAT is effective for the detection of viruses which are able to replicate in CHO cells. Due to the restricted virus susceptibility of CHO cells and the routine AAT of bulk harvests, our results provide re-assurance for the very high safety margins of CHO cell-derived biopharmaceuticals. © 2010 Wiley Periodicals, Inc.

Kreil T.R.,Global Pathogen Safety
Emerging Infectious Diseases | Year: 2015

Clinical evidence suggests that antibodies from reconvales- cent donors (persons who have recovered from infection) may be effective in the treatment of Ebola virus infection. Administration of this treatment to Ebola virus-infected pa tients while preventing the transmission of other pathogenic viruses may be best accomplished by use of virus-inactivat- ed reconvalescent plasma. © 2015, Centers for Disease Control and Prevention (CDC). All rights reserved.

Farcet M.R.,Global Pathogen Safety | Kindermann J.,Global Pathogen Safety | Modrof J.,Global Pathogen Safety | Kreil T.R.,Global Pathogen Safety
Transfusion | Year: 2012

BACKGROUND: Pasteurization of human serum albumin (HSA) is detailed in the US and European Pharmacopoeial monographs and therefore a process that allows for little variation in physiochemical variables. Nevertheless, differences of up to 3.9 log in hepatitis A virus (HAV) inactivation by pasteurization have been reported. Here, the hypothesis that the choice of HAV variant used in the pasteurization might contribute to this inactivation variability is evaluated experimentally. STUDY DESIGN AND METHODS: The identity of four widely used cytopathic variants of the original HAV HM175 strain was determined by partial sequencing. These variants were used in pasteurization studies conducted under the principles of good laboratory practice, for which HAV-spiked HSA of 5 or 25% protein content was kept at 58 ± 1°C for 600 ± 10 minutes, and the virus inactivation was assessed. In addition, data from previous pasteurization studies were included in the analysis. RESULTS: The four HAV variants could be divided into two subgroups, with significantly different (p ≤ 0.0001) virus inactivation by pasteurization (4.7 and 4.8 log vs. 2.3 and 2.6 log, respectively). Also, the protein concentration of the HSA solution used for pasteurization had a significant effect on the achieved HAV inactivation, with reduction factors obtained in 5% HSA significantly lower than in 25% HSA (p < 0.002). CONCLUSION: HAV variant and protein concentration of the HSA solution affect the overall HAV inactivation that is achieved during pasteurization. As the HAV inactivation capacity should not be overestimated, an HAV variant more resistant to heat inactivation should be used for studies investigating the viral safety profiles of plasma derivatives. © 2011 American Association of Blood Banks.

Leydold S.M.,Global Pathogen Safety | Farcet M.R.,Global Pathogen Safety | Kindermann J.,Global Pathogen Safety | Modrof J.,Global Pathogen Safety | And 5 more authors.
Transfusion | Year: 2012

BACKGROUND: Chikungunya virus (CHIKV) outbreaks were previously restricted to parts of Africa, Indian Ocean Islands, South Asia, and Southeast Asia. In 2007, however, the first autochthonous CHIKV transmission was reported in Europe. High-level viremia, a mosquito vector that is also present in large urban areas of Europe and America, and uncertainty around the resistance of this Alphavirus toward physiochemical inactivation processes raised concerns about the safety of plasma derivatives. To verify the safety margins of plasma products with respect to CHIKV, commonly used virus inactivation steps were investigated for their effectiveness to inactivate this newly emerging virus. STUDY DESIGN AND METHODS: Pasteurization for human serum albumin (HSA), vapor heating for Factor VIII inhibitor bypassing activity, solvent/detergent (S/D) treatment for intravenous immunoglobulin (IVIG), and incubation at low pH for IVIG were investigated for their capacity to inactivate CHIKV and the closely related Sindbis virus (SINV). The obtained results were compared to previous studies with West Nile virus and the commonly used model virus bovine viral diarrhea virus. RESULTS: The data generated demonstrate the effective inactivation of CHIKV as well as SINV by the inactivation steps investigated and thereby support results from earlier validation studies in which model viruses were used. CONCLUSION: High inactivation capacities with respect to CHIKV were demonstrated. This provides solid reassurance for the safety of plasma products and the results verify that the use of model viruses is appropriate to predict the inactivation characteristics of newly emerging viruses when their physicochemical properties are well characterized. © 2012 American Association of Blood Banks.

Rabel P.O.,Global Pathogen Safety | Planitzer C.B.,Global Pathogen Safety | Farcet M.R.,Global Pathogen Safety | Kreil T.R.,Global Pathogen Safety
Clinical and Vaccine Immunology | Year: 2012

Patients with primary immunodeficiency (PIDs) depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG). Using the tick-borne encephalitis virus (TBEV), geographic variability in IVIG antibody content was shown. Care should therefore be exercised when treating PIDs in a given geography, as only locally sourced plasma contains the antibody specificities against the circulating pathogens in the given locality. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Hessel A.,Vaccine RandD | Savidis-Dacho H.,Pharmacology | Coulibaly S.,Pharmacology | Portsmouth D.,Vaccine RandD | And 7 more authors.
PLoS ONE | Year: 2014

Background: The availability of a universal influenza vaccine able to induce broad cross-reactive immune responses against diverse influenza viruses would provide an alternative to currently available strain-specific vaccines. We evaluated the ability of vectors based on modified vaccinia virus Ankara (MVA) expressing conserved influenza proteins to protect mice against lethal challenge with multiple influenza subtypes. Methods: Mice were immunized with MVA vectors expressing H5N1-derived nucleoprotein (NP), the stem region of hemagglutinin (HA), matrix proteins 1 and 2 (M1 and M2), the viral polymerase basic protein 1 (PB1), or the HA stem fused to a quadrivalent matrix protein 2 extracellular domain (M2e). Immunized mice were challenged with lethal doses of H5N1, H7N1 or H9N2 virus and monitored for disease symptoms and weight loss. To investigate the influence of previous exposure to influenza virus on protective immune responses induced by conserved influenza proteins, mice were infected with pandemic H1N1 virus (H1N1pdm09) prior to immunization and subsequently challenged with H5N1 virus. Antibody and T cell responses were assessed by ELISA and flow cytometry, respectively. Results: MVA vectors expressing NP alone, or co-expressed with other conserved influenza proteins, protected mice against lethal challenge with H5N1, H7N1 or H9N2 virus. Pre-exposure to H1N1pdm09 increased protective efficacy against lethal H5N1 challenge. None of the other conserved influenza proteins provided significant levels of protection against lethal challenge. NP-expressing vectors induced high numbers of influenza-specific CD4+ and CD8+ T cells and high titer influenzaspecific antibody responses. Higher influenza-specific CD4+ T cell responses and NP-specific CD8+ T cell responses were associated with increased protective efficacy. Conclusions: MVA vectors expressing influenza NP protect mice against lethal challenge with H5N1, H7N1 and H9N2 viruses by a mechanism involving influenza-specific CD4+ and CD8+ T cell responses. © 2014 Hessel et al.

PubMed | University of South Alabama, Global Pathogen Safety, University of Edinburgh, University of Texas M. D. Anderson Cancer Center and U.S. National Institutes of Health
Type: Journal Article | Journal: Transfusion | Year: 2016

Four secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease.Whole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion.No clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrP(TSE) in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Strussler-Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months.Blood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period.

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