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PubMed2000

Human intravenous immunoglobulin preparation and virus inactivation by pasteurization and solvent detergent treatment.

Human intravenous immunoglobulin (IVIG) solutions were prepared by two different methods and compared to each other. The crude immunoglobulin fraction obtained from Cohn-Oncley fractionation of plasma was further purified and subjected to virus inactivation, either by polyethylene glycol precipitation and pasteurization at 60 degrees C for 10 hours, or by ion exchange chromatography and solvent/detergent treatment. The final preparations, formulated in 5% immunoglobulin solutions were characterized by in vitro analyses of biochemical and biological properties and compared with the samples of other manufacturer's IVIG solution products. The critical properties evaluated in this study were purity, molecular intactness, and the biological functions such as Fc function and anticomplementary activity. Virus inactivation and removal by processing steps and by deliberate virucidal steps, as described above, were tested on various human pathogenic viruses, such as human immunodeficiency and experimental model viruses. The tested viruses were successfully inactivated and removed. We conclude that the intravenous immunoglobulins prepared by two different methods, as described above, provide an equivalent viral safety and quality.

Antibodies↗
PubMed1998

Characterization of F VIII concentrates produced by two methods incorporating double virus inactivation.

The trend toward the production of high purity factor VIII concentrates for clinical use is still in progress. Although all plasma derivatives must undergo viral inactivation procedures, the possibility of transmission of viral diseases is not completely eliminated. In order to reduce such risk, we have included double virus inactivation in the procedure of factor VIII concentrate production. In a scale-up procedure for isolation of factor VIII cryoprecipitate, two methods were used. The first is based on the chromatographic purification of factor VIII after pasteurization of cryoprecipitate solution and solvent/detergent (S/D) inactivation of viruses. The second is based on multistep precipitation of factor VIII by sodium chloride and glycine. Viral inactivation was performed by combination of S/D treatment and heating of final freeze-dried product 30 min at 100 degrees C. The typical yield of factor VIII activity in the freeze-dried product was about 20% for the first method, and 25-30% for the second. Electrophoretic analyses of both factor VIII preparations by SDS-PAGE and IEF show very low content of contaminant proteins, in accordance with observed 400-650-fold increase of their specific activity over plasma. Both factor VIII products were stable in the liquid state for more than 24 h at room temperature. The final products, after double viral inactivation, are considered to be suitable for clinical evaluations.

Antiviral Agents↗
PubMed1991

[Important laboratory parameters of deep frozen coagulation active fresh plasma and virus inactivated lyophilized pool plasma].

Fresh Frozen Plasma is the most important therapeutic agent in acquired coagulation disorders. We investigated the quality of a new virus-inactivated lyophilisated human pool-plasma (VFL) and conventional fresh frozen plasma (FFP). In VFL we found a significantly reduced coagulation activity, a significantly higher pH-value, a highly significant rise of heparin values and a significantly lower number of thrombocytes. Electrolytes, protein levels and complement activity showed no significant difference. In conclusion, this virus-inactivated lyophilisated human pool plasma does not seem to be susceptible to therapy coagulation disorders like the conventional fresh frozen plasma.

Antiviral Agents↗
PubMed2000

Rabies vaccination: comparison of neutralizing antibody responses after priming and boosting with different combinations of DNA, inactivated virus, or recombinant vaccinia virus vaccines.

Long-term levels of neutralizing antibody were evaluated in mice after a single immunization with experimental DNA or recombinant vaccinia virus (RVV) vaccines encoding the rabies virus glycoprotein (G), or the commercially available inactivated virus human diploid cell vaccine (HDCV). Anamnestic antibody titers were also evaluated after two booster immunizations with vaccines that were identical to or different from the priming vaccine. Five hundred and forty days (1.5 year) after a single immunization with any of the three vaccines, neutralizing antibody titers remained greater than the minimal acceptable human level of antibody titer (0.5 International Units (IU)/ml). In addition, either an HDCV or DNA booster elicited early and elevated anamnestic antibody responses in mice that had been primed with any of the three vaccines. In contrast, RVV boosters failed to elevate titers in mice that had been previously primed with RVV, and elicited slowly rising titers in mice that had been primed with either DNA or HDCV. Thus, a single vaccination with any of the three different vaccines elicited long-term levels of neutralizing antibody that exceeded 0.5 IU/ml. In contrast, different prime-booster vaccine combinations elicited anamnestic neutralizing antibody responses that increased quickly, increased slowly or failed to increase.

Animals↗
PubMed1998

Duck hepatitis B virus inactivation and 8-methoxypsoralen photoadduct formation in human platelet concentrates.

Photochemical inactivation (PCI) of virus and bacteria in platelet concentrates (PC) has been demonstrated using 8-methoxypsoralen (8-MOP) and long-wavelength UV light (UVA). To study inactivation of blood-borne virus, we have employed duck hepatitis B virus (DHBV), a model for human hepatitis B virus. A specific hepatocyte culture infectivity assay, with PCR detection, could measure 5-6 log10 virus kill. The DHBV inactivation in PC was dependent on UVA dose, was enhanced when plasma was reduced from 100% to 20% and was limited by 8-MOP solubility in the reduced-plasma medium. Optimum conditions for PCI were 100 micrograms/mL 8-MOP in 20% plasma and 80% synthetic platelet storage medium. A radiolabeling assay for 8-MOP photoadducts in hepatocytes seeded into PC confirmed that DHBV inactivation reflected DNA modification and indicated that adduct formation was insensitive to minor variations in conditions. Kinetic modeling indicated that optimum adduct formation was a compromise between 8-MOP dark binding and optical transmittance and that plasma proteins competed for 8-MOP binding. The PCI results in various media correlated with corresponding DNA modification densities and were compared to statistical models incorporating DHBV characteristics and predictions of 8-MOP crosslink formation between DNA strands. Behavior was consistent with one or a small number of lethal modifications per DNA strand, including monoadducts, but probably not crosslinks alone. A minor subpopulation of DHBV was found to be somewhat more difficult to inactivate, consistent with three-fold lower modification, due possibly to single-stranded DNA character or host repair of photoadducts.

Blood Platelets↗
PubMed1993

A comparison of polymerase chain reaction and an infectivity assay for human immunodeficiency virus type 1 titration during virus inactivation of blood components.

Three examples of human plasma-derived concentrates, intermediate-purity factors VIII and IX, and fibrinogen were spiked with tissue culture-grown human immunodeficiency virus type 1 (HIV-1) strain RF. All examples were freeze-dried and heated at 80 degrees C for 72 hours by using validated production process models. HIV-1 infectivity was measured by a syncytial infectivity assay in C8166 cells and then compared with levels determined by nested HIV polymerase chain reaction (PCR). The infectivity assay demonstrated a reduction index of at least 4.5 log10, while PCR showed an average 1.7 log10. Large amounts of HIV-1 RNA (10(5)) were still detectable by PCR in samples in which infectivity assays failed to detect any HIV-1. These data suggest that HIV-1 PCR levels do not parallel HIV-1 infectivity levels during virus-inactivation procedures involved in coagulation factor concentrate production. PCR was able to detect the RNA associated with inactivated HIV-1 particles in the factor concentrates, which allows the conclusion that PCR is not a useful test with which to monitor virus-inactivation procedures such as heating at 80 degrees C for 72 hours. This judgment contrasts with the more definite and sensitive role of PCR in diagnosing HIV-1 infection in patients in whom a positive HIV-1 PCR result correlates with active HIV-1 infection and with PCR's usefulness in monitoring virus removal.

DNA, Viral↗
PubMed1991

[No HCV seroconversion in hemophilia following substitution with virus-inactivated coagulation factor VIII and IX concentrates].

Since 1986 the factor VIII and IX concentrates of the Central Laboratory, Swiss Red Cross Blood Transfusion Service have been virus inactivated with tri-(n-butyl) phosphate and Tween 80. Clinical studies had shown that both preparations were well tolerated and hemostatically effective; no HIV infection was transmitted. However, safety from transmission of non-A/non-B hepatitis could not be shown since the study included no previously untreated patients. In the meantime, a laboratory test has become available which allows retrospective testing for anti-hepatitis C antibodies in frozen sera of the study patients. 5 of the 26 patients, observed during a 2-year follow-up study, had no HCV antibodies before entering the long-term trial. During this trial, each of these 5 patients substituted an average quantity of 40,200 coagulation factor units (7500-69,000) from 45 production lots. None of these 5 patients developed anti-HCV antibodies, nor did any of them show clinical signs of infection with hepatitis. This suggests that virus inactivation using solvent/detergent treatment reduces the risk of transmission of HCV.

Blood Coagulation Disorders↗
PubMed2001

Virus inactivation of plasma-derived proteins by pasteurization in the presence of guanidine hydrochloride.

BACKGROUND: Viruses, among them parvovirus B19 and other small, nonenveloped viruses, may be present in human blood and may contaminate plasma-derived therapeutics. Efficient inactivation or removal of such viruses, especially parvoviruses, represents a current problem and corresponding technologies are under investigation. In this report, such a technology is described. STUDY DESIGN AND METHODS: A recently developed pasteurization of human apolipoprotein A-I (apoA-I), which is performed at 60 degrees C for 10 hours in the presence of guanidine hydrochloride (GdnHCl), was validated by using a series of model viruses, including members of the families parvoviridae and picornaviridae. The model viruses were spiked into the apoA-I- and GdnHCl-containing solutions, and virus inactivation was evaluated by infectivity assays in cell cultures. The mechanism of virus inactivation was studied by virus sedimentation analysis using the picornavirus model. RESULTS: All viruses tested were inactivated to levels below the limit of detection, although different inactivation kinetics were obtained for the different viruses. The mechanism of virus inactivation by this pasteurization was disassembly of the virus particles into single proteins or small noninfectious viral subunits. CONCLUSION: The pasteurization validated in this report has the potential to inactivate a wide range of transfusion-relevant viruses including parvoviruses and picornaviruses.

Animals↗
PubMed1986

Study of the efficacy of an inactivated virus vaccine against porcine parvovirus.

The efficacy of an inactivated virus vaccine against porcine parvovirus has been studied by immunizing 4 sows during pregnancy. A parvovirus virulent strain has been inoculated to these sows and to two other unvaccinated sows used as controls. The infection was performed between the 52nd and the 57th day of gestation. In the litters born from the vaccinated sows, 82% of the piglets were alive and normal. Neither PPV antibodies nor antigen could be revealed in the stillborn fetuses born from the 4 vaccinated sows. Reversely, only 9.5% of the piglets born from the 2 unvaccinated sows were alive at birth, although they were probably infected during pregnancy. In total, 86% of fetuses in these 2 litters were mummified. A field study allowed to show that the double vaccination antibodies induced, persisted with constant titers for, at least, 13 months. Moreover, the reproductive performance of 413 gilts, vaccinated twice before mating, were not affected by this treatment.

Animals↗
PubMed1979

Interferon induction with Newcastle disease virus in FS-4 cells: effect of priming with interferon and of virus inactivating treatments.

Inoculation of human FS-4 cells with Newcastle disease virus (NDV) resulted in the induction of two distinct interferon responses, one that peaked at about 5 hr (early response) and one that reached a maximum between 10 to 24 hr after inoculation (second response). The early interferon response was enhanced by previous treatment of the cells with interferon (priming), whereas the second response decreased after interferon treatment in a dose-dependent manner. The early response diminished with decreasing multiplicities of infection, the magnitude of the second response in unprimed cells was relatively independent of the dose of NDV employed. The early interferon response was sensitive to inhibition by actinomycin D for only 1 hr after inoculation. In marked contrast, the second response remained sensitive to inhibition by actinomycin D until 12 hr after inoculation. The ability of NDV to induce the second response was greatly diminished by irradiation of the virus with ultraviolet light or by its treatment with hydroxylamine, whereas the ability to stimulate the early response was relatively resistant to these virus-inactivating treatments. Treatment of NDV with hydroxylamine abolished the virus to induce the second response at the same rate as it destroyed infectivity. The results suggest the existence of at least two distinct mechanisms of interferon induction by NDV; the early response is triggered either by a virion component or by a product of primary transcription, whereas induction of the second response requires the expression of some functions of the virus not needed for triggering the early response.

Animals↗
PubMed2005

Mucosal immunization of CD4+ T cell-deficient mice with an inactivated virus induces IgG and IgA responses in serum and mucosal secretions.

Immunoglobulin (Ig) class switching can occur in the absence of alphabeta+ or gammadelta+ T cells when mice are infected with certain live viruses, although CD4 T helper cells are believed to be essential for induction of a high-affinity antibody response and for efficient isotype switching from IgM to IgG and IgA production. However, little information is available about the immune responses after mucosal immunization of CD4+ T cell-deficient mice with inactivated virus. In this study, we show that intranasal immunization with formalin-inactivated influenza A/PR8/34 virus induces IgG and IgA responses in serum and IgA responses in mucosal secretions in CD4+ T cell-deficient mice. All four subclasses of IgG were produced. IgG1/IgG2a ratios were found to be from 1 to 1.75, indicating that both Th1 and Th2 immune responses are induced by the inactivated influenza virus. The sera and mucosal secretions were found to have neutralizing activity against influenza virus in vitro. In addition, the mucosally immunized CD4+ T cell-deficient mice were protected completely from challenge with a lethal dose of live, pathogenic influenza virus. To our knowledge, this is the first demonstration that mucosal immunization with an inactivated virus induces immune responses in serum and mucosal secretions in CD4+ T cell-deficient mice.

Animals↗
PubMed1991

[Quality control studies of 3 deep-frozen coagulation-active fresh frozen plasma preparations from various suppliers and a new virus-inactivated lyophilized pooled plasma preparation].

Fresh frozen plasma is the most important therapeutic agent in acquired coagulation disorders. We investigated the quality of three conventional fresh-frozen plasma preparations (groups I, II, IV) and one new virus-inactivated lyophilised pooled plasma preparation (group III). In the new plasma preparation we found a significant reduction in coagulation activity, a significantly higher pH value and a highly significant rise in plasma heparin levels. No significant difference in electrolytes, protein levels and concentration or complement activity was found in any of the groups. In conclusion, unlike conventional fresh-frozen plasma, this new virus-inactivated lyophilised pooled plasma preparation does not seem to be suitable for use in therapy of coagulation disorders.

Antiviral Agents↗
PubMed1994

Antibody Fc functional activity of intravenous immunoglobulin preparations treated with solvent-detergent for virus inactivation.

We report here results of in vitro comparisons of the Fc functional activity of a second-generation intravenous immunoglobulin (IGIV) preparation (Venoglobulin-I) and a third-generation IGIV product that includes a deliberate virus-inactivation step (Venoglobulin-S). Both formulations showed equivalent Fc-mediated function against viral antigens (rubella, influenza A, and influenza B) by single-radial hemolysis test, and against group B Streptococcus, Staphylococcus aureus and Escherichia coli by opsonophagocytosis assay. In addition, we showed by three different immunochemical reactions and by HPLC analysis that both preparations consisted of mostly monomeric IgG and contained very low levels of complement-fixing IgG aggregates. However, IgG aggregation induced by heating at 63 degrees C markedly enhanced fixation of Clq and C3 and binding to Raji cells, indicating that the IgG molecules retained their complement-fixing capacity. Thus, the incorporation of a virus inactivation step in the manufacture of our third-generation IGIV did not alter the Fc functional activities of the IgG, as measured by these in vitro assay systems.

Antibodies, Bacterial↗
PubMed2003

Virus inactivation by high intensity broad spectrum pulsed light.

The inactivation of a range of enveloped and non-enveloped viruses by treatment with high intensity broad spectrum pulsed light (PureBright) has been investigated. In phosphate buffered saline, a dose of 1.0 J/cm2 was sufficient to effectively inactivate, i.e. >4.8->7.2 log of all the viruses tested, i.e. Sindbis, HSV-1, vaccinia, polio-1, EMC, HAV, CPV, BPV and SV40. However, in the presence of protein, i.e. 5% v/v foetal-calf serum (0.2% w/v protein), virus inactivation was less effective. At a dose of 2.0 J/cm2, virus inactivation was 5.0->6.4 log, however, HSV-1 (3.8 log), BPV (2.4 log) and SV40 (2.9 log) were all relatively resistant. This virus inactivation procedure may have application for increasing the safety of therapeutic biological products.

Animals↗
PubMed1980

Rabies virus inactivation by binary ethylenimine: new method for inactivated vaccine production.

The inactivation dynamics of rabies virus (PV strain) by binary ethylenimine, and the immunogenic properites and the stability of the vaccines prepared using this agent, were studied. Binary ethylenimine at a final concentration of 0.01 M was prepared wtih 2-bromoethylamine hydrobromide in alkaline solutions, either separately from or in suspensions of rabies virus propagated in BHK cells. The infectivity of virus suspensions containing more than 108 plaque-forming units per 0.1 ml was inactivated in 2 h when the inactivating agent was prepared before its addition to the suspensions, and in3 h when prepared directly in the suspensions. Liquid vaccines prepared in this manner and stored at different temperatures maintained potency for 1 month at 37 degrees C and for 6 months at 4 degrees C and 22 to 25 degrees C. Lyophilized vaccine maintained its potency for 6 months at the three temperatures. The inactivated vaccine mixed with aluminum or oil adjuvant at high dilutions protected guinea pigs against challenge. This safer procedure for rabies virus inactivation offers promise for the production of effective vaccines for the immunization of dogs and cattle.

Adjuvants, Immunologic↗
PubMed1994

[Activity and concentration determinations of coagulation factors in conventional and virus-inactivated coagulation-active plasma].

Deep-frozen conventional plasma without viral inactivation [fresh frozen plasma (FFP)] and virus-inactivated plasma units [solvent/detergent (SD) procedure, methylene blue/illumination (MB) procedure] were investigated with regard to their contents of particles and their activities and concentrations, respectively, of blood clotting factors. Particles could be proved in FFP and in MB-treated plasma, but not in SD-treated plasma. Results of the global tests prothrombin time, partial thromboplastin time and thrombin time as well as the activities of blood clotting factors were located in normal range in SD-treated plasma. However, pathological results were partly found in MB-treated plasma. Activities of protein S and alpha 2-antiplasmin were lessened in SD-treated plasma. FFP and MB-treated plasma showed interindividual variations of outcomes (single-donor plasma units) in contrast to SD-treated plasma (pooled donor plasma units).

Blood Coagulation Factors↗