Safety of pasteurised factor VIII (haemate HS)
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Cold Temperature↗
Biomedical subjects
R Mauler
Publications and source records attributed to R Mauler.
Adaptation of hepatitis A virus to high titre growth in diploid and permanent cell cultures.
A hepatitis A virus isolate originally obtained from the feces of a clinically ill patient and passaged in diploid human embryonic kidney and lung cells was adapted to grow in MRC-5, Cercopithecus aethiops muscle and in Vero cells. Three different adaptation methods were applied. Either method proved to be suitable to finally give high virus titres of cell-bound as well as cell-free virus in the supernatant of infected cultures during 10 to 15 passages. An easily performable immunoperoxidase staining method was used for the titration of hepatitis A virus in microtitre plates. Cytopathogenic changes in MRC-5 cell cultures infected with fully adapted virus are described.
Cells, Cultured↗
Inactivation of HTLV-III/LAV, hepatitis B and non-A/non-B viruses by pasteurization in human plasma protein preparations.
Pasteurization (heat treatment at +60 degrees C for 10 hours in solution) during the production of human plasma protein preparations has proved useful 1. to inactivate a broad spectrum of viruses and 2. in combination with stabilizers to leave the nativity of the products unaffected. Their efficacy has been experimentally tested for HTLV-III/LAV, Hepatitis B and non-A/non-B viruses. The following preparations were tested: with HTLV-III/LAV: Factor VIII, Factor IX, AT III, AHC and PPSB; with Hepatitis B virus: Factor VIII, Factor XIII, AT III, PPSB and Fibrinogen; with Hepatitis non-A/non-B virus: Factor VIII and AT III.
Animals↗
Biometrical aspects in the design and analysis of chimpanzees trials assessing hepatitis virus inactivation.
Hepatitis virus safety of products derived from blood is achieved by screening of individual blood donations and by production processes efficient in eliminating and inactivating residual amounts of hepatitis viruses. A quantitative measure of process inactivation efficiency is the inactivation factor derived from process overchallenging experiments. A product is safe if the corresponding process inactivation factor is as high as the one of a product whose safety has been clinically established. Reliable information on hepatitis safety cannot be obtained by testing commercial end product samples in chimpanzees.
Animals↗
Virus safety of a pasteurized antithrombin III concentrate. Preclinical and clinical data.
Blood derived products carry the risk of virus transmission, especially for the hepatitis B virus (HBV), non-A/non-B virus(es) (NANBV) and human immunodeficiency virus (HIV). The precautionary measures for guaranteeing the virus safety of the pasteurized antithrombin III concentrate Kybernin HS/P are described and the efficacy of these measures is demonstrated by in vitro studies and by chimpanzee trials. The inactivation rate is greater than or equal to 10(6.7) for HIV, greater than or equal to 10(6.7) for HBV, and greater than or equal to 10(5.3) for NANBV (Hutchinson Pool). Clinically, virus safety was demonstrated by long-term drug surveillance as well as by both a retrospective and prospective clinical trial. The 13 participants of the prospective study were checked clinically and biochemically according to the standards of the International Committee of Thrombosis and Hemostasis (ICTH). Within an observation period of 12 months, no seroconversion has been detected for HIV or HBV. Neither have any increases in the transaminases occurred which would indicate NANB hepatitis.
Alanine Transaminase↗
Inactivation of the AIDS-causing retrovirus and other human viruses in antihemophilic plasma protein preparations by pasteurization.
Heat treatment at 60 degrees C for 10 h in solution (pasteurization) was introduced into the manufacturing process of antihemophilic cryoprecipitate (AHC) and factor VIII concentrates (F VIII) to reduce the risk of transmission of hepatitis to hemophiliacs. Since the acquired immunodeficiency syndrome (AIDS) may also be transmitted to hemophiliacs by antihemophilic plasma protein preparations, we have investigated inactivation of the AIDS virus HTLV III by pasteurization in AHC or F VIII and included in this study cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), poliovirus and vaccinia virus. Each of these viruses was efficiently inactivated by pasteurization although considerable differences were observed between the different viruses HTLV III was rapidly inactivated, becoming nondetectable within 30-60 min. Our findings indicate that pasteurized AHC or F VIII should have a high margin of safety regarding the transmission of AIDS or any other infectious disease caused by viruses such as those tested.
Acquired Immunodeficiency Syndrome↗
Safety of human blood products: inactivation of retroviruses by heat treatment at 60 degrees C.
Acquired immune deficiency syndrome (AIDS) can be transferred to patients by blood transfusions or human blood preparations, such as cryoprecipitates or factor VIII concentrates. Retroviruses have been discussed as infectious AIDS agents and more recently human T-lymphotropic retroviruses designated as HTLV type III and LAV (lymphadenopathy-associated virus) have been isolated from AIDS patients. Whether heat treatment at 60 degrees C (pasteurization) of liquid human plasma protein preparations inactivates retroviruses was therefore investigated. Pasteurization had already been included in the routine manufacturing process of human plasma protein preparations in order to guarantee safety with regard to hepatitis B. Since high titer preparations of human retroviruses were not available, heat inactivation was studied using Rous sarcoma virus added to the various plasma protein preparations tested. This retrovirus which was obtained in preparations of 6.0 log10 FFU/ml was shown to be at least as heat stable as two mammalian retroviruses studied, i.e., feline and simian sarcoma virus. In all of eight different plasma protein preparations tested, Rous sarcoma virus was completely inactivated after a heat treatment lasting no longer than 4 hr. It is thus concluded that pasteurization of liquid plasma protein preparations at 60 degrees C over a period of 10 hr must confer safety to these products with respect to AIDS, provided that the AIDS agents are retroviruses of comparable heat stability as Rous sarcoma virus and the mammalian retroviruses tested.
Acquired Immunodeficiency Syndrome↗
[Inactivation of viruses in Factor XIII concentrate by pasteurization].
The use of a pasteurization step (heating in solution to 60 degrees C for 10 h) makes it possible to inactivate viruses, thus increasing the safety of the preparations. Using Factor XIII concentrate solution, it can be shown that hepatitis B virus and 10 other virus species are inactivated. Pasteurized Factor XIII was produced from starting material containing a total of 10(5.7) CID50 hepatitis-B virus (10(3.5) CID50/ml; CID = chimpanzee infectious dose). This Factor XIII preparation was injected in 4 chimpanzees; they remained healthy over an observation period of 37 weeks, whereas the 2 chimpanzees that received nonheated starting material developed hepatitis B. Furthermore, Rous-sarcoma, Epstein-Barr, cytomegalo, herpes simplex, measles, and rubella virus added to Factor XIII solution are inactivated by pasteurization within 2 h, mumps virus within 8 h, and adeno, polio, and vaccinia virus within 10 h. Pasteurizing of clotting factor preparations during the manufacturing process is a suitable for inactivating viruses and thereby increasing the safety of the preparations.
Animals↗
Amino acid utilization by Vero cells in microcarrier culture.
Vero cells were grown in microcarrier culture and subsequently infected with herpes simplex virus (type 1). Amino acid analyses were conducted on culture supernatants using a rapid reverse-phase high performance liquid chromatography method. The utilization of amino acids by the cells during cell growth and virus production phases was examined. During cell growth, glutamine and histidine were rapidly depleted (80-90%) by Vero cells while arginine and tryptophan-menthionine (peaks not resolved) were only moderately reduced (ca. 40%). In contrast, a marked increase in the concentrations of alanine and serine in the culture medium was observed. During virus production, the rapid depletion of glutamine, as well as the release of alanine and serine, was again observed, while the concentrations of isoleucine, lysine, threonine and valine increased only moderately.
Amino Acids↗
Herpes simplex virus subunit vaccine: characterization of the virus strain used and testing of the vaccine.
Herpes simplex virus type 1 (HSV-1) used for vaccine production was isolated from a nasal recurrent infection and propagated over a limited number of passages in human diploid cells only. It was designated as HSV-1 BW3 and has been characterized by neutralizing antibodies as a typical HSV type 1 strain. In vitro transformation studies performed with this isolate in mouse or hamster cells revealed only very low, if any, transforming capacity. A preparation of HSV-1 BW3 which can be used as seed lot for vaccine production has been proven to be free of any adventitious agents such as bacteria, fungi mycoplasma or viruses other than HSV-1 BW3. An envelope antigen (EAG) preparation was obtained from purified HSV-1 particles. It was free of detectable viral DNA and could be proven to be efficacious in mouse models against challenge infections with either HSV-1 or HSV-2. The potency of the vaccine was greatly enhanced by the addition of poly-inosinic-poly-cytidylic acid complexed with poly L-lysine and carboxymethylcellulose (PICLC) as adjuvant. A single vaccine dose was sufficient to protect mice from morbidity and the fatal outcome of HSV infection, but not from the establishment of latency. Persistent ganglionic infections could be, however, significantly reduced by repeated administration of the vaccine before primary infection.
Adult↗
Pharmacokinetics of human interferon-beta in monkeys.
Human fibroblast-derived interferon (HuIFN-beta) was administered to cynomolgus monkeys i.m. (2 x 10(5) iu/kg), i.v. (2 x 10(5) iu/kg) or intrathecally (3 x 10(5) iu/monkey) or given by a 3 hr i.v. infusion (2 x 10(5) iu/kg). One hr after intrathecal administration, interferon titers in the CSF were 1000-2000 iu/ml, and declined to less than 10 iu/ml during the first 24 hr. At the same time only minute amounts of HuIFN-beta were found in the sera of these animals. After i.m. administration, 5 iu/ml were found on average in the serum during the first 8 hr, with no interferon titer ever exceeding 10 iu/ml. No antiviral activity was found 24 hr after HuIFN-beta injection. HuIFN-beta injected i.v. resulted in serum interferon titers of approx. 300 iu/ml 30 min after administration, which then decreased to about 5 iu/ml during the first 8 hr 24 hr after injection no antiviral activity was detectable. Daily HuIFN-beta i.v. administrations over a period of four days did not affect the interferon clearance from the circulation. During HuIFN-beta infusion, constant HuIFN-beta titers of about 80 iu/ml were observed which then decreased during the following 5 hr to 2 iu/ml. The choice between a single i.v. injection, resulting in high serum titers for a few minutes, and a 3 hr infusion, resulting in an about fourfold lower but constant interferon level for over two hr, will depend on the mechanism of interferon action in vivo and on the question as to whether side effects can be diminished by infusion.
Animals↗
Correlation of herpes simplex virus antibody titers and specific lymphocyte stimulation in adult blood donors.
Antibody titers to herpes simplex virus type 1 in sera from healthy adult donors were assayed by complement fixation, microneutralization, and an enzyme immunoassay (ELISA). This last test proved to be the most sensitive method for antibody detection. It was estimated that ELISA antibody titers were up to 40-fold higher than neutralizing antibody titers and up to 100-fold higher than complement fixation antibody titers. Due to the higher sensitivity of ELISA, only 3 of 36 blood donors tested in this assay were shown to be seronegative, whereas 6 additional persons of the same group were termed seronegative by the microneutralization assay. Furthermore, four of the latter also did not respond in the complement fixation test. In vitro stimulation of peripheral lymphocytes by using a partially purified herpes simplex virus type 1 particle antigen was achieved for all seropositive blood donors. Only those three donors who were ELISA negative reacted negatively in this stimulation assay. From these results it may be concluded that ELISA is an appropriate method not only for rapid and sensitive antibody determination but also for selecting herpes simplex virus-negative patients.
Adult↗
[A purified rabies vaccine from human diploid cell cultures (author's transl)].
In order to improve the tolerance of rabies vaccine from human diploid cell cultures, the rabies virus antigen is purified in the sucrose density gradient by means of a flow ultracentrifuge. The purified virus has a specific infectiosity of 10(9) LD50 and a speicific activity of 250 units "relative activity" per 1 mg protein. The purified vaccine has been shown to be well tolerated, effective and stable.
Animals↗
Diarrhea in newborn cynomologus monkeys infected with human rotavirus.
Of six newborn cynomolgus monkeys (Macaca fascicularis) naturally delivered and normally nursed five developed diarrhea after oral administration of human rotavirus. Virus excretion was observed in the stool of four animals. This virus was transmitted to four out of six other monkeys causing diarrhea in only one animal.
Animals↗
On stability of oral poliovirus vaccines.
A stabilizer which prevents oral poliovirus from degradation is described. It contains mainly phosphate buffer 0.3 mol, at a pH of 6.7.
Buffers↗
A purified human diploid cell rabies vaccine.
Continuous-flow isopycnic banding of rabies virus in sucrose gradient was used to purify the antigen for the preparation of a human diploid cell rabies vaccine. Prior to the addition of the stabilizer, the average specific potency of several vaccine batches was 234 antigenic values per 1.0 mg of protein. Further data regarding potency and stability of this vaccine are presented.
Antigens, Viral↗
[Epidemiological effect of influenza vaccination (author's transl)].
No influenza-A virus epidemic occurred in the Federal Republic of Germany during 1971-1975. The neighbouring countries, however, reported up to three such epidemics. The vaccines used had differences: contrary to neighbouring countries, in the FRG largely those were used which had mineral adjuvants, and they more frequently had viral subgroups. Comparison between the USA and FRG with respect to influenza death-rates over 20 years revealed a strict correlation from 1956 up to 1965. But since 1966 the death-rate has decreased progressively in the FRG while it has remained unchanged in the USA. Immunisation methods in the two countries have differed since 1966 in that the Public Health Authorities of the two countries have recommended immunisation of different population groups: in the USA it has been only for patients at risk, while in the FRG the rest of the population has also been urged to be immunised. As a result, immunisation rates differ markedly between the two countries. Absence of an influenza epidemic, accompanied by a reduction in death-rate due to influenza, strongly suggests that the two phenomena are the result of a break in the infection chain. This seems to be more successful when both part of the total population and the risk groups are immunised.
Cross-Cultural Comparison↗
Results of chromosome analysis of rabies virus infected human diploid cells (WI-38).
Fixed rabies virus strains did not induce mitotic or chromosome abnormalities in infected WI-38 cultures. Infected cells were shown to undergo mitosis thus indicating an endosymbiotic type of infection.
Antigens, Viral↗