WO1996016672A1 - Serially passaged african green monkey kidney cells - Google Patents
Serially passaged african green monkey kidney cells Download PDFInfo
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- WO1996016672A1 WO1996016672A1 PCT/US1995/015118 US9515118W WO9616672A1 WO 1996016672 A1 WO1996016672 A1 WO 1996016672A1 US 9515118 W US9515118 W US 9515118W WO 9616672 A1 WO9616672 A1 WO 9616672A1
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Definitions
- the invention relates to a novel African Green Monkey Kidney (AGMK) cell substrate that supports the efficient replication of human and animal rotaviruses, astroviruses, enteroviruses including the Sabin live attenuated poliovirus vaccine strain.;, hepatitis A virus and respiratory viruses such as respiratory syncytial virus, parainfluenza viruses, and influen--a ⁇ and B viruses
- the invention is also useful for the production of virus suspensions suitable for use in vaccines for immunizauon of bumans
- Rotaviruses are major causal agents of acute gastroenteritis in man with a world-wide distribution. Enteroviruses have been implicated in infections ot the gastrointestinal tract, the respiratory system and in aseptic meningitis. Respirator-)' syncytial virus (RSV), the parainfiuen-.a viruses and the influenz-. viruses have been shown to be the major causal agents of serious pedi ⁇ tric diseases such as croup, bronchiolitis and pneumonia, while the influenza viruses are the major cause of serious febrile respiratory tract illness in adults. Hepatitis A virus is the cause of hepatitis A, one of the major infectious diseases of the liver.
- Rotavirus infections occur world-wide and are responsible for a large proportion of severe, life-threatening, often fatal diarrheal disease. Most rotavirus disease is caused by the four major human rotavirus serotypes but other serotypes are being discovered continuously. The latter are usually restricted in geographic distribution, but they could become a larger problem at any time. World-wide, the human rotaviruses are the major etiologic agents of serious acute gastroenteritis in infants and young children and on occasion can cause debilitating diarrhea in adults. It has been estimated by the World Health Organization that rotaviruses are responsible for one million fatal diarrheal illnesses each year in infants and young children in developing countries.
- the most important cause of serious viral respiratory illness in children is respiratory syncytial virus (RSV).
- the parainfluenza viruses, influenza viruses, and adenoviruses are also important in this regard.
- immunity does not appear to be long-lasting and re-infections can and do occur with high frequency during infancy, through the pre-school period, and throughout adult life.
- the parainfluenza viruses, of which there are four major types — 1, 2, 3 and 4 — have been implicated as important causes of croup, bronchiolitis and pneumonia in infants and young children. These viruses are
- influenza viruses are a major cause of mortality in older persons with underlying acute or chronic cardiac or pulmonary disease.
- the serious systemic disease manifestations of influenza virus infections are well known and the frequent antigenic shifts in serotype [A/H1N1, A/H3N2 and B] necessitate changes in the composition of the strains included in the yearly vaccine preparations.
- enteroviruses which are a subgroup of picomaviruses consisting of polioviruses, Coxsackie viruses and echoviruses, have been shown to cause a broad spectrum of illnesses. These illnesses include paralytic disease, encephalitis, aseptic meningitis, pleurodynia, exanthems, and pericarditis with some of the infections resulting in debilitating sequelae.
- Hepatitis A virus also a picomavirus, is a major cause of sporadic as well as epidemic hepatitis.
- cell strains semi-continuous cell systems which are diploid and have a finite longevity in terms of the number of passages that can be achieved in the laboratory are designated as cell strains
- continuous cell systems that are aneuploid and can be passaged indefinitely in the laboratory are designated as cell lines.
- a limiting factor in the development of vaccines for combating the maladies caused by a number of these infectious agents has been the lack of availability of an acceptable cell strain or line capable of supporting the growth of these viruses to a concentration suitable for use in vaccine production.
- Convenient and susceptible cell strains and/or lines that can be cultured using relatively high split ratios i.e., the preparation of
- Semi-continuous or continuous cell culture systems capable of supporting the growth of hybrid rotaviruses hereafter designated human x animal rotavirus reassortants, have included the simian cell strain, FRhL-2, and the simian cell lines, CV-I and Vero. Live virus vaccines produced in these cells have received CBER, FDA approval for Phase I and II studies. Henceforth, we will refer to these cell strains or lines as certified cell strains or lines to distinguish them from cell strains or lines that have been licensed for production of human vaccines. To date, only two semi-continuous cell culture systems, WI-38 and MRC-5, both human fetal diploid cell strains, have been licensed for use in virus vaccines. These cell strains will be referred to as licensed cell strains. Currently, there are no licensed continuous cell lines.
- FRhL-2, CV-1 and Vero certified cell strain or lines
- FRhL-2, CV-1 and Vero certified cell strain or lines
- FRhL-2, CV-1 and Vero are limited in their ability to support the growth of completely homologous human rotaviruses, i.e. , rotaviruses that derive each of their 11 RNA gene segments from a human rotavirus.
- the FRhL-2 cell strain with a maximum 1:3 split ratio capability, is limited in its ability to support the growth of important RSV.
- the CV-1 cells, with a maximum 1 :4 split ratio capability have not supported the growth of many viral agents to a level satisfactory for
- Vero cells with a split ratio of 1:6 - 1: 10, are limited in their ability to support the growth of a number of enteroviruses and fail to support the efficient growth of completely homologous human rotaviruses.
- HAV hepatitis A virus
- a picomavirus distantly related to the enteroviruses do not grow well in any cell type during primary isolation and must be adapted to growth in cells of primate origin before the level of virus replication required for vaccine development and production can be achieved.
- Inactivated whole-virus HAV vaccines grown in fetal human fibroblast MRC-5 cells have been developed, but the low split ratio of 1 :2 required by these cells, the low viral titers achieved, and the prolonged cultivation time of up to two weeks necessary for maximum yield of viral antigen make such vaccines expensive.
- HAV HAV in simian CV-1 , FRhK-4 (a fetal rhesus monkey kidney cell line), FRhK-6 (another fetal rhesus monkey kidney cell line) and Vero cells has been variable depending on the strain and passage level of virus, but generally is suboptimal. Best growth has been obtained in a cloned cell line, designated clone 11-1 , derived from FRhK-4 cells, but these cells contain bovine papilloma virus sequences and thus, are not suitable for vaccine development.
- Candidate live attenuated and inactivated HAV vaccines have been developed by adaptation of the virus to growth in primary African green monkey (AGMK) cells but such vaccines are not economically feasible because of the extreme difficulty of obtaining sufficient primary AGMK cells that are free of extraneous viral agents of monkey origin.
- Live attenuated and inactivated HAV vaccine candidates have been adapted to growth in MRC-5 cells, a human fetal diploid cell strain, but such adaptation has consistently led, respectively, to over- attenuation of the live attenuated virus for humans and a relatively sparse yield of inactivated virus vaccine.
- a cell strain or line capable of supporting the efficient growth of a large number of human viral pathogens such as the human rotaviruses, enteroviruses, HAV, and respiratory viruses of major medical importance including RSV, influenza viruses and parainfluenza viruses.
- Such a cell strain or line would facilitate the development and production of commercially useful and effective vaccines.
- vaccines against these viruses there is a pressing need for the development of vaccines against these viruses in order to prevent severe viral diseases of infants, children, adults and the elderly.
- the present invention is directed to a cell substrate that substantially overcomes the limitations of previously established cell strains or lines.
- the serially passaged cells of the present invention are derived from the paired kidneys of an African green monkey and support the efficient growth of medically important human rotaviruses, astroviruses, picomaviruses such as
- enteroviruses including the Sabin live attenuated poliovirus vaccine strains and hepatitis A virus, and respiratory viruses such as respiratory syncytial virus, parainfluenza viruses, and influenza A and B viruses.
- the AGMK cells of the invention are designated as a cell substrate because it is not clear at this time whether they constitute a cell strain or cell line. It is probable that they are a cell line because they are aneuploid, an essential and defining property of cell lines.
- the AGMK cells have been passaged serially only 30 times and assignment of cell immortality, one of the other defining features of a cell line, requires more than 50 serial passages. At the 30th passage there was no diminution of viability, or ability to grow nor was there any other outward sign of senescence.
- the AGMK cells have been split 1 :4 or 1:8 at each of these passages, a split ratio that is characteristic of cell lines but not cell strains which usually can not be split more than 1:2.
- the cell substrate based on currently promulgated guidelines (i.e., "Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals” (May 1993)) and state-of-the-art testing, has been demonstrated to be free of detectable adventitious microbial agents.
- This feature allows the cell substrate to be employed for the growth of viruses, such as the human rotaviruses and hepatitis A virus, which have a very highly restricted and narrow tissue culture host range. The unavailability of such a clean cell system prior to this invention has hampered vaccine development for these viruses.
- the cell substrate based on currently promulgated guidelines (i.e., "Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals" (May 1993)) and state-of-the-art testing, has been demonstrated to be free of detectable adventitious microbial agents.
- viruses such as the human rotaviruses and hepatitis A virus, which have a very highly restricted and narrow tissue culture host
- This invention also offers the advantage of a cell substrate which can be trypsinized and split in ratios ranging from 1 :4 to 1 :8 depending upon vessel size and time constraints imposed by vaccine production deadlines.
- the invention provides a cell line derived from the paired kidneys of an African green monkey, which is free of demonstrable adventitious microbial agents.
- the invention also provides a method for establishing the cell line by the enzymatic disaggregation of the paired kidneys from an African green monkey and continuous cultivation of the resulting cells.
- the invention provides a method for recovering and serially propagating specific viruses in the cell line that subsequently can be used for production of a viral vaccine.
- the present invention provides a cell line derived from a pair of African green monkey kidneys.
- the cell line is free of demonstrable viable adventitious microbial agents.
- the cell line is capable of supporting the growth of viruses such as human rotaviruses, astroviruses, enteroviruses, respiratory viruses and hepatitis A and is, therefore, useful for propagating viruses necessary for the production and formulation of a number of effective vaccines on a scale that makes such vaccines commercially feasible.
- the present invention relates to an aneuploid cell substrate with chromosome counts in the diploid range which was initiated by the enzymatic disaggregation of paired kidneys from a female Cercopithecus African green monkey.
- a deposit of the cell line at passage No. 13, Lot 6500 has been made with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, MD 20852, USA, on November 4th and has been assigned accession No. ATCC# CRL 11756.
- the present invention also provides a method of establishing a cell substrate capable of at least 30 serial passages that is initially derived by the enzymatic disaggregation of kidneys from an African green monkey.
- the invention provides a method for recovery and growth of specific viruses, a necessary first step for subsequent vaccine production.
- the cell substrate was derived from the kidneys of an African green monkey from a colony that had been established on Barbados.
- the cells are free of any demonstrable viable adventitious microbial agents.
- the microbial agents include, but are not limited to bacteria, fungi, mycobacteria, mycoplasma and simian agents such as retroviruses, foamy viruses, hemadsorbing viruses, herpes- like viruses and multi-nucleating or syncytial viruses.
- the kidneys were processed using conventional enzymatic disaggregation technology.
- the resulting kidney cell suspension was used to initiate 3 primary flask [T150 cm 2 ] cultures with the remainder, designated as Freeze #2129, distributed into multiple ampules and frozen for storage in a liquid nitrogen freezer.
- the primary flask cultures labelled A, B and C, were processed as follows:
- the maintenance medium consisted of Eagle's Minimal Essential Medium (EMEM) + 5% fetal bovine serum (heat inactivated at 56°C for 30 min.) + 1 % glutamine (200 mM). All flask cultures were refed with 100 ml of fresh maintenance medium on a weekly basis for a total incubation period of 9 weeks based on the initial planting date. The cultures were negative for hemadsorption and CPE (cytopathic effect), the latter determined by microscopic examination after fixation and staining.
- EMEM Eagle's Minimal Essential Medium
- CPE cytopathic effect
- Films were disaggregated by the addition of a trypsin-EDTA solution and incubation at 36°C ⁇ 1°C for 4-5 minutes.
- KARYOTYPING AND SPECIES IDENTIFICATION Passage 7A, Lot 94214 was characterized by Giemsa banded chromosome analysis and reaction with species-specific antisera and isoenzyme analysis.
- a. Cytogenic Characterization Conventional chromosome staining (non- banded) was utilized to determine chromosome count ploidy distribution per 100 metaphases. Identifiable markers and aberrations were analyzed for 50 metaphases.
- Chromosome banding by trypsin-Giemsa was utilized to analyze the karyotype and identify specific chromosome markers. Species confirmation was made using G-banding patterns and chromosome morphology. The procedures used were modifications of those described by Peterson, W.D., Jr., Simpson, W.F. , and Hukku, B. , Cell culture characteristics: Monitoring for cell identification, in Jakoby, W.B. and Pastan, I.H., eds., Methods in Enzymology 58:164-178, 1979; and Seabright, M., A rapid banding technique for human chromosomes, Lancet, ii:971-972, 1971.
- the cell line was identified as an aneuploid female Cercopithecus (African green) monkey (XX) with chromosome counts in the diploid range. Most of the
- chromosome D was monosomic and a single marker D chromosome was observed.
- Species Identification of Cell Culture The ability of the test cell preparation to react with species-specific antisera was determined using the fluorescent antibody technique as described by Peterson et al., supra. The cells reacted with monkey antiserum but not with mouse or hamster antiserum.
- Isoenzyme Analysis Enzyme preparations were made from the test article cells. The electrophoretic migration distances of the enzymes were compared with known migration distances of enzymes in various mammalian species as described by Halton, D.M., Peterson, W.D., Jr.
- the electrophoretic mobilities of enzymes glucose-6-phosphate dehydrogenase (G6PD), nucleoside phosphorylase (NP), malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) present in an extract prepared from the test cells were comparable to those of a Cercopithecus (African green) monkey control cell preparation. No extra bands were observed on the electrophoresis films that might suggest the presence of cells of a species other than that of the cell culture.
- a cell pellet of the test article cells (MWCB, Passage 7A, Lot# 4214) was prepared and examined for the presence of virus particles by transmission electron microscopy. No retrovirus-like particles were found in the 200 cells observed. b. Detection of Retrovirus Reverse Transcriptase in the Presence of
- DNA-Dependent DNA Polymerase The test article (MWCB, Passage 7A, Lot# 4214) was analyzed for the presence of types B, C and D retrovirus reverse transcriptase and cellular DNA polymerase activity. No evidence of the presence of retrovirus reverse transcriptase was observed. The results are presented in Table I - A, B and C.
- Sample 1 116 10 1 ,898 198 Sample 2 187 0 2,634 0 Sample 3 547 6 6,690 119 Sample 4 574 3 8,529 81 Sample 5 1,196 27 14,315 1,222 a DNA polymerase prepared from mink lung cells. b Expressed as counts per minute 3 H-thymidine triphosphate inco ⁇ orated [mean duplicates minus background (medium)l.
- the AGMK cells at Passage 17A, Lot #4706 were characterized by Giemsa banded chromosome analysis and reaction with species-specific antisera and isoenzyme analysis.
- the cells were identified as aneuploid female Cercopithecus (African green) monkey (XX, XXX) with chromosome counts in the hypodiploid to hyperdiploid range. All karyotypes examined contained a single normal Cercopithecus monkey marker chromosome (Group D) and a second partially deleted Cercopithecus monkey D group marker chromosome.
- the electrophoretic mobilities of the enzymes G6PD, NP, MDH and LDH present in an extract prepared from the test cells were comparable to those of Cercopithecus (African green) monkey control cell preparation. No extra bands were observed on the electrophoresis films that might suggest the presence of cells of a different species in the cell culture. The cells reacted with monkey antiserum but not with mouse antiserum.
- Retroviruses a.
- the cells were grown in the presence of 30 ⁇ g/ml bromodeoxyuridine for 24 hours (day 0 to day 1) and then refed with medium without inducer. Culture fluids (unconcentrated and concentrated 20-fold) were harvested on days 2, 3 and 4. No evidence of the presence of retrovirus reverse transcriptase activity was observed in the test article. The results are presented in Table II - A, B and C. b. Detection of Retrovirus Particles by Electron Microscopic
- PCR Polymerase Chain Reaction
- STLV-specific product When tested with the STLV pol primers SK110/SK111, STLV-specific product was not detected in test article reactions, each of which represented 1.0 ⁇ g nucleic acid extracted from the test article.
- the positive control series which contained the equivalent of 0.001 ⁇ g, 0.01 ⁇ g, 0.1 ⁇ g or 1 ⁇ g of nucleic acid extracted from a cell line infected by STLV (STLV ⁇ )
- STLV-specific product was detected in all reactions.
- the test article On the basis of failure to detect reactivity with STLV primers, the test article was judged to be negative for STLV nucleic acid sequences. d.
- LTR LTR and are capable of amplifying all subtypes of SIV agm .
- the predicted 200 bp fragment was amplified from DNA extracted from a chronically-SIV
- mice were inoculated subcutaneously with approximately 1 x 10 7 test article cells (AGMK Passage 17A, Lot #4889). Athymic nude mice were similarly inoculated with positive control cells. All 10 positive control inoculated mice had tumors at the site of inoculation. No metastases were observed in the inoculation site (skin), lung, lymph nodes, liver, kidney, spleen or brain of mice inoculated with the test article.
- Bacterial Sterility in Fluid Thioglycollate Medium Each of 10 culture tubes (9-10 ml medium per tube) was inoculated with 1.0 ml of the AGMK cell suspension (Passage 17A, Lot #4706) containing approx. 5 x 10 5 cells per ml. Each of 5 tubes was inoculated with 1.0 ml of the original growth medium. Ten cultures were included as uninoculated controls. All cultures were vortex mixed and incubated at 32°C ⁇ 2°C for 21 days with observations made on days 1, 3, 6, 8, 10, 13, 15, 17, 20 and 21. No growth was observed in any of the 25 cultures.
- Mycoplasma Sterility The assay for mycoplasma was performed using both the direct Broth Enrichment and Agar Procedures and the indirect Indicator Cell Culture Procedure with the AGMK cell suspension (Passage 17A, Lot #4706) containing approximately 5 x 10 5 cells per ml. The cell suspension was found to be negative for mycoplasmas by all procedures.
- AGMK Primary Human Amnion
- PHA Primary Human Amnion
- PRK Primary Rabbit Kidney
- Fl 5000 Whole Human Embryo Fibroblast
- H.Ep-2 Human Carcinoma of the Larynx
- Cultures were maintained on Medium EMEM containing 2- 10% fetal bovine serum (gamma irradiated) plus antibiotics: gentamicin, 100 ⁇ g/ml; neomycin, 50 ⁇ g/ml; and fungizone, 2.5 ⁇ g/ml. Cultures were refed with 2 ml of maintenance medium prior to inoculation.
- the cell suspensions (Lots #4742/3, #4755 or #4889 containing approximately 5 x 10 5 cells per ml) were inoculated in 0.5 ml amount per each of 28 roller tubes per tissue culture system. Cultures were incubated at 36°C ⁇ 1 °C for 14 days with periodic microscopic examination for any cytopathic effect (CPE) and/or cellular degeneration. When necessary to maintain the integrity of the cell films, cultures were refed with 2 ml of fresh maintenance medium. Additional groups of 28 roller tubes per tissue culture system were included as uninoculated controls.
- CPE cytopathic effect
- tubes were incubated at 2° - 8°C for a minimum of 30 minutes and examined microscopically for any signs of hemadsorption. Following manual shaking, tubes were incubated at 35° - 37°C for a minimum of 30 minutes and re-examined microscopically for hemadsorption. All cultures were negative for hemadsorption with all 3 suspensions and at both temperatures. On day 14, after final microscopic examination, the cultures were divided, depending on the specific tissue culture system for final testing. AGMK, PHA and FI5000 Tube Cultures were divided as follows: 1. 9 tubes from each series were tested for hemadsorption with the 3
- Vero, PRK and H.Ep-2 Tube Cultures were divided as follows: 1. 12 tubes from each series were tested for hemadsorption with the 3 RBC suspensions as described above for day 7-8;
- SUBSTTTUTE SHEET (RULE 26) 2. 7 tubes from each series were fixed and stained with a solution of 5% glutaraldehyde + 0.025% crystal violet and, after drying, examined microscopically for any signs of CPE.
- Vero Cells - Passage 143, LOT #4813.
- AGMK Controls AGMK Controls
- AGMK Controls AGMK Controls
- AGMK Controls AGMK Controls
- AGMK Controls AGMK Controls
- SUBSTTTUTE SHEET (RULE 26) the I.Cer. and I.P. routes: each pool into 10 newborns from mixed litters. An additional litter of 10 sucklings was included as uninoculated controls for this blind passage. All sucklings were observed daily for 14 days for deaths and/or signs of illness or distress. There were no deaths recorded for the AGMK or culture medium inoculated pups or for the uninoculated control group; however, on day 3, 4 sucklings were missing and presumed cannibalized in (c) the passaged control group. None of the sucklings exhibited any signs of illness or distress over this final 14 day observation period.
- mice were observed daily for deaths and/or signs of illness or distress over a 21 day period. There were no deaths recorded and all mice survived the entire 21 day observation period with no evidence of lymphocytic choriomeningitis virus infection or any other viral infection. This test in adult mice was considered satisfactory.
- the average temperatures (°C) for the AGMK inoculated guinea pigs were: 39.26, 39.30, 39.40, 39.46 and 39.53; for the medium inoculated guinea pig: 39.32; and for the control; 39.37. There were no significant temperature rises indicative of either bacterial or viral infection. All guinea pigs appeared healthy and survived the entire 42-day observation period at which time they were necropsied following euthanasia with Halothane and exsanguination. Inspection of the abdominal and thoracic cavities by the consulting veterinarian did not identify gross lesions or pathological changes. This assay in adult guinea pigs was considered satisfactory. d.
- Allantoic fluids were harvested individually, incubated in a 37°C water bath for 60 minutes to elute any adsorbed agent(s), and then clarified by centrifugation at 2500 rpm for 15 minutes at 20 °C. Pools were prepared for each of the 3 sets of eggs employing equal volumes from each individual harvest. The pools were assayed for hemagglutination both undiluted and at a 1: 10 dilution with incubation at 2°-8°C and at room temperature (15°-30°C) using the following erythrocytes in PBS at (pH 7.2): guinea pig at 0.6%; chick at 0.4%; and human at 0.6% .
- All fluids were negative for hemagglutination at both dilutions and at both temperatures with all 3 RBC suspensions.
- the sample pools were subpassaged in 0.5 ml amounts into 10-day old embryonated eggs via the allantoic route as follows: the pool from the AGMK cell suspension into 10 eggs; the pool from the medium into 5 eggs; and the pool from the uninoculated eggs into 5 eggs. An additional 5 eggs were included as uninoculated controls. Eggs were incubated at 36°C ⁇ 1 °C for 72 hours and then candled for deaths (none recorded) and chilled overnight at 2° - 8°C. Allantoic fluids were harvested, handled and tested as described above. All 4 pools were negative for hemagglutination at both dilutions and at both temperatures with all 3 RBC suspensions. There were no deaths recorded for any of the eggs inoculated with the
- the AGMK cells are the only characterized cells tested to date that are suitable for vaccine purposes and support the efficient growth of completely homologous human rotaviruses, i.e. , rotaviruses that derive each of their 11 gene segments from a human rotavirus. This is particularly important because a number of candidate homologous human rotavirus vaccine strains are now under development, including those shown in Table V.
- Roller tube cultures are inoculated with a 0.5 ml volume of the stool/trypsin mixture which is allowed to adsorb at 36 °C ⁇ 1°C for 60 minutes while rotating on a roller drum apparatus.
- Cultures are washed once and fed with 3 ml volumes of (EMEM) containing 1 % of 10X SPG (sucrose, 2.18M; KH 2 PO 4 , 0.038M; K 2 HPO 4 , 0.072M; and mono-sodium glutamate, 0.054M) and 1 ⁇ g/ml trypsin.
- Cell cultures in which trypsin is omitted are also included to control for the effect of trypsin. Incubation is at 36°C ⁇ 1°C.
- CPE cytopathic effect
- Virus and control cultures are treated similarly with 10% of 10X SPG (v/v) and subjected to one freeze-thaw cycle prior to harvest, sterility testing, distribution for storage, and serial passage. All subsequent passages are carried out either in roller tube cultures or in 25 cm 2 flask cultures employing similar procedures but with variation in trypsin concentration in both pre-treatment and in the final overlay.
- An efficient system for producing virus plaques in AGMK cells is developed using methods that are routine in the art so that the virus can be plaque purified in order to obtain a homogeneous population of virus for subsequent vaccine development.
- the harvest fluids are routinely titrated in the simian MA- 104 cells to measure the virus yield obtained.
- the virus is then triply-plaque-purified in AGMK cells and the resulting clone is amplified by
- the human rotaviruses exhibit a very narrow tissue culture host range.
- isolation and serial passage of various strains are usually performed in commercially available laboratory cell cultures such as simian MA- 104 or primary monkey kidney, both of which are unsuitable for vaccine production.
- the former cells have not been validated as a substrate for vaccine production and the latter cells are notorious for their contamination with various simian microbial agents including retroviruses.
- cell substrates certified for vaccine production such as simian FRhL-2 or Vero cells, either fail to support growth of completely homologous human rotaviruses or allow only poor growth.
- rotaviruses have been isolated, serially passaged and triply plaque-purified in commercially available laboratory cell culture systems not suitable for vaccine production. In those instances where it was necessary to use such viruses in vaccine development, the viruses were subsequently passaged and biologically cloned in a cell substrate certified for vaccine development and production. Ideally, virus to be used in vaccines should be isolated and passaged only in tissue culture cells certified to be acceptable for vaccine production.
- the AGMK cells of this invention meet this requirement because they support efficient growth of fully homologous human rotaviruses (Table V).
- Primary Seed Virus Pool A pool of virus and serially passaged tissue culture control fluids supplemented with 10% of 10X SPG (v/v) are prepared and, after sterility is confirmed, and potency is determined, the fluids are distributed into small aliquots for storage at or below -70°C to serve as 3rd level back-up to final vaccine production. Total volume may range from 30 ml to 100 ml.
- Secondary Seed Virus Pool A pool of virus and serially passaged tissue culture control fluids supplemented with 10% of 10X SPG (v/v) is prepared.
- the fluids are distributed into small aliquots for storage at or below -70°C to serve as 2nd level back-up to final vaccine production.
- Total volume may range from 100 ml to 300 ml.
- Master Seed Virus Pool or Pre-Production Seed Virus Pool A pool of virus and serially passaged tissue culture control fluids supplemented with 10% of 10X SPG (v/v) is prepared. After sterility is confirmed, potency is determined, and identity is confirmed by both serology and electrophoretic pattern, the fluids are distributed into multi-sized aliquots with storage at or below -70°C. These pools serve as first level back-up to final production. These fluids are subjected to the Tissue Culture Purity (Safety) Testing simultaneously with the vaccine lot. Total volume may range from 500 ml to 1 liter.
- Live Virus Vaccine Production Volume to be produced is based on the number of doses and containers required plus a minimum of 400 ml of crude fluid for safety testing. In addition to the virus pool, the production of a small pool (200 - 400 ml) of the passaged tissue culture control fluid is recommended for subsequent safety testing together with the crude virus harvest.
- Culture vessel fluids supplemented with 10% of 10X SPG (v/v) are subjected to one (1) freeze-thaw cycle prior to individual harvest and sterility testing. A sample pool is prepared and assayed for potency. Identity is confirmed by both serology and electrophoretic pattern. The individual harvests are stored at or below -70°C.
- Live attenuated rotavirus vaccines can be made using reassortant rotaviruses that derive ten of their eleven gene segments from their animal rotavirus parent and only one gene segment from their human rotavirus parent (usually the gene that encodes the major protective antigen VP7).
- human x rhesus monkey rotavirus reassortants are in a late stage of vaccine development and an application for a license has been submitted to the FDA. All vaccine candidate human X animal reassortant rotaviruses studied to date have exhibited a very broad tissue culture host range attributable to the animal rotavirus parent, which contributes ten of its eleven gene segments to the reassortant.
- the AGMK cell substrate has other advantages: (a) pre-treatment of virus with trypsin is not required; (b) the concentration of trypsin required in culture medium is reduced; (c) there is a significant reduction in the amount of virus required in the inoculum; (d) incubation time is shortened; and (e) the infected cell monolayer is completely lysed. Vaccine production is carried out as outlined above.
- the virus harvest was treated with ether (1 part ether to 4 parts virus suspension for 60 minutes at room temperature followed by a 30 minute bubbling with N 2 to drive off ether) to eliminate any ether sensitive simian virus that may have been picked up during passage and plaquing in the commercially available laboratory cell culture systems. Fluid production was similar to that outlined for the human rotavirus.
- the Sabin live attenuated oral poliovirus vaccine strains were grown in the AGMK cells at passages 15 and 16. Each of the vaccine strains grew to high titer in AGMK cells (type 1 virus 10 8 - 3 TCID 50 /ml, type 2 virus 10 8 1 TCID 50 /ml, and type 3 virus These titers translate into 100 to 1000 vaccine doses per ml of tissue culture harvest and are equivalent to the amount of virus produced by licensed primary AGMK cells and MRC-5 cells.
- Live Virus Suspension and/or Vaccine Production in the Characterized AGMK Cell Substrate Enteroviruses such as Coxsackie A9 virus were adapted to growth and serial passage in the characterized AGMK cells. These cells are used to produce live virus suspensions and vaccine. Several seed virus pools have been produced. Live Virus Vaccine and/or Suspension Production
- Primary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared and after sterility is confirmed and potency is determined, the fluids are distributed into small aliquots for storage at or below -70°C to serve as 3rd level back-up to final vaccine production. Total volume may range from 30 ml to 100 ml.
- Secondary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared. After sterility is confirmed, and potency determined, the fluids are distributed into small aliquots for storage at or below -70 °C to serve as 2nd level back-up to final vaccine production. Total volume may range from 100 ml to 300 ml.
- Master Seed Virus Pool or Pre-Production Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared. After sterility is confirmed, potency is determined, and identity confirmed by serology. The fluids are distributed into multi-sized aliquots with storage at or below -70°C. These pools serve as first level back-up to final production. These fluids are subjected to the Tissue Culmre Purity (Safety) Testing simultaneously with the vaccine lot. Total volume may range from 500 ml to 1 liter. 4.
- Live Virus Vaccine Production Volume to be produced is based on the number of doses and containers needed plus a minimum of 400 ml of crude fluid for the required safety testing. In addition to the virus pool, the production of a small pool (200 - 400 ml) of the passaged tissue culmre control fluid is recommended for subsequent safety testing together with the crude virus harvest. Culmre vessel fluids supplemented with 10% of 10X SPG (v/v) are subjected to one (1) freeze-thaw cycle prior to individual harvest and sterility testing. A sample pool is prepared and assayed for potency and identity is confirmed by serology. The individual harvests are stored at or below -70°C. When sterility, potency and identity are confirmed, crude harvests are thawed and pooled.
- Samples of about 400 ml are removed for safety testing.
- the remainder of the fluid is clarified by centrifiigation at 1200 g for 20 min. at 5°C, re-pooled, and distributed into final containers.
- Respiratory syncytial viruses subgroup A and B types, have been readily isolated in these AGMK cell culmres directly from human nasal and/or throat secretions. Specimens are centrifuged at 3000 rpm for 10 minutes to remove any articulate matter and then treated with antibiotics (200 ⁇ g/ml gentamicin; 100 ⁇ g/ml neomycin; and 5 ⁇ g/ml fungizone) for 60 minutes at room temperature. The antibiotic-treated specimens are inoculated into roller tube cultures of the AGMK cells and incubated at 36°C ⁇ 1 °C on a roller drum.
- antibiotics 200 ⁇ g/ml gentamicin; 100 ⁇ g/ml neomycin; and 5 ⁇ g/ml fungizone
- culmres are harvested and further passages are carried out either in roller tubes or in flask culmres with subsequent serial passage and plaque purification. Subsequently, virus mutants are produced by chemical mutagenesis or are selected by passage at suboptimal temperamre using the AGMK cells in either instance. Live virus vaccine is then prepared using the AGMK cells.
- Final viral yield of candidate live attenuated RSV vaccine strains grown in the AGMK cells was greater than that of these viruses grown in Vero cells, which were previously the most efficient cell substrate certified for production of RSV vaccines.
- An example is seen in Table VI, where the virus yield of a cold- passaged, temperamre sensitive mutant of RSV (designated RSV A2 cpts248/404) is shown to be 4- to 16-fold higher in the AGMK cell line than in Vero cells.
- the amount of RSV produced by the human fetal diploid cell line MRC-5 which has been licensed for use in production of virus vaccines, is 10- to 100- fold less than in AGMK cells.
- This mutant is highly attenuated but still capable of inducing resistance to RSV in susceptible chimpanzees, which represent the most relevant animal surrogate for evaluation of attenuation and protective efficacy of RSV mutants prior to initiation of clinical trials in humans.
- Live attenuated RSV vaccines are designed to be used in very young infants, the population at greatest risk of life-threatening RSV disease. Because of the need to immunize such young individuals, the live vaccine must be very attenuated (i.e., demonstrably weakened). Thus, it is noteworthy that the RSV A2 cpts248/404 mutant was able to attain a high titer in AGMK cells. Clearly, success of a vaccine containing this mutant and live RSV vaccines in general will require attainment of a high level of viral yield. To produce live virus vaccine, conditions for good growth and viral yield, such as temperamre of incubation and inoculum size, are determined by routine methods with production proceeding as follows: Live Virus Vaccine and/or Suspension Production
- Primary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared and after sterility is confirmed and potency is determined, the fluids are distributed into small aliquots for storage at or be low -70°C to serve as 3rd level back-up to final vaccine production. Total volume may range from 30 ml to 100 ml.
- Secondary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) is prepared.
- Total volume may range from 100 ml to 300 ml.
- Master Seed Virus Pool or Pre-Production Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared. Sterility is confirmed, potency is determined, and identity confirmed by serology. The fluids are distributed into multi-sized aliquots with storage at or below -70°C. These pools serve as first level back-up to final production. These fluids are subjected to the Tissue Culmre Purity (Safety) Testing simultaneously with the vaccine lot. Total volume may range from 500 ml to 1 liter.
- Live Virus Vaccine Production Volume to be produced is based on the number of doses and containers needed plus a minimum of 400 ml of crude fluid for the required safety testing. In addition to the virus pool, the production of a small pool (200 - 400 ml) of the passaged tissue culmre control fluid is recommended for subsequent safety testing together with the crude virus harvest. Culmre vessel fluids supplemented with 10% of 10X SPG (v/v) are harvested directly without undergoing a freeze - thaw cycle. A sample pool is prepared and assayed for potency and identity is confirmed by serology. The crude harvests are pooled and aliquots of about 400 ml are removed for safety testing. The remainder of the fluid is clarified by centrifiigation at 1200 g for 20 min. at 5°C, re-pooled, and distributed into final containers.
- Parainfluenza viruses types 1, 2 and 3 were isolated previously in primary AGMK cell culmres directly from human nasal and/or throat specimens. Subsequently, virus types 1, 2 and 3 were readily adapted to growth in the characterized AGMK cells. For isolation in the characterized AGMK cell substrate clinical specimens are centrifuged at 3000 rpm for 10 minutes to remove any paniculate matter and then treated with antibiotics (200 ⁇ g/ml gentamicin; 100 ⁇ g/ml neomycin; and 5 ⁇ g/ml fungizone) for 60 minutes at room temperamre.
- antibiotics 200 ⁇ g/ml gentamicin; 100 ⁇ g/ml neomycin; and 5 ⁇ g/ml fungizone
- the antibiotic-treated specimens are inoculated into the AGMK cell substrate roller tube cultures and incubated at 36°C ⁇ 1 °C on a roller drum. Once cytopathic effects and/or hemadsorption (with 0.1 % guinea pig RBC in PBS, pH 7.2) is evident, culmres are harvested with further passages carried out either in roller tubes or in flask culmres with subsequent serial passage followed by plaque purification. Subsequently, virus mutants are produced by chemical mutagenesis or are selected by passage at suboptimal temperamre, using the AGMK cell substrate in either instance.
- An attenuated cold-adapted ⁇ ca) mutant of parainfluenza virus type 3 (designated PIV3 ca cold passage 45) was successfully grown to high titer in the AGMK cell substrate. Growth yield of the mutant was similar to the yield obtained in Vero cells, a certified simian cell line that has not yet been licensed for production of live virus vaccine for use in humans. However, as shown in Table VII, final viral yields in the AGMK cells were approximately 30-fold higher than in the commonly used, certified fetal rhesus lung cell strain, FRhL-2, which also has not been licensed as yet for production of human viral vaccines.
- the PIV3 ca cold passage 45 mutant which is now in Phase II clinical trials, is satisfactorily attenuated for young infants who have not been previously infected with naturally occurring PIV3. Although the mutant is very attenuated in young infants, it nonetheless stimulates production of protective levels of serum PIV3 antibodies. Based upon the results of clinical trials of the ca mutant in young infants, we calculate that 1 ml of the viral yield from infected AGMK cells contains 30 vaccine doses of PIV3 ca cold passage 45. Attainment of this level of viral growth during vaccine production is particularly noteworthy because the live PIV3 vaccine has been weakened so that it can be administered safely to infants and young children, the target population for immunization.
- Primary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared and, after sterility is confirmed and potency is determined, the fluids are distributed into small aliquots for storage at or below -70°C to serve as 3rd level back-up to final vaccine production. Total volume may range from 30 ml to 100 ml.
- Secondary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) is prepared. After sterility is confirmed, and potency determined, the fluids are distributed into small aliquots for storage at or below -70°C to serve as 2nd level back-up to final vaccine production. Total volume may range from 100 ml to 300 ml.
- Master Seed Virus Pool or Pre-Production Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared. Sterility is confirmed, potency is determined, and identity confirmed by serology. The fluids are distributed into multi-sized aliquots with storage at or below -70°C. These pools serve as first level back-up to final production. These fluids are subjected to the Tissue Culmre Purity (Safety) Testing simultaneously with the vaccine lot. Total volume may range from 500 ml to 1 liter.
- Live Virus Vaccine Production Volume to be produced is based on the number of doses and containers needed plus a minimum of 400 ml of crude fluid for the required safety testing. In addition to the virus pool, the production of a small pool (200 - 400 ml) of the passaged tissue culmre control fluid is recommended for subsequent safety testing together with the crude virus harvest. Culmre vessel fluids supplemented with 10% of 10X SPG (v/v) are subjected to one (1) freeze-thaw cycle prior to individual harvest and sterility testing. A sample pool is prepared and assayed for potency and identity. The individual harvests are stored at or below -70 °C.
- Influenza viruses type A, subtypes H3N2, and H1N1 and type B have been readily adapted to growth in this characterized AGMK cell line.
- a significant advantage of isolating and growing influenza viruses in a mammalian cell line rather than in embryonated chicken eggs stems from the fact that the hemagglutinin (the major protective viral protein of influenza virus) retains the same amino acid sequence and conformation as that present in a virus isolated from humans.
- mutants bearing mutations affecting the hemagglutinin are selected during adaptation of virus to growth in eggs. These mutations confer upon the mutant a growth advantage in eggs.
- the advantages of producing influenza virus vaccines, either live or killed, in a mammalian tissue culture system rather than in embryonated eggs derive from retention of the major protective antigenic sites on the influenza virus hemagglutinin (HA) when virus is grown in mammalian tissue culmre.
- Adaptation of influenza A or B virus to efficient growth in embryonated chicken eggs frequently results in selection of viral mutants that possess mutations affecting one of the major protective antigenic sites on the viral HA.
- influenza viruses isolated and propagated only in mammalian cell culmre are more closely related antigenically to namrally circulating viruses than are egg-adapted influenza virus strains. For this reason it would be advantageous to isolate and maintain influenza A and B virus vaccine strains in a mammalian cell culmre system, preferably primate, so as to maintain authentic antigenic strucmre of HA which is the major protective protein of these viruses.
- influenza A viruses of subtype H1N1 or H3N2 grew efficiently in the AGMK cell substrate.
- Various influenza B virus strains also grow in the AGMK cells, albeit somewhat less well than the influenza A viruses. Since egg-propagated viruses were used as the inoculum in this experiment, the viral yields shown in Table VIII are minimal estimates because egg adaptation would be expected to select for mutants able to grow efficiently in eggs. Such mutants often grow less well in primate cells than the original namrally occurring virus as a consequence of the mutations responsible for egg adaptation.
- the AGMK cells can be used to isolate influenza A and B viruses from infected humans and serve as a cell substrate for production of virus that is used to produce an inactivated vaccine.
- the AGMK cells can be used to isolate and propagate virus during the derivation of attenuated mutants that are used for formulation of a live attenuated virus vaccine.
- HAV replicated to the same titer and at the same rate in the AGMK cell substrate, which is suitable for vaccine development and production, as in FRhK-4, clone 11-1 cells, which are not suitable for vaccine development. Furthermore, the size of the HAV plaques, as measured by the radioimmunofocus assay, was the same in both cell types. In contrast, HAV strain HM-175 (HAV/7) did not replicate efficiently in MRC5 cells (a cell strain licensable for vaccine development) without extensive adaptation by serial passage. Live Virus Vaccine and/or Suspension Production
- Primary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared and after sterility is confirmed and potency is determined, the fluids are distributed into small aliquots for storage at or below -70°C to serve as 3rd level back-up to final vaccine production. Total volume may range from 30 ml to 100 ml.
- Secondary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) are prepared. After sterility is confirmed and potency determined, the fluids are distributed into small aliquots for storage at or below -70 °C to serve as 2nd level back-up to final vaccine production. Total volume may range from 100 ml to 300 ml.
- Master Seed Virus Pool or Pre-Production Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG (v/v) is prepared. Sterility is confirmed, potency is determined, and identity confirmed by serology. The fluids are distributed into multi-sized aliquots with storage at or below -70°C. These pools serve as first level back-up to final production. These fluids are subjected to the Tissue Culmre Purity (Safety) Testing simultaneously with the vaccine lot. Total volume may range from 500 ml to 1 liter.
- Live Virus Vaccine Production Volume to be produced is based on the number of doses and containers needed plus a minimum of 400 ml of crude fluid for the required safety testing. In addition to the virus pool, the production of a small pool (200 - 400 ml) of the passaged tissue culmre control fluid is recommended for subsequent safety testing together with the crude virus harvest.
- Primary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG [v/v] that are sterility confirmed, potency determined and distributed into small aliquots for storage at - 70°C, or below, to serve as 3rd level back-up to final vaccine production. Total volume may range from 30 ml to 100 ml. 2.
- Secondary Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG [v/v] that are sterility confirmed, potency determined and distributed into small aliquots with storage at -70°C, or below, to serve as 2nd level back-up to final vaccine production.
- Master Seed Virus Pool or Pre-Production Seed Virus Pool A pool of virus and serially passaged tissue culmre control fluids supplemented with 10% of 10X SPG [v/v] that are sterility confirmed, potency determined, identity confirmed, and distributed into multi-sized aliquots with storage at -70°C, or
- Pools serve as 1st level back-up to final production. Fluids to be subjected to the Tissue Culmre Purity (Safety) Testing simultaneously with the vaccine lot. Total volume may range from 500 ml to 1 liter. 4. Inactivated Virus Vaccine Production: Volume to be produced is based on the number of doses and containers contracted for plus a minimum of 400 ml of crude fluid needed for the required safety testing. In addition to the virus pool, the production of a small pool [200 - 400 ml] of the passaged tissue culmre control fluid is recommended for subsequent safety testing together with the crude virus harvest.
- Culmre vessel fluids supplemented with 10% of 10X SPG [v/v] are subjected to one (1) freeze-thaw cycle prior to individual harvest and sterility testing.
- a sample pool is prepared and assayed for potency and identity and the individual harvests stored at -70 °C, or below.
- sterility, potency and identity are confirmed, crude harvests are thawed, pooled, clarified and purified before inactivation with formalin under standard conditions. The vaccine is then distributed into final containers and safety-tested for sterility.
- Neonatal G3;P2 5.8 Inconsistent, Inconsistent, No Growth poor growth poor growth
- AGMK cells were used at passages 10, 11, 14 or 15.
- a Inoculum was FRhL2 cell grown virus currently being evaluated in clinical trials.
- the titer of this FRhL2 cell virus suspension was 10 6 0 pfu/ml.
- b Inoculated cell cultures harvested after 14 days of incubation except 32 °C AGMK cultures which were harvested at 7 days because of accelerated development of viral cell destructive effects.
- a Passage in AGMK cell substrate initiated with egg grown influenza virus at a dilution of 10 - " 3 o 10 "4 .
- the inoculum for passage in cell culture was also 10 "3 or 10 "4 (except B/Victoria 2/87 which was 10 "2 ) in order to minimize generation of defective, interfering virus particles.
- Tissue culture medium and agarose overlay in plaque assays contained 0.5 ⁇ g/ml of trypsin.
- b MDCK is a continuous cell line of canine kidney cells often used for titration of human influenza viruses.
- FRhK-4(l l-l) HAV- permissive cell clone derived from fetal rhesus kidney-4 cells (Funkhouser AW, Purcell RH, D'Hondt E, Emerson SU, Attenuated hepatitis A virus: Genetic determinants of adaptation to growth in MRC-5 cells. J Virol 68:148-157; 1994).
- MRC-5 fetal human lung fibroblast cell substrate.
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002201585A CA2201585A1 (en) | 1994-11-30 | 1995-11-30 | Serially passaged african green monkey kidney cells |
DE0790836T DE790836T1 (en) | 1994-11-30 | 1995-11-30 | SERIES PASSENGED KIDNEY CELLS FROM AFRICAN GREEN MONKEY |
AU42857/96A AU708482B2 (en) | 1994-11-30 | 1995-11-30 | Serially passaged african green monkey kidney cells |
EP95941434A EP0790836A4 (en) | 1994-11-30 | 1995-11-30 | Serially passaged african green monkey kidney cells |
JP51889396A JPH10510708A (en) | 1994-11-30 | 1995-11-30 | African green monkey kidney cells serially passaged |
GR970300041T GR970300041T1 (en) | 1994-11-30 | 1997-11-28 | Serially passaged african green monkey kidney cells |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/351,079 US5646033A (en) | 1994-11-30 | 1994-11-30 | African green monkey kidney cell lines useful for maintaining viruses and for preparation of viral vaccines |
US08/351,079 | 1994-11-30 |
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WO1996016672A1 true WO1996016672A1 (en) | 1996-06-06 |
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ID=23379484
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PCT/US1995/015118 WO1996016672A1 (en) | 1994-11-30 | 1995-11-30 | Serially passaged african green monkey kidney cells |
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US (4) | US5646033A (en) |
EP (1) | EP0790836A4 (en) |
JP (1) | JPH10510708A (en) |
AU (1) | AU708482B2 (en) |
DE (1) | DE790836T1 (en) |
ES (1) | ES2107984T1 (en) |
GR (1) | GR970300041T1 (en) |
WO (1) | WO1996016672A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000012684A2 (en) * | 1998-09-01 | 2000-03-09 | St. Louis University | Temperature-sensitive and cold-adapted human parainfluenza virus type 2 (hpiv-2) and vaccines based on such virus |
WO2012004323A1 (en) * | 2010-07-08 | 2012-01-12 | Glaxosmithkline Biologicals S.A. | Process for removing adventitious agents during the production of a virus in cell culture |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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DE19612966B4 (en) * | 1996-04-01 | 2009-12-10 | Novartis Vaccines And Diagnostics Gmbh & Co. Kg | MDCK cells and methods of propagating influenza viruses |
DE19612967A1 (en) * | 1996-04-01 | 1997-10-02 | Behringwerke Ag | Process for the propagation of influenza viruses in cell culture, and the influenza viruses obtainable by the process |
CA2355270A1 (en) | 1998-12-17 | 2000-06-22 | Aventis Pasteur Limited | Multivalent immunogenic composition containing rsv subunit composition and influenza virus preparation |
US6514502B1 (en) | 1999-01-26 | 2003-02-04 | Schering-Plough Veterinary Corporation | Propagation of bovine cononavirus in chinese hamster ovary cells |
US6821741B1 (en) * | 2001-04-27 | 2004-11-23 | University Hospitals Of Cleveland | Cells for detection of enteroviruses |
DE10144906B4 (en) * | 2001-09-12 | 2013-11-28 | Novartis Vaccines And Diagnostics Gmbh | Process for the large-scale production of vaccines |
WO2004075861A2 (en) * | 2003-02-26 | 2004-09-10 | Children's Hospital, Inc. | Recombinant adeno-associated virus production |
WO2010144797A2 (en) | 2009-06-12 | 2010-12-16 | Vaccine Technologies, Incorporated | Influenza vaccines with enhanced immunogenicity and uses thereof |
RU2529792C1 (en) * | 2013-03-20 | 2014-09-27 | Людмила Викторовна Ганковская | METHOD FOR ASSESSING ANTI-HERPETIC EFFICACY in vitro OF PHOTODYNAMIC EXPOSURE ON HERPES SIMPLEX VIRUS (HSV) |
GB201603192D0 (en) * | 2016-02-24 | 2016-04-06 | Univ Warwick | Method |
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US4040905A (en) * | 1971-10-27 | 1977-08-09 | The United States Government | Sub-human primate diploid cell lines as substrates for virus vaccine production |
US4571385A (en) * | 1983-06-27 | 1986-02-18 | The United States Of America As Represented By The Department Of Health And Human Services | Genetic reassortment of rotaviruses for production of vaccines and vaccine precursors |
US4783407A (en) * | 1985-09-30 | 1988-11-08 | Merck & Co., Inc. | Growth of hepatitus A virus in vero cells |
Family Cites Families (1)
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US5610049A (en) * | 1991-05-01 | 1997-03-11 | The Wistar Institute Of Anatomy And Biology | Human rotavirus HCR3A and method of growing said rotavirus |
-
1994
- 1994-11-30 US US08/351,079 patent/US5646033A/en not_active Expired - Lifetime
-
1995
- 1995-11-30 WO PCT/US1995/015118 patent/WO1996016672A1/en not_active Application Discontinuation
- 1995-11-30 ES ES95941434T patent/ES2107984T1/en active Pending
- 1995-11-30 EP EP95941434A patent/EP0790836A4/en not_active Withdrawn
- 1995-11-30 AU AU42857/96A patent/AU708482B2/en not_active Ceased
- 1995-11-30 DE DE0790836T patent/DE790836T1/en active Pending
- 1995-11-30 JP JP51889396A patent/JPH10510708A/en not_active Ceased
-
1997
- 1997-01-29 US US08/790,598 patent/US5911998A/en not_active Expired - Lifetime
- 1997-11-28 GR GR970300041T patent/GR970300041T1/en unknown
-
1998
- 1998-03-26 US US09/048,308 patent/US6025182A/en not_active Expired - Lifetime
-
1999
- 1999-06-21 US US09/336,740 patent/US6117667A/en not_active Expired - Fee Related
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US4040905A (en) * | 1971-10-27 | 1977-08-09 | The United States Government | Sub-human primate diploid cell lines as substrates for virus vaccine production |
US4571385A (en) * | 1983-06-27 | 1986-02-18 | The United States Of America As Represented By The Department Of Health And Human Services | Genetic reassortment of rotaviruses for production of vaccines and vaccine precursors |
US4783407A (en) * | 1985-09-30 | 1988-11-08 | Merck & Co., Inc. | Growth of hepatitus A virus in vero cells |
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Title |
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ABSTRACT OF THE ANNUAL MEETING OF THE AMERICAN SOCIETY FOR MICROBIOLOGY, 23rd Annual Meeting, issued March 1983, PRICE et al., "The Use of Serially Propagated Monkey Kidney Cell Cultures for the Preparation of High-Titered Hemagglutinin and/or Complement-Fixing Antigens of the Human Parainfluenza Viruses-Types 1, 2 and 3", * |
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JOURNAL OF GENERAL VIROLOGY, Volume 57, issued 1981, LEE et al., "Serial Propagation of Astrovirus in Tissue Culture with the Aid of Trypsin", pages 421-424. * |
See also references of EP0790836A4 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000012684A2 (en) * | 1998-09-01 | 2000-03-09 | St. Louis University | Temperature-sensitive and cold-adapted human parainfluenza virus type 2 (hpiv-2) and vaccines based on such virus |
WO2000012684A3 (en) * | 1998-09-01 | 2000-07-27 | Univ St Louis | Temperature-sensitive and cold-adapted human parainfluenza virus type 2 (hpiv-2) and vaccines based on such virus |
US6946136B2 (en) | 1998-09-01 | 2005-09-20 | St. Louis University | Temperature-sensitive and cold-adapted human parainfluenza virus type 2 (HPIV-2) and vaccines based on such virus |
WO2012004323A1 (en) * | 2010-07-08 | 2012-01-12 | Glaxosmithkline Biologicals S.A. | Process for removing adventitious agents during the production of a virus in cell culture |
US20130095135A1 (en) * | 2010-07-08 | 2013-04-18 | Glaxosmithkline Biologicals S.A. | Process for removing adventitious agents during the production of a virus in cell culture |
CN103080304A (en) * | 2010-07-08 | 2013-05-01 | 葛兰素史密丝克莱恩生物有限公司 | Process for removing adventitious agents during the production of a virus in cell culture |
Also Published As
Publication number | Publication date |
---|---|
GR970300041T1 (en) | 1997-11-28 |
EP0790836A4 (en) | 2003-05-28 |
US6025182A (en) | 2000-02-15 |
EP0790836A1 (en) | 1997-08-27 |
ES2107984T1 (en) | 1997-12-16 |
US5646033A (en) | 1997-07-08 |
DE790836T1 (en) | 1998-03-26 |
JPH10510708A (en) | 1998-10-20 |
US6117667A (en) | 2000-09-12 |
AU4285796A (en) | 1996-06-19 |
US5911998A (en) | 1999-06-15 |
AU708482B2 (en) | 1999-08-05 |
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