GB1560185A - Respiratory syncytical virus vaccine - Google Patents
Respiratory syncytical virus vaccine Download PDFInfo
- Publication number
- GB1560185A GB1560185A GB4692/78A GB469278A GB1560185A GB 1560185 A GB1560185 A GB 1560185A GB 4692/78 A GB4692/78 A GB 4692/78A GB 469278 A GB469278 A GB 469278A GB 1560185 A GB1560185 A GB 1560185A
- Authority
- GB
- United Kingdom
- Prior art keywords
- virus
- vaccine
- stabilizer
- process according
- gelatin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- 241000700605 Viruses Species 0.000 title claims abstract description 42
- 229960005486 vaccine Drugs 0.000 title claims abstract description 29
- 230000000241 respiratory effect Effects 0.000 title claims description 5
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 24
- 210000004072 lung Anatomy 0.000 claims abstract description 19
- 241000725643 Respiratory syncytial virus Species 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims description 21
- 230000002238 attenuated effect Effects 0.000 claims description 17
- 239000003381 stabilizer Substances 0.000 claims description 17
- 108010010803 Gelatin Proteins 0.000 claims description 12
- 229920000159 gelatin Polymers 0.000 claims description 12
- 239000008273 gelatin Substances 0.000 claims description 12
- 235000019322 gelatine Nutrition 0.000 claims description 12
- 235000011852 gelatine desserts Nutrition 0.000 claims description 12
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 11
- 239000000600 sorbitol Substances 0.000 claims description 11
- 238000011534 incubation Methods 0.000 claims description 10
- 238000003306 harvesting Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 230000003612 virological effect Effects 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 230000005847 immunogenicity Effects 0.000 claims description 4
- 230000003472 neutralizing effect Effects 0.000 claims description 4
- 230000000890 antigenic effect Effects 0.000 claims description 3
- 230000002163 immunogen Effects 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 238000002255 vaccination Methods 0.000 claims description 3
- 241000581444 Clinidae Species 0.000 claims description 2
- 238000010257 thawing Methods 0.000 claims description 2
- 230000001717 pathogenic effect Effects 0.000 abstract 1
- 238000004113 cell culture Methods 0.000 description 7
- 238000002955 isolation Methods 0.000 description 6
- 241000282693 Cercopithecidae Species 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000007640 basal medium Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 239000003855 balanced salt solution Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 description 2
- 238000009781 safety test method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000012568 clinical material Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5254—Virus avirulent or attenuated
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus
- C12N2760/18534—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
By serial passage of the virulent RS virus (respiratory syncytial virus) in human diploid lung fibroblasts, a non-pathogenic, but antigenically active, live RS virus is produced. The virus is suitable for the production of vaccine from live virus.
Description
(54) RESPIRATORY SYNCYTICAL VIRUS VACCINE
(71) We, MERCK & CO. INC., a corporation duly organized and existing under the laws of the State of New Jersey, United
States of America, of Rahway, New Jersey,
United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:
This invention is concerned with the adaption and propagation of respiratory syncytial virus in cultures of human diploid lung fibroblasts. The WI-38 fibroblasts, originally derived from a single human lung, have been extensively characterized biologically, biochemically, virologically, and genetically. Likewise, the MRC-5 fibroblasts, also derived from a single human lung but from a different individual, are also standardized. WI-38 fibroblasts are described in Exper. Cell Res. 25, 585 (1961) and are deposited with the American
Type Culture Collection (ATCC CCL-75).
MRC-5 fibroblasts are described in Nature 227, 168, (July 11, 1970) and are deposited with the American type culture collection (ATCC CCL 171). Propagation of human diploid lung fibroblasts may be carried out by any of the standard methods described in the literature. For example, a culture of human diploid lung fibroblasts is prepared in glass bottles using BME (GIB-Diploid) supplemented with 10 per cent unheated calf serum as growth medium. Following incubation at 36"C for 48-72 hours cultures can be used for serial passage or vaccine preperation.
The present invention provides a live repiratory syncytial vaccine comprising an attenuated yet antigenic and immunogenic respiratory syncytial virus suitable for parenteral administration.
In accordance with the present invention, attenuated respiratory syncytial virus is prepared by serially passaging a respiratory syncytial virus in a culture of human diploid lung fibroblasts at an incubation temperature of from 30 to 38"C for from 3 to 30 serial passages in order to attenuate the virus yet retain its antigenicity and immunogenicity, and harvesting the resulting virus.
The preferred procedure of the present invention involves the steps of (A) the isolation of the virulent virus in any of a variety of cells in culture, and its adaption to human diploid lung fibroblasts; (B) the development of the attenuated live virus by from 3 to 30 passages in a culture of human diploid lung fibroblasts; and (C) the preparation of the vaccine from this attenuated live virus.
These steps will be separately explained.
A. Isolation and adaptation of virulent virus
Isolation and adaptation of respiratory syncytial virus can be accomplished in a culture of human diploid lung fibroblasts using virus previously propagated in known manner in another kind of cell culture, for example, monkey kidney. Isolation in cell culture such as, e.g. monkey kidney, can be from clinical material (e.g. throat swab). Isolation may be carried out by one or more serial passages in such cell culture. After isolation, the virus is subjected to from 3 to 30 and preferably from 4 to 15 serial passages in a culture of human diploid lung fibroblasts. These passages serve to adapt and attenuate the virus. Incubation of infected cultures in human diploid lung fibroblasts can be carried out at any temperature between 30"C and 38"C, preferably from 30 to 34"C (optimally about 323C), or from 35 to 38"C), or from 35 to 38"C (optimally about 36"C).
B. Development of attenuated live respiratory syncytial vaccine
The virus, after it has been isolated and adapted as described in (A), is added to glass bottles containing a culture of human diploid lung fibroblasts. The culture medium may be any of those that supports cell growth, for example, the known Eagle's basal medium (BME) or Eagle's minimal essential medium (MEM) in Eagle's balanced salt solution (BSS) supplemented with pre-screened calf serium. After the addition of the virus, the infected cell cultures are incubated in from 3 to 30 successive passages at from 30 to 38"C and preferably at from 30 to 34"C (optimally about 32"C) or from 35 to 38"C (optimally about 36"C) in order to attenuate the virus yet retain its antigenicity and immunogenicity.
Preferably the virus is incubated in from 4 to 15 successive passages. During these passages the virus is replicated in large amount and becomes attenuated.
The above serial passages are performed using undiluted or diluted inoculum and multiple harvests are collected at various intervals. Titrations are performed in
HEP-2 cell cultures, either in tubes or Falcon micro-titer plates.
The harvested virus is then stored frozen or at low temperature to preserve its potency. Prior to freezing a suitable stabilizer or a mixture of suitable stabilizers for the virus, for example soritol or gelatin, is added in appropriate amounts as determined from stability tests on frozen and lyophilized viral products.
C. Preperation of vaccine from attenuated virus
The respiratory syncytial virus harvested after from 30 to 30 repeated serial passages is found to be nonpathogenic for monkeys and rodents, to cause little or no clinical reactions in human recipients, and to evoke a satisfactory level of neutralizing antibody. After titration to establish its potency, the virus pool is subdivided and filled into appropriate vials for use. The product can be stored frozen or preferably dried from the frozen state and kept free of moisture.
The following examples illustrate but do not limit the present invention.
EXAMPLE 1
A respiratory syncytial virus is isolated from a throat swab specimen. This initial inoculum is subjected to two passages in monkey kidney cell culture and four passages in WI-38 human diploid lung fibroblasts. The culture of WI-38 human diploid lung fibroblasts is prepared in glass bottles using BME supplemented with 10 percent unheated fetal calf serum as growth medium. Two days post-planting the growth medium is decanted, and the cultures inoculated with 5.0ml of undiluted fourth passage seed virus per bottle (diluted seed virus may be used is desired). Following an adsorption period of one hour at 30-34"C, 100 milliliters of MEM containing 2 percent unheated fetal calf serum are added to each bottle, and re-incubated at 30-34"C. Three to four days post-seeding, the bottle cultures are washed four times with Hank's BSS, 100 milliliters of per wash. Following the washing procedure, 100 milliliers of MEM containing a suitable viral stabilizer, e.g., human albumin is added to each bottle and the cultures incubated at 30-340C. Neomycin at a concentration of 50 mcg/ml is incorporated in the growth and maintenance medium. Multiple harvests are collected at 2-4 day intervals and the bottle cultures are re-fed with fresh maintenance medium containing stabilizer. A viral stabilizer consisting of a mixture of equal parts of sorbitol and gelatin is added prior to shell freezing and storage at -70"C (electrically operated).
One or more appropriate harvests are selected following completion of infectivity titrations. The selected material is removed from the freezer and thawed. A sample is removed for control and safety testing. The remaining fluid is clarified and a sample removed for monkey safety testing. The fluids are distributed into individual vials and lyophilized. Following the lyophilization cycle, the vials are capped, sealed, and retained for reconstitution as a vaccine by the addition of sterile water (Water for
Injection, U.S.P.).
The potency of the product is based on infectivity titration in HEP-2 cell culture.
EXAMPLE 2
The procedure of Example 1 is repeated except that nine serial passages in WI-38 diploid fibroblasts are employed rather than four.
EXAMPLE 3
The procedure of Example 1 is repeated except that the incubation temperature of respiratory syncytial virus is in the 35-38"C range rather than 30-34"C.
EXAMPLE 4
Eight children without previous respiratory syncytial virus infection were administered a dose of the attenuated respiratory syncytial virus vaccine of Example 1 by the parenteral route. Essentially all of these developed a significant level of neutralizing antibody within six weeks after vaccination.
There were no untoward clinical reactions.
EXAMPLES
Eleven children without previous respiratory syncytial virus infection were administered a dose of the attenuated respiratory syncytial virus vaccine of Example 2 by the parenteral route. Essentially all of these developed a significant level of neutralizing antibody with six weeks after vaccination. There were no untoward clini cal reactions.
EXAMPLE 6
Samples of viruses prepared as described in Examples 1 and 2 are frozen and stored at -70"C for over 18 months. On thawing the potency of the samples is found to be essentially unchanged.
EXAMPLE 7
Samples of viruses prepared as described in Examples 1 and 2 are lyophilized and stored at -20"C for over 18 months. On reconstituion the potency of the samples is found to be essentially unchanged.
WHAT WE CLAIM IS:
1. A process of preparing an attenuated respiratory syncytial virus comprising serially passaging a respiratory syncytial virus in a culture of human diploid lung fibroblasts at an incubation temperature of from 30 to 38"C for from 3 to 30 serial passages in order to attenuate the virus yet retain its antigenicity and immunogenicity, and harvesting the resulting virus.
2. A process according to Claim 1 in which the number of serial passages is from 4to15.
3. A process according to Claim 1 or 2 in which the human diploid lung fibroblasts are WI-38 fibroblasts.
4. A process according to any one of
Claims 1 to 3 in which the incubation is carried out at from 30 to 34"C.
5. A process according to any one of
Claims 1 to 3 in which the incubation is carried out at from 35 to 38"C.
6. A process according to Claim 1, substantially as hereinbefore described in
Example 1,2or3.
7. A vaccine comprising attenuated virus obtained by a process according to any one of Claims 1 to 6 in frozen form together with a stabilizer for the virus.
8. A vaccine according to Claim 7 in which the stabilizer is sorbitol, gelatin or a mixture of sorbitol and gelatin.
9. A vaccine comprising the attenuated virus obtained by a process according to any one of Claims 1 to 6 in lyophilized form together with a stabilizer for the virus.
10. A vaccine according to Claim 9 in which the stabilizer is sorbitol, gelatin or a mixture of sorbitol and gelatin.
11. A live respiratory syncytial vaccine comprising an attenuated yet antigenic and immunogenic respiratory syncytial virus suitable for parenteral administration.
12. A vaccine according to Claim 11 containing a viral stabilizer.
13. A vaccine according to Claim 12 in which the stabilizer comprises sorbitol or gelatin.
14. A vaccine according to Claim 11, 12 or 13 in lyophilized form.
15. A vaccine according to Claim 11, 12 or 13 in frozen form.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (15)
1. A process of preparing an attenuated respiratory syncytial virus comprising serially passaging a respiratory syncytial virus in a culture of human diploid lung fibroblasts at an incubation temperature of from 30 to 38"C for from 3 to 30 serial passages in order to attenuate the virus yet retain its antigenicity and immunogenicity, and harvesting the resulting virus.
2. A process according to Claim 1 in which the number of serial passages is from 4to15.
3. A process according to Claim 1 or 2 in which the human diploid lung fibroblasts are WI-38 fibroblasts.
4. A process according to any one of
Claims 1 to 3 in which the incubation is carried out at from 30 to 34"C.
5. A process according to any one of
Claims 1 to 3 in which the incubation is carried out at from 35 to 38"C.
6. A process according to Claim 1, substantially as hereinbefore described in
Example 1,2or3.
7. A vaccine comprising attenuated virus obtained by a process according to any one of Claims 1 to 6 in frozen form together with a stabilizer for the virus.
8. A vaccine according to Claim 7 in which the stabilizer is sorbitol, gelatin or a mixture of sorbitol and gelatin.
9. A vaccine comprising the attenuated virus obtained by a process according to any one of Claims 1 to 6 in lyophilized form together with a stabilizer for the virus.
10. A vaccine according to Claim 9 in which the stabilizer is sorbitol, gelatin or a mixture of sorbitol and gelatin.
11. A live respiratory syncytial vaccine comprising an attenuated yet antigenic and immunogenic respiratory syncytial virus suitable for parenteral administration.
12. A vaccine according to Claim 11 containing a viral stabilizer.
13. A vaccine according to Claim 12 in which the stabilizer comprises sorbitol or gelatin.
14. A vaccine according to Claim 11, 12 or 13 in lyophilized form.
15. A vaccine according to Claim 11, 12 or 13 in frozen form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76699577A | 1977-02-09 | 1977-02-09 | |
| US05/825,520 US4122167A (en) | 1977-02-09 | 1977-08-17 | Respiratory synctial vaccine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1560185A true GB1560185A (en) | 1980-01-30 |
Family
ID=27117836
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB4692/78A Expired GB1560185A (en) | 1977-02-09 | 1978-02-06 | Respiratory syncytical virus vaccine |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS53121924A (en) |
| AR (1) | AR218895A1 (en) |
| CA (1) | CA1097219A (en) |
| CH (1) | CH639420A5 (en) |
| DE (1) | DE2805311A1 (en) |
| EG (1) | EG13482A (en) |
| ES (1) | ES466758A1 (en) |
| FR (2) | FR2385799A1 (en) |
| GB (1) | GB1560185A (en) |
| IT (1) | IT7847914A0 (en) |
| NL (1) | NL7801060A (en) |
| PT (1) | PT67632B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0043272A1 (en) * | 1980-07-01 | 1982-01-06 | National Research Development Corporation | Production of viral antigens |
| US5069902A (en) * | 1987-05-21 | 1991-12-03 | British Poultry Federation Research Association | Virus and vaccine therefrom for use against turkey rhinotracheitis |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4215107A (en) * | 1978-12-29 | 1980-07-29 | Merck & Co., Inc. | Parainfluenza virus vaccine and its preparation |
| NL8301996A (en) * | 1983-06-06 | 1985-01-02 | Duphar Int Res | METHOD FOR PREPARING ADVISED LIVE VACCINES AND SO OBTAINED VACCINES OBTAINED. |
| JPS60196187A (en) * | 1984-03-16 | 1985-10-04 | Biseibutsu Kagaku Kenkyusho:Kk | Attenuated strain of bovine rs virus |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2879202A (en) * | 1954-11-05 | 1959-03-24 | American Cyanamid Co | Stabilization of live viral vaccines by hexahydric alcohols |
| FR1296510A (en) * | 1958-05-09 | 1962-06-22 | American Cyanamid Co | Method of preparing an attenuated poliomyelitis virus |
-
1978
- 1978-01-30 NL NL7801060A patent/NL7801060A/en not_active Application Discontinuation
- 1978-02-02 AR AR270938A patent/AR218895A1/en active
- 1978-02-03 IT IT7847914A patent/IT7847914A0/en unknown
- 1978-02-06 CH CH130778A patent/CH639420A5/en not_active IP Right Cessation
- 1978-02-06 GB GB4692/78A patent/GB1560185A/en not_active Expired
- 1978-02-07 FR FR7803359A patent/FR2385799A1/en active Granted
- 1978-02-07 ES ES466758A patent/ES466758A1/en not_active Expired
- 1978-02-08 CA CA296,623A patent/CA1097219A/en not_active Expired
- 1978-02-08 DE DE19782805311 patent/DE2805311A1/en not_active Withdrawn
- 1978-02-08 EG EG83/78A patent/EG13482A/en active
- 1978-02-08 PT PT67632A patent/PT67632B/en unknown
- 1978-02-09 JP JP1305178A patent/JPS53121924A/en active Pending
- 1978-07-25 FR FR7821944A patent/FR2385401A1/en active Granted
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0043272A1 (en) * | 1980-07-01 | 1982-01-06 | National Research Development Corporation | Production of viral antigens |
| US4517304A (en) * | 1980-07-01 | 1985-05-14 | National Research Development Corporation | Production of viral antigens |
| US5071758A (en) * | 1980-07-01 | 1991-12-10 | National Research Development Corporation | Production of cell strains capable of propagating respiratory syncytial virus, compositions containing such virus and their use in diagnosis of respiratory syncytial virus infection |
| US5069902A (en) * | 1987-05-21 | 1991-12-03 | British Poultry Federation Research Association | Virus and vaccine therefrom for use against turkey rhinotracheitis |
Also Published As
| Publication number | Publication date |
|---|---|
| EG13482A (en) | 1982-03-31 |
| NL7801060A (en) | 1978-08-11 |
| JPS53121924A (en) | 1978-10-24 |
| IT7847914A0 (en) | 1978-02-03 |
| AR218895A1 (en) | 1980-07-15 |
| CA1097219A (en) | 1981-03-10 |
| ES466758A1 (en) | 1979-08-01 |
| FR2385799B1 (en) | 1980-05-16 |
| FR2385799A1 (en) | 1978-10-27 |
| CH639420A5 (en) | 1983-11-15 |
| FR2385401B1 (en) | 1981-07-17 |
| DE2805311A1 (en) | 1978-09-21 |
| FR2385401A1 (en) | 1978-10-27 |
| PT67632B (en) | 1980-03-03 |
| PT67632A (en) | 1978-03-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |