DE1131846B - Method for inactivating poliomyelitis viruses - Google Patents
Method for inactivating poliomyelitis virusesInfo
- Publication number
- DE1131846B DE1131846B DEB55993A DEB0055993A DE1131846B DE 1131846 B DE1131846 B DE 1131846B DE B55993 A DEB55993 A DE B55993A DE B0055993 A DEB0055993 A DE B0055993A DE 1131846 B DE1131846 B DE 1131846B
- Authority
- DE
- Germany
- Prior art keywords
- formaldehyde
- inactivating
- poliomyelitis
- viruses
- inactivation
- 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.)
- Pending
Links
- 241000700605 Viruses Species 0.000 title claims description 13
- 208000000474 Poliomyelitis Diseases 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 8
- 230000000415 inactivating effect Effects 0.000 title claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 23
- 230000002779 inactivation Effects 0.000 claims description 9
- 239000002738 chelating agent Substances 0.000 claims description 7
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims 1
- 210000002966 serum Anatomy 0.000 description 6
- 238000013459 approach Methods 0.000 description 5
- 229960005486 vaccine Drugs 0.000 description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 3
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 2
- RNMCCPMYXUKHAZ-UHFFFAOYSA-N 2-[3,3-diamino-1,2,2-tris(carboxymethyl)cyclohexyl]acetic acid Chemical compound NC1(N)CCCC(CC(O)=O)(CC(O)=O)C1(CC(O)=O)CC(O)=O RNMCCPMYXUKHAZ-UHFFFAOYSA-N 0.000 description 1
- QDHGQJQZPJPKJK-UHFFFAOYSA-N 2-[carboxymethyl-(2,4,6-trioxo-1,3-diazinan-5-yl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C1C(=O)NC(=O)NC1=O QDHGQJQZPJPKJK-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical class CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 210000000605 viral structure Anatomy 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
- A61K39/125—Picornaviridae, e.g. calicivirus
- A61K39/13—Poliovirus
-
- 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
-
- 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
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- 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
- A61K2039/5252—Virus inactivated (killed)
-
- 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
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32611—Poliovirus
- C12N2770/32634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32611—Poliovirus
- C12N2770/32661—Methods of inactivation or attenuation
- C12N2770/32663—Methods of inactivation or attenuation by chemical treatment
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Mycology (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
Verfahren zur In aktivierung von Poliomyelitisviren Gegenstand der Erfindung ist ein Verfahren zur Inaktivierung von Poliomyelitisviren mit Formaldehyd in Gegenwart von Chelatbildnern.Process for the activation of poliomyelitis viruses is the subject of Invention is a method for inactivating poliomyelitis viruses with formaldehyde in the presence of chelating agents.
Es sind Verfahren bekannt, bei denen man Poliomyelitisviren mit Formaldehyd inaktiviert. Diese Verfahren haben auch Eingang in die industrielle Herstellung einer Vaccine gegen das Poliomyelitisvirus aller drei Typen gefunden. Es hat sich gezeigt, daß in vielen Fällen die Antigenität nach der Inaktivierung mit Formaldehyd niedrig ist. Es hat daher nicht an Versuchen gefehlt, die Inaktivierung unter anderen Bedingungen auszuführen, sei es durch Änderung des Inaktivierungsreagenzes, sei es durch thermische oder Strahlungsenergie. So haben z. B. Haas und Mitarbeiter das Poliomyelitisvirus durch Erwärmen auf 450 C ohne Verwendung von Formaldehyd inaktiviert und beobachtet, daß diese thermische Inaktivierung in Anwesenheit von Dinatrium-dihydrogen-äthylen-diamin-N,N'-tetraacetat verzögert wird. (R.Thomssen, V.Dostal, R. Methods are known in which poliomyelitis viruses are treated with formaldehyde inactivated. These processes are also used in industrial production of a vaccine against the poliomyelitis virus of all three types. It has demonstrated that in many cases the antigenicity after inactivation with formaldehyde is low. There has therefore been no shortage of attempts, including inactivation Execute conditions, be it by changing the inactivation reagent, be it by thermal or radiant energy. So have z. B. Haas et al the poliomyelitis virus by heating to 450 C without using formaldehyde inactivated and observed that this thermal inactivation in the presence of Disodium-dihydrogen-ethylene-diamine-N, N'-tetraacetate is delayed. (R.Thomssen, V. Dostal, R.
Haas und E.Ruschmann,Vortrag auf dem VI.Haas and E. Ruschmann, lecture on the VI.
Symposium der Europäischen Vereinigung zur Bekämpfung der Kinderlähmung vom 6. bis 9. September 1959 in München).Symposium of the European Association to Combat Polio from 6 to 9 September 1959 in Munich).
Es wurde nun ein Verfahren zur Inaktivierung von Poliomyelitisviren mittels Formaldehyd gefunden, das überraschenderweise zu einer besseren Antigenität und einer höheren Immunisierungsfähigkeit der inaktiven Viren führt und dadurch gekennzeichnet ist, daß die Inaktivierung durch Formaldehyd in Gegenwart eines Chelatbildners, der nicht zu Fällungen Anlaß gibt, ausgeführt wird. There has now been a method for inactivating poliomyelitis viruses found by means of formaldehyde, which surprisingly leads to better antigenicity and a higher immunization capacity of the inactive viruses and thereby is characterized in that the inactivation by formaldehyde in the presence of a chelating agent, which does not give rise to felling is carried out.
Die Konzentration des Chelatbildners kann in weiten Grenzen variiert werden und liegt vorzugsweise zwischen 0,2 und 0,00002% und der pu-Wert der Reaktion bei 5 bis 9, vorzugsweise 7. Die Inaktivierung erfolgt vorteilhaft bei 0 bis 60° C, vorzugsweise bei 37° C, und zwar in einer Zeit von 3 bis 60 Tagen. The concentration of the chelating agent can be varied within wide limits and is preferably between 0.2 and 0.00002% and the pu value of the reaction at 5 to 9, preferably 7. Inactivation takes place advantageously at 0 to 60 ° C, preferably at 37 ° C, in a period of 3 to 60 days.
Als Chelatbildner dienen z. B. Nitrilotriessigsäure, Diaminocyclohexantetraessigsäure, Uramildiessigsäure, vorzugsweise Dinatrium-dihydrogen-äthylendiamin-N,N'-tetraacetat. Ferner können beispielsweise herangezogen werden Acetessigsäureester und Siderophilin (Transferrin). As chelating agents, for. B. nitrilotriacetic acid, diaminocyclohexanetetraacetic acid, Uramildiacetic acid, preferably disodium-dihydrogen-ethylenediamine-N, N'-tetraacetate. Acetoacetic acid esters and siderophilin can also be used, for example (Transferrin).
Man geht erfindungsgemäß so vor, daß man eine Formaldehydlösung gleichzeitig mit einer Lösung eines Chelatbildners der Virussuspension zufügt. Die weiteren Stufen der Inaktivierung erfolgen ill an sich bekannter Weise. According to the invention, a formaldehyde solution is used at the same time with a solution of a chelating agent to the virus suspension. The further stages the inactivation takes place in a manner known per se.
Die nach dem erfindungsgemäßen Verfahren inaktivieren Viren dienen, gegebenenfalls nach Adsorption an Aluminiumhydroxyd oder anderen Tragerstoffen, als Impfstoffe. Wie an Meerschweinchen und Hühnchen, die mit diesem Impfstoff immunisiert werden, gezeigt werden kann, vermitteln diese Impfstoffe eine erheblich bessere Antikörperbildung als solche, deren Virusanteil nur mit Formaldehyd ohne Chelatbildner inaktiviert wurde. The viruses inactivated by the method according to the invention are used possibly after adsorption on aluminum hydroxide or other carrier materials, as vaccines. Like on guinea pigs and chickens immunized with this vaccine As can be shown, these vaccines impart a vastly better effect Antibody formation as such, whose virus component only contains formaldehyde without a chelating agent has been inactivated.
Beispiel 1 Ein in der üblichen Weise hergestellter Ansatz von Poliomyelitisvirus wird wie gewöhnlich filtriert und in zwei gleiche Teile aufgeteilt. Der Titer beider Teile ist je 107 4 ID50 je Milliliter Virus Typ 1 Teil A wird sodann mit konzentrierter wäßriger Formaldehydlösung in der üblichen Konzentration sowie außerdem mit Dinatrium-dihydrogen-äthylendiamin-N,N'-tetraacetat 1: 5000 versetzt. Teil B erhält die gleiche Formaldehydkonzentration, jedoch kein Dinatrium-dihydrogen-äthylendiamin-N,N~t traacetat. Example 1 A batch of poliomyelitis virus prepared in the usual way is filtered as usual and divided into two equal parts. The titer of both Parts is 107 4 ID50 each per milliliter of virus type 1 Part A is then concentrated with aqueous formaldehyde solution in the usual concentration and also with disodium dihydrogen-ethylenediamine-N, N'-tetraacetate 1: 5000 offset. Part B receives the same concentration of formaldehyde, but none Disodium-dihydrogen-ethylenediamine-N, N ~ ttraacetate.
Beide Ansätze werden in gleicher Weise und gleich lang bei 37° C inaktiviert. Nach Beendigung der Inaktivierung und der für beide Teile gleichartig durchgeführten Zwischenfiltration werden die Ansätze auf ihre Wirksamkeit analog den in der dritten Fassung der »Vorläufige Vorschriften für die staatliche Prüfung von Impfstoffen gegen Kinderlähmung (Poliomyelitis)« vorgesehenen Verfahren geprüft. Both approaches are done in the same way and with the same length at 37 ° C inactivated. After the end of the inactivation and the same for both parts carried out intermediate filtration, the approaches are analogous to their effectiveness those in the third version of the »Provisional Rules for State Examination of vaccines against poliomyelitis «.
Teil A zeigt eine Wirksamkeit von 533 328 ID50 je Milliliter Serum (Titer 1: 1626 bei 82 ID50 je 0,25 ml). Part A shows an effectiveness of 533,328 ID50 per milliliter of serum (Titer 1: 1626 at 82 ID50 0.25 ml each).
Die Wirksamkeit von Teil B beläuft sich auf 41 948 IDso je Milliliter Serum (Titer 1: I28 bei 82 ID50 je 0,25 ml). The effectiveness of Part B is 41,948 IDs per milliliter Serum (titer 1: I28 at 82 ID50 0.25 ml each).
Die Wirksamkeitssteigerung des Dinatrium-dihydrogen-äthylendiamin-N,N'-tetraacetat enthaltenden Ansatzes im Vergleich zur Kontrolle beträgt demnach in diesem Falle das 12,7fache. The increase in effectiveness of disodium dihydrogen-ethylenediamine-N, N'-tetraacetate containing approach compared to the control is accordingly in this case 12.7 times.
Beispiel 2 In einem Versuchsverfahren, das dem unter Beispiel 1 entspricht, werden zwei Inaktivierungsansätn aus gleichem Material hergestellt, von denen der eine statt Dinatrium-dihydrogen-äthylendiamin-N,N'-tetraacetat das Natriumsalz der Nitrilotriessigsäure (Trimethylamin-a, a', a"-tricarbonsäure) enthält. Example 2 In a test procedure which corresponds to that in Example 1, two Inaktivierungsansätn are made of the same material, of which the instead of disodium-dihydrogen-ethylenediamine-N, N'-tetraacetate the sodium salt of Contains nitrilotriacetic acid (trimethylamine-a, a ', a "-tricarboxylic acid).
Die Wirksamkeitsprüfung nach gleichartiger Behandlung der beiden Ansätze zeigt folgendes Ergebnis: Teil A: 1 080 824 ID50 je Milliliter Serum (Titer 1:1618 bei 167 ID50 je 0,25 ml).The effectiveness test after treating the two approaches in the same way shows the following result: Part A: 1 080 824 ID50 per milliliter of serum (titer 1: 1618 at 167 ID50 0.25 ml each).
TeilB: 85 504 ID5" je Milliliter Serum (Titer 1:128 bei 167 ID50 je 0,25 mal).Part B: 85 504 ID5 "per milliliter of serum (titer 1: 128 at 167 ID50 each 0.25 times).
TeilA ist also 12,6mal wirksamer als Teile. Part A is therefore 12.6 times more effective than Part.
Beispiel 3 Um den Effekt der löslichen chelatbildenden Substanzen noch eindeutiger nachzuweisen, wird in einem Versuchsansatz ein an sich unwirksames Material (Titer <107IDso je Milliliter) in gleicher Weise wie oben mit Dinatrium-dihydrogen-äthylendiamin-N,N'-tetraacetat behandelt. Example 3 To the effect of the soluble chelating substances can be proven even more clearly in an experimental approach is in itself ineffective Material (titer <107IDso per milliliter) in the same way as above with disodium-dihydrogen-ethylenediamine-N, N'-tetraacetate treated.
Die Wirksamkeitsprüfung ergibt für Teil A (mit Dinatriumdihydrogen- äthylendiamin-N,N'-tetraacetat): 339 968 ID50 je Milliliter Serum (Titer 1: 1024 bei 83 IDso je 0,25 ml). The effectiveness test results for part A (with disodium dihydrogen ethylenediamine-N, N'-tetraacetate): 339 968 ID50 per milliliter of serum (titer 1: 1024 at 83 ID so each 0.25 ml).
Teil B (ohne Dinatrium-dihydrogen-äthylendiamin-N,N'-tetraacetat: <5312 IDso je Milliliter Serum (Titer schlechter als 1:16 bei 83 IDso je 0,25 ml).Part B (without disodium-dihydrogen-ethylenediamine-N, N'-tetraacetate: <5312 ID 50 per milliliter of serum (titre worse than 1:16 with 83 ID 50 each 0.25 ml).
TeilA ist also mehr als 64mal so wirksam wie Teil B. Part A is therefore more than 64 times as effective as Part B.
Claims (1)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB55993A DE1131846B (en) | 1959-12-22 | 1959-12-22 | Method for inactivating poliomyelitis viruses |
| CH1412560A CH399653A (en) | 1959-12-22 | 1960-12-16 | Method for inactivating poliomyelitis viruses |
| GB43811/60A GB949684A (en) | 1959-12-22 | 1960-12-20 | Process for inactivating poliomyelitis virus |
| BE598471A BE598471A (en) | 1959-12-22 | 1960-12-22 | Method for making polio viruses inactive |
| SE12424/60A SE309826B (en) | 1959-12-22 | 1960-12-22 | |
| FR856343A FR1023M (en) | 1959-12-22 | 1961-03-21 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEB55993A DE1131846B (en) | 1959-12-22 | 1959-12-22 | Method for inactivating poliomyelitis viruses |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1131846B true DE1131846B (en) | 1962-06-20 |
Family
ID=6971173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEB55993A Pending DE1131846B (en) | 1959-12-22 | 1959-12-22 | Method for inactivating poliomyelitis viruses |
Country Status (6)
| Country | Link |
|---|---|
| BE (1) | BE598471A (en) |
| CH (1) | CH399653A (en) |
| DE (1) | DE1131846B (en) |
| FR (1) | FR1023M (en) |
| GB (1) | GB949684A (en) |
| SE (1) | SE309826B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1042179B (en) * | 1957-07-11 | 1958-10-30 | Pasteur Institut | Process for the preparation of antigen-containing vaccines |
-
1959
- 1959-12-22 DE DEB55993A patent/DE1131846B/en active Pending
-
1960
- 1960-12-16 CH CH1412560A patent/CH399653A/en unknown
- 1960-12-20 GB GB43811/60A patent/GB949684A/en not_active Expired
- 1960-12-22 SE SE12424/60A patent/SE309826B/xx unknown
- 1960-12-22 BE BE598471A patent/BE598471A/en unknown
-
1961
- 1961-03-21 FR FR856343A patent/FR1023M/fr active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1042179B (en) * | 1957-07-11 | 1958-10-30 | Pasteur Institut | Process for the preparation of antigen-containing vaccines |
Also Published As
| Publication number | Publication date |
|---|---|
| GB949684A (en) | 1964-02-19 |
| SE309826B (en) | 1969-04-08 |
| FR1023M (en) | 1961-12-26 |
| BE598471A (en) | 1961-06-22 |
| CH399653A (en) | 1965-09-30 |
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