WO2014137248A1 - Method for producing antirabies vaccine - Google Patents
Method for producing antirabies vaccine Download PDFInfo
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- WO2014137248A1 WO2014137248A1 PCT/RU2014/000150 RU2014000150W WO2014137248A1 WO 2014137248 A1 WO2014137248 A1 WO 2014137248A1 RU 2014000150 W RU2014000150 W RU 2014000150W WO 2014137248 A1 WO2014137248 A1 WO 2014137248A1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- 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)
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- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
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- 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
- C12N2760/20011—Rhabdoviridae
- C12N2760/20111—Lyssavirus, e.g. rabies virus
- C12N2760/20134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- the invention relates to veterinary microbiology and biotechnology, can be used in the development of means of specific prophylaxis, and in particular to obtain a vaccine against rabies in animals.
- a known method of producing rabies vaccine for animals including the preparation of seed from a strain of rabies virus, infection with seed culture of inoculated cells, cultivation of rabies virus, collecting virus-containing suspension, followed by its inactivation and preparation of the target product. Inactivation of the virus is carried out by ⁇ - propiolactone.
- the disadvantages of the known vaccine is the difficulty of collecting virus-containing suspension, insufficient shelf life of the target product.
- the objective of the claimed technical solution is to simplify the method and improve the quality of the product by increasing the shelf life of the target product.
- the problem is solved in that in a method for producing an anti-rabies vaccine for animals, including the preparation of seed from a strain of rabies virus, infection with seed culture of inoculated cells, cultivation of rabies virus, collecting virus-containing suspension, followed by its inactivation and preparation of the target product, according to the invention, inactivation carried out by adding to the virus-containing suspension of ethanol in a final concentration of 18-20%, exposure of 20-22 hours at a temperature of 36-37 ° C at constant yann stirring, then add 4-6% aluminum hydroxide in the ratio to the reaction mixture 1: (4.5-5.0).
- the proposal is feasible in laboratory and industrial conditions, aimed at solving a real technical problem, i.e. the proposal is “industrially applicable”.
- Example 1 The cultivation of rabies virus infected BHK-21 cells is carried out in suspension in a 10-liter bioreactor with constant stirring. After 1, 2 and 3 days, samples are taken to control the infectious activity and the absence of contamination by extraneous microflora. Upon reaching the virus infectivity titer of 7.0 lg LD 50 / cm, a 96% aqueous solution of ethanol is added to the virus-containing suspension with constant stirring to a final concentration of 18%, while the suspension continues to be mixed and the temperature is maintained at 36 ° C. After 20 h, virus-containing suspension with inactivated virus add 4% aluminum hydroxide in the ratio to the reaction mixture 1: 4,5.
- Example 2 The cultivation of infected cells is carried out as in example 1, but to 7 l of virus-containing suspension add 98% aqueous solution of ethanol to a final concentration of 20%, while stirring the suspension continues and maintaining the temperature at 37 ° C. After 22 hours, 6% aluminum hydroxide was added to the virus-containing suspension with inactivated virus in a ratio of 1: 5.0 to the reaction mixture.
- the initial vaccine series (Ser-1 and Ser-2) did not contain live rabies virus and had almost the same immunogenic activity when tested on mice at 2.53 IU / ml and 2.5 IU / ml, respectively. After 18 months of storage at 6-8 ° C, these indicators decreased to 2.05 IU / ml and 2.1 IU / ml, respectively (16-19%), but continued to meet international requirements for anti-rabies vaccines, while similar indicators of the reference vaccine and prototype decreased by 40 and 55%, respectively.
- Ethanol in the liquid rabies vaccine in concentrations of 18-20% completely inactivated the infectivity of the virus and reliably protected the vaccine from accidental contamination by extraneous agents without loss of immunologically active material.
- the proposed vaccine had a high antibody-inducing activity for target animals.
- antibodies were determined after 27 days at a level of 3.4 IU / ml (puppies) and 2.2 (kittens) ), which indicates their reliable protection against rabies.
- the vaccine in its quality indicators meets the most stringent modern requirements of environmental and biosafety, it does not contain antibiotics, mercury-containing drugs and ⁇ -propiolactone. It remains active during long-term storage and in a wide temperature range. Suitable for reliable protection of animals from rabies. The vaccine is competitive with the best international drugs.
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
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Abstract
The invention relates to veterinary microbiology and biotechnology, and can be used in the development of means of specific prophylaxis, in particular for producing a vaccine against rabies in animals. A method for producing an antirabies vaccine for animals is proposed, which comprises preparation of an inoculum from a rabies virus strain, inoculation with the inoculum of a transferable cell culture, cultivation of the rabies virus, harvesting a virus-containing suspension followed by inactivation and preparation of the end product. The inactivation is conducted by adding ethanol to the virus-containing suspension in a final concentration of 18-20%, maintenance at a temperature of 36-37°C for 20-22 hours while stirring continuously, followed by the addition of 4-6% aluminium hydroxide in a ratio to the reaction mixture of 1:(4.5-5.0).
Description
СПОСОБ ПОЛУЧЕНИЯ АНТИРАБИЧЕСКОЙ ВАКЦИНЫ METHOD FOR OBTAINING ANTIRABIC VACCINE
Изобретение относится к ветеринарной микробиологии и биотехнологии, может быть использовано при разработке средств специфической профилактики, и в частности для получения вакцины против бешенства животных. The invention relates to veterinary microbiology and biotechnology, can be used in the development of means of specific prophylaxis, and in particular to obtain a vaccine against rabies in animals.
Известен способ получения антирабической вакцины для животных, включающий приготовление посевного материала из штамма вируса бешенства, инфицирование посевным материалом культуры перевиваемых клеток, культивирование вируса бешенства, сбор вируссодержащей суспензии с последующим её инактивацией и приготовлением целевого продукта. Инактивацию вируса проводят β— пропиолактоном. (Патент РФ Ν_> 2287343, «Способ получения антирабической вакцины», МПК А 61 К 39/205,Бюл. Jte 26, 31.05.2005). A known method of producing rabies vaccine for animals, including the preparation of seed from a strain of rabies virus, infection with seed culture of inoculated cells, cultivation of rabies virus, collecting virus-containing suspension, followed by its inactivation and preparation of the target product. Inactivation of the virus is carried out by β - propiolactone. (RF patent Ν_> 2287343, “Method for the production of rabies vaccine”, IPC A 61 K 39/205, Bull. Jte 26, 05/31/2005).
Недостатками известной вакцины является сложность сбора вируссодержащей суспензии, недостаточный срок хранения целевого продукта. The disadvantages of the known vaccine is the difficulty of collecting virus-containing suspension, insufficient shelf life of the target product.
Задачей заявленного технического решения является упрощение способа и повышение качества продукта за счет увеличения срока хранения целевого продукта. The objective of the claimed technical solution is to simplify the method and improve the quality of the product by increasing the shelf life of the target product.
Поставленная задача решается тем, что в способе получения антирабической вакцины для животных, включающем приготовление посевного материала из штамма вируса бешенства, инфицирование посевным материалом культуры перевиваемых клеток, культивирование вируса бешенства, сбор вируссодержащей суспензии с последующей её инактивацией и приготовлением целевого продукта, согласно изобретению, инактивацию проводят добавлением к вируссодержащей суспензии этанола в конечной концентрации 18-20%, экспозицией 20-22 часа при температуре 36-37°С при постоянном
перемешивании, далее добавляют 4-6%-ную гидроокись алюминия в соотношении к реакционной смеси 1 :(4,5-5,0). The problem is solved in that in a method for producing an anti-rabies vaccine for animals, including the preparation of seed from a strain of rabies virus, infection with seed culture of inoculated cells, cultivation of rabies virus, collecting virus-containing suspension, followed by its inactivation and preparation of the target product, according to the invention, inactivation carried out by adding to the virus-containing suspension of ethanol in a final concentration of 18-20%, exposure of 20-22 hours at a temperature of 36-37 ° C at constant yann stirring, then add 4-6% aluminum hydroxide in the ratio to the reaction mixture 1: (4.5-5.0).
В патентной и научно-технической литературе не известны технические решения, содержащие признаки, аналогичные заявляемым, т.е. предложение соответствует критерию «новизна». In the patent and scientific and technical literature, technical solutions are not known containing signs similar to those claimed, i.e. the proposal meets the criterion of "novelty."
Предложение осуществимо в лабораторных и промышленных условиях, направлено на решение реальной технической задачи, т.е. предложение «промышленно применимо». The proposal is feasible in laboratory and industrial conditions, aimed at solving a real technical problem, i.e. the proposal is “industrially applicable”.
Нами впервые установлено, что инактивация вируссодержащей суспензии при определенных режимах этанолом приводит к получению целевого продукта без потери иммунологически активного материала, что недопустимо при производстве эффективной инактивированной антирабической вакцины для животных, что позволяет получить неочевидный положительный эффект - упрощение и ускорение способа, увеличение срока хранения целевого продукта без потери его качества, т.е. предложение соответствует критериям «новизна» и «изобретательский уровень». We found for the first time that inactivation of a virus-containing suspension under certain conditions with ethanol leads to the production of the target product without loss of immunologically active material, which is unacceptable in the production of an effective inactivated rabies vaccine for animals, which allows to obtain an unobvious positive effect - simplification and acceleration of the method, increase the shelf life of the target product without losing its quality, i.e. the proposal meets the criteria of "novelty" and "inventive step".
Способ иллюстрируется на следующих примерах. The method is illustrated in the following examples.
Пример 1. Культивирование зараженных вирусом бешенства клеток ВНК-21 проводят в суспензии в 10-литровом биореакторе при постоянном перемешивании. Через 1 ,2 и 3 сутки отбирают пробы для контроля инфекционной активности и отсутствия контаминации посторонней микрофлорой. По достижении титра инфекционности вируса 7,0 lg ЛД50/см к вируссодержащей суспензии добавляют при постоянном перемешивании 96%-ный водный раствор этанола до конечной его концентрации 18%, при этом продолжается перемешивание суспензии и поддержание температуры 36° С. Через 20 ч к вируссодержащей суспензии с инактивированным вирусом
добавляют 4%-ную гидроокись алюминия в соотношении к реакционной смеси 1 :4,5. Example 1. The cultivation of rabies virus infected BHK-21 cells is carried out in suspension in a 10-liter bioreactor with constant stirring. After 1, 2 and 3 days, samples are taken to control the infectious activity and the absence of contamination by extraneous microflora. Upon reaching the virus infectivity titer of 7.0 lg LD 50 / cm, a 96% aqueous solution of ethanol is added to the virus-containing suspension with constant stirring to a final concentration of 18%, while the suspension continues to be mixed and the temperature is maintained at 36 ° C. After 20 h, virus-containing suspension with inactivated virus add 4% aluminum hydroxide in the ratio to the reaction mixture 1: 4,5.
Пример 2. Культивирование инфицированных клеток проводят как в примере 1 , но к 7 л вируссодержащей суспензии добавляют 98%-ный водный раствор этанола до конечной концентрации 20%, при этом продолжается перемешивание суспензии и поддержание температуры 37°С. Через 22 ч к вируссодержащей суспензии с инактивированным вирусом добавляют 6%-ную гидроокись алюминия в соотношении к реакционной смеси 1 :5,0. Example 2. The cultivation of infected cells is carried out as in example 1, but to 7 l of virus-containing suspension add 98% aqueous solution of ethanol to a final concentration of 20%, while stirring the suspension continues and maintaining the temperature at 37 ° C. After 22 hours, 6% aluminum hydroxide was added to the virus-containing suspension with inactivated virus in a ratio of 1: 5.0 to the reaction mixture.
Контроль вакцин, полученных согласно примерам 1 и 2 (Сер-1 и Сер-2) относительно национальной референс-вакцины и прототипа на остаточную инфекционность проводили через 1,5 года хранения их путем интрацеребральной инокуляции исследуемого материала мышам массой 10-12 г. Иммуногенность исследовали методом NIH. Результаты выражали в международных единицах (ME). Антителоиндуцирующую активность определяли путем исследования сыворотки крови вакцинированных однократно в дозе 1 мл собак и кошек в реакции нейтрализации (РН). Сыворотку получали через 27 дней после иммунизации животных. РН проводили на мышах против стандартного вируса бешенства nrr.CVS относительно национальной референс-сыворотки с активностью 20 МЕ/мл. The control of vaccines obtained according to examples 1 and 2 (Ser-1 and Ser-2) relative to the national reference vaccine and prototype for residual infectivity was carried out after 1.5 years of storage by intracerebral inoculation of the test material to mice weighing 10-12 g. Immunogenicity was studied NIH method. The results were expressed in international units (ME). Antibody-inducing activity was determined by examining the blood serum of those vaccinated once at a dose of 1 ml of dogs and cats in a neutralization reaction (PH). Serum was obtained 27 days after immunization of animals. PH was performed in mice against the standard rabies virus nrr.CVS relative to the national reference serum with an activity of 20 IU / ml.
Исходные серии вакцины (Сер- 1 и Сер-2) не содержали в своем составе живого вируса бешенства и обладали практически одинаковой иммуногенной активностью при испытании их на мышах на уровне 2,53 МЕ/мл и 2,5 МЕ/мл соответственно. Через 18 месяцев хранения при 6-8°С эти показатели снизились до 2,05 МЕ/мл и 2, 1 МЕ/мл соответственно (на 16-19%), но продолжали отвечать международным требованиям, предъявляемым к антирабическим
вакцинам, в то время как аналогичные показатели референс-вакцины и прототипа снизились на 40 и 55%, соответственно. The initial vaccine series (Ser-1 and Ser-2) did not contain live rabies virus and had almost the same immunogenic activity when tested on mice at 2.53 IU / ml and 2.5 IU / ml, respectively. After 18 months of storage at 6-8 ° C, these indicators decreased to 2.05 IU / ml and 2.1 IU / ml, respectively (16-19%), but continued to meet international requirements for anti-rabies vaccines, while similar indicators of the reference vaccine and prototype decreased by 40 and 55%, respectively.
Этанол в составе жидкой антирабической вакцины в концентрациях 18-20% полностью инактивировал инфекционность вируса и надежно защищал вакцину от случайных загрязнений посторонними агентами без потери иммунологически активного материала. Ethanol in the liquid rabies vaccine in concentrations of 18-20% completely inactivated the infectivity of the virus and reliably protected the vaccine from accidental contamination by extraneous agents without loss of immunologically active material.
Предлагаемая вакцина обладала высокой антителоиндуцирующей активностью для целевых животных. В сыворотке крови вакцинированных щенят и котят вакциной, хранившейся в течение 1 ,5 года в условиях бытового холодильника (6-8°С), антитела определялись через 27 дней на уровне 3,4 МЕ/мл (щенята) и 2,2 (котята), что свидетельствует о надежной защите их от бешенства. The proposed vaccine had a high antibody-inducing activity for target animals. In the blood serum of vaccinated puppies and kittens with a vaccine stored for 1, 5 years in a domestic refrigerator (6-8 ° C), antibodies were determined after 27 days at a level of 3.4 IU / ml (puppies) and 2.2 (kittens) ), which indicates their reliable protection against rabies.
Вакцина по своим качественным показателям соответствует самым строгим современным требованиям экологической и биобезопасности, она не содержит антибиотиков, ртутьсодержащих препаратов и β-пропиолактона. Сохраняет активность при длительном хранении и в при широком температурном диапазоне. Пригодна для надежной защиты животных от бешенства. Вакцина является конкурентоспособной лучшим международным препаратам.
The vaccine in its quality indicators meets the most stringent modern requirements of environmental and biosafety, it does not contain antibiotics, mercury-containing drugs and β-propiolactone. It remains active during long-term storage and in a wide temperature range. Suitable for reliable protection of animals from rabies. The vaccine is competitive with the best international drugs.
Claims
ФОРМУЛА ИЗОБРЕТЕНИЯ CLAIM
Способ получения антирабической вакцины для животных, включающий приготовление посевного материала из штамма вируса бешенства, инфицирование посевным материалом культуры перевиваемых клеток, культивирование вируса бешенства, сбор вируссодержащей суспензии с последующей её инактивацией и приготовлением целевого продукта, отличающийся тем, что инактивацию проводят добавлением к вируссодержащей суспензии этанола в конечной концентрации 18-20%, экспозицией 20-22 часа при температуре 36-37°С при постоянном перемешивании, далее добавляют 4-6%-ную гидроокись алюминия в соотношении к реакционной смеси 1 :(4,5-5,0).
A method for producing an anti-rabies vaccine for animals, comprising preparing seed from a rabies virus strain, infecting a culture of inoculated cells with seed, culturing a rabies virus, collecting the virus-containing suspension, followed by its inactivation and preparing the target product, characterized in that the inactivation is carried out by adding ethanol to the virus-containing suspension in a final concentration of 18-20%, exposure time of 20-22 hours at a temperature of 36-37 ° C with constant stirring, then add 4-6% -n aluminum hydroxide in the ratio to the reaction mixture 1: (4.5-5.0).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2013109993/15A RU2522866C1 (en) | 2013-03-06 | 2013-03-06 | Method of production of antirabic vaccine |
| RU2013109993 | 2013-03-06 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989005631A1 (en) * | 1987-12-21 | 1989-06-29 | Institut Pasteur | Compositions possessing immunostimulating properties and their applications in human and veterinary medecine |
| UZ2968C (en) * | 2003-09-22 | 2006-02-28 | Uzbek Res Inst Of Veterinary Science | Antirabies fluid inactivated vaccine |
| RU2287343C1 (en) * | 2005-05-31 | 2006-11-20 | ОАО "Институт биотехнологий ветеринарной медицины" | Method for preparing antirabic vaccine |
| RU2366457C1 (en) * | 2008-02-27 | 2009-09-10 | Государственное научное учреждение Всероссийский научно-исследовательский и технологический институт биологической промышленности РАСХН | Antirabic vaccine for animals ("унирэв") |
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2013
- 2013-03-06 RU RU2013109993/15A patent/RU2522866C1/en active IP Right Revival
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2014
- 2014-03-06 WO PCT/RU2014/000150 patent/WO2014137248A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989005631A1 (en) * | 1987-12-21 | 1989-06-29 | Institut Pasteur | Compositions possessing immunostimulating properties and their applications in human and veterinary medecine |
| UZ2968C (en) * | 2003-09-22 | 2006-02-28 | Uzbek Res Inst Of Veterinary Science | Antirabies fluid inactivated vaccine |
| RU2287343C1 (en) * | 2005-05-31 | 2006-11-20 | ОАО "Институт биотехнологий ветеринарной медицины" | Method for preparing antirabic vaccine |
| RU2366457C1 (en) * | 2008-02-27 | 2009-09-10 | Государственное научное учреждение Всероссийский научно-исследовательский и технологический институт биологической промышленности РАСХН | Antirabic vaccine for animals ("унирэв") |
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