Strain "lt-21/07" of aujeszky virus for manufacturing vaccines and diagnostic preparations

FIELD: medicine.

SUBSTANCE: strain "АС-21/07" of Aujeszky's disease virus was deposited in collection of VGNKI under registration number "АС-21/07"-DEP. Strain is obtained from original strain MK-25 by selection. In culture of cells PSGK-60 and PSGK-60S virus 19-20 passage is accumulated to 8.0-8.5 lg TCD50/cm3.

EFFECT: strain is attenuated for pigs, sheep, rabbits and possesses high biological, antigenic and immunogenic activity in native form and after inactivation.

2 dwg, 3 tbl, 4 ex

 

The invention relates to the field of veterinary Virology and biotechnology and can be used in the manufacture of means of specific prophylaxis and diagnosis of Aujeszky's disease.

Aujeszky's disease (AD) or pseudoselector causes DNA-containing virus of the family Herpesviridae genus Varicellavirus. Sick all kinds of farm animals, fur-bearing animals and rodents. Along with signs of brain lesions in patients with animals except pigs, there are severe itching and scratching. In Russia Aujeszky's disease was established in the early 20th century (1909), and from that time are registered in its territory in the form of sporadic cases.

In pigs, the disease may occur in acute, subacute, chronic and latent forms. The virus BA receptive all age groups of pigs, especially newborn piglets, mortality may reach 100%.

The vaccine against Aujeszky's disease occupies a leading position in the complex antiepizootic measures aimed at combating this disease. For its prevention are used as live and inactivated vaccines derived from a virus, reproduced in different cultures cells [1-6]. Received a number of vaccine strains used for the preparation of preventive drugs, such as 622 BEECH, BEECH 900, VGNKI, MK-25, etc. that vary in St. what they immunobiological properties, as well as technological methods of their cultivation.

For the production of vaccines using attenuated strains of viruses of different origin. They were received serial passirovannym in primary and transplantable cultures at different temperatures (37,0 and 28.0°C)or in the presence of mutagens. Received attenuated strains differ in many characteristics, including pathogenicity for laboratory animals. All used vaccine strains of virulent for pigs of different age, but differ in pathogenicity for sheep, rabbits, Guinea pigs, fur animals.

In our country the most widely used virusvaktsinu derived from an attenuated strain VGNKI obtained by a long passage in chicken embryos and cell cultures of chicken fibroblasts (227 passages). Long-term use of this vaccine, as well as live VirusWall from strain BEECH-628 (unive), helped to stabilize the epizootic situation in Russia and significantly reduce the number of outbreaks. However, conducted in the late 80-ies of the research VirusWall of strains BEECH-628 and VGNKI showed that the virulent strain of BWA prizhivlyaetsya and persists in the body in 100% of vaccinated pigs [5]. In ARRIAH was developed inactivated vaccine against Aujeszky's disease from strain WNIIE THE-WS, cultivated in suspension transplantable cell line KSS 21/2-17.

The highest accumulation struc-628, Geneva, UNIIM-S, MK-25. High cytopathic activity of the strains in the primary cell line SP, transplantable cell lines PSGC-30, KSS-21, the lowest activity MDVK and CPD. All the studied strains thermolabile. For production of live vaccines while and used attenuated strains, however, they can cause complications on the immune background in animals. This can occur due to reactivation or recombination vaccine virus with the field. Epizooticae strains used in the production of inactivated vaccines, but they are in the case of incomplete inactivation of viral materials can cause an outbreak.

Attenuated vaccine strain MK-25, used for the production of live and inactivated vaccines has several advantages: it tech, provides the accumulation of virus in the credits of 6.75-8,00 lg TCD50/cm3and less pathogenic for rabbits and Guinea pigs [7].

The aim of the present invention is to obtain a new safe (attenuated) production of vaccine virus strain BA with high biological, antigenic and immunogenic activity, preserving their native immunobiological properties after inactivation and is suitable for manufacturing the mould is increasing highly immunogenic vaccines.

The technical result from the use of the invention consists in expanding Arsenal of safe (attenuated) virus strains BA with high biological antigenic and immunogenic activity, preserving their native immunobiological properties after inactivation and suitable for the manufacture of highly effective vaccines.

This technical result is achieved by obtaining strain "as-21/07 virus BA. The strain of the as-21/07"is a new previously unknown. The original virus strain MK-25 was used to obtain the strain "as-21/07 by selection on the basis of maximum accumulation and high immunogenicity during multiple passages in the sensitive cell system.

The resulting strain deposited at the Russian state collection of strains of microorganisms used in veterinary medicine and animal husbandry, all-Russian scientific research Institute of control, standardization and certification of veterinary preparations (VGNKI) of the Ministry of agriculture of the Russian Federation may 14, 2010 under registration code "as-21/07-DEPT.

The strain of the as-21/07 virus BA differs from prototype homogeneity of the population and higher biological, antigenic and immunogenic activity. Experimentally confirmed the possibility of its use for the manufacture of diagnostic tools and prevention and BA.

The strain of the as-21/07 provides serological diagnosis of BA and the production of an effective inactivated vaccine BA, creating a reliable protection of animals (pigs, sheep, rabbits) from the causative agent of the disease, as well as production associated with an inactivated vaccine against Aujeszky's disease and Teschen.

The strain of the as-21/07 virus ad is characterized by the following features and properties.

Taksonomicheskaya feature is that the strain of the as-21/07 has the shape and dimensions typical of herpes. species strain "as-21/07 virus Aujeszky's disease using the neutralization (PH) and by the method of fluorescent antibody (IFA). In serological reactions (RN, RAC, ELISA and other) are identified antigens that are common to all strains of BWA. The main marker characteristics of the strain of the as-21/07 virus BA given in the table.

The presence of the outer shell, the number of capsomeres
The basic properties characterizing the strain "as-21/07 virus BA
1.TaxonomyHerpesviridae
2.The type of nucleic acidLinear double-stranded DNA, has infektsionistu
3.Two-layer membrane containing lipids and over 40% of the proteins of the virion. The number of capsomeres - 162
4.The size of the virion150-180 nm
5.Symmetry virionicosahedral
6.Physico-chemical properties of the virionFloating density of virions in the caesium chloride B g/cm3constant sedimentation 54 S
7.Genetic markerMarked for deletion of the genome in the fragment. The deletion is detected by restriction of the genome by You-N1 or PCR with primers flanking the K-fragment
8.The predominant strain tropismPnevmotropnye, with a predominance of nervous tissue is parenchymatous organs (liver, spleen, lungs, kidneys)
9.Pathogenicity for laboratory, C.-H. animalsCauses the death of rabbits intramuscular infection
10. The sensitivity of cell culturesKF, CPD-666, KSS-21/13, PSGK-60 and others with the manifestation of the JRS. The accumulation of the virus to 7.5 to 8.5 lg TCD50/cm3
11.Serological propertiesInduces formation of complimentative, precipitating and neutralizing antibodies.
12.Harmlessnessharmless
13.Stability of genetic and immunological characteristicsStability of genetic and immunological signs of strain remained at his passirovannye in the culture of cells susceptible to the virus BA, for at least 20 passages (observation period)
14.The type of stabilization and storageDried vaccinated material aa, peptone-lactose gelatin stabilizer; 1 cm3/amp., at minus 40°C
15.The frequency of refreshing the strainOnce in 5 years, with activity above 4.0 lg TCD50/cm3, shelf life is extended
16.In what form is given strain, recommendations on the transport"In dried form in ampoules sealed under vacuum. Conveying compliance with
rules SP 1.2.036.95 "accounting, storage, transfer, transportation of microorganisms of I-IV groups of pathogenicity at a temperature below zero in a thermos or cool bag with any freon"
17.Additional informationFree from bacterial, fungal, mycoplasmal microflora

The essence of the invention is illustrated by examples of its execution.

EXAMPLE 1. Given that the production of inactivated vaccines, usually associated with the use of a substantial amount of viral raw materials, highly infectious activity, as well as the fact that the virus of Aujeszky's disease model no heterogeneity, the choice of strain is suitable for construction of inactivated vaccine, conducted on the basis of maximum accumulation in cell cultures. With this purpose available in the collection of microorganisms of the GSI Vniivvim strains Beech-622, M-Bracia, VGNKI and MK-25 virus BA, infectious activity which was 5.5 to 6.5 lg TCD50/cm3were cultured in different cell substra the Ah: PTP, CPD-D, KSS-21/13, PSGK-60, PSGK-60C and CF.

Each cell culture was performed at least 5 consecutive passages of the indicated strains. Contagious virus was determined by titration in cell culture PSGC-60 ACC-D using a supportive environment Needle-MEM without serum.

As a result of experiments it was shown (table 1), at the level of the 5-th passage in these cell cultures with more infectious activity accumulated strain MK-25 virus BA. In higher titers (up to 7.50 lg TCD50/ cm3he was bred in transplantable cell cultures PSGC-60 ACC. Along with this strain MK-25 well-bred and in suspension culture PSGC-60C, making it possible to obtain simultaneously, depending on the capacity of the reactor, large amounts of viral material required in the production of inactivated vaccines. Given these data, strain MC-25 was selected to conduct selective passages of the virus in human cell culture PSGC-60 to improve infectious activity and immunogenicity. Level 19-21 passages its accumulation in the cell culture PSGC-60 and PSGC-60C reached up to 8,0-8,5 lg TCD50/ cm3. Virus passage 21 in cell cultures PSGC-60 was identified and have been certified as a production strain "as-21/07 virus BA. Over the next 10 passages strain "as-21/07 virus BA NAK who was levelsa in the range of 8.00-8.75 lg TCD 50/ cm3(observation period).

Table 1
Veryrapidly activity of cell cultures in relation to different strains of the virus BA
n=3
Cell cultureAccumulation of virus Aujeszky's disease
AC-21/07MK-25Beech-622M-BraciaVGNKI
PSGC-608,0-8,56,75-7,56,5-7,06,0-6,56,0-6,5
PSGC-60C8,0-8,57,56,0-6,336,06,0-6,5
PTP7.23 percent and 7.56,56,0NiNi
CPD-DNi 7,0-7,56,5-7,57,0-7,25Ni
KSS-21/138,0-8,236,5-7,06,5-7,07,0Ni
KF8,07,5-8,0NiNifrom 6.25 to 7.25

To obtain the results of molecular-genetic characteristics of the strain of the as-21/07 virus BA conducted by restriction analysis mirinoi DNA extracted from purified, after breeding, drugs. Based on these data it is concluded that the strain is marked for deletion of the genome in the K fragment. The deletion is detected by restriction of the genome by You-N1 or PCR with primers flanking To the fragment.

The resulting virus was subjected to a comprehensive inspection in accordance with the guidelines of the OIE standard diagnostic methods and vaccines (1996) and level 2 passage after lyophilization laid on storage at minus 60°C as manufacturing with the titer of infectious activity of 6.5 lg TCD50/ml. Obtained virus strain BA assigned author's name "al-21/07".

EXAMPLE 2

Studied PA is hennoste this strain most sensitive to the virus BA animals the rabbits. As a control rabbits were also infected by the virulent strain of P. (epizootic) and vaccine strain MK-25. These strains were inoculable rabbits weighing 2.5 to 3.0 kg intramuscularly at a dose of 105TCD50.

The results of these experiments are shown in table 2.

Table 2
The pathogenicity of different strains of BWA for rabbits intramuscular infection
№ p/pStrains of BWAThe number of rabbitsTime of death (days)The results of the experiment
1P (epizootic)333/3
2MK-2535-63/3
3AC-21/0736-83/3
Note: numerator - the number of rabbits in the experience, in the denominator - the number of the fallen to Alikov.

In the course of the observation noted the death of the rabbits from strain P and MK-25 on 3 and 5-6 days, respectively, while the death of animals infected with strain as-21/07, noted for 6-8 hours.

The obtained data suggested that the most pathogenic strain for rabbits and probably the most attenuated, is the strain AC-21/07 of BWA.

EXAMPLE 4

Study of safety and immunogenicity of the strain

When injecting a virus to pigs (2 heads) in the dose of 10-7TCD50they did not observe any rise in body temperature and the animals remained healthy throughout the observation period (30 days).

Inoculation with sheep (4 heads) virus at a dose of 106TCD50the animals remained clinically healthy during 30 days (observation period).

Immunization of pigs (3 heads) 2-3 months of age strain AC-21/07 of BWA caused the formation after 21 days in the blood serum of VN antibodies in titer of 1:8-1:16. Strain AC-21/07 is harmless for pigs and adult sheep when their intramuscular infection.

EXAMPLE 5

Determined the stability of attenuation (no reversion) samples strain "as-21/07 virus Aujeszky's disease, deposited in the collection of strains of microorganisms of the FGI "VGNKI" on target animals - pigs 4 weeks of age. 5 vials of lyophilized piece is MMA "as-21/07 virus Aujeszky's disease spread environment Needle MEM with pH 7.0 up to the original volume, brought together in the overall sample was diluted so that the final dilution contained 106,0TCD50/cm3and was administered intranasally at 1.0 cm3in each nostril two piglets with a live weight of 8-10 kg (1 passage). On day 7 after inoculation of the nasal cavity piglets were collected with a sterile probe with a cotton swab length of 150 mm, the samples of nasal secretions (mucus) at a depth of 10 cm Probe was placed in a test tube, which contributed 1.0 cm3eagle medium MEM. The tubes were frozen at minus 40°C, and then held a defrost cycle when the temperature (37±0,5)°C. the resulting material was osvetleni low-speed centrifugation at 2000 rpm for 20 min, were collected supernatant, which were combined and diluted with medium Needle MEM 1:10. The resulting material was injected at 1.0 cm3in each nostril two piglets with a live weight of 8-10 kg (2nd passage). Was held on 5 passages in vivo in pigs. Between 2 and 3 passages in vivo, was performed 1 passage in vitro in cell culture PSGC. The supernatant after centrifugation was diluted with medium Needle MEM 1:10 and have made 2 disposable sterile plastic bottles for cell culture (firm "GRAINER", an area of 75 cm2), with a fully-formed monolayer cells PSGC, after removing the growth medium. Infected culture cells were incubated for 1 h at (37±0.5°C.,and then the monolayer was washed 3 times with medium Needle MEM, then in bottles made by 10.0 cm3fresh eagle medium MEM with 2% fetal cattle serum and antibiotics. The vials were incubated at (37±0,5)°C. Inkubiruemykh cell culture daily viewed under a microscope for the presence of destructive changes in the form of a cytopathic effect. On the 3rd day watched the manifestation cytopathogenic of the virus. On the 4th day of the JRS was 80-90%. The vials were frozen at minus 40°C, and then held a defrost cycle when the temperature (37±0,5)°C. the resulting material was osvetleni low-speed centrifugation at 2000 rpm for 20 min, were collected supernatant, which were combined and diluted with medium Needle MEM 1:10. The resulting material was injected at 1.0 cm3in each nostril two piglets with a live weight of 8-10 kg (3 passage in vivo).

It is established that in piglets inoculated intranasally strain "as-21/07" BWA for 5 passages temperature remained within the physiological norm. During the whole observation period, all animals remained clinically healthy, typical signs of Aujeszky's disease were not observed. This suggests that the strain of the as-21/07" BWA stably attenuated.

Preparation associated with an inactivated vaccine against the disease Teschen and Aujeszky's disease and the study of its immunogenicity.

Based on this, the Tamm "as-21/07 was manufactured sample of inactivated vaccine against disease Teschen, aujesky.

Immunogenicity associated inactivated vaccine was studied on 6 rabbits and 4 pigs with a live weight of 20-25 kg of the Drug was administered to the animals intramuscularly twice, rabbits by 1.0 cm3the pigs by 2.0 cm3. In vaccinated animals after the first (21 days) and second (14 days) immunization were collected blood samples for studies of sera for the presence of VN antibodies. Observation of the animals were within 60 days after immunization.

It is established that immunization of rabbits associated with the vaccine caused the formation of VN antibodies in titer of 6.5 log2against viruses BA and BT. After the second immunization level VL of the antibody was 6.5 log2against the BWA and 8.3 log2against WBC (figure 1).

When immunization is associated with an inactivated vaccine of the pigs the VN titer antibodies in their blood serum after the first vaccination against BWA rate of 6.0 log2and against WBC 8,5 log2, after repeated administration of the drug - 7,8 log2against the BWA and 8.3 log2against WBC (figure 2).

Thus, strain SA-21/07 virus BA in high titers accumulates in human cell cultures at stationary and roller methods of cultivation; is safe, immunogenic for pigs, may be recommended for the production of vaccine and diagnostic products.

Sources of information

1. Antigenic Akti is of inactivated virus pseudoleskeella on various kinds of animals / Gagalababa, Raguso, Aeasily [and other] // Scientific basis for the protection of animals from toxicants, radionuclide and pathogens of infectious diseases: Mat. The Intern. the Symposium. / - Kazan, 28-30 November 2005 (part II), s-181.

2. Baborenko H.E. Immunobiological properties of strains of the virus Aujeszky's disease: author. dis.... Kida. Biol. Sciences. - Vladimir, 1996. - 23 S.

3. Inactivated vaccine against Aujeszky's disease for immunization of farm animals and fur-bearing animals. / Waimana, Vmichael, Aigunov [and other] // Viral and microbial diseases of animals: a collection of scientific papers. - Vladimir, 1995. - S-201.

4. Malaret PV Aujeszky's Disease (review of literature). / Pivalates, Ephysema, Taimuria. - Vladimir, 1995. - 72 S.

5. Sergeev V.A. Viruses and viral vaccines. / V.A. Sergeev, Nepoklonov E.A., Aliper TI M: ' Bibliophika", 2007. - 524 S.

6. Assessment VirusWall for the prevention of Aujeszky's disease of pigs. / AAA, Vasavan, Ifficial [and others]. // Veterinary - 1991. No. 1. - P.31-33.

7. Shishkov A.A. development of the technology associated with an inactivated vaccine against Aujeszky's disease and enterovirus encephalomyelitis pigs: author. dis.... Kida. wind. Sciences. - Cover, 2008. - 23 S.

8. Viral diseases of animals. / Vinculin and others - M.: UNITEMP, 1998. - 928 S.

9. Viruses and viral vaccines. Sergeev V.A., Napolo the s EA, Aliper TI / M: Bibliophika", 2007. - 524 S.

The strain of the virus Aujeszky's disease, the family Herpesviridae, genus Varicello subtype Herpesvirus bovis 1, collection VGNKI, registration name "AC-21/07-DEPOT, for the manufacture of vaccine and diagnostic products.



 

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2 cl, 3 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to RSV replication inhibitors of formula (I) or salts thereof or stereochemically isomeric forms, where R is a radical of formula (a) or (b) . Q is hydrogen or C1-6alkyl substituted with a heterocycle selected from oxazolidine, morpholinyl and hexahydrooxazepine. Alk denotes C1-6alkanediyl. X is O; -a1=a2-a3=a4 - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R1 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrrolyl. R2 is C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, Ar-C1-6alkyloxyC1-6alkyl, C3-7cycloalkyl, Ar-C1-6alkyl. R3 is cyano. Ar is phenyl o substituted phenyl. The invention also relates to pharmaceutical compositions containing compounds (I) and a method of producing compounds (I).

EFFECT: high efficiency of the compositions.

9 cl, 20 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, namely to infection diseases, hepatology, and can be applied for prevention or treatment of viral disease, caused by virus of hepatitis C. For this purpose therapeutic medication, as active ingredients in it are combined 22β-methoxyolean-12-en-3β,24(4β)-diol and interferon, is introduced to patient. High therapeutic effect of claimed medication is associated with synergetic effect of 22β-methoxyolean-12-en-3β,24(4β)-diol and interferon, manifested in inhibition of hepatitis C virus.

EFFECT: insuring high therapeutic effect.

6 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular, to gynecology and can be applied for treatment of precancerous diseases of uterus neck. Medicine is made in form of vaginal suppository, containing recombinant composition of proteins E7 of human papilloma virus of 16 and 18 types, bound with amino acid by sequence of heat sock protein m.m. 70 kDa from M. tuberculosis, hydrophobic base, polyethylene glycol 1500, polyethylene glycol 400, preservative, chitosan with degree of deacetylation 86%.

EFFECT: invention ensures stability of recombinant proteins, included into its composition, during long time.

1 tbl, 4 ex

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