The method of immunization against infection caused by tick-borne encephalitis virus

 

(57) Abstract:

The invention is intended for a specific prophylaxis of tick-borne encephalitis. For immunization apply a live recombinant vaccine against tick-borne encephalitis on the basis of vaccinia virus. The vaccine is prepared on the basis of strain KV 7,5 CMENS 123 (strain GKV N 945) or strain WR 7,5 CMENS 123. Using a pipette or a special syringe vaccine is injected into the body intranasally in the region of the olfactory neuroepithelium lining of the nose in dose (0.5 to 5.0) 106AOE. The most optimal dose of 106AOE with volume 50 μl inoculum. The invention allows to simplify the method of vaccination of the body without breaking the skin. While protecting the brain from tick-borne encephalitis virus in parenteral infection due to the formation of local immunity of the mucous of the nasal cavity, and also reduces the load on the system the immune system and decreases the amount entered in the body of the drug. 1 C.p. f-crystals, 3 tables.

The invention relates to medicine, namely to methods of specific prophylaxis of viral infections.

The tick-borne encephalitis virus (TBE) belongs to the family of flaviviruses and alsoby immunization against infection, caused by tick-borne encephalitis virus inactivated culture vaccine or live vaccine against tick-borne encephalitis [1] . Inactivated vaccine made from a strain sofjin by virus inactivation by formalin. Live vaccine is produced by attenuate pathogenic strains of tick-borne encephalitis virus. Vaccines are injected into the body by intramuscular or subcutaneous injection. As a result of vaccination formed a system of immunity, preventing spread in the body of the tick-borne encephalitis virus and the brain.

Developed a recombinant vaccine against tick-borne encephalitis on the basis of strain LIVP of vaccinia virus with insertions in the genome of this virus genes encoding structural and non-structural proteins of tick-borne encephalitis virus [2] . Recombinant vaccine is injected into the body by scarification of the skin.

The disadvantages of these methods of immunization [1, 2] is a complex technology the introduction of vaccine into the body, which requires the involvement of qualified personnel, special conditions of preparation of injecting equipment, and the process of immunization is associated with disruption of the integrity of the skin and possible complications visions of vaccines ways creates an additional load on the system the immune system.

The closest technical solution of the present invention (the prototype) is a method of vaccination against tick-borne encephalitis by subcutaneous injection of inactivated adsorbed vaccine EC on the basis of strain 205 [3]. The vaccine is administered in the amount of 1.0 ml three times with an interval of 30 and 105 days or twice with an interval of 30 days.

The disadvantages of this method of immunization [3] is a complex technology the introduction of vaccine into the body, which requires the involvement of qualified personnel, special conditions of preparation of injecting equipment, and the process of immunization is associated with disruption of the integrity of the skin and possible complications due to penetration in the vaccine pathogenic microorganisms or viruses. In addition, after the introduction of the vaccine in this way creates an additional load on the system the immune system.

The objective of the proposed technical solution is the creation of a more simple method of vaccination of the body without breaking the skin, which would provide brain protection from viral infection tick-borne encephalitis in parenteral infection by forming local immunity with the body of the drug.

This task is solved in that in the method of immunization against infection caused by tick-borne encephalitis virus, comprising the introduction into the organism vaccine against tick-borne encephalitis, according to the invention as a vaccine using recombinant vaccine against tick-borne encephalitis on the basis of vaccinia virus, and found the vaccine injected into the body intranasally in the region of the olfactory neuroepithelium lining of the nose in dose (0.5 to 5.0)106OOE.

As a recombinant vaccine against tick-borne encephalitis based on the use of vaccinia virus vaccine prepared from strain KV 7,5 CMENS 123 (strain GKV N 945) or WR 7,5 CMENS 123.

When introduced into the body of a live recombinant vaccine against TBE dose of less 0,5106OOE is not provided 100% protection from this infection.

When introduced into the body of a live recombinant vaccine against TBE dose of more than 5.0 06OOE observed overrun this vaccine without increasing the effectiveness of its actions and increasing the load on the system immunity, because the title of a live vaccine in the body for several days can increase to the desired level.

Strain KV 7,5 CMENS 123 (strain GKV N 945) japonisme name KV 26). At the specified strain has a patent RF N 2112038, IPC C 12 N 15/40, publ. 27.05.98, which shows its detailed characteristics and production technology.

Strain WR 7,5 CMENS 123 deposited in the state collection of viruses of the State research center of Virology and biotechnology Vector (SRC VB "Vector") under number GKV N 295. Characteristics of the strain posted in:

Khromykh, A. A. protein Expression of tick-borne encephalitis virus recombinant viruses ospowiki. The dissertation on competition of a scientific degree of the candidate of Biol. Sciences. - Novosibirsk, 1990, S. 17-67.

Passport strain WR 7,5 CMENS 123 (GKV 295) contains the following characteristics:

1. Morphology, signs of strain. Recombinant strain WR 7,5 SMENS 123 has properties typical representative of the family of orthopoxviruses. The strain virions have a size 200x300 nm, characteristic biketours the form and according to electron microscopy does not differ from the original strain.

2. Virus. Vaccinia virus containing the structural genes (C, M, E) and nonstructural (NS1, NS2a, NS2b, NS3) protein of the virus of tick encephal.

3. Strain refers to the WR strain of vaccinia virus

4. Source: Culturing the cell culture Hu-143.

5. Pas is -1

6. Conditions for maintaining: Cultivation at 37oC on cell cultures Hu-143, CV-1 or HAO RCA.

7. The system of cultivation: Cultivation on the monolayer of cells in the environment of the Needle MEM with 2.5% fetal serum.

8. Properties of strain: gene timedancing of vaccinia virus (strain WR) cloned the genes encoding the structural (C, M, E) and nonstructural (NS1, NS2a NS2b, NS3) of tick-borne encephalitis virus of strain sofjin under the control of the promoter of the vaccinia virus to 7.5 K. Protein C, M, E, NS1, NS2a, NS2b, NS3 expressed in the infected cell cultures. The strain has lost neuroinvasiveness in mice with peripheral infection methods.

9. Virulent and toxicogenic properties: Strain harmless in the test on Guinea pigs and outbred mice. When intracerebral administration to rabbits at a dose of 5104OOE does not cause death.

10. Storage conditions: Guaranteed, in lyophilized state at - 20oC.

For many strains of neurotropic viruses shown that the pathogen can penetrate into the brain, infecting olfactory nerve endings located on the surface of the mucous membrane of the nasal cavity [6-12]. In particular for virus Venezuelan encephalomyelitis of horses shown that mmunicate [11], and for a representative collection flavivirus virus St. Louis shows that it spreads to the brain, infecting cells of the olfactory neuroepithelium and the olfactory tract [12]. In previous experimental studies that led to the creation of the proposed technical solutions, and literature data we can conclude that viruses that do not generate high levels of viremia, in particular some flavivirus and the representative of the tick-borne encephalitis virus, penetrate into the CNS after peripheral infection in the following way: "blood - cells Romanovich glands - the surface of the mucous membrane of the nose - olfactory nerve endings - vnutriskalnyh transport - CNS". Thus the area of the olfactory neuroepithelium is a Central part of the pathway flaviviruses in the brain. Therefore, blocking the spread of tick-borne encephalitis virus through sensitive to the virus cells in the olfactory neuroepithelium by intranasal infection of the cells lining the nasal vaccine viral strain and thus forming a local mucosal immunity, you can protect the brain against penetration of tick-borne encephalitis virus.

Known speciespages live attenuated or recombinant strains able to multiply in the cells of the respiratory tract. Intranasal vaccination against respiratory viral infections provides for the formation of local mucosal immunity in the respiratory tract, which prevents the penetration of specified infections of the body through the respiratory tract.

In the proposed method, intranasal vaccination against TBE virus also provides for the formation of local immunity of the mucous of the nasal cavity. However, in contrast to known methods of vaccination [11, 12] proposed method provides brain protection against the penetration of viral infection tick-borne encephalitis in parenteral infection (tick bite).

Intranasal application of live vaccines from strains of tick-borne encephalitis virus known sources of information are not described.

Thus, the set of essential features of the invention, which differs from the essential features of the prototype, unknown from published sources of information that allows to make a conclusion on the conformity of the proposed technical solutions to the criterion of "inventive step".

Example 1. The proposed method of immunization against infection, visesio encephalitis on the basis of vaccinia virus. The vaccine is prepared on the basis of strain KV 7,5 CMENS 123 (strain GKV N 945) or strain WR 7,5 CMENS 123. Using a pipette or a special syringe vaccine is injected into the body intranasally in the region of the olfactory neuroepithelium lining of the nose in dose (0.5 to 5.0)106OOE. Experiments show that the most optimal dose of 106OOE when the amount of inoculum of 0.02 ml of this in a few days is 100% protective effect of the organism in the case of parenteral be infected with tick-borne encephalitis virus, for example through the bite of an infected tick.

Example 2. Experimental study of the effectiveness of immunization of the body against infections caused by TBE virus in traditional ways (intradermally and subcutaneously)

To compare the effectiveness of vaccination of commercial inactivated vaccine against tick-borne encephalitis and two recombinant strains of vaccinia virus (strain WR 7,5CMENS123 from the parent strain WR vaccinia virus and a strain of 7 KV,5CMENS123 from the parent strain of vaccinia virus LIVP) with integrated genes structural and non-structural proteins of tick-borne encephalitis virus conduct intradermal vaccination (in the tail) mice of BALB/C recombinant strains based strains is 106OOE (volume inoculum of 0.02 ml), and inactivated commercial vaccine is injected subcutaneously in a volume of 0.2 ml of the Control group injected subcutaneously sterile Hanks solution in a volume of 0.2 ml. three weeks after vaccination, all animals infect intraperitoneally with tick-borne encephalitis virus (strain sofjin) different dilutions (with a ten-fold increments) initial viral material, which is a ten percent homogenate brain of infected mice with activity 9,0 lg LD50 intracerebrally infected mice. From table 1 it is evident that the maximum degree of protection is observed at a subcutaneous application of commercial inactivated vaccine against tick-borne encephalitis (died 8.3% of the total number of infected animals), and the minimum protection is observed at intradermal application of recombinant vaccines kv 7,5CMENS123 (died 49,2% of the animals).

Example 3. Experimental study of the effectiveness of immunization of the body against infections caused by TBE virus offered intranasal way

Protective effect of intranasal immunization with live recombinant and inactivated commercial vaccines against tick-borne encephalitis demonstrated in experiments tion of strain at a dose of 106OOE). The control group is administered intranasally 50 μl of Hanks solution. Three weeks after immunization, all animals infect intraperitoneally various dilutions of tick-borne encephalitis virus (strain sofjin), which represents the ten percent homogenate brain of infected mice with activity 9,0 lg LD50 intracerebral titration in mice. Table 2 shows that in contrast to the results presented in table 1 (tables 1-3, see the end of the description), gives maximum protection intranasal introduction of recombinant strain WR 7,5CMENS123 (protected 100% of infected animals), whereas intranasal introduction of inactivated commercial vaccines against tick-borne encephalitis does not practically significant protection (died 81,6% of infected animals).

Example 4. Analysis of the experimental data obtained in examples 1, 2

Presented in tables 1,2 experimental data are compared by Chi-square significance of difference in the probability of death of the animals [13] . The results of the statistical evaluation of the experimental data presented in table 3.

Check the Chi-square null hypothesis that the compared groups of animals (NN1-8) is the industry (%), which rejected the null hypothesis of indistinguishability groups.

The analysis of table 3 allows us to draw the following conclusions.

1. Subcutaneous immunization with a commercial vaccine and intranasal immunization with recombinant vaccines (group of animals 3 and 5, 6) are not significantly different (at the level of more than 99.9%) on the effectiveness of protection.

2. The effectiveness of protection at the intranasal administration of recombinant vaccines wr7,5CMENS123 and kv7,5CMENS123 no different with a probability of more than 99.9%, group of animals 5 and 6.

3. The protective properties of the recombinant strain wr7,5CMENS123 not change when intranasal or intradermal use (probability of 97.5%), group of animals 1 and 5.

4. In contrast to the recombinant strain (p. 3) the effectiveness of protection when intranasal and subcutaneous application of commercial inactivated vaccine differs significantly (probability of more than 99.9%), group of animals 3 and 7.

5. Intranasal immunization with recombinant strains significantly exceeds protectively intranasal immunization with an inactivated vaccine (99% likely), group of animals, 7 and 5, 6.

6. Subcutaneous immunization with a commercial inactivated vaccine and nutriton is on protectively (probability 97.5%), groups of animals 1 and 3.

7. Intradermal vaccination with recombinant strain kv7,5CMENS123 does not provide a high level of protection and is significantly different in protectively from subcutaneous vaccination of commercial inactivated vaccine (the probability of more than 95%), group of animals 2 and 3.

Thus the protective properties of intranasal method of vaccination using recombinant vaccines are not worse than the traditional method of subcutaneous vaccination with an inactivated vaccine against tick-borne encephalitis, but the proposed method has several significant advantages.

The advantages of the proposed method.

1. When intranasal vaccination does not violate the integrity of the skin, resulting eliminated possible complications.

2. Formed local immunity of the mucous membrane of the nasal cavity directly in the field penetration of tick-borne encephalitis virus in the brain, because they will not create an additional load on the system immunity and is not a General sensitization and allergization of an organism, which is very important for persons with a weakened immune system.

3. The immunity of the mucous slightly affected by the age islandmagee way.

4. The amount of vaccine needed to create a certain level of protection is reduced compared with the method of the prototype several times (4-5 times for mice), and using a special catheter or an aerosol can in a few dozen times.

Sources of scientific, technical and patent information

1. Smorodintsev A. A., Oaks, A. C. Tick-borne encephalitis and its prevention. HP: Medicine, 1986, p. lasts 175-190.

2. Auth. mon. SU N 1490963, MKI C 12 N 15/00, publ. 07.07.93.

3. Auth. mon. SU N 1722503, MKI A 61 K 39/12, publ. 30.03.92. (prototype).

4. Larson. E. W., Dominik, J. W., Slone. Th.W. - Aerosol stability and respiratory infectivity of In Japanese encephalitis virus. - Infect. Immun., 1980, v. 30, p. 397-401.

5. Nir. Y., A. Beemer, Goldwasser, R. A. West Nile virus infection in mice following exposure to a virus aerosol. - Brit. J. Exp. Pathol., 1965, v. 46, p. 443.

6. Grimley, P. M., Friedman, R. M. - Development of Semliki Forest virus in mouse brain: an electron microscopic study. - Exp. Mol. Pathol., 1970, v. 12., p. 1.

7. Davis, L. E., Johnson, R. T. - An explanation for the localisation of herpes simplex encephalitis? - Ann. Neurol., 1979, v. 5, p. 2.

8. Goto, N., Harada, N., Aiuchi, M., Hayashi, T., Fujiwara, K. - Nasoencephalopathy of mice infected intranasally with mouse hepatitis virus JHM strain. - Jap. J. Exp. Med., 1977, v. 47, p. 59-70.

9. Ryzhikov, A. C., Ryabchikova E. I., Sergeev, A. N., N. V. Tkacheva Venezuelan equine encephalitis virus propagation in humans tract of normal and immune mice// Arch.Virol. - 1995, v. 140, p. 2243-2254.

10. Monath, >/P>11. Auth. mon. SU N 1731811, MKI C 12 N 7/00, publ. 07.05.92.

12. Small, P. A., Smith, G. L., Moss B. In: Vaccines 85. Ed. Cold Spring Harbor Lab. Intranasal Vaccination with a Recombinant Vaccinia Virus Containing Influenza Hemagglutinin Prevents Both Influenza Virus Pneumonia and Nasal Infection: Intradermal Vaccination Prevents Onlu Viral Pneumonia. - 1985, pp. 175-176.

13. Ashmarin I. P., Vorobiev A. A. Statistical techniques in microbiological research. HP: Medgiz, 1962.

1. The method of immunization against infection caused by tick-borne encephalitis virus, comprising the introduction into the organism vaccine against tick-borne encephalitis, characterized in that as a vaccine using recombinant vaccine against tick-borne encephalitis on the basis of vaccinia virus, and found the vaccine injected into the body intranasally in the region of the olfactory neuroepithelium lining of the nose in dose (0.5 to 5.0)106OOE.

2. The method according to p. 1, characterized in that as a recombinant vaccine against tick-borne encephalitis based on the use of vaccinia virus vaccine prepared from strain KV 7,5 NS 123 (strain GKV 945) or WR 7,5 NS 123.

 

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