Poly-specific hyperimmune serum against rota-, corona-, herpes viruses, and e. coli k-99, a-20) for local protection and immunotherapy mixed forms of diarrhea of newborn calves

 

(57) Abstract:

The invention is intended for specific immunotherapy and passive prophylaxis of mixed forms of infectious enteritis and enterocolitis of newborn calves. Ox-producers hyperimmunizing polyvalent viral and esherihioznae antigens. To do this, as viral antigens are used culture suspension Rota-, corona-, herpes viruses. The viruses are grown separately on transplantable cell cultures, respectively, on the culture of kidney cells of the embryo pig (line SPM), kidney embryo cows (line MDC) and cell cultures of tracheal embryo cows (line TR). As esherihioznae antigen using somatic adhesive antigens (C, A20) and TL-, TC-toxoids E. coli. Hyperimmunization oxen-producers is carried out by intravenous infusion of a mixture of viral antigens and subcutaneous injection esherihioznae antigen in increasing doses with an interval of 14 to 16 days. Poly-specific hyperimmune serum is used for local protection of the intestine and immunotherapy mixed Rota-, corona-, herpes and exericises diarrhea of newborn calves. The invention provides passive immunity in a very to the and veterinary Virology, Microbiology and biotechnology, in particular to the production of a biological product intended for specific immunotherapy and passive prophylaxis of mixed forms of infectious enteritis and enterocolitis of newborn calves.

In the structure of morbidity of the newborn gastrointestinal diseases bacterial and viral etiology, clinically manifested by diarrhea, occupy a special place and are one of the main causes of death of young animals. So, according to some published data annually in dairy farms of the Russian Federation ill 70-90% of newborn calves and about one third of them killed in the first days of life due to acute gastroenteritis with symptoms of diarrhoea (Gaffarov H. H., 1983, - veterinary, N 4, pp. 73-76; Volkov, K., Barannikov C. D., 1997, - veterinary, No. 2, pp. 7-10; Sidorov, M. A., Subbotin centuries, 1998, - veterinary, No. 1, pp. 3-7; and others).

This group of diseases causing farms enormous economic damage resulting from the high mortality of the patients, the high cost of treatment, reduction in weight and holding of General and specific measures.

Without effective protection of infants from infectious diseases, the circulation of which in e possible to get healthy young and biologically valuable livestock products.

Available in the literature data of the last years and our accumulated knowledge and experience testify that the mass enteritis and enterocolitis of newborn calves with clinical signs of diarrhea caused various etiological factors: if the onset of non-communicable diseases are functional disorders of the gastrointestinal tract of the newborn, is closely associated with metabolic disorders in cows-mothers due to inadequate feeding and violations of the rules of detention, for infectious diarrhoea huge role Rota-, corona-, herpes viruses and enterotoxigenic serotypes of E. coli synthesizing adhesive K99 antigens, A20, K88, and to a lesser extent - to parvovirus virus diarrhea, bovine, chlamydia, some bacteria and Cryptosporidium (C. A. Mebus with the employees., 1971, - Canad. Vet. J., V. 12, pp. 69-72; Wood C. N. with the employees., 1974, Res. Vet. Sci. , V. 16, pp. 102-105; Wyn-Jones A. P. with the employees., 1978, - Zbl. , Veterinarmed., Bd. 25, pp. 168-170; Koves B., 1979, - Acta environ. Acad. Sci. Hung., V. 26, pp. 225-232; Samoilov PP, Panteleev Y. C., Sorin C. N., 1982, Issues of Virology, No. 1, pp. 61-64; Gogolev M. M. et al. , 1983, Bulletin of VIEW, pages 49-52; Stashenko N. J., Hudenko E. C., 1988, Infectious pathology C. farm animals and bees in the far Vdat", page 3-235).

The infectious process is compounded by the fact that these agents act on the naked body of a newborn in combination with each other (virus + virus virus + bacteria) causing the mixed infection, leading to more severe disease and more deaths (Zygraich N. et al., 1975, Ann. Med. Veter., 119, 2, pp. 105-113; Mebus, C., 1976, - J. Dairy Sci., 59, 6, 1175-1178; H. Moon et al., 1978, - J. Am. Vet. Med. Assn., 173, 5p, 577-583; Optenbosch E. et al., 1979, - Session Cenerale du Cometede J. O. J. E, Paris., 21-26 Mai, Rapport, N 100, 25; raisers using, F. et al., 1980, - "Agriculture abroad", N 6, 51-54; Wetzke T. J. et al., 1982, - Tierzucht. , 36, 10, 446-449; Scherrer R., Laporte J., 1983, Rec. Med. Veter., 159, 3, 173-183).

Diarrhea of newborn calves of mixed etiology characterized by stationarity, long and severe course. Newborn calves infected in infected maternity wards in the first minutes of life with the first breath contaminated air or with the first breath of infected colostrum and then in 2-5 days is the death against the background of progressive developing irreversible pathological changes.

The emergence and development of infectious process caused by the high concentration of livestock, latent persistence of pathogens in oleanane and effective way to protect newborn calves from agents, involved in the pathogenesis of mixed infection by type a virus+virus or virus+bacteria E. coli, is to increase the specific resistance of the body by feeding colostrum from vaccinated cows-mothers.

In recent years development has allowed us to create mono-, bivalent and associated vaccines, which gives the effect of immunity in calves to enteritis in many countries, including in the Russian Federation (Snodgrass D. R., 1983, Ann. Rech. Veter., 14, 4, 519-521; Freitag. et al., 1984, - Tierarztl. Umsch., 39, 10, pp. 731-736; Kaloyanov J. et al. , 1988, - Bemep. Coll., 86, 5, page 40; Gogolev M. M. et al., 1987, - Proceedings of VIEW, 64, pp. 13-15; Transfiguration D. et al., 1988, Bulletin of VIEW, 86, pp. 21-26; Ramishvili L., et al., 1993, Issues of Virology, No. 5, pp. 233-234; Gaffarov X. Z. et al., 1998, proceedings of the international scientific conference dedicated to the 125th anniversary of the Academy, Kazan, part 1, page 31).

Antibodies obtained from the colostrum of cows, protect calves from disease up until they will not develop their own mechanisms of immunity. For various reasons, some calves after birth does not receive the necessary amount of this natural protection, which is associated with insufficient intake immunoglo or violation of the mechanism of absorption of immunoglobulins in the colostrum intestine of the newborn (Fedorov, Y. N., 1988, - veterinary, No. 1, pp. 26-29).

Wide variability and the variability of Escherichia, and the emergence of their resistance to the use of antibiotics and other chemotherapeutic drugs, often minimizes their effectiveness.

Therefore, only antibodies, entered calves oral, protect them from diseases, provide full protection from the development of clinically apparent disease and stop the excretion of viruses and bacteria.

Given this situation, with the specific purpose of passive prophylaxis and treatment in different countries practiced oral and parenteral administration of hyperimmune serum or immunoglobulins obtained from hyperimmunizing animal-producers, gamma-globulin isolated from the colostrum of the first divania or from allogeneic bovine serum (Bejric A. et al. , 1976, - Veterinaria, Sarajevo, V. 25, No. 1/2, pp. 201-206; Snodgrass, D. R., Wells P., 1978, - J. Amer. Vet. Met. Assn., 173, 5P11, 565-569, - Vet. Rec. , 1978, 102, 7, 146-148; Chantal J. et al., 1984, - Rev. Med. Veter., 135, 12, 754-774; Anon The Wind. SB., 1984, 82, 3, 34; De Cregorio R. M., 1991, - Proc. Cornellnutiton Conf. for feed manufact animals, Jthaca, N 4, 102-108).

In Russia applies polyvalent antitoxic serum against paratyphoid and colibacillus , cluchuis 30 24 strains of serogroups and serovars enteropathogenic Escherichia; bivalent antitoxic serum against paratyphoid and colibacillus calves ("Wet. drugs", M.: Kolos, S. 226).

Main disadvantages is the lack of therapeutic and prophylactic efficiency when colibacillosis flowing in forms caligiuri and colienterobacterial, due to the low titer of antibodies to adhesion antigens C and K, thermolabile and thermostable to enterotoxins and absence of antibodies to adhesion antigens R and G.

Proposed as a method of obtaining a serum, adhesive and antitoxic against escherichiosis C. agricultural animals", which is the neutralization of pathogenic action of Escherichia animals of different species (Malakhov Y. A., Tugarinov, O. A., Pies, M. K., Solodkov C. S., 1993, patent RU 2043772 C1), which is selected as a prototype.

However, the known biological products, including prototype, do not provide a therapeutic effect when mixed forms of infectious diarrhea of newborn calves (usually in 75-85% of cases are co-infected), because it does not have specific activity against Rota-, corona-, herpes - major pathogens E. the serum against Rota-, crown, herpes and exericises diarrhea of newborn calves, providing passive immunity in the shortest time possible and emergency treatment with advanced disease.

This goal is achieved hyperimmunization oxen-producers mixture of culture viral suspensions and inactivated antigens of E. coli containing somatic adhesive (K, A20) antigens in physiological solution, toxoids in the cultural medium (broth of Hottinger) in the following ratio of their components in two different immunogenic (vol.%):

1. Culture viral suspension for intravenous immunization:

Rotavirus cattle with title 107,0- 107,8TCD50/ml - 30 - 35

Coronavirus cattle with title 105,0- 105,8TCD50/ml - 30 - 35

Herpes virus of cattle with a titer of 107,6- 108,0TCD50/ml - 30 - 35

2. Exericise antigens for subcutaneous immunization:

Somatic and adhesive antigens C with a concentration of 10-15 billion, M. K. 1 cm3- 23 - 27

Somatic and adhesive antigens A20 with a concentration of 10-15 billion, M. K. 1 cm3- 23 - 27

The toxoid K + A20 E. coli - 45 - 52

Formalin - 0,4 - 0,5

Example 1. The method of manufacture of viral antigens for hyperimmunization oxen-producers is as follows.

Rotavirus bovine strain "W-1") propagated in three-liter roller bottles with raised single-layer transplantable culture of kidney cells of the embryo pig (line SPM) on the combined growth medium consisting of hydrolyzed milk albumin (GLA) - 45%, medium 199 - 45%, bovine serum at 10% and antibiotics. The culture is grown for 3-4 days at a seeding concentration of 100-120 thousand cells per 1 ml of medium. Before entering to culture the virus activates trypsin (0.6 ml of 0.25% trypsin in 100 ml of viral suspension for 30-35 minutes at 37-38oC) in a ratio of 1: 10 to 1:12 and add it in a supportive environment without savored stowey environment is drained, bring in bottles with culture maintenance medium in the amount of 350-370 ml and incubated at 37-38oC for 24-49 hours After a pronounced destruction of the monolayer cell culture titers of virus should be 107,0- 107,8TCD50/ml. For the liberation of virus culture three freeze at minus 18-20oC and later quickly thawed at 36-37oC. the Obtained suspension culture lighten by centrifugation for 40 minutes at 3000 rpm/min

Coronavirus bovine (strain CM-1) was propagated in human culture of kidney cells of the embryo cows (line MDVC) grown in three-liter roller bottles on a mixed medium consisting of medium 199 - 60%, CHAP 30% fetal bovine serum at 10%. The monolayer is formed on 3-4 days when seeding concentration 120-150 thousand cells per 1 ml of medium.

For the seed of coronavirus bovine growth environment is drained, make a support medium (medium 199 (50%) and CHAP - 50%) in the number of 350-370 ml, which previously contributed virus based 15-20 ml per 500 ml of medium, of 0.25% trypsin - 3 ml, 3% solution of glutamine 5 ml and antibiotics. Bottles incubated in roller installed at 37-38oC is: granulation of cytoplasm, the collapse of the isolated cells, the formation of simpleton with subsequent degeneration. Collecting the culture fluid is produced in a period of pronounced cytopathic effect. The titer of the virus should not be below 105,0- 105,8TCD50/ml.

The release of virus from cells is carried out by freezing and thawing, received the virus suspension clarify by centrifugation.

Herpesvirus bovine strain "TKA-VIEW-B2") propagated in human cell cultures of tracheal embryo cows (TR) grown in three-liter roller bottles on a combination srde consisting of medium 199 - 10%, CLAY - 40%, eagle medium MEM - 40% and bovine serum at 10%. The culture is grown for 3-4 days at a seeding concentration of 140-150 thousand cells per 1 ml of medium. Growth medium is drained, make a support medium (medium 199 - 20%, CHAP 40% and the Needle MEM - 40%) in the number of 350-370 ml, in which pre-make the virus at the rate of 10 ml per 500 ml of medium, 3% solution of glutamine 5 ml and antibiotics. Bottles incubated in roller installed at 37-38oC for 3-4 days.

The release of virus from the cells by freezing and thawing, the resulting suspension, containing not less than 30-35 mg/ml of a specific protein are pooled in equal proportions and used to hyperimmunization oxen-producers.

Example 2. The method of obtaining exericising antigens.

As production strains when receiving hyperimmune serum production use enterotoxigenic strains of Escherichia: "KV-1" - synthesizing adhesive antigen C; "PZ-3" - synthesizing adhesive A20 antigen that kill white mice weighing 14-16 g within two days after intraperitoneal infection at a dose of 0.5 cm3suspension of the daily culture containing 1 billion, M. K. 1 cm3for bacterial or optical standard turbidity.

Somatic adhesive antigens produced by seeding daily broth cultures of E. coli on MPA (synthesizing adhesive antigen A20) and the environment minka (synthesizing adhesive antigen C) and cultivation in an incubator at 37oC for 24 h Grown culture of Escherichia washed with sterile saline solution with a content of 0.4-0.5% formalin in a sterile flask with a concentration of 15 billion m K. in 1 ml and incubated in a thermostat at 37oC for 3 days.

To obtain toxoid enterotoxin C. Then to the culture of formalin is added to 0.4-0.5% and kept in a thermostat at 37oC 10-12 days. The resulting toxoid precipitated by 10% sterile solution of potassium alum at the rate of up to 1% on the entire amount. After settling toxoid within 2-3 days the supernatant is sucked off.

Then the resulting toxoid and somatic adhesive antigens are mixed in equal volume ratios and used to hyperimmunization animals.

Example 3. Hyperimmunization oxen-producers.

Ox, intended for hyperimmunization, quarantinious, subjected to investigation and appropriate treatment against infectious diseases according to the existing instructions on the procedure of preparation and sanitary treatment of animals used for production of biologics. For operation allow animals 2-5 years of age, weighing not less than 400 kg

For hyperimmunization use polietilene consisting of Rota-, corona-, herpes viruses and Escherichia coli containing adhesive antigens C and A20.

Hyperimmunization animals is carried out according to the scheme given in table 1. A mixture of antigens Rota-, corona-, herpes viruses administered intravenously four times in naroon injected a mixture of viral antigens in a tenfold lower dose. Esherihioznae antigen is injected subcutaneously in the neck region for the first time with incomplete adjuvant's adjuvant, in the future - without adjuvant. Test blood sample is carried out from the jugular vein into sterile test tubes on the 20th day after the last injection of antigens. The resulting serum from each producer using serological reactions is examined for the presence of antibodies. Producers in serum which antibody titers below in example 4, the injected antigen again in doses according to a recent introduction, and the blood sample is not produced.

Example 4. Specimen collection and handling blood.

Production krovavaya permitted in the presence of antibodies in the serum producers to ranavirus not below 1:3200 in IFA; coronavirus - not less than 1: 512 in rtga; herpesvirus - not less than 1:256 in PH; Escherichia - not less than 1:1600 in RA and subject to the temperature not exceeding 39,5oC, and after the preliminary exposure on the starvation diet for 12 h with unlimited watering.

The first krovavaya from producers by volume should not exceed 0.6 l of blood per 100 kg of animal body weight, followed by a 1.6 liter On day 20 after blood collection producers enter polianthes in doses according to a recent introduction. Annually delaye what they sell in the prescribed manner.

The ox-producers of blood taken from the jugular vein. To prevent blood from clotting used anticoagulant - 10% solution of citric acid sodium, prepared with a 5% solution of sodium chloride and sterilized by autoclaving.

In sterile bottles for blood collection pour a solution of citric acid sodium based 34 ml per 1 l of blood. The inner surface of the bottles to hydrate this solution, so that it had no traces of condensation. In the process of blood collection and after the solution of anticoagulant and blood mixed, shaking the bottle gentle circular movements.

For the separation of blood cells obtained tsitirovaniyu blood is subjected to separation (separator type AC-2ZH). The resulting plasma defibrinated to transfer liquid protein, fibrinogen, into an insoluble state - fibrin. Defibrinating blood plasma is produced in a sterile defibrilator with stirrer (reactor). For defibrinate in plasma add 30% solution of calcium chloride based 1.3 ml per 1 l of freshly prepared serum containing the enzyme thrombin, at the rate of 10 ml per 1 l the Process of defibrinate plasma usually lasts 25-30 minutes the resulting serum is 5-6 ml of a saturated solution of calcium chloride, the mixture was thoroughly shaken and leave to rest for 10-15 minutes the Transparency of the mixture indicates the completeness of the transition of fibrinogen to fibrin. In the received check serum calcium, the presence of which should not exceed 35 mg %. Next, the serum can a 5% solution of chemically pure phenol to a final concentration of 0.5% and with the aid of the vacuum pump is pumped into a sterile tank, where it stand for 2 months at 4 to 10oC. Upon expiration of sludge serum is subjected sequentially filtering and sterilization through asbestosrelated plate. After filtering the serum control on the activity, sterility and safety, as described in example 5. Proven serum Packed into vials closed with rubber stoppers, running-metal caps and etecetera.

Example 5. Control serum on appearance, sterility, safety and potency.

To determine the appearance, color, presence of impurities, mold, presbyacusis flakes, integrity capping all serum vials shaken, viewing in transmitted light and turn down the tubes.

The sterility of Siri 37-38oC. After 48 h of liquid media do subcultures on MPA, MPB, MPB under paraffin oil. The primary crops of the stand 10 and the secondary - 8 days. Growth on nutrient media should not be.

Harmlessness serum test 10 white mice in which the drug is administered subcutaneously at a dose of 0.5 cm3. The serum is considered harmless if all animals remain clinically healthy for 10 days.

The activity of serum tested for 40 white mice weighing 15-18 g, of which 20 animals injected subcutaneously with 0.5 cm3drug, and 20 mice serve as a control. After 24 h after injection of the serum of all animals infect intraperitoneally podarowano lethal dose of the cultures of the virus and Escherichia producing adhesive antigens A20 and C. The serum is considered active when the survival of at least 15 experimental and death 18-20 control mice within 2 days.

Evaluating the effectiveness of poly-specific hyperimmune serum is carried out in the acute experience in newborn calves.

Preventive properties of serum tested on 5 calves, divided into 2 groups. Animals of the experimental group (3 animals) with the preventive purpose immediately after birth is administered twice with an interval of 12 hours is ol.) at the same time and in the same doses feeding normal serum of cattle, seronegative against the causative agents of diarrhea. After 30-36 h after birth calves of both groups infect oral mixture cultural Rota-, corona-, herpes virus suspensions, and enteropathogenic strains of Escherichia (C and A20).

therapeutic properties of the serum study on 5 calves, also divided into 2 groups. To this end calves of both groups in the first 1.5-2 h after birth infect oral culture suspensions Rota-, corona-, herpes viruses and enteropathogenic strains of Escherichia (A20, C). With the appearance of the first clinical signs of diarrhea calves from the experimental group (3 animals) enter intravenous polyspecific serum in a dose of 2 cm31 kg of live weight. The calves of the control group (2 heads) when signs of illness injected normal serum of cattle in the same dose as polyspecific.

The results of tests of treatment-and-prophylactic properties of serum in the acute experience in newborn calves is presented in table 2.

Example 6. Production test pilot series poly-specific hyperimmune serum.

During 1994-1998 in the laboratory of epidemiology, unive made 9 batches of serum total had pronounced preventive properties. Indicators of the specific activity separate experimental series serum are presented in table 3.

Evaluation of preventive and curative efficacy of poly-specific hyperimmune serum was carried out in disadvantaged by Rota-, corona-, herpes and esherichiosis the diarrhea farms of the Republic of Tatarstan. Prophylactic serum is administered orally at a dose of 60-80 cm3on reception to the first portion of colostrum and re-introduction was carried out not later than 24-30 hours after the first in the same dose.

For therapeutic purposes serum was used intravenously in severe intoxication at a dose of 60-80 cm3at low - dose 40-60 cm3. If necessary, the serum was injected again after 24 hours subcutaneously at a dose of 50 cm3.

To improve therapeutic properties of serum drug is injected in a mixture with 40% glucose solution in equal volumes with the addition of 2-3 ml caffeine-sodium benzoate.

The results of the evaluation of therapeutic and prophylactic efficacy of serum are presented in tables 4 and 5, from which it follows that the proposed poly-specific hyperimmune serum has a strong preventive effect.

Poly-specific hyperimmune serum is designed for specific immunotherapy and passive prophylaxis of mixed forms of infectious diarrhea of newborn calves, due to Rota-, corona-, herpesviruses and enterotoxigenic strains of Escherichia producing factors of adhesion A20 and C.

The serum is made by hyperimmunization Polyethene clinically healthy oxen-producers, free from leukemia.

The serum is a clear, slightly opalescense liquid yellowish-reddish color. At the bottom of the bottles, especially during prolonged storage, falls minor protein precipitate, which when shaken can be easily broken in a uniform suspension.

The serum is suitable for use for 12 months from date of manufacture when kept in a dark, dry place at temperatures no higher than 8oC. serum Vials should be tightly closed with rubber corks and rolled metal caps. With shaking and turning the bottle serum should not leak through the tube. Before applying the serum vials you tatel the falling flakes, mold, in violation of the integrity of the bottle, no label, and if not the day of the opening of the vial serum to be wypracowania.

Poly-specific hyperimmune serum against Rota-, corona-, herpes viruses, and Escherichia coli (K and A20) of newborn calves is used for prophylactic and therapeutic purposes against mixed Rota-, corona-, herpes and exericises diarrhoea in households where these diseases are confirmed virological and bacteriological or serological studies.

Prophylactic serum administered orally at a dose of 60-80 ml on admission to first portions of colostrum (the first 1-1 .5 hours life of the calf) and re-introduction is carried out not later than 24-30 hours after the first in the same dose.

For therapeutic purposes serum used:

a) in case of severe intoxication intravenous dose of 60-80 ml in a mixture with 40% glucose solution in equal volumes with the addition of 2-3 ml caffeine-sodium benzoate and subcutaneously at a dose of 50 ml;

b) with weak toxicity - intravenous dose of 40-60 ml

Passive immunity in animals maintained for a period of 10-15 days.

For the period 1994-1998 made 750 liters of serum and the use of the good results (table 6).

Poly-specific hyperimmune serum against Rota-, corona-, herpes viruses, and E. coli (99, 20) for local protection and immunotherapy mixed forms of diarrhea of newborn calves, characterized in that it contains antibodies in the credits: rotavirus is not less than 1 : 3200 (ELISA), the coronavirus is not less than 1 : 512 (TPHA), herpesvirus - 1 : 256 (PH), Escherichia having adhesin To 99 and 20 is not less than 1 : 1600 (RA), to heat-stable enterotoxin of E. coli is not less than 1 : 2 (RDP), thermo-labile enterotoxin of E. coli is not less than 1 : 4 (RDP) obtained by hyperimmunization oxen-producers polyvalent viral antigen containing a mixture of culture viral suspensions rotavirus cattle with title 107,0- 107,8TCD50/ml, coronavirus cattle with title 105,0- 105,8TCD50/ml, herpesvirus cattle with title 107,6- 108TCD50/ml, intravenous and polyvalent antigen of Escherichia containing inactivated suspensions of E. coli cells with adesanmi To 99 and 20 with the concentration of each strain 10 - 15 billion cells in 1 ml of physiological solution, and toxoids in the environment of cultivation with a title in the RDP 1 : 4 - 1 : 8 subcutaneously with subsequent blood sampling, konstruirovanie

 

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