Method of producing vaccine for preventive treatment and curing of urinary duct infection

专利摘要:
This invention relates to the field of medical microbiology, in particular to the preparation of therapeutic vaccines. The essence of the method is that ten uropathogenic strains in all patients, "which include 6 strains of E. coli and 1 st strain K1. pneumoniae, P. morganis, P. mirobilis and S. faecalis, separately cultivated in vitro or on a dense nutrient medium, the resulting biomass inactivates various -. These methods (heat treatment, J-irradiation or chemical treatment). Then the treated biomass is mixed to a final concentration of 2-10 cells / ml. The mixture of bacteria is sorbed on aluminum phosphate at a concentration of -. traction last 1.5-10 mg / ml vaccine. To preserve the properties of the vaccine, thiomersal is added and, if necessary, lyophilized. 9 tab. WITH
公开号:SU1452462A3
申请号:SU853946994
申请日:1985-08-30
公开日:1989-01-15
发明作者:Стойкович Любинко；Павич Радмила；Спасоевич Вера
申请人:Золько Базель Аг (Фирма)；
IPC主号:

专利说明:

ate
tc
This invention relates to medicine microbiology, and specifically to methods for producing therapeutic vaccines.
Example. First, from patients: who suffered from infection of the intestinal tract, they take urine samples (medium jet urine) and immediately transfer to MacConkey agar. After sowing, the plates with agar are incubated for 16–18 h at 37 ° C, then the formed colonies are formed and identified by determining their biochemical and biological properties.
Identification of Streptococcus faecalis (enterococcus) using the G-framing method of the characteristic small COLONI 11 and the following tests:
catalase (in the presence of heated blood) + hemolysis- / b
growth at
growth at pH 9.6 + growth in 6.5% NaCl solution. -f
p (zT on 40% of bile +. definition of polysaccharide - antigen D, +
In tab. Table 1 lists the criteria used to identify Escherichia coli, Proteus and Klebsie la strains.
The colonies thus identified were left on agar plates for 24 hours at 37 ° C for further growth, then sodium chloride was suspended in physiological solution, tested for purity using the Gram stain method and frozen in a dry form.
The resulting individual strains of Escherichia coli are characterized by the traits given in table. 2
In tab. 3 shows the biochemical properties of Escherichia coli strains. . In tab. 4 shows the characteristics of the strains Proteus and Klebsiella.
The biochemical properties of the Proteus and Klebsiella strains are presented in
tab. five.
. In tab. 6 shows the characteristics of the strain Streptococcus
faecalis.
  -
The biochemical properties of the strain Streptoco.ccus faecalis are given in table. 7
- Q
five
0
0
-

The morphological properties of the isolated strains can be summarized as follows.
Escherichia coli: Gram-negative rolls, 1.1-1.5 2.0-6, OC (m (live form), motile due to flagella.
Proteus rairabilis and Proteus mor-ganii: Gram-negative rods, 0.4-0.60.1-3.0 without a shell, are mobile, with flagella (not all).
Klebsiella pneumoniae: Gram-negative, fixed sticks, 0.3-1.5-0.6-6.0 | UM.
Strept, ococcus faecalisi gram-negative spherical cocci, 0.5-1.0 HIM, immobile.
The strains of Escherichia coli are then examined for their serological properties, and for this purpose, first, a slide test is performed on the slide for multivalent OK-shorts A, B, C, D, E. The data are shown in Table. 8, These 10 strains were deposited in the Central Mold Culture Bureau (Nvänderland) under the names CBS 516.84 to CBS 525. transferred to the German Microorganism Collection (Germany) under the incoming numbers DSM 3229-DSM 3238.
To obtain the vaccine, the strains are separately cultured on solid or liquid nutrient st; Preferably, solid nutrition is used. nutrient agar, which has the following composition, g / l:
Mecna extract (Difco Beef Extract) 3 Bacto peptone 5 Sodium chloride 5 Bacto agar15 The medium is sterilized for 15 min at 121 C, it has a pH of about 7.2.
Roux balloons are used for industrial production, and Petri dishes are used in the laboratory for production. Inoculation is carried out with a seed, a few millimeters of which is evenly distributed over the entire surface. Roux balloons are closed with a paper stopper and the medium is stored in the warehouse with the inoculated surface down. Inoculated cultures are incubated for 5 h at 37 ° C.
The growth surface of the bacterial colony is consumed with the necessary amount (depending on the growth density of the culture in the vessel) of phosphate buffer solution — sodium chloride solution (PBS) with a slight rocking without disturbing the surface of the agar.
A smear is taken from each cylinder or from each Petri dish, stained using the Gram method and checked for purity. Cylinders or Petri dishes that will be contaminated will choose 2.5–10, a total of 1.5–10 microbes .-;
Proteus mirabilis 1 strain, 7.5-10
microbes; Proteus morganii. I strain
7.510
moniae
Stregtococcus faecali.s 1 strain.
microbes; Klebsiella pneu-1 strain, 310 microbes;
ten
5-10 microbes. Together - 2-10 microbes / ml.
Since an aluminum phosphate gel is added, the concentration should accordingly be higher. An apuminium phosphate gel was prepared as follows.
854 g of potassium aluminum sulphate
they eat Suspensions, which originate from 15 x 12 N, 0 are dissolved in 6 liters of water and filtot from one strain or from collection, are mixed using a sterile nylon sieve.
Inactivation, as well as the cultivation itself, is carried out separately for each strain. It can be carried out by heating at a temperature of about 55-60 ° C for approximately I h, by treatment with a solution
ru. Then, 685 g of tri-sodium phosphate 12 in 6 liters of water are dissolved. The aluminum solution is kept at 37 C. Both solutions are simultaneously poured into 21 liters of water. The precipitate is centrifuged, re-suspended in 13 liters of water, and the suspension is centrifuged again.
Next, the precipitate is re-suspended. - JCg-1 "" V "-. J.X i rnj V-.J IJ JSG1.CI
formaldehyde or radiation by irradiation, 25 rut, brought to a total volume of 8.1
Received YIPMYAG G KT PPO TTtlucrtrtfriggtlt-tchotmr "t
The resulting biomass is combined, inactivated in a water bath at 6 ° C for 1 hour, and after thermal inactivation phenol is added (maximum concentration 0.35%).
A sample of the suspension is taken for sterility testing and for identity testing and the concentrated reserve amount is stored in a refrigerator.
If the sterility tests after 3 days did not show any contamination, the preparation process is carried on. The sterility test is monitored for 14 days and if the sterility test shows the growth of any organisms, this collection is eliminated.
The contents of the collections (inactivated suspensions that originate from the same base) are centrifuged at 3000 rpm for 1 hour in a cooled centrifuge (Sorval 4 CR, centrifugal rotor 2000), the supernatant is removed, and the sediment of bacteria is suspended in sodium chloride solution which contains 0.01% thiomersal. The suspension is stored at 4 ° (+2 s).
 Concentrated suspensions of 10 strains of E. coli, Proteus mirabilis, Proteus morganis, Klebsiella pneumoniae. Streptococcus faecalis is mixed in such a way that E. coli contains 6 strains, each 30 ml.
liters, set using 5 n. NaOH pH 6.0 and held in an autoclave for 1 h at 121 C. This amount is sufficient.
35
40
45
50
to get 66 l of vaccine with 3 mg A1P04 / ML or 0.66 mg A1 / ML.
The adsorbed vaccine, after checking the pH, which should be between 6.2 and 7.0, is poured into sterile pyrogen-free ampoules with a capacity of 1 ml in an amount of 0.5 ml per dose. The vaccine is stirred during spilling.
The total number of inactivated microorganisms in one dose, i.e. 0.5 ml is about 1-10.
Finally, the vaccine is tested:
on sterility according to the European Pharmacopoeia;
toxicity as prescribed by the World Health Organization (weight gain in mice);
for abnormal toxicity according to the European Pharmacopoeia.
The vaccine can be obtained in lyophilized form.
Concentrated inactivated. the suspension obtained in the same manner as described above is diluted so that it contains about I lO inactivated bacteria of the indicated composition in 0.5 ml. For dilution, a 1% humanalbumin solution is used.
52462
about 2.5-10, only 1.5-10 microbes .-;
Proteus mirabilis 1 strain, 7.5-10
microbes; Proteus morganii. I strain
7.510
moniae
Stregtococcus faecali.s 1 strain.
microbes; Klebsiella pneu-1 strain, 310 microbes;
ten
5-10 microbes. Together - 2-10 microbes / ml.
Since an aluminum phosphate gel is added, the concentration should accordingly be higher. An apuminium phosphate gel was prepared as follows.
854 g of potassium aluminum sulphate
15 x 12 N, 0 is dissolved in 6 liters of water and filth 12 N, 0 is dissolved in 6 liters of water and filtered. Then, 685 g of tri-sodium phosphate 12 in 6 liters of water are dissolved. The aluminum solution is kept at 37 ° C. Both solutions are simultaneously poured into 21 liters of water. The precipitate is centrifuged, re-suspended in 13 liters of water, and the suspension is centrifuged again.
Next, the sediment re-suspendig-1 "" V "-. J.X i rnj V-.J IJ JSG1.CI
ruted, adjusted to a total volume of 8.1
ggtlt-tchotmr "t
0
liters, set using 5 n. NaOH pH 6.0 and held in an autoclave for 1 h at 121 C. This amount is sufficient.
five
0
five
0
to get 66 l of vaccine with 3 mg A1P04 / ML or 0.66 mg A1 / ML.
The adsorbed vaccine, after checking the pH, which should be between 6.2 and 7.0, is poured into sterile pyrogen-free ampoules with a capacity of 1 ml in an amount of 0.5 ml per dose. The vaccine is stirred during spilling.
The total number of inactivated microorganisms in one dose, i.e. 0.5 ml is about 1-10.
Finally, the vaccine is tested:
on sterility according to the European Pharmacopoeia;
toxicity as prescribed by the World Health Organization (weight gain in mice);
for abnormal toxicity according to the European Pharmacopoeia.
The vaccine can be obtained in lyophilized form.
Concentrated inactivated. the suspension obtained in the same manner as described above is diluted so that it contains about I lO inactivated bacteria of the indicated composition in 0.5 ml. For dilution, a 1% humanalbumin solution is used.
or plasma substitute with 0.01% thiomer-sal in 0.85 n. NaCl solution.
2 ml vials are filled under sterile conditions with 0.5 ml of the described diluted suspension, frozen at about -45 ° C, then dried under vacuum in a lyophilization apparatus. Temperature
Bacterial strains are suspended from 9 ml of nutrient medium and culture is incubated at 37 ° C for 24 hours. The second auxiliary culture is used to prepare antigens. 600 ml of the nutrient medium are inoculated using a seed culture (each strain separately). Culture
Drying should not exceed + 3b. The whole 10-incubate jipH З7 s for 36 hours. The process of lyophilization continues. Formalin is added for up to 24 hours. After lyophilization, the vials are closed with rubber stoppers in a nitrogen atmosphere and an aluminum cap 15
kami.
For the administration of the alumina ... lyphosphate, which is simultaneously used as a re-dissolving solvent, an aqueous aluminum phosphate gel with an AlPG concentration of 2 mg / ml is used before administration. The aluminum phosphate gel, before being poured into ampoules, is diluted with a solution of sodium chloride to such an extent (about 12 times) so that the final concentration is 2 mg / ml.
The amount dispensed in 1 ml ampoules is 0.5 ml.
To test a vaccine for storage stability, its ability to form antibodies is determined twice.
at MOSH1I.
Immunization of mice.
Six groups of 10 mice each (male, NMRl strain, weight 16-20 g) were immunized with intraperitoneal administration of the vaccine. Two doses (0.5 ml of vaccine) are injected at intervals of two weeks. Only an aluminum phosphate gel (0.5 ml) is injected into 20 mice from the same growth and with the same weight, which serve as a control group. Two weeks after the second injection. They take sterile blood and group them together. After coagulation, a short cut is obtained from each pool by centrifugation and stored with deep freezing at -22 ° C until serological testing.
Preparation of antigens (agglutinogens).
Nine homologous bacteria that are contained in a vaccine are used to produce antigens; The strain EC 654 cannot be agglutinated (R-form) and cannot be used as agglutinogen. Lyophilized cultures
final concentration of 0.1%. The cultures are incubated at 37 ° C for 7 days. Each culture is then tested for the absence of live bacteria and for sterility. The inactivated bacterial suspension is centrifuged in a cooling centrifuge for 1 hour at 3000 rpm. Sediment re
20 is suspended in a phosphate buffer solution — a sodium chloride solution (pH 7.2) —to achieve a concentration of about 20-25 bacteria / ml. For agglutination test
25, about 2-10 bacteria / ml are used as agglutinogen.
Experience on agglutination.
Mouse sera at 1: 2 stages of dilution were diluted with phosphate buffer solution — a physiological solution of sodium chloride with a pH of 7.2. After 1 hour at 37 ° C and the remaining 24 hours at 4 ° C, the reaction readings are recorded. The maximum dilution is taken as the titer of the corresponding serum, at which it was still possible to establish the visible agglutination of bacteria.
For agglutinin titers with a short current, the geometric mean values given in Table 2 were found. 9.
From these results, it follows that the vaccine, when stored at 4 ° C, retains its full efficacy for at least two years.
Vaccine indications are especially cystitis, prostatitis, cystopielitis and pyelonephritis. .
5Q Patients who do not have an acute febrile condition (contraindicated) receive only 3 intramuscular injections of 0.5 ml of vaccine at intervals of 1 to 2 months.
gg If there are strong reactions to the vaccine, treatment should be discontinued.
A year later, revaccination should be performed at the same dose.
Bacterial strains are suspended from 9 ml of nutrient medium and culture is incubated at 37 ° C for 24 hours. The second auxiliary culture is used to prepare antigens. 600 ml of the nutrient medium are inoculated using a seed culture (each strain separately). Culture
incubated with jipH 377 for 36 hours. After that, formalin is added to
- incubate jipH 3 7 sec for 36 h. After that, formalin is added until
final concentration of 0.1%. Cultures are incubated at 37 ° C for 7 days. Each culture is then tested for the absence of live bacteria and for sterility. The inactivated bacterial suspension is centrifuged in a cooling centrifuge for 1 hour at 3000 rpm. Sediment re
suspended in a phosphate buffer solution — a solution of sodium chloride (pH 7.2) —to achieve a concentration of about 20 to 10 bacteria / ml. For agglutination test
about 2-10 bacteria / ml are used as agglutinogen.
Experiment on agglutination .:
Mouse sera at 1: 2 dilution stages were diluted with phosphate buffered saline, physiological saline with pH 7.2. After 1 hour at 37 ° C and the remaining 24 hours at 4 ° C, the reaction readings are recorded. As the titer of the corresponding serum take the maximum dilution, at which it was still possible to establish the visible agglutination of bacteria.
For agglutinin titers, smaller ones were found, the geometric mean values found in Table 2 were found. 9.
From these results, it follows that the vaccine, when stored at 4 ° C, retains its full effectiveness for at least two years.
Vaccine indications are especially cystitis, prostatitis, cystopielitis and pyelonephritis. .
Patients who do not have an acute and ominous condition (contraindication) receive only 3 intramuscular injections of 0.5 ml of vaccine at intervals of 1 to 2 months.
If there are strong reactions to the vaccine, treatment should be discontinued.
A year later, revaccination should be performed in the same dose.

权利要求:
Claims (1)
[1]
Invention Formula
A method for producing a vaccine for the prevention and treatment of urinary tract infection, which consists in using ten uropathogenic bacteria strains, of which six are Escherichia coli strains Her 455 UB, Her 525 UB, EU 560 Yves, EU 616 Yves, EU 654 UB and EU 719 willows and one strain of Klebsiallala pneumoniae 16B, Proteus mirabilis 63B, Proteus morganis 58B and
Streptococcus faecalis 676, in this case all strains are grown separately, they are activated by heat treatment at 55-60 ° C, or formaldegnd, or gamma-irradiation, then the cultures are mixed, and the final concentration of all bacteria in the vaccine is 2-10 cells / ml the resulting mixture of bacteria is sorbed on aluminum phosphate at a concentration of 1.5-10 mg / ml of vaccine, and then thiomersal is added to the target product.
Table 1
Mobility Growth in KCN-environment Citrate as a C-source
Glucose carbohydrate gas
Acid lactose sucrose maltose mannitol trealose xylose
Gelatin Hydrolysis Indole Urease
Hj S TS1
(triple sugar-iron agar)
Lizindegidrokarboks Shaza
+
- (d)
+ (d)
+ +
 (d)
+ +
1452462
Carbohydrate fermentation
10 Table 2
Strain Escherichia coli
Experience
455 willows 525 UB 560 UB 616 UB j 654 UB I 719 UB
po

echai
ABOUT
Oh oh
ABOUT
Oh oh
I- + O O + +
oh oh
+
about
+
oh oh
about
about
about
and e: + - positive for 24 hours;
O - negative after 72 hours
Table 4 Fermentation of carbohydrates
ABOUT
oh oh
about
about
about
oh oh
+
about
+
Galactose
Sorbitol
Arabinose
Glucose
Mannose
Fructose
Adonite (ribit)
note: + - acid.
Table 5
Urea
Hemolysis on blood plates with agar
Gelatin Hzrolysis
Indole citrate
H, S
oh oh
O O + O
oh oh
+ About About
ABOUT
about
15
Mobility
about
Treatment: + - positive for 24 hours; About -negative after 72 hours
Carbohydrate fermentation table
Lactose
Sucrose
Mannitol maltose
Melibioz for
Raffinosa
Rash
Trealose
Salicin
Ribose
Amygdain
Galactose
Sorbitol
Arabinosis
Glucose Mancose
Fructose
Adonite (ribit)
Inositol Dulcite
1452462
Continuation of table.5
sixteen
+ +
Oh oh
+ + + +
+ +
about
+ +
about
oh oh
17
Cellobi-za
Xylose
Note: + - acid „
Table 7
Experience
Urea Type of hemolysis
Gelatin Hydrolysis
Litmus milk recovery
Indole
Esculin
Growth on nutritional
40% bile
6.5% chloride
sodium pH 9.6 Heat resistance
60 C for
30 min
Note: + About
I
1452462 18
Continued tab.
+ About
Streptococcus faeca-lis 676
About non-hemolytic
ABOUT
positive;
negative.
not determined
nineteen
145246220
Table 9

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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CH4181/84A|CH664497A5|1984-08-31|1984-08-31|VACCINE FOR TREATING UTILITY INFECTION.|

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