UA126438C2 - Polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of the nasopharynx, mouth and eyes, a method of its manufacture and a method of treatment and prevention thereof - Google Patents

Abstract

The invention relates to a polyvalent combined inactivated liquid vaccine against bacterial and fungal agents of diseases of the nasopharynx, mouth, and eyes. It contains strains isolated from various acute and chronic inflammatory diseases of bacterial and fungal etiology, including strains deposited in the Depository of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine, namely Staphylococcus aureus deposited under registration number B-7684; Staphylococcus aureus, deposited under registration number B-7756; Staphylococcus aureus, deposited under registration number B-7665; Staphylococcus aureus, deposited under registration number B-7666; Staphylococcus haemolyticus, deposited under registration number B-7712; Staphylococcus haemolyticus, deposited under registration number B-7731; Staphylococcus haemolyticus, deposited under registration number B-7766; Streptococcus pyogenes, deposited under registration number B-7683; Streptococcus pyogenes, deposited under registration number B-7757; Streptococcus pneumoniae, deposited under registration number B-7716; Streptococcus pneumoniae, deposited under registration number B-7770; Streptococcus viridans, deposited under registration number B-7714; Enterococcus faecium, deposited under registration number B-7729; Enterococcus durans, deposited under registration number B-7769: Escherichia coli, deposited under registration number B-7748; Escherichia coli, deposited under registration number B-7628; Klebsiella pneumonia, deposited under registration number B-7686; Klebsiella oxytoca, deposited under registration number B-7630; Enterobacter aerogenes, deposited under registration number B-7734; Enterobacter aerogenes, deposited under registration number (B-7760); Enterobacter cloacae, deposited under registration number B-7657; Proteus vulgaris, deposited under registration number B-7762; Citrobacter freundii, deposited under registration number 7761; Alcaligenes faecalis, deposited under registration number 7767; Morganella morganii, deposited under registration number B-7709; Pseudomonas aeruginosa, deposited under registration number B-7710; Pseudomonas aeruginosa, deposited under registration number B-7758; Pseudomonas alcaligenes, deposited under registration number B-7663; Candida albicans, deposited under registration number Y-5087; Candida krusei, deposited under registration number Y-5091; Candida krusei, deposited under registration number Y-5097; Candida glabrata, deposited under registration number Y-5088. The invention also relates to a method for producing such a polyvalent combined inactivated liquid vaccine and a method for the treatment and prevention of diseases of the nasopharynx, mouth, and eyes using the aforementioned polyvalent combined inactivated liquid vaccine against bacterial and fungal agents.

Description

which were isolated in various acute and chronic inflammatory diseases of bacterial and fungal etiology, including strains deposited in the Depository of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine, namely biarpuyusossiv ageiv deposited under registration number B-7684; Yeyarnu!osossikh asheiv, deposited under the registration number B-7756; eYiarpusossivh asheiv, deposited under the registration number B-7665; eYegarnu!osossivykh aygeiz, deposited under registration number B-7666; оиарнуюсоссивз Naeto/uisiv, deposited under the registration number B-7712; iyarnuyuosssiv

Raeto!uisikh, deposited under registration number B-7731; YegarnuIosossiv Naetouisiv, deposited under registration number B-7766; Yegeriosossivkh ruodepez, deposited under registration number B-7683; Etmeriosossivkh ruodepez, deposited under registration number B-7757; 5geriosossi5 rpeitopiae, deposited under registration number B-7716; otgeriosossiz rpeshtopiaye, deposited under registration number B-7770; Egeriosossiv uipdape, deposited under the registration number B-7714; Eliegosossiv Iaesiit, deposited under registration number B-7729); Epiegosossibe aigap5, deposited under registration number B-7769: EzsPegisnia soii, deposited under registration number B-7748; E5spPegisnia soii, deposited under registration number B-7628; Yuebzie/la rpeitopia, filed under registration number B-7686; Yuebzie Ohuiosa, deposited under the registration number B-7630; Epiegobasiei aegodepe5, deposited under registration number B-7734; Epiegobasieg aegodepezh, deposited under the registration number (B-7760); Epiegobasiei sioasavie, deposited under registration number B-7657; Рииоиейе миийидаг5, deposited under the registration number В-7762; Spygobasieg iTeiypoiiii, deposited under registration number 7761; A/sa/depez of Iaes/them, deposited under registration number 7767; Mogdape/la then, deposited under registration number B-7709; Rzeiyotopav aegidipoz, deposited under the registration number B-7710; Rzkheidotopa5 aegidipoza, deposited under the registration number B-7758; Rzheidotopakh aisaidepe5, deposited under registration number B-7663;

Sapaiaa a!risapv, deposited under the registration number U-5087; Sapaida Kgizei, deposited under registration number U-5091; Sapadida Kgizeii, deposited under the registration number U-5097; Sapaida Diabgaz, deposited under the registration number U-5088. The invention also relates to the method of manufacturing such a polyvalent combined inactivated liquid vaccine and the method of treatment and prevention with the specified polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes.

The group of inventions belongs to medical microbiology, the pharmaceutical industry, in particular to vaccines, namely, to vaccines against bacterial and fungal pathogens, methods of their production and methods of treatment and prevention, and can be used for the treatment and prevention of local and systemic, acute and chronic diseases of bacterial and fungal etiology in children and adults: nose, additional sinuses, pharynx, tonsils, ears, eyes, oral cavity, tongue, gums, teeth as an alternative to antibiotics or as a method of additional treatment compatible with antibiotics in septic conditions that pose a threat for life.

Polyvalent vaccine (roiumaiepi massipe) Games. roiu - many and maIepii5 - strong - a vaccine made on the basis of several serological variants of the causative agent of one infectious disease and causes an immune response to several infectious agents or different epitopes (epitope - a part of a macromolecule recognized by the immune system, in particular antibodies, B cells or T cells) of one molecule.

An associated vaccine is known, containing strains of EzspPegisnia soi, Zaitopeiiia and Urpitipitis, Zigeriosossis5 rpeshtopiae and Zigeriosossis5 Taesaiiii5 | KO Mo 2 316 345 C1, AbIK 39/116, 20081.

This vaccine is intended for the treatment of colibacteriosis, salmonellosis, streptococcus and enterococcal infection of nutria.

An associated vaccine is known, containing the causative agents of escherichia (Exsp.

AbIK 39/116, 2015).

The indicated vaccine was developed against escherichia, streptococcus | bovine staphylococcus.

An associated vaccine is known, containing EzsPegispia soii, Zigeriosossi5 Roma and Epiegosossiv5

Ttayesaiiv (Ko Mo 2 429 012 C1, AbIK 39/116, 20111.

The well-known vaccine was developed against colibacteriosis, streptococcus and enterococcal infection of calves and piglets.

An associated vaccine is known, which contains strains of E5spPegispia soya that produce exotoxins, hemolytic strains of 5bigeriosossi5 romib5 and Epiegosossi5 Taesai5 (KO Mo VO 2650 628 C1, AbIK 39/116, 20181.

Zo This vaccine, like the previous analogue, was developed against colibacteriosis, streptococcus and enterococcal infection of calves and piglets.

All these vaccines are intended for immunization of animals, they cannot be used for humans.

The closest to the claimed invention is a multicomponent vaccine (VP-4) for the immunotherapy of diseases, which includes the following strains: KierziePa rpeshtopiae, Rgoiei5 mycYidagiv, EvsPegispia soii, etarpuiosossi5 atsygei5. The vaccine can be administered subcutaneously, as well as by combined intranasal-subcutaneous and intranasal-oral methods

IKO Mo 94 019 810 JSC, AbIK 39/116, 19961.

This vaccine is intended for the treatment and prevention of chronic diseases caused by opportunistic microorganisms in humans. In this vaccine, an insufficient number of strains against Klebsiella, staphylococcus, and Escherichia coli were used, as a result of which the vaccine is insufficiently effective. The specified vaccine has insufficiently broad functional capabilities, because it is used only in the treatment of inflammatory obstructive diseases of the respiratory organs - chronic bronchitis, an infection-dependent form of bronchial asthma.

A method of manufacturing a multicomponent vaccine (VP-4) for immunotherapy of diseases is known

IKO Mo 94 019 810 JSC, AbIK 39/116, 19961.

For preparation, 4 strains are selected: Kierzieia rpeshtopia, Rgoivy5 mcidagiv, Evsnegisnia soiy, Harpuiosossiv aiygeiv.

Preliminarily, protein-lipopolysaccharide complexes are obtained from the first 3 types of microorganisms. To do this, Klebsiella is sown in mattresses with Warfel's medium

Ferguson After 18-24 hours, the grown culture is washed off, standardized and hydrochloric acid hydroxylamine is added. Incubate for 48 hours at 37 "C. Centrifuge for 2 days against tap water and then dry in vials. The same is done with strains of Proteus and Escherichia coli, but they are grown in mattresses on a medium of acid hydrolyzate of casein.

The staphylococcal component of the vaccine is prepared immediately before its composition and drying. Egarnuiosossis aigei5 strains grow in mattresses on a casein hydrolyzate medium, incubated for 16-24 hours at 37 "C. The culture is washed with distilled water. The thick microbial suspension is standardized and mixed in equal amounts from all 4 strains of bacteria.

The resulting microbial mass is treated three times with acetone. The dry microbial mass inactivated by acetone is subjected to three times aqueous extraction, centrifuged. Dry antigenic complexes of Klebsiella pneumoniae, Proteus, Escherichia coli are mixed with aqueous extract of staphylococcus. To prepare 100.0 ml of vaccine, 60.0 mg of dry antigens should be taken. After that, sterilizing filtration is carried out, 4 ml is poured into ampoules, lyophilized and the ampoules are sealed under vacuum.

In this method of making the vaccine, an insufficient number of strains against Klebsiella, staphylococcus, and Escherichia coli are used, as a result of which the resulting vaccine is insufficiently effective. The manufacturing method is quite complicated and time-consuming.

There is a known method of treatment with a multicomponent vaccine containing antigens of Klebsiella pneumoniae, Proteus, staphylococcus, and Escherichia coli. Vaccination can be carried out by the subcutaneous method, as well as by combined intranasal-subcutaneous and intranasal-oral methods

IKO Me 94019 810 JSC, AbIK 39/116, 19961.

In this method of treatment with a multicomponent vaccine, an insufficient number of strains is used, as a result of which the resulting vaccine is insufficiently effective. The vaccine does not have sufficiently broad functional capabilities, because it is used only in the treatment of inflammatory obstructive diseases of the respiratory organs - chronic bronchitis, an infection-dependent form of bronchial asthma.

The closest to the claimed method of treatment is the method of treatment with an immunostimulating drug IRS-19, which includes the strains of bigeriosossiv rpeshytopiaye, 5igeriosossiv5 rusdepez, Zigeriosossiv auzdaiasiiaye, etarpuiosossiy5 ashteiv, Naetornishv ipPshepgaye, KiebzieYa rpeshtopiaye, Asipeiyyubasivg sai repIsoaseizyiiyyy, , Epiegosossiv5

Taesisht The drug is used intranasally by aerosol administration of 1 dose (1 dose - 1 short push of the nebulizer).

For the purpose of prevention, adults and children from 3 months old are injected with 1 dose of the drug in each nostril 2 times a day for 2 weeks (it is recommended to start the course of treatment 2-3 weeks before the expected rise in morbidity).

For the treatment of acute and chronic diseases of the upper respiratory tract and bronchi, children aged from 3 months to 3 years are prescribed 1 dose of the drug in each nostril 2 times a day after preliminary release of mucus until the symptoms of infection disappear; children older than 3 years and adults - 1 dose of the drug in each nostril from 2 to 5 times a day until the symptoms disappear

From an infection.

To restore local immunity after the flu and other respiratory viral infections, children and adults are prescribed 1 dose of the drug in each nostril 2 times a day for 2 weeks.

In preparation for planned surgical intervention and in the postoperative period, adults and children are prescribed 1 dose of the drug in each nostril 2 times a day for 2 weeks (it is recommended to start the course of treatment 1 week before the planned surgical intervention) (perz://poyPyK.pentu. sopt/Liki2/10211.

This vaccine treats only diseases of the upper respiratory tract and bronchi, which narrows its functional capabilities.

The drug IRS-19 is administered by an aerosol method, as a result of which the effect of the drug is insufficiently effective.

The drug IRS-19 has a local effect due to aerosol spraying on the mucous membrane of the nasopharynx, stimulating only local immunity.

The prototype cannot be used in autoimmune diseases.

The invention is based on the task of creating a polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which would be more effective and have wider functional capabilities.

The second task, set as the basis of the invention, is the creation of a method of manufacturing a polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which would be less complicated and time-consuming and would allow obtaining a more effective vaccine with wider functional capabilities.

The third task, which is the basis of the invention, is the creation of a method of treatment and prevention with a polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which would allow achieving a stable positive clinical effect and a more prolonged general and local immunostimulating effect and had would have wide functionality.

The task is solved by the fact that the polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which includes strains of Kierzieya rpeshiptopiae, Euspegispia soii, eiarpuiosossyv ashtsygeiv5, according to the 60 invention, additionally contains strains of 5iarpuiosossiv Naetoiiuisiv, Zigeriosossiv ruodepev,

zigeriosossiv rpeshtopia, bBigeriossiossiv5 migpdiape, Epiegosossi5 Taesaiii5, Epivgosossi5 Taesiit,

Epiegosossiv digapz5, Kierzieia ohuisa, Epiegorasiei aegodepev5, Epiegobasieg sioasaye, Rgoiviv5 miidagiv, Rgoivy5 tigaryiv, Sypobrasiyei peshypai, AiIsaidepe5 Taesaiyi5, MogdapeMa togodapii,

Rzendotopavh ayegidiposa, Rzeidotopah aisaiiidepe5, Sapaida aiBisap5, Sapaida Kyizei, Sapaida diangaga, a total of no less than 20 species of bacteria and Z species of Sapaida fungi, including no less than 38 strains of bacteria and 5 strains of fungi of the Sapaida genus, namely: Ziarpuiosossi5 atsgei5 - 5 . .

Rzeeidotopaz aisaiidepev - 1, Sapaida aiIrisap5 - 2, Sapaida Kpyzei - 2, Sapaida diabgaia - 1, isolated in various acute and chronic inflammatory diseases of bacterial and fungal etiology, including strains deposited deposited in the Depository of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine: Earnuiosossiv5 aigei5 deposited under the registration number B-7684; ziarpuiosossiv5 aigei5, deposited under registration number B-7756; ziarpuiosossiv5 aigei5, deposited under registration number B-7665; ziarpuiosossiv5 aigei5, deposited under registration number B-7666; ziarpuiosossi5 paetoiuisi5, deposited under registration number B-7712; ziarpuiosossi5 paetoiuisi5, deposited under registration number B-7731; ziarpuiosossi5 paetoiuisi5, deposited under registration number B-7766; zigeriosossiv ruodepe5, deposited under registration number B-7683; zigeriosossi5 ruodepez, deposited under registration number B-7757; zigeriosossi5 rpeshtopiaye, deposited under registration number B-7716; zigeriosossi5 rpeshtopiaye, deposited under registration number B-7770; zigeriosossiz migidap5, deposited under the registration number B-7714;

Epiegosossiz Taesiit, deposited under registration number B-7729;

Epiegososis digap5, deposited under registration number B-7769;

EzspPegispia soybean, deposited under registration number B-7748;

EU Petition filed under registration number B-7628;

KierbzienPa rpeshtopia, deposited under the registration number B-7686;

KiebziePa ohuiosa, deposited under the registration number B-7630;

Epiegobasieg aegodepe5, deposited under registration number B-7 734;

Epiegobasieg aegodepe5, deposited under registration number B-7 760;

Epiegobasieg sioasaye, deposited under the registration number B-7657;

Rgoieiz miiYidagi5, deposited under registration number B-7762;

Sitobasieg Itetsypaiyi, deposited under registration number 7761;

AiIsaiiidepez Gaesaiiii5, deposited under registration number 7767;

Mogdapeya Togodapiya, deposited under registration number B-7709;

Rzeidotopazh aegidipoz, deposited under the registration number B-7710;

Rzepdotopaz aegidipoz, deposited under the registration number B-7758;

Rzeidotopaz aiIsaiidepev5, deposited under the registration number B-7663;

Sapayida airisap5, deposited under the registration number U-5087;

Sapayida Kgizei, deposited under the registration number U-5091;

Sapayida Kgizeyi, deposited under the registration number U-5097;

Sapadida diabgaga, deposited under the registration number U-5088.

Compared to the prototype, the proposed RinodentaPrimavak vaccine has wider functional capabilities due to its use for the treatment and prevention of local and systemic, acute and chronic diseases of bacterial and fungal etiology in children and adults: nose, additional sinuses, pharynx, tonsils, ears, oral cavities, tongue, gums, teeth, conjunctiva and eyes, while the prototype is used only in the treatment of inflammatory obstructive diseases of the respiratory organs - chronic bronchitis, an infection-dependent form of bronchial asthma.

At least 20 types of bacteria and 3 types of fungi were used in the RhinodentaPrimavak vaccine

Sapaida, including at least 38 original strains of bacteria and 5 strains of fungi of the genus

Sapaiyda, while 3 strains were used in the prototype, so RinodentaPrimavak has greater effectiveness.

The second task is solved by the fact that in the method of manufacturing a polyvalent 60 combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which includes the cultivation of strains of Kierziwiia rpeshtopiae, Ezspegispia soii, eiarpuiosossyv acygeci5, inactivation of strains, mixing, according to the invention, additionally, the strains 5yarpuiosossi5 paeptoiuis5, zigeriosossi5 ruodepev, zigeriosossiv rpeshtopia, bBigeriosossiv migpdiape, Epiegosossi5 Taesaiii5, Epivgosossi5 Taesiit,

Epiegosossiv digapz5, Kierzieia ohuiosa, Epiegorasiei ayeegodepev5, Epiegorasieg sioasaye, Rgoiei5 miidagiv, Rgoivy5 tigariiv, Sypobrasiei peshypai, AiIsaidepe5 Taesaii5, MogdapeMa togodapii,

Rzenidotopavh ayegidiposa, Rzeidotopah aisaiidepe5, Sapaida aiIrisap5, Sapaida Kgizvi, Sapaida diangaga, a total of no less than 20 species of bacteria and Z species of Sapaida fungi, including no less than 38 strains of bacteria and 5 strains of fungi of the genus Sapaida, namely: Ziarpuiosossi5 atsgei5 - 5 . .

Rzeeidotopaz aisaiidepev - 1, Sapaida aiIrisap5 - 2, Sapaida Kpyzei - 2, Sapaida diabgaia - 1, isolated in various acute and chronic inflammatory diseases of bacterial etiology, including strains deposited in the National Depository of Microorganism Strains

of Ukraine, with varying degrees of antibiotic resistance and resistance to antifungal drugs, the agar culture of bacteria or fungi is washed off the surface of the solid nutrient medium with pyrogenic distilled water and placed in sterile containers, and to eliminate impurities in the nutrient medium, bacterial strains are washed with distilled water by centrifugation at 1500-3000 rpm /min. for 10-15 minutes, pouring out the supernatant liquid, the obtained biomass sediment of the culture of the bacteriological strain, grown individually, is suspended in pyrogenic distilled water for injections and standardized, and the strains of microorganisms are taken in equal quantities, the standardized suspension of strains is inactivated in an autoclave at a temperature of 115- 125 "C and a pressure of 1 atm. for 15-40 minutes, in a container with inactivated bacteria and fungi, equal amounts of a preparation of embryonic origin, or a physiological solution, or water for injections are added, and a suspension of microbial cells is obtained, to control the sterility of the samples vaccines are sown on nutrient broth, sown

They are incubated in a thermostat at a temperature of 35-40 "С for 24-48 hours, and if there is no growth, a preservative is added and the vaccine is poured into sterile ampoules.

The method uses a 24-hour agar culture.

Erbisol or inflamafertin are used as a drug of embryonic origin.

Bacterial strains are washed with distilled water by centrifugation three times.

The precipitate is standardized according to the Farland MAC standard (MeE) with an optical density of 1.0, which corresponds to 3 billion (3.0 x 109) microbial cells in 1 ml of the finished vaccine.

In the method, a suspension of microbial cells of 1.5 billion (1.5 x 109) in 1 ml of the finished vaccine is obtained.

The vaccine is poured into ampoules of 1 ml.

Poured and sealed ampoules are checked for tightness, labeled and packed in 10 ampoules for vaccination, leaving 2 ampoules of each series for control.

The claimed production method allows to obtain the RinodentaPrimavak vaccine with wider functionality compared to the prototype, with a high general and local immunogenic effect and positive clinical responses after vaccination. The method is simpler and less time-consuming compared to the prototype.

The third problem is solved by the fact that in the method of treatment and prevention with a polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which includes the administration of the vaccine in appropriate increasing doses, according to the invention, the course of vaccination consists of 10-12 injections, which are performed every other day, while on the first day in a dose of 0.1 ml intradermally into the inner surface of the forearm with the formation of "lemon peel", and the following ones - subcutaneously, in a circle, alternately into the right shoulder/thigh, left thigh/ shoulder, with a gradual increase in the dose of the drug.

For children of the first year of life, vaccination is carried out according to the scheme of 0.1-0.2-0.3-0.4-0.45-0.5-0.55-0.6-0.65-0.7 ml.

For children from one to five years old, vaccination is carried out according to the scheme 0.1-0.2-0.3-0.4-0.5-0.6- 0.65-0.7-0.75-0 .8 ml.

For children over five years old and adults, vaccination is carried out according to the scheme 0.1-0.2-0.3-0.4- 0.5-0.6-0.7-0.8-0.9-1 ,0 ml.

The prototype contains lysates: 19 strains of bacteria of 7 species (streptococci, staphylococci, neisseria, enterococci and enterobacteria: klebsiella, moraxella, acinetobacter). RinodentaPrimavak - 60 combined polyvalent vaccine, which contains at least 20 types of bacteria and 3 types of fungi

Sapaida, including at least 38 original strains of bacteria and 5 strains of Sapaida fungi, which increases the effectiveness of vaccine treatment and prevention.

The drug IRS-19 is used for diseases of the upper respiratory tract and bronchi, and

RinodentaPrimavak is prescribed for acute and chronic inflammatory diseases of bacterial and fungal etiology of the nose and sinuses, pharynx, tonsils, ears, oral cavity, tongue, gums, teeth, conjunctiva and eyes, which expands the functional possibilities of using the vaccine.

The drug IRS-19 is administered by an aerosol method, RinodentaPrimavak - by injection, which increases the effectiveness of the vaccine.

The drug IRS-19 has a local effect due to aerosol spraying on the mucous membrane of the nasopharynx, stimulating local immunity. RinodentaPrimavak has a systemic effect due to parenteral administration (subcutaneous injections), stimulating local and general immunity.

RinodentaPrimavak vaccine has no side effects. Only local (hyperemia, swelling and pain at the injection sites) and general (increased body temperature, skin rash, as a manifestation of bacterial toxicoderma) reactions to the administration of the vaccine are possible. Such reactions are of a natural physiological nature and are caused by the activation of local immunity (at the site of vaccine administration) and the general immune response with the release of toxins from the bacteria against which the specific RinodentaPrimavak vaccine is directed, due to the rapid destruction of bacteria after their immune recognition by the adjusted immune system.

The prototype can cause dermatological reactions (erythema-like and eczema-like), autoimmune (erythema nodosum, thrombocytopenic purpura), allergic (urticaria, angioneurotic edema), as well as from the respiratory system (asthma attacks, cough, laryngitis, bronchitis), digestive system ( nausea, vomiting, abdominal pain, diarrhea), etc. RinodentaPrimavak has no side effects. Moreover, the proposed vaccine RinodentaPrimavak does not have allergic reactions and causes a hypoallergenic effect with a significant reduction of pre-treatment elevated ЭЭ levels.

The prototype cannot be used in autoimmune diseases. And the application

RinodentaPrimavak for autoimmune diseases is not limited.

Polyvalent combined inactivated liquid vaccine RinodentaPrimavak against

Bacterial and fungal causative agents of diseases of the nasopharynx, mouth and eyes include strains

Kiebzieya rpeshiptopiae, Ezspegispia soii, ebharpuiosossiv acygei5, ebarpuiosossiv Naeto|uissiv, zigeriosossiv ruodepev, bBigeriosossy5 rpeitopia, bigeriosossiv mipdiapv, Epiegosossis Gaesai v,

Eptiegosossiv Tayesisht, Epiegosossi5 ygap5, Kierzieia oohuiosa, Epiegobrasiei aegodepev,

Epiegorasieg sioasaye, Rhoivy5 mytYidagiv, Rgoiei5 tigabriev, Spgobrasieg Ppetspaii, AiIsaiiidepez Taesaiiv,

MogdapeiPa todapii, Rzepdotopaz aegidipoza, Rzepdotopav aisaidepe5, Sapaida airisapv,

Sapaida Kgizei, Sapaida diabgaga, at least 20 species of bacteria and 3 species of Sapaida fungi, including at least 38 strains of bacteria and 5 strains of fungi of the genus Sapaida, namely: Ziarpuiosossis5 atsgeiv - 5, eiarpuiosossiv Naetoiuisiv - 3, mGeriosossis ruodepe5 - 4 .

Epiegosossiv digape - 1, Euspegispia soii - Z, Kierzieia rpeshtopia - 2, KierzivPa ohuiosa - 1,

Epiegorasiei ayegodepev - 2, Epiegobasieg sioasaye -1, Rgoivy5 miyYidagiv - 1, Rgoivyv tigaryiv - 1,

Sikorasieg Itetspaii - 1, Aisaiiidepez Gayesaiiv - 1, MogdapePa todgapii - 1, Rzendotopavh ayegidiposa - 3, Rheeidotopaz aisaiiidepez - 1, Sapaida aibisapz - 2, Sapaida Kiizei - 2, Sapaida diabgaiya - 1, which were isolated in various acute and chronic inflammatory diseases bacterial and fungal etiology of the nose, paranasal sinuses, pharynx, tonsils, ears, oral cavity, tongue, gums, teeth, conjunctiva and eyes, including strains deposited in

Depositories of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine, listed in

Tables.

Table

Mo. . Mo strain Date . Mo of the strain in Date n/p Name of the strain From where the customer was isolated Heredachi in the Depository of the depository of the depository

EusNetisnia soi Isolated From 1 Resistance 95 95 |Clinical 463 09/12/17 | B-7628 26.10.17 material (ziv) 2 I clinical 238 19.09.17 | B-7657 26.10.17

Resistance 10 95 : . of material

Table

Mo. . Mo strain Date . Mo strain in Data

The name of the strain From where the transmission was isolated in the client's m/s - |Depositories | depository deposits

Epiegobvasieg Isolated Z

From |aeegodepev5 clinical 930 03.13.18 | B-7734 23.03.18

Resistance 0 95 | of material

Kierziea ohuyusa Isolated Z

A Resistance 095 | SLinichny 174 12.09.17 | B-7630 26.10.17 of the material (ref

KiIerziePa rpeshtopiae Isolated From 5 . of clinical 680 01.11.17 |8-7686 17.01.18

Resistance 10 95 : . of material

Mogdapeiia togadapii Isolated from Z

Resistance 1095 | SLinichny 13.12.17 | B-7709 23.03.18 of material (ziv)

Rzepdotopav Isolated From 7 |ayegidiposis clinical 58 13.12.17. | B-7710 23.03.18

Resistance 20 95 | of material

Isolated by Z

Rzepdotopav clinical aisaiidepev5 material 883 09/27/17 | 8-7663 10/26/17

Resistance 100 95| (secretion of Kk! ear) zpgeriosossiv5 Isolated From ruodepe5 clinical 269 1.11.17 v-7683 17.01.18

Resistance 0 95 | of material (ziv) zigeriosossiv migidap5 Isolated From : clinical 252 20.12.17. | B-7714 23.03.18

Resistance 0 95 : . of material

Epiegosossizv Taesiitis Isolated From 11: clinical 517 20.02.18. | B-7729 03/23/18

Resistance 0 95 : . of material (ziv) earnuiosossiv Isolated from 12 Haigeiv clinical 776 01.11.17 |8-7684 17.01.18

Resistance 10 95 | of material

Sapaida aIrisap5 Isolated From 13 : clinical 659 11.10.17 | x-5087 25.11.17

Resistance 20 95 : . material (ziv) ! Isolated by Z

Sapaida diabgaia p. material (pron

Sapaid stevia Isolated From : clinical 826 11.10.17 | M-5091 25.11.17

Resistance 0 95 : . of material

Sapaid stevia Isolated From 16 : clinical ZA 18.10.17 | x-5097 22.12.17

Resistance 10 95 : . of material

Eusnetisnia soi Isolated From 17 . clinical 726 11.04.18 | B-7748 05/07/18

Resistance 0 95 : . of material

Isolated from zpgeriosossiv5 clinical 18 |ruodepe5 | of material (slime from 780 04.18.18 | B-7757 05.07.18

Resistance 0 95 nose)

Isolated by Z

Rzepdotopav of clinical 19 | ayegidiposis: 857 04/18/18 | 8-7758 05/07/18. material (oil

Resistance 20 95 from the nose)

The table of azva strain From where the transmission is isolated in the customer's s/p - |Depositories | depository deposits

Isolated by Z

Rgoivyz miiYidagiv clinical 20 Resistance 10 95 | material (mucus from the nose)

Epiegobvasieg Isolated From 21 | aegodepe5 clinical 25.04.18. | B-7760 05/14/18

Resistance 0 95 | of material

Isolated from zpgeriosossyv5 kpinichnych 22 | rpeitopiae of material (mazo 234 20.12.17. | B-7716 14.05.18

Resistance 0 95 from nose) earnuiosossiv Isolated From 23 | clinical studies 579 05/23/18 | B-7766 31.10.18

Resistance 0 95 | material (nose)

OVEOTEKHOI Shota | you call, 24 and clinical 604 05/23/18 | B-7767 31.10.18

Resistance 0 95 : . material (nose)

Isolated by Z

Epiegosossiv digapv | clinical 25 Resistance 100 95| material (mucus from 887 30.05.18 /8-7769 81.10.18 nose zpgeriosossiv5 Isolated From 26. | rpeshtopiaye clinical 812 06.06.18 |B-7770 31.10.18

Resistance 0 95 | of material

Many thorns | Oz Tu Nov 27: clinical 50 06.06.18. |8-7761 11.06.18

Resistance 20 95 : . material (ziv) earnuiosossiv Isolated from 28 |aigeib5 clinical 308 09/27/17 | B-7666 26.10.17

Resistance 0 95 | material (urine)

Isolated from the earnuiosossiv of clinical 29 | added 5 material 908 13.12.17 | B-7712 03/23/18

Resistance 20 95 | (urogenital secretions) earnuiosossiv Isolated Z

ZO | employed clinical 502 20.02.18 | B-7731 23.03.18

Resistance 0 95 | material (urine) earnuiosossiv Isolated Z

З1 |айгайв5 clinical 681 09/27/17 | B-7665 26.10.17

Resistance10 95 | material (wound)

Isolated by Z

Ziarpuiosossiv5 clinical 32 | isave5 material 627 04/18/18 | B-7756 05/07/18

Resistance 0 95 (phlegm)

Спосіб виготовлення полівалентної комбінованої інактивованої рідкої вакцини проти бактеріальних і грибкових збудників захворювань носоглотки, рота та очей включає вирощування штамів Кіерзіейа рпешйтопіає, Е5сПпегіспіа соїї, еїарпуососсиб5 ашцйгецв5, еарпуїососсив Наетоїуїісив, Зіеріососсив руодепе5, Зперіососсив рпештопіа, бігеріососсив5 мітідіанпе1, Епіегососсив Таесаїї5, Епівегососсив5 Таеєсішт, Епіегососсив5 дигапз5 , Kierzieia ohuiyusa,

Епіегорасієї аегодепев, Епіегорасієї сіоасає, Ргоїєи5 мпцідагівх, Ргоїви5 тігабіїйв, Сйгобасієг їецйпаїй, АїІсаїдепеб5 Таесаїй5, Могдапейа тогдапії, Рзепдотопа5 аеєгидіпоза, Рзепдотопав5 аісаійдепе5, Сапаїда аїБрбісап5, Сапаїда Кгизеї, Сапаіда діаргаїа, всього не менше 20 видів бактерій і З виду грибів Сападіда, в тому including at least 38 strains of bacteria and 5 strains of fungi of the Sapadida genus, namely: Arpuiosossiv atzgeiz - 5, Arpuiosossiv paetoiiuisiv - Z, Zigeriosossiv5 ruodepez - 4, Zperiiosossiv rpeitopia - 2, Zigeriosossiv migpdiapv - 1, Epiegosossis Taesaiiv - Z,

Epiegosossiv Taesiit - 1, Epiegosossi5 digapv - 1, Eusnetgisnia soii - Z, Kierzieia rpeshtopia - 2,

KierziePa ohuiosa - 1, Epiegobrasieg aegodepev - 2, Epiegobasieg sioasaye -1, Rgoiviv myidagiv - 1,

Rgoivy5 tigkariaiv - 1, Spgobrasieg iteshpai - 1, AiIsaidepev Taesaiii5 - 1, Mogdapeiia todgapii - 1,

Rzeidotopaz ayegidipoz - 3, Rzendotopaz aisaYiydepez - 1, Sapaida aiIrisapv - 2, Sapaida Kgivei - 2, Sapaida diabgaia - 1, which were isolated in various acute and chronic inflammatory diseases of bacterial and fungal etiology in children and adults from smears from mucous membranes (nose , pharynx, oral cavity, gums, conjunctiva), from the tongue, as well as from various biological substrates, including patented strains deposited in the National Depository of Microorganism Strains of Ukraine, with varying degrees of antibiotic resistance and resistance to antifungal drugs.

At least 20 types of bacteria and 3 types of fungi are used in the production of vaccines

Sapaiida, including at least 38 original strains of bacteria and 5 strains of fungi of the Sapaiida genus with varying degrees of resistance to existing antibiotics (from 0 95 resistance - sensitive to all antibiotics, and up to 100 95 resistance - hospital strains not sensitive to all antibiotics at all) and to antifungal drugs, the 24-hour agar culture of bacteria and fungi is washed off the surface of the solid nutrient medium with pyrogen-free distilled water and placed in sterile containers, and to eliminate impurities in the nutrient medium, strains of bacteria and fungi are washed with distilled water by three times centrifugation at 1500-3000 rpm min. for 10-15 minutes, pouring out the supernatant, the obtained sediment of the culture of the bacteriological strain, grown separately, is suspended in pyrogenic distilled water for injections and standardized according to the MAK Farland standard (MeE) with an optical density of 1.0, which corresponds to Z billion. (3.0 x 109) microbial cells in 1 ml, and strains of microorganisms are taken in equal quantities, the standardized suspension of strains is inactivated in an autoclave at a temperature of 115-125 C and a pressure of 1 atm. within 15-40 minutes, in a container with inactivated bacteria and fungi, equal amounts of a preparation of embryonic origin, or a physiological solution, or water for injections, or another solvent are added in accordance with the production technical regulations and a suspension of microbial cells is obtained

Of 1.5 billion (1.5 x 109) in 1 ml of the finished vaccine, to control sterility, vaccine samples are sown on nutrient broth, the sows are incubated in a thermostat at a temperature of 37 "C for 24-48 hours, and if there is no growth, a preservative is added and other ingredients according to the production technical regulations and pour the vaccine 1 ml into sterile ampoules.The poured and sealed ampoules are checked for tightness, labeled and packed into 10 ampoules for vaccination, leaving 2 ampoules of each series for control.

The vaccination course consists of 10 injections given every other day, while on the first day - at a dose of 0.1 ml intradermally into the inner surface of the forearm with the formation of a "lemon peel", and the following - subcutaneously, in a circle, alternately on the right shoulder/thigh, left thigh/shoulder with a gradual increase in the dose of the drug.

For children of the first year of life, vaccination is carried out according to the scheme of 0.1-0.2-0.3-0.4-0.45-0.5-0.55-0.6-0.65-0.7 ml.

For children from one to five years old, vaccination is carried out according to the scheme 0.1-0.2-0.3-0.4-0.5-0.6- 0.65-0.7-0.75-0 .8 ml.

For children over five years old and adults, vaccination is carried out according to the scheme 0.1-0.2-0.3-0.4- 0.5-0.6-0.7-0.8-0.9-1 ,0 ml.

The expiration date of the RinodentaPrimavak vaccine is 24 months.

The invention is not limited to the production of a liquid vaccine. The vaccine can also be made in the form of sublingual lozenges, capsules for oral administration, nasal drops or spray, ointment, solution for irrigation of mucous membranes.

The invention is explained by treatment examples.

Example 1

Husband K., 52 years old, suffered from frequent colds and chronic often recurring sinusitis since childhood. After hypothermia, the fisherman developed another relapse of sinusitis with copious discharge of purulent mucus from the nose with a sharp fecal odor and forcing air from the oral cavity through the nose. During the CT examination, a diagnosis of osteomyelitis of the upper jaw on the left with the formation of a bone defect of 9-10 mm in size (conjunctiva) between the oral cavity and the left maxillary sinus in the area of the left upper 6th tooth was established. A maxillofacial operation was prescribed to clean up the purulent focus of the infection and close the formed bone defect with mucous flaps with the simultaneous appointment of 3-4 antibiotics in the preoperative and postoperative period. The patient refused surgery and antibiotics (on receipt). During 8 months, he underwent 5 courses of immunization with bacterial vaccines Rinodenta-Primavak (3 times), StaphyloPrimavak (1 course) and

EcoPrimavak for 10 injections each with simultaneous implementation according to an individually developed scheme of local dental and ENT procedures (including injections into transitional folds of drugs that have a local and general regenerative effect). 8 months after the start of treatment, the bone defect between the oral cavity and the maxillary sinus was completely closed during a control CT scan. During the next 5 years, about 20 courses of immunization with Primavak bacterial vaccines were carried out consecutively, which made it possible to achieve complete clinical remission: there were no more relapses of chronic sinusitis.

Example 2

Husband N., 72 years old, has been treated for diabetes (insulin-dependent) for 7 years.

He went to the clinic with complaints of glossitis, which has been constantly recurring for the past 6-7 months, with pronounced pain and inflammatory changes on the tongue, hyperesthesia (increased sensitivity to hot, cold, sour), periodic fever, an increase in the size of the tongue (cannot close the mouth, cannot eat and breathe freely), sleep disturbance - for several months he is forced to sleep sitting in a chair. Courses of treatment with antibiotics did not give a tangible positive clinical result. During the bacteriological examination, enterococcus (Epiegosossi5 Taesaiye) was isolated from the tongue, and staphylococcus aureus (Etarpuiosossi5 atsgei5) from the nose and throat. Two courses of immunization with bacterial vaccines were conducted

RinodentaPrimavak and StaphyloPrimavak, 10 injections each. Clinical recovery occurred 12-14 days after the start of treatment. 2 months after the end of the treatment, a second (prophylactic) course of immunization with a polyvalent vaccine was carried out

RinodentaPrimavak of 10 injections according to the standard scheme. During 3 years, there were no further recurrences of glossitis, and he continued to receive regular treatment for diabetes.

Claims (13)

FORMULA OF THE INVENTION 1. Polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes, which includes strains of Keb5/eLla rpeitopiae, EsseRegisnia soii, Eiarnpuiosossis aigeiv, which is distinguished by the fact that it additionally contains strains of bEiarnpuyusossis Raetoiuissikh, eigperiosossiv ruodepez, eGgeriosossiv rpechitopiae , огперіососсив мігпідіапе1, Епіегососсив5 Іаесаїїв, Епіегососсив їаесійт, Епіегососсив адигапв, КіІерзіела охуюса, Епіегобасіеї аегодепе5, Епіегорасієї сіоасаеє, Ргоївивє умиїдагі5, Ргоїеив5 тігабіїїв, Спгобасіег нешпаї!, АіІса!їдепев їаеса!їїх, МогудапеПа тогдапії, Рзендотопаз аєгидіпоза, Рзеидотопазх аїсаїїдепев, Сапаїда а !risap5, Sapaida Kgivzei, Sapaida diabgaga, a total of at least 20 species of bacteria and 3 species of Sapoiia fungi, including at least 38 strains of bacteria and 5 strains of fungi of the Sapaida genus, namely: YeyarnuIosossiv atsgeiv - 5, Yeyarnpuosossyv Naeto !uisiz - Z, Ogeriosossiv ruodepez - 4, Egeriosossiv rpeitopia - 2, Egeriosossiv uigidia pv - 1, Epiegosossiv iaesa!yv - Z, Epiegosossiv Taesiit - 1, Epiegosossiv digape - 1, EvsPepisnpia soii - Z, Kiervzive/a rpeitopia - 2, KiebziePa ohuiyusa - 1, Epiegorasieg aegodepez - 2, Epiegobasieg sioasaye - 1, Rioiei5 upidagiv - 1, Rgoivyz Tigaryiv - 1, Sitobasieg teiipdii - 1, AiIsaiidepez Iaesaii" - 1, Mogdape/a todgapii - 1, Rveiyotopaz aegidipoza - 3, Rvendotopavh a!saidepev - 1, Sapaida a!irisap5 - 2, Sapaida Kpyvzei - 2, Sapaida diabgata - 1, which were isolated from various acute and chronic inflammatory diseases of bacterial and fungal etiology, including strains deposited in the Depository of the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine: oyarnpuIosossiv ashgeiv deposited under registration number B-7684; oiarnpuIosossyv ashgeiv, deposited under the registration number B-7756; oiarnpuIosossiv ashgeiv, deposited under registration number B-7665; oiarnpuIosossiv ashgeiv, deposited under registration number B-7666; OiarnpuIosossiz Naeto/uiysiv, deposited under the registration number B-7712; OiarnpuIosossiz Naeto/uissiv, deposited under the registration number B-7731; OiarnpuIosossiz Naeto/uissiv, deposited under the registration number B-7766; ogeriosossiv ruodepez, deposited under registration number B-7683; ogeriosossiv ruodepez, deposited under registration number B-7757; ogeriosossi5 rpeitopiae, deposited under registration number B-7716; ogeriosossi5 rpeitopiae, deposited under registration number B-7770; ogeriosossiv uihidapv5, deposited under registration number B-7714; Epiegosossikh Iaesiit, deposited under the registration number B-7729; 60 Eptegosossiv digapv, deposited under registration number B-7769; EheNepsnia soii, deposited under the registration number B-7748; EheNepsnia soii, deposited under the registration number B-7628; Kierziepa rpeitopia, deposited under registration number B-7686; Kierziv!a ohuiosa, deposited under the registration number B-7630; Epiegobasieg aegodepev, deposited under registration number B-7 734; Epiegobasieg aegodepev, deposited under registration number B-7 760; Epiegobasieg sioasaye, deposited under the registration number B-7657; Rioivy" miidagih, deposited under the registration number B-7762; Sigobasieg Geiypaii, deposited under registration number 7761; Aiisaiidepez iaesaii5, deposited under registration number 7767; Mogdape!a then, deposited under registration number B-7709; Rzeiyotopazh aegidipoza, deposited under the registration number B-7710; Rzeiyotopazh aegidipoza, deposited under the registration number B-7758; Rzeiyotopaz a!isa!idepez, deposited under registration number B-7663; Sapaida airisapv, deposited under the registration number U-5087; Sapaida Kgizei, deposited under registration number U-5091; Sapaida Kgizei, deposited under registration number U-5097; Sapaida Diabgaga, deposited under the registration number U-5088. 2. The method of manufacturing a polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes according to claim 1, which includes the cultivation of strains of H/herziella rpeitopiae, Ev5spPegispia soii, biarnuosossivs asheiv, inactivation of the strains, mixing, which is additionally distinguished by the fact that вирощують штами оїарнпуососсивз Наето!уїсив, 5Ггеріососсив руодепев, 5Ггеріососсив рпеитопіа, 5геріососсив мігідіапв 1, Епіегососсив Іаесаї!/їх, Епіегососсив Іаесіит, Епіегососсив5 агапв, Кіерзіела охуюса, Епіегорасієї аєгодепевз, Епіегорасіеї сіоасае, Ргоївеив миїдагів, Ргоїеив тігаріїйв, Сігорасіег теийпаїй, АїІсаїїдепеб5 аесаїїх, Mogdapena todgapii, Rzeidotopa5 aegidiposa, Rheiyotopae aIsa!idepev, Sapaida a!risap5, Sapaida Kgyzei, Sapaida diabgaia, a total of at least 20 species of bacteria and 3 species of Sapaida fungi, including at least 38 strains of bacteria and 5 strains of fungi of the genus Sapaida, namely: biarnuIosossiv aigeiyv - 5, Yeiarnu!osssiv Naeto/uiissiv - 3, 6geri osossiv ruodepez - 4, 5Ggeriosossiv rpeitopia - 2, bgeriosossiv uigidiapv - 1, Epiegosossiv Iaesaiiv - Z, Eptegosossix Taesiiyt - 1, Epiegosossi5 agap - 1, EusNepsnia soi - Z, Kiierchieia rpeitopia - 2, KiIerziepa ohuiosa - 1, Aepiegorasii - 2 Epiegobasieg sioasaye - 1, Rioieiv miidagiv - 1, Rgoieiz tigarbiiiv - 1, Spgobrasieg iteiypai! - 1, A/saiidepez Iaesa!/yv - 1, Mogdape!La toghdpii - 1, Rezeiyotopah aegidiposa - 3, Rgenyotopazh a!isaidepez - 1, Sapaida a!risapz - 2, Sapaida Kgizei - 2, Sapaida diabgaia - 1, which were isolated in various acute and chronic inflammatory diseases of bacterial and fungal etiology, including strains deposited in the National Depository of Microorganism Strains of Ukraine, with varying degrees of antibiotic resistance and resistance to antifungal drugs, the agar culture of bacteria or fungi is washed off the surface of a solid nutrient medium with pyrogenic distilled water and placed in sterile containers, and to eliminate impurities in the nutrient medium, bacterial strains are washed with distilled water by centrifugation at 1500-3000 rpm. for 10-15 minutes, pouring out the supernatant liquid, the obtained biomass sediment of the culture of the bacteriological strain, grown individually, is suspended in pyrogenic distilled water for injections and standardized, and the strains of microorganisms are taken in equal quantities, the standardized suspension of strains is inactivated in an autoclave at a temperature of 115- 125 "C and a pressure of 1 atm for 15-40 minutes, in a container with inactivated bacteria and fungi, equal amounts of a preparation of embryonic origin or physiological solution or water for injections are added and a suspension of microbial cells is obtained, to control sterility, vaccine samples are sown on nutrient broth, the seeds are incubated in a thermostat at a temperature of 35-40 "C for 24-48 hours, and if there is no growth, a preservative is added and the vaccine is poured into sterile ampoules. 3. The method according to claim 2, which differs in that a 24-hour agar culture is used. 4. The method according to claim 2, which differs in that erbisol or inflamafertin is used as a drug of embryonic origin. 5. The method according to claim 2, which differs in that the bacterial strains are washed with distilled water by centrifugation three times. 6. The method according to claim 2, which differs in that it is standardized according to the Farland MAC standard (MeE) with an optical density of 1.0, which corresponds to 3 billion (3.0x109) microbial cells in 1 ml of the finished vaccine. 7. The method according to claim 2, which differs in that a suspension of 1.5 billion (1.5x109) microbial cells is obtained in 1 ml of the finished vaccine. 8. The method according to claim 2, which differs in that the vaccine is poured into ampoules of 1 ml. 9. The method according to claim 2, which differs in that the poured and sealed ampoules are checked for tightness, labeled and packed in 10 ampoules for vaccination, leaving 2 ampoules of each series for control. 10. The method of treatment and prevention with a polyvalent combined inactivated liquid vaccine against bacterial and fungal pathogens of diseases of the nasopharynx, mouth and eyes according to claim 1, which includes the administration of the vaccine in appropriate increasing doses, which is characterized by the fact that the course of vaccination consists of 10-12 injections , which are done every other day, while on the first day - in a dose of 0.1 ml intradermally into the inner surface of the forearm with the formation of "lemon peel", and the following - subcutaneously, in a circle, alternately into the right shoulder/thigh, left thigh/shoulder , with a gradual increase in the dose of the drug. 11. The method according to claim 10, which differs in that for children of the first year of life, vaccination is carried out according to the scheme 0.1-0.2-0.3-0.4-0.45-0.5-0.55-0 ,6-0.65-0.7 ml. 12. The method according to claim 10, which differs in that for children from one to five years of age, vaccination is carried out according to the scheme 0.1-0.2-0.3-0.4-0.5-0.6-0 .65-0.7-0.75-0.8 ml. 13. The method according to claim 10, which differs in that for children over five years old and adults, vaccination is carried out according to the 0.1-0.2-0.3-0.4-0.5-0.6-0 scheme ,7-0.8-0.9-1.0 ml.