RU2294757C1 - Method for preventing acute respiratory diseases of the upper respiratory tract in children at insulin-dependent diabetes mellitus - Google Patents

Abstract

FIELD: medicine, pediatrics, otolaryngology, endocrinology.

SUBSTANCE: the present innovation deals with preventing acute respiratory diseases of the upper respiratory tract in children at insulin-dependent diabetes mellitus during the period of compensation and subcompensation. Before vaccination it is necessary to determine the concentration of antibodies to total antigens of "Pneumo 23" vaccine in blood serum and detect the coefficient of balance capacity (Cbc) in saliva. At the titer of total antibodies to total antigens of "Pneumo 23" vaccine being below 30 CU/ml and Cbc being above 2.1 one should be fulfill vaccination due to single introduction of "Pneumo 23" vaccine into area of deltoid muscle at the dosage of 0.5 ml simultaneously with immunomodulator "IRS-19" introduced per a dose for each nasal meatus twice daily for 14 d including the day of vaccination. The innovation suggested provides the stable maintenance of a stable high titer of antibodies to antigens of "Pneumo 23" vaccine, higher lysozyme activity and secretory immunoglobulin A and prevents acute respiratory diseases in postvaccinal period.

EFFECT: higher accuracy and efficiency of prophylaxis.

3 ex, 1 tbl

Description

The invention relates to medicine, pediatrics, otolaryngology and endocrinology and can be used to prevent acute respiratory diseases of the upper respiratory tract in children with insulin-dependent diabetes mellitus.

Over the past decades in the world and in Europe, the number of patients with diabetes has increased significantly, including in childhood.

Each year, the number of patients with insulin-dependent diabetes mellitus (type 1 diabetes) increases by 5-7%, and doubles every 12-15 years (Efimov A.S. et al. Clinical Diabetology. Kiev: Zdorovya, 1998, 320 pp.).

It is estimated that by 2010 the incidence rate of type 1 diabetes will average 30 people per 100,000 population per year. The peak incidence of diabetes mellitus occurs in early puberty, but recently there has been an increase in the incidence of diabetes in preschool children.

The etiology of diabetes is not yet fully established. Autoimmune disorders leading to the development of the disease are believed to be associated with a genetic predisposition and environmental factors.

The genes of the main histocompatibility complex of class 2 are of the greatest importance. A number of genes are also described, the defect of which leads to a disruption in the regulation of apoptosis, antiviral and microbial protection, that is, factors that indirectly contribute to the development and course of diabetes mellitus.

The gene for the regulatory factor α-interferon is known, the locus of which is located on chromosome 4q35. The activity of α-interferon is induced by the enzyme 2'-5 'oligoadenylate synthetase, the content of which in the blood of patients with diabetes is increased regardless of the duration of the disease. The specified enzyme plays a role in the innate defense of the body against viruses.

The state of immunity in patients with diabetes is determined by extrapancreatic factors, and above all, a congenital defect in genes that control both insulin secretion and certain links of the metabolism and functioning of the immune system, which can exist even before the development of the disease and contribute to the development and influence of the course of the disease.

It is known that in children with a weakened system of natural killers, which are the basis of the natural antiviral defense system, which include children with diabetes, various viral diseases are more acute. At the same time, viruses infect many vital organs, including the islets of Langerhans.

The pathogenetic basis of frequent acute respiratory infections in patients suffering from this endocrinopathy is a decrease in local immunity against the background of an imbalance of cellular and humoral links.

ARI refers to viral and bacterial etiology of respiratory tract infections. In this case, one of the main pathogens of acute respiratory infections is streptococcus pneumonia (pneumococcus).

Moreover, acute respiratory infections are triggers, i.e., triggers of exacerbation of persistent viral or bacterial infections, and can contribute to the progression of diabetes mellitus per se and the appearance of vascular complications, which makes us pay attention to the vaccine prophylaxis of viral and bacterial infections of the upper respiratory tract (otitis, pharyngitis, rhinosinusitis, bronchitis), in particular in children of preschool and school age.

One of these diseases that can dramatically disrupt the course of insulin-dependent diabetes mellitus in children is considered chronic tonsillitis, which is a constant focus of bacterial infection (Martynova M.I. et al. The state of specific and nonspecific resistance in children with insulin-dependent diabetes mellitus with concomitant chronic tonsillitis Issues of Maternal and Child Welfare. M: Medicine, 1991, No. 10, p.21-23).

The frequency of chronic tonsillitis in children with type 1 diabetes mellitus according to the literature reaches 33.6%.

In previous years, it was believed that the surgical treatment of chronic tonsillitis in children with insulin-dependent diabetes mellitus has advantages over the conservative one, in particular, in restoring lysozyme in saliva and in blood serum, secretory immunoglobulin A (sig A) and normalizing serum immunoglobulins G and A ( Martynova MI and others. The state of specific and nonspecific resistance in children with insulin-dependent diabetes mellitus with concomitant chronic tonsillitis. Issues of maternal and child health, M .: editsina 1991, №10, str.21-23).

Since tonsillectomy, being a stress factor, can dramatically worsen the condition of a patient with diabetes mellitus, at present, preference is given to conservative methods of treating chronic tonsillitis in children with diabetes mellitus.

In addition, severe diabetes mellitus is a contraindication to tonsillectomy.

Thus, conservative treatment methods are currently of particular importance in the rehabilitation of the oral and nasopharynx in patients with diabetes mellitus.

However, even new drugs, in particular anti-inflammatory drugs, do not solve the problem of recurrence of respiratory infections and chronic tonsillitis in patients with type 1 diabetes.

There is a method of preventing the incidence of acute respiratory viral infections, in particular influenza, in children, aimed at restoring the immunity of the nasopharynx and oropharynx (Patent No. 2223783 of 02.20.2004. A method for the prevention of influenza and acute respiratory diseases in frequently ill children).

In this source, “IRS 19” is used as a vaccine of bacterial origin, which is administered no later than one month before the planned vaccination against influenza; 1-3 months after the onset of IRS-9, an inactivated influenza vaccine is administered.

The specified method increases the content of secretory IgA on the mucous membranes of the upper respiratory tract and helps to reduce the incidence of acute respiratory infections, influenza in particular.

However, this effect is temporary.

A known method for the prevention of pneumococcosis in organized groups of military personnel by sharing the vaccine "Pneumo 23", dibazole and ascorbic acid (Patent No. 99103415 from 10.12.2000).

This method prevents the occurrence of acute pneumoconiosis, rhinosinusitis, bronchitis and pneumonia.

However, this method does not prevent the occurrence of acute respiratory infections, since the use of ascorbic acid does not enhance the specific antibody response to polysaccharides of pneumococci, which are the main cause of acute respiratory infections.

The closest analogue of the claimed invention is not, because in the available literature we did not find mention of the prevention of acute respiratory diseases of the upper respiratory tract in children with insulin-dependent diabetes mellitus.

The aim of the invention is to reduce the frequency of decompensation of diabetes mellitus, the trigger of which are bacterial and viral infections, as well as exacerbations of the chronic pathology of the nasopharynx and oropharynx in children with type 1 diabetes mellitus during the period of compensation and subcompensation by vaccination of acute respiratory infections.

The technical result to which the present invention is directed is to increase lysozyme activity, increase secretory immunoglobulin A (sIgA) and decrease salivary IgG, as well as increase specific antibodies to pneumococcal polysaccharides.

The essence of the method lies in the fact that during the period of compensation and subcompensation of diabetes mellitus for children and adolescents with insulin-dependent diabetes mellitus simultaneously with the introduction of the vaccine "Pneumo 23" (produced by the pharmaceutical company Aventis Pasteur, France) in a dose of 0.5 ml , enter the immunomodulator "IRS-19" (production of the pharmaceutical company "Solvey Pharma", France). In this case, IRS-19 is administered in a single dose in each nasal passage 2 times a day for 14 days, including the day of vaccination.

Prior to the above preventive measures, patients take into account anamnestic, clinical and laboratory data, which include: determining the level of antibodies in the blood serum to the total antigens of the vaccine "Pneumo 23", and in saliva - the level of immunoglobulin A (IgA) and G (IgG ) and lysozyme activity necessary to calculate the balance of local immunity factors (Ksb).

In this case, the coefficient of balance of local immunity factors (CSF) is calculated according to a certain formula.

The above laboratory examination is repeated 1, 5, 3 and 12 months after vaccination.

To assess the parameters of secretory immunity, saliva is used, since it plays an important role in the neutralization of antigenic material entering the body under various stressful conditions, including infection, due to the action of the so-called hemato-salivary barrier.

The Pneumo 23 vaccine was chosen because it contains 23 serotypes of pneumonia streptococci, which are most often found in Europe and are the main etiological cause of acute respiratory diseases and their complications, therefore, the level of antibodies to the total Pneumo 23 vaccine antigens is determined.

A high level of antibodies, as you know, is acquired, including through natural immunization, that is, after a disease.

Therefore, when determining antibody titers in some patients, high antibody titers can be determined for various pneumococcal serotypes, including those that are part of the Pneumo 23 vaccine.

"IRS 19" is an immunomodulator with the properties of a vaccine, contains bacterial lysates of 19 pathogens, which are the main causative agents of infections of ENT organs, pneumonia and are important in the development of rheumatism, nephritis, vasculitis.

Moreover, the composition of the drug "IRS 19" includes 6 serotypes of S. pneumoniae (1, 2, 3, 5, 8 and 12); therefore, the simultaneous administration of the Pneumo 23 vaccine with the IRS 19 immunomodulator on the day of vaccination enhances the specific antibody response to polysaccharides of pneumonia streptococci and simultaneously sanitizes the nasopharynx, thereby increasing the clinical efficacy of vaccination as opposed to isolated administration or the Pneumo 23 vaccine , or immunomodulator "IRS 19".

Table 1
The effectiveness of the prevention of acute respiratory infections with the joint use of the vaccine "Pneumo 23" and immunomodulator "IRS 19" Indicator Vaccination
"Pneumo 23" Vaccination "Pneumo 23" together with "IRS 19" The average number of acute respiratory infections per year Before vaccination After vaccination Before vaccination After vaccination 3.12 2.2 3.12 1.1 * * p <0.05

The intranasal route of administration of the drug "IRS 19" was chosen because the introduction of a vaccine in this way carries out training of the immune system with the formation of immunological memory and protective antibodies. The dose of the immunomodulator IRS-19 has not been specifically developed and is traditional for administration to children.

Moreover, the bacterial lysates that make up the IRS 19, along with the indicated effect, also form local protection of the mucosal epithelium due to the enhanced production of antibodies, in particular IgA, which neutralize viruses and toxins and, thus, prevent the colonization of the mucous membranes of the upper respiratory pathogens by enhancing the functional properties of phagocytic cells, and also prevent the penetration of antigens through the mucous membrane of the respiratory tract by increasing the production of anti-inflammatory cytokines.

In our method, we selected a group of children with type 1 diabetes mellitus in the amount of 11 people aged 13.4 ± 0.7 years (9 to 16 years old) suffering from recurrent respiratory infections with signs of tonsil hypertrophy or chronic tonsillitis. (Table .one)

Clinical examination method.

During a clinical examination, a medical history is collected and patient complaints are taken into account.

Each child is examined by an otolaryngologist (before vaccination and 1.5 and 3 months after vaccination):

- examination of the nasal cavity is carried out by the method of anterior rhinoscopy, while assessing the condition of the mucous membrane, the degree of its swelling, the nature of the discharge;

- when examining the oral cavity and pharynx, pay attention to the size and color of the tonsils, as well as the front and rear arches, the back of the pharynx and the contents of the gaps;

- palpation examines the cervical and submandibular lymph nodes.

Laboratory research methods

A laboratory study includes, as mentioned above: a study of salivary indicators of local immunity: secretory immunoglobulins: A, M, G, secretory component of IgA, lysozyme, balance factor of local immunity factors; indicators of humoral immunity: serum immunoglobulins: A, M, G; microbiological examination of microflora of the nasal cavity and pharynx.

Blood sampling for research is carried out in the treatment room in compliance with aseptic and antiseptic disposable syringes in sterile tubes.

The collection of mixed saliva is carried out in the morning on an empty stomach without stimulation.

The state of local immunity is assessed by the production of secretory Ig A, which is determined using a specific diagnostic serum against human secretory immunoglobulin A (production of the Biomed medical plant named after II Mechnikov).

The level of immunoglobulins of classes G, A, M is determined by the Mancini method in blood serum and saliva using monospecific serums against Ig G, A, M (produced by the Nizhny Novgorod Research Institute of Epidemiology and Microbiology of the Ministry of Health of the Russian Federation).

Lysozyme activity - by the nephelometric method (according to the method of V.G. Dorofeychuk, 1987).

The balance coefficient (Ksb) of lysozyme with immunoglobulins in saliva is calculated using a mathematical model for integratively evaluating the nature of the interaction between local immunity factors developed by N.I. Tolkacheva (1987).

Moreover, if Ksb = 0.1-1.0, then the balance is not upset, at 1.1 Ksb = 2.0 - the borderline state, and at Ksb> 2.1 - an imbalance in saliva.

Determination of Ig G antibodies to antigens of the vaccine "Pneumo 23" was performed by ELISA according to the method developed in NIIVS them. I.I. Mechnikova RAMS (Moscow). Used ELISA based on the polysaccharides of serotypes of pneumococci that are part of the vaccine. The technique was developed at the NIIVS them. I.I. Mechnikov RAMS. A comparison system for determining antibodies to polysaccharides of serotypes of S. pneumoniae is currently not available.

The qualitative and quantitative composition of the microflora of the pharynx and nasal cavity is evaluated by the cultural method. The material is taken with different swabs from the throat and nose in the morning on an empty stomach. Identification of bacteria is carried out using classical nutrient media: 5% blood agar, yolk-salt agar, chocolate agar, Endo medium, Saburo medium.

The quantitative content of microorganisms is determined taking into account the norms calculated in CFU / swab according to the method described in the order of the Ministry of Health of the USSR No. 535 of 04/22/1985:

Staphilococcus aureus 10 ¹ -10 ² ,

Streptococcus haemolyticus 10 ³ -10 ⁴ ,

Enterococcus 10 ¹ -10 ² ,

Escherichia coli 10 ¹ -10 ² ,

Candida albicans 10 ¹ -10 ² ,

Staphilococcus saprophyticus 10 ¹ .

Statistical data processing.

Statistical data processing is carried out using the program Statistica 6.0 ("StatSoft", USA), Excel using parametric and non-parametric methods.

We first established the following: the indication for vaccination with the use of the Pneumo 23 vaccine in combination with the IRS 19 immunomodulator according to the claimed method is the presence in the blood serum of patients of the concentration of antibodies to the Pneumo 23 vaccine antigens below 30 U / ml, as well as the value Ksb> 2.1.

And when the initial content of antibodies to the Pneumo 23 vaccine antigens is higher than 30 UE / ml, there is no reaction on the part of SIg A in saliva in the form of an increase in their concentration, and when Ksb> 2.1 1.5 months after vaccination, the body's immune response in the form the increase in antibodies to vaccine antigens will be lower or absent altogether, i.e. vaccination effectiveness will decrease, which will require the search for other ways to increase non-specific immunity.

These data confirm the following clinical examples.

Example 1

The boy is Alyosha M., 13 years old. Diagnosis: Type 1 diabetes. Goiter 1 degree, euthyroid. Recurrent ARVI. Lipodystrophy on the abdomen. Tuberculosis.

From the anamnesis: a child from 1 pregnancy proceeding with toxicosis of 1 half, childbirth at 37 weeks of pregnancy. On natural feeding up to 1 year. Received vaccinations by age. Since 2000, has not been vaccinated in connection with the refusal of vaccinations after the onset of the underlying disease.

Heredity is burdened: the mother has urolithiasis, the sister has drug and food intolerance.

Diabetes experience 2 years 11 months. The manifestation of the disease - after acute respiratory infections. The course of diabetes is characterized by frequent hypoglycemia (up to 2 times a week). A boy often does not follow a bread-based diet. He suffered from upper respiratory infections up to 6 times a year, each episode for 7 days, with complications in the form of bronchitis, laryngitis, otitis media, and therefore received antibacterial therapy several times.

At the time of inspection: satisfactory condition. Lipodystrophy on the abdomen (+ tissue). The daily dose of insulin was 54 units per day (1.08 units / kg) (Actropid 32 units, Protafan 22 units). Temperature 36.4 ° C. Complaints of moderate nasal congestion, dryness, perspiration and hoarseness. The skin is clean. In the throat: tonsils of the 1st degree, hyperemia of the arches and hypertrophy of the follicles of the posterior pharyngeal wall. The nasal mucosa is moderately cyanotic. Cervical lymph nodes up to 0.5 cm, painless, elastic on palpation. Vesicular breathing. Heart sounds are clear, rhythmic.

During laboratory examination: fasting glucose level of 8 mmol / l, glucosuric profile - 100 g / day, Hb Alc content of 14.7%. The content of Ig G in saliva was increased to 0.062 g / l and lysozyme to 55%, Ig A was reduced to 0.024 g / l and secretory Ig A to 0.5 g / l compared with the age norm, balance coefficient = 3.1. Neisseria catarrhalis, flava, perflava in the amount of 3.2 · 10 ⁴ CFU / ml and Staphilococcus epidermidis in the amount of 6 · 10 ⁴ CFU / ml were isolated from the throat. Prior to vaccination, the content of Ig G to polysaccharides of the vaccine is 3.7 U / ml.

With the consent of the parents, the boy was vaccinated with “Pneumo 23” v / m, in the region of the deltoid muscle, at a dose of 0.5 ml and at the same time a 2-week course of “IRS 19” was started, with 1 insufflation in each nasal passage 2 times a day.

30 days after vaccination, the boy was admitted to the hospital in the stage of diabetes mellitus decompensation after chickenpox, in connection with which the dose of insulin was increased to 60 units / day.

On examination: cyanosis of the nasal mucosa, hyperemia and hypertrophy of follicles of the posterior pharyngeal wall are absent. No complaints.

In saliva, the content of IgA increased to 0.9 g / l, secretory IgA and lysozyme decreased to 0.25 g / l and 52%, respectively. In the inoculation from the nose, the content of epidermal staphylococcus decreased to 1.6 · 10 ² CFU / ml, in the inoculation from the pharynx, the flora was not sown. The content of Ig G to polysaccharides 1.5 months after vaccination increased to 35.4 UE / ml, i.e., 9.57 times.

After 3 months, perspiration and dryness in the throat did not bother.

An objective examination of the oropharynx and nasopharynx showed no signs of inflammation. In saliva, the content of IgA decreased to 0.03 g / l, but was higher than the initial values.

No pathogenic microflora growth was detected in the inoculation from the nose; the content of microorganisms of the newly emerged family of neisseria and epidermal staphylococcus was within 1 degree dysbacteriosis. The content of Ig G to vaccine polysaccharides 3 months after vaccination was at the level of 33.6 UE / ml, i.e., 8.8 times higher than the initial level.

Within a year after vaccination of the child, the number of acute respiratory diseases decreased from 6-7 to 4, of which 2 times - mild acute respiratory viral infections, 2 times - SARS, complicated by bronchitis.

The content of Ig G to polysaccharides of the vaccine one year after vaccination is 21.6 UE / ml, i.e., 5.8 times higher than the initial level.

Example 2. The girl is Irina B., age 14 years, 4 months. Diagnosis: type 1 diabetes. Pollinosis (allergic rhinitis, conjunctivitis), remission. Scoliosis. Tuberculosis.

From the anamnesis it is known that a child from 1 pregnancy, which was uneventful, gave birth at 37 weeks of pregnancy. Weight at birth 2200 (twin baby). On natural feeding up to 1 month. Received vaccinations by age. From the past diseases: chickenpox, mumps. Heredity burdened: grandmother's arterial hypertension on the mother's side.

Diabetes experience 6 years 4 months. The disease began after the flu. The course of diabetes is relatively stable: the frequency of hypoglycemia is rare, glycemia above 10 mmol / l - every other day. During the year before vaccination with acute respiratory infections, she was ill 5 times, to a mild degree, but the flu was marked by a severe course.

At the time of vaccination, the condition is satisfactory. An objective examination in the throat revealed hyperemia of the tonsils, the sizes of which were 1-2 degrees. Complaints during examination of nasal congestion and a feeling of dryness in the throat.

Rhinoscopically: swelling of the nasal mucosa.

In sowing from the throat - Staphylococcus aureus in an increased amount of 1 · 10 ³ CFU / ml, from the nose - epidermal staphylococcus in an amount of 1.2 · 10 ² CFU / ml.

The daily dose of insulin was 50 units / day (0.98 units / kg). The blood glucose level is 9.0 mmol / l, glycated hemoglobin is 8.5%. The initial content of Ig G to the polysaccharides of the vaccine "Pneumo 23" before vaccination is 12 UE / ml.

Within 1.5 months after vaccination, ARI was not sick, blood sugar - 8.8 mmol / L, glycated hemoglobin - 10%. The sensation of dryness in the throat disappeared; submandibular lymph nodes decreased.

When otolaryngological examination: no change. In sowing from the throat, Staphylococcus aureus is preserved in an increased amount: 1 · 10 ³ CFU / ml.

In saliva, the content of the coefficient of balance of factors of local immunity was still increased: 3.5. The content of Ig G to vaccine polysaccharides 1.5 months after vaccination increased to 92 UE / ml, i.e., it became 7.67 times higher than the initial data.

Within 3 months, ARI was not sick.

With an objective examination, the size of the tonsils decreased, there were no subjective complaints. In sowing from the throat only from the enrichment medium, a small amount of Staphylococcus aureus was sown in a small amount: 1.5 × 10 ² CFU, no pathogenic microflora growth was detected in the sowing from the nose.

The balance coefficient in saliva decreased to 2.7 despite exacerbation of stomatitis during the examination.

The content of Ig G to vaccine polysaccharides 3 months after vaccination decreased to 89 U / ml, but remained 7.14 times higher than the initial data.

During the year she suffered acute rhinosinusitis and acute rhinitis in a mild form. The glycated hemoglobin content returned to normal (7.1%). The content of Ig G to vaccine polysaccharides remained at a high level: 77 U / ml, i.e., 6.4 times higher than the initial level.

The given examples indicate an increased incidence of acute respiratory infections in children with insulin-dependent diabetes mellitus and low-symptom chronic lesions of the nasopharynx and oropharynx in these patients, and therefore it makes sense to vaccinate this category of patients against acute respiratory infections.

The post-vaccination period for vaccination against pneumococcal infection can be supplemented with therapy for sluggish diseases of the nasopharynx to prevent their exacerbation.

In a similar way, 11 children with insulin-dependent diabetes mellitus having a chronic pathology of the lymphopharyngeal ring were inoculated.

The following example demonstrates an increase in the incidence of respiratory infections in the absence of vaccination against pneumococcal infection.

Example 3. Daria A., 9 years old. Diagnosis: type 1 diabetes mellitus complicated by diabetic polyneuropathy. Concomitant diseases: chronic gastroduodenitis. Biliary dyskinesia. Inflection of the gallbladder. Acute cystitis. Neurogenic bladder dysfunction by hypotonic type. Small abnormality of the heart. Dysmetabolic nephropathy. Atopic dermatitis. Food, drug sensitization. Recurrent ARI. Tuberculosis.

From 1 normal pregnancy, 1 urgent birth. Birth weight 3000 g. Naturally fed up to 1.5 years. Past diseases: rubella, chickenpox. The heredity is burdened: the grandmother has type 2 diabetes.

Diabetes experience 4 years. Diabetes mellitus is characterized by daily mild hypoglycemia. Sugar level is more than 10 mmol / l up to 1 time per week. The daily dose of insulin 17 U / day - 0.68 U / kg.

1 year before the examination, she had ARI up to 5 times a year, in the autumn-winter period. The average disease duration was 8.2 days. During acute respiratory infections, the sugar level did not increase, insulin correction was not required.

Since October 2004, she began to get sick monthly, the duration of the disease increased to 13.25 days. ARIs were complicated by rhinosinusitis, bronchitis. Twice marked decompensation of diabetes. The concentration of Ig G antibodies to the Pneumo 23 vaccine antigens a year later increased from 5 UE / ml to 11.9 UE / ml.

Thus, the simultaneous use of bacterial vaccines of systemic (vaccine "Pneumo 23") and local (immunomodulator "IRS 19") action helps prevent acute respiratory infections in the post-vaccination period in children and adolescents with diabetes and increase the effectiveness of preventive vaccination.

The claimed method can be recommended for use in a hospital and outpatient in clinical practice with the aim of vaccinating children and adolescents with diabetes.

Claims (1)

A method for the prevention of acute respiratory infections of the upper respiratory tract in children with insulin-dependent diabetes mellitus during the period of compensation and subcompensation using vaccination, which consists in determining the concentration of antibodies to the total antigens of the Pneumo 23 vaccine in the blood serum and determining the balance coefficient in saliva before vaccination (Ksb); and when the titer of antibodies to the total antigens of the vaccine "Pneumo 23" is lower than 30 UE / ml and Ksb more than 2.1, vaccination is carried out by a single injection of the vaccine "Pneumo 23" at a dose of 0.5 ml into the deltoid muscle simultaneously with the immunomodulator "IRS-19 "which is administered in a single dose in each nasal passage 2 times a day for 14 days, including the day of vaccination.