Prevention of tuberculosis (BCG vaccination)

Tuberculosis is a social and medical problem, therefore, for the prevention of tuberculosis, a set of social and medical measures is carried out.

Social activities eliminate (or minimize) social risk factors that contribute to the spread of infection.

Medical preventive measures are designed to reduce the risk of infection of healthy people and limit the spread of tuberculosis infection (antiepidemic work, timely detection and treatment of patients), and prevent tuberculosis (vaccination, chemoprophylaxis). They assume an impact on all links of the epidemic process - the source of mycobacterium tuberculosis, the conditions of transmission and transmission of infection, the susceptibility of the person to pathogens.

Such approach allows to coordinate various preventive measures and to allocate social, sanitary and specific prevention of tuberculosis.

Specific prophylaxis of tuberculosis is aimed at increasing the resistance of the body to the causative agent of tuberculosis and is targeted at a particular individual who is undergoing an attack from mycobacteria. Stability of a healthy person to tuberculosis infection can be increased by immunization - vaccination. Another way to increase the immunity of the organism to the action of pathogens involves the use of chemotherapy drugs that have a harmful effect on mycobacteria.

To reduce the severity of the problem of tuberculosis, international health authorities identified the identification of patients and immunization against tuberculosis as the main components of the tuberculosis control program. BCG vaccination has gained recognition in many countries. It is mandatory in 64 countries, officially recommended in 118 countries. This vaccination is carried out by approximately 2 billion people of all ages and remains the main form of tuberculosis prevention in most countries, preventing the development of severe forms of the disease associated with the hematogenous spread of mycobacteria.

[1], [2], [3], [4], [5], [6], [7],

Prevention of tuberculosis: BCG vaccination

Mass vaccination against tuberculosis of newborns is carried out by two drugs: a tuberculosis vaccine (BCG) and a tuberculosis vaccine for sparing primary immunization (BCG-M). Vaccine preparations BCG and BCG-M are living mycobacteria of the vaccine strain BCG-1 lyophilized in a 1.5% solution of sodium glutamate. The BCG-M vaccine is a preparation with a halved weight content of mycobacteria BCG in the vaccine dose, mainly due to dead cells.

Live mycobacteria strain BCG-1, multiplying in the body of the vaccinated, contributes to the development of long-term specific immunity to tuberculosis. Immunity induced by the vaccine

BCG is formed approximately 6 weeks after immunization. The mechanism of protection after vaccination against tuberculosis is to suppress the hematogenous spread of bacteria from the site of the primary infection, which reduces the risk of disease development and reactivation of the process. The BCG-1 Russia domestic BCG-1 Russia occupies an average position for residual virulence among other sub-strains with high immunogenicity. This means that, with high protective properties, the vaccine, prepared from domestic substrates, has low reactogenicity. Causing no more than 0.06% of postvaccinal lymphadenitis.

The basic theses on which the preparations of the vaccine BCG and BCG-M are controlled

• Specific harmlessness. Avirulent Russian strain BCG-1. As well as other substems, has some stable residual virulence sufficient to ensure the reproduction of mycobacteria BCG in the grafted organism. However, the test of the drug on this test provides a constant control over the absence of a tendency to increase the virulence of the strain and to prevent the accidental production of the virulent strain of mycobacteria.
• Absence of extraneous microflora. The production technology of the BCG vaccine does not provide for the use of a preservative, so the possibility of contamination of the preparation must be controlled especially carefully.
• The total content of bacteria. This test is an important indicator of the standard of the drug. An inadequate amount of bacteria can lead to a low intensity of antituberculous immunity, and excessive - to undesirable post-vaccination complications.
• The number of viable bacteria in the preparation (specific activity of the vaccine). Reducing the number of viable individuals in the preparation results in a disruption in the ratio of the number of live and killed bacteria, which leads to an inadequate protective effect of the vaccine. An increase in the number of viable cells can cause an increase in the incidence of complications in the administration of the vaccine.
• Dispersion. The BCG vaccine after dissolution has the appearance of a coarsely dispersed suspension. However, the content of a large number of bacterial conglomerates can cause an excessive local reaction and lymphadenitis in vaccinated. Therefore, the dispersion index should be at least 1.5.
• Thermal stability. The BCG vaccine is quite thermostable. When stored in a thermostat for 28 days, not less than 30% of viable BCG are conserved. This test confirms that, provided the product is properly stored, the vaccine will maintain its original viability for the entire shelf life indicated on the label.
• Solubility. When the solvent is added to the ampoule for 1 minute, the vaccine must dissolve.
• Presence of vacuum. The vaccine is in an ampoule under vacuum. According to the instruction for the use of the drug, the personnel carrying out the vaccination must check the integrity of the ampoule and the condition of the tablet, and also be able to open the ampoule properly.

The National Control Authority - Federal State Institution of Science The State Scientific Research Institute for Standardization and Control of Biomedical Medicines named after. L.A. Tarasevich (FGUN GISK) - monitors each series of vaccines for individual tests, and selectively about 10% of the series for all tests. All of the above is intended to ensure the high quality of domestic vaccines BCG and BCG-M.

Form release: in ampoules sealed under vacuum, containing 0.5 or 1.0 mg of BCG preparation (10 or 20 doses, respectively) and 0.5 mg of BCG-M preparation (20 doses) complete with a solvent (0.9% sodium solution chloride) 1.0 or 2.0 ml in the ampoule for the BCG vaccine, respectively, and 2.0 ml in the ampoule for the BCG-M vaccine. One box contains 5 ampoules of BCG or BCG-M vaccine and 5 ampoules of solvent (5 sets). The drug should be stored at a temperature not higher than 8 ^o C. The shelf life of BCG vaccine is 2 years and BCG-M is 1 year.

The vaccine dose of BCG vaccine contains 0.05 mg of the drug (500 000-1500 000 viable bacteria) in 0.1 ml of the solvent. The vaccine dose of the BCG-M vaccine contains 0.025 mg of the drug (500,000-750,000 viable bacteria).

BCG vaccination: indications

Primary vaccination is performed in healthy, full-term newborn children on the 3rd-7th day of life.

Children aged 7 and 14 years are subject to revaccination. Having a negative reaction to the Mantoux test with 2 TE.

The first revaccination of children vaccinated at birth is performed at the age of 7 years (1st grade students).

The second revaccination of children is made at the age of 14 years (students of 9th grades and adolescents of secondary special educational institutions in the first year of training).

[8], [9], [10], [11], [12], [13],

Indications for the use of vaccines BCG-M:

• in the maternity hospital the day before discharge to the house - premature newborns with a body weight of 2000-2500 g when restoring the original body weight;
• in the departments of nursing preterm infants before discharge from the hospital home - children with a body weight of 2300 g and more;
• in children's polyclinics - children who were not vaccinated in the maternity hospital for medical contraindications and are subject to vaccination in connection with the removal of contraindications;
• in territories with satisfactory epidemiological situation of tuberculosis - all newborns; in territories with a TB incidence of up to 80 per 100 thousand population by decision of local health authorities - all newborns.

BCG vaccination: contraindications

Contraindications to vaccination of BCG and BCG-M in neonates:

• prematurity less than 2500 g for BCG and less than 2000 g for BCG-M;
• acute diseases:
  • intrauterine infection;
  • purulent-septic diseases;
  • hemolytic disease of the newborn with moderate to severe severity;
  • severe lesions of the nervous system with severe neurologic symptoms;
  • generalized skin lesions;
• primary immunodeficiency;
• malignant neoplasms;
• generalized BCG infection, found in other children in the family;
• HIV infection:
  • a child with clinical manifestations of secondary diseases;
  • the mother of the newborn, if she did not receive antiretroviral therapy during pregnancy.

Children vaccinated at the maternity hospital are treated sparing vaccination with BCG-M after 1-6 months after recovery. In the appointment of immunosuppressants and radiation therapy, the vaccine is given 12 months after the end of treatment.

There are a number of contraindications and limitations to revaccination of children and adolescents.

Persons temporarily released from vaccinations should be monitored and vaccinated after complete recovery or withdrawal of contraindications. In each individual case not included in this list, immunization against tuberculosis is carried out at the permission of the relevant specialist doctor.

[14], [15], [16], [17], [18], [19],

The method of BCG vaccination

Vaccination against tuberculosis is carried out by specially trained medical personnel of the maternity hospital, nursing department of premature babies, a children's polyclinic or a feldsher-midwife point.

Vaccination of newborns is carried out in the morning in a specially allocated room after a pediatrician examines the children. Inoculation at home is prohibited. In polyclinics, a doctor (feldsher) with a mandatory thermometer on the day of vaccination, taking into account medical contraindications and history data, with mandatory clinical examination of blood and urine, preliminarily selects children to be vaccinated. To avoid contamination, it is unacceptable to combine in one day a vaccination against tuberculosis with other parenteral manipulations, including blood sampling. If the requirements for vaccination are not met, the risk of post-vaccination complications increases. Children who were not vaccinated in the first days of life are vaccinated within the first two months in a children's polyclinic or in another preventive institution without preliminary tuberculosis diagnostics. Children older than 2 months before immunization need a preliminary setting of Mantoux with 2 TE. Vaccinate children with a negative reaction to tuberculin (with complete absence of infiltration, hyperemia or with a stick response up to 1 mm). The interval between the Mantoux test and immunization should be at least 3 days (the day of taking into account the reaction to the Mantoux test) and no more than 2 weeks. Other prophylactic vaccinations can be performed at intervals of at least 1 month before or after vaccination against tuberculosis.

The BCG vaccine is administered intradermally at a dose of 0.05 mg in 0.1 ml of the solvent, the BCG-M vaccine at a dose of 0.025 mg in 0.1 ml of the solvent. Ampoules with the vaccine are carefully examined before opening.

The preparation is not subject to application in the following cases:

• if there is no label or incorrect filling on the ampoule;
• with expired shelf life;
• in the presence of cracks and incisions on the ampoule;
• when the physical properties change (wrinkling of the tablet, discoloration, etc.);
• in the presence of foreign inclusions or undiluted flakes in the diluted preparation.

Dry vaccine is diluted immediately before use with sterile 0.9% sodium chloride solution, applied to the vaccine. The solvent should be clear, colorless and free from foreign impurities. Since the vaccine in the ampoule is under vacuum, first, wiping the neck with the alcohol and the ampoule head, cut the glass and carefully break off the place of sealing with the help of tweezers (head). Only after this, you can nail and break off the neck of the ampoule, wrapping the cut end in a sterile gauze napkin.

In the ampoule with the vaccine is transferred with a sterile syringe with a long needle the required amount of 0.9% sodium chloride solution. The vaccine should completely dissolve within 1 min after two or three shakes. It is inadmissible to precipitate precipitation or the formation of flakes that do not break when shaken. The diluted vaccine should be protected from sunlight and daylight (a cylinder of black paper) and consumed immediately after breeding. For immunization, a separate disposable sterile 1.0 ml syringe with tightly fitting pistons and thin needles (No. 0415) with a short cut is used for each child. Before each set, the vaccine must be thoroughly mixed with a syringe 2-3 times.

For one inoculation, 0.2 ml (2 doses) of the diluted vaccine is collected by a sterile syringe, then 0.1 ml of the vaccine is released through a needle into the cotton swab to expel the air and bring the syringe plunger to the desired calibration of 0.1 ml. It is inadmissible to release the vaccine into the air or the protective cap of the needle, as this leads to contamination of the environment and the hands of the nurses with live mycobacteria.

The vaccine is administered strictly intradermally at the border of the upper and middle third of the outer surface of the left shoulder after preliminary treatment of the skin with a 70% solution of ethyl alcohol. The needle is injected upward into the surface layer of the skin. First, an insignificant amount of vaccine is administered to make sure that the needle has entered exactly intracutaneously, and then the entire dose of the drug (0.1 ml in total). The introduction of the drug under the skin is unacceptable, since it forms a cold abscess. With the correct technique of administration, a papule of a whitish color of at least 7-8 mm is formed. Disappearing usually in 15-20 minutes. It is forbidden to apply a dressing and treatment with iodine and other disinfectant solutions of the vaccine site.

In the vaccination room, the vaccine is diluted and stored in the refrigerator (under lock and key). Persons. Not related to BCG and BCG-M immunization, are not allowed in the vaccination room. After each injection, a syringe with a needle and cotton swabs are soaked in a disinfectant solution (5% chloramine solution), then centrally destroyed.

In exceptional cases, the diluted vaccine can be used with strict adherence to sterility and protection against sunlight and daylight for 2 hours. Unused vaccine is destroyed by boiling or immersion in a disinfectant solution (5% chloramine solution).

BCG vaccination: response to vaccine administration

At the site of intradermal administration of the BCG and BCG-M vaccine, a specific reaction develops in the form of an infiltrate with a diameter of 5-10 mm with a small knot in the center and with a crust type as a small one. In some cases, the appearance of pustules. Sometimes in the center of the infiltrate there is a small necrosis with a slight serous discharge.

In newborns a normal vaccination reaction appears after 4-6 weeks. In revaccinated local vaccination reaction develops after 1-2 weeks. The reaction site should be protected from mechanical irritation, especially during water procedures. Do not apply bandages or handle the reaction site, which parents should be warned about. The reaction is reversed within 2-3 months sometimes and for longer periods. 90-95% of grafts inoculated on the site of the grafting are formed by a superficial scissor with a diameter of up to 10 mm. Monitoring of vaccinated children is carried out by doctors and medical sisters of the general medical network who, at 1, 3 and 12 months after immunization, should check the vaccination response and register its size and nature of local changes (papule, pustule with crust formation, with or without separation, hem , pigmentation, etc.).

[20], [21],

BCG vaccination: the prospects for the development of new anti-tuberculosis vaccines

The classical anti-tuberculosis vaccine BCG, used in many countries to this day, is a live attenuated M. bovis strain . With the introduction of BCG, the immune system encounters an extremely complex set of antigens, which determines both its advantages and disadvantages. On the one hand, the whole-cell vaccines are very often immunogenic and contain their own built-in immunostimulatory molecules in the membrane. In addition, a large number of presented epitopes ensures the effectiveness of the drug when vaccinating a genetically heterogeneous population. On the other hand, numerous antigens of such vaccines compete for presenting cells, and immunodominant antigens do not always induce maximum protection or their transient expression. In addition to this, there is always the possibility of a complex mixture of immunosuppressive elements or molecules.

The opposite spectrum of problems arises when subunit vaccines are used. On the one hand, the amount of antigens in the vaccine can be reduced to a limited set of molecules important for the induction of protective immunity and constantly expressed by the pathogen. On the other hand, the simplicity of the structure of the protein subunits often leads to a decrease in their immunogenicity, which necessitates the use of powerful immunostimulants or adjuvants in vaccines, thereby significantly increasing the risk of vaccination side effects. A limited number of potential T-cell epitopes dictates the need for a thorough check of the components of the vaccine on the ability to induce an answer in a heterogeneous population.

In a sense, the so-called DNA vaccines, in which the polynucleotide sequence encoding it instead of a microbial antigen, is an alternative to subunit vaccines. The advantages of this type of vaccine include their comparative safety, simplicity and cheapness of manufacture and introduction (the so-called "genetic pistol" allows you to dispense with a syringe for vaccination), as well as stability in the body. Disadvantages are - in part, common with subunit vaccines - weak immunogenicity and a limited number of antigenic determinants.

Among the main directions of the search for new whole-cell vaccines, the following are the most developed ones.

1. Modified BCG vaccines. Among the variety of assumptions that explain the inability of the BCG vaccine to protect the adult population from tuberculosis, three can be distinguished based on immunological data:
   • in BCG, there are no important "protective" antigens; Indeed, in the genome of virulent M. bovis and in clinical isolates of M. tuberculosis, at least two clusters of genes (RD1, RD2), absent from BCG, have been identified;
   • in BCG, there are "suppressive" antigens that interfere with the development of patronage; So. On the model of mouse tuberculosis by the staff of the Central Research Institute of the Russian Academy of Medical Sciences, in close cooperation with the group of Professor D. Young from the Royal Medical University in London, it was shown that the introduction of a 19 kDa gene , which is common in M. Tuberculosis and BCG, absent in rapidly growing mycobacterial strains, M. Vaccae or M. Smegmatis leads to a weakening of the vaccine efficacy of these mycobacteria;
   • BCG are unable to stimulate the "right" combination of T-lymphocyte subpopulations necessary to create protection (both CD4 ⁺ and CD8 ⁺ T cells). They stimulate mainly CD4 ⁺ T cells.
2. Live attenuated strains of M. Tuberculosis. The ideology of this approach is based on the assumption that. That the antigenic composition of the vaccine strain should be as close as possible to the composition of the pathogen. Thus, mutant M. Tuberculosis strain H37Rv (mc23026), lacking the gene lysA and. Accordingly, unable to grow in the absence of an exogenous source of lysine, in a model on non-microbial mice C57BL / 6 creates a level of protection comparable to BCG.
3. Living vaccines are of non-microbacterial origin. The potential of vectors such as Vaccinia, aroA, mutants Salmonella and several others are actively being investigated .
4. The natural way is attenuated mycobacteria. They study the possibility of using a number of naturally attenuated mycobacterial environments, such as M. Vaccae, M. Microti, M. Habana, as therapeutic or prophylactic vaccines.

Accordingly, in paragraph 1, a strategy is being developed for the development of new vaccines based on BCG. First, attempts to supplement the BCG genome with M. Tuberculosis genes from the RD1 or RD2 sites. However, it is necessary to consider the possibility of restoring the virulence of the vaccine strain. Secondly, it is possible to remove "suppressive" sequences from the BCG genome. Creating so-called knockout strains for this gene. Third, they develop ways to overcome the "hard" distribution of antigens delivered by BCG vaccine to certain cellular structures, by creating a recombinant vaccine expressing the genes of proteins - cytolysins. An interesting idea in this connection was realized by K. Demangel et al. (1998) using BCG loaded dendritic cells to immunize mice against tuberculosis.

[22], [23], [24], [25], [26], [27],

Subunit vaccines against tuberculosis

At present, the use of secreted proteins of mycobacteria (with adjuvants) seems to be the most promising from the point of view of designing new tuberculosis subunit vaccines, which is well associated with the greater efficacy of live vaccine preparations compared to those killed. In such works, encouraging results were obtained. Thus, by screening the immunodominant epitopes of mycobacterial proteins using T cells from healthy PPD-positive donors, a number of protective antigens have been identified. The combination of these epitopes in the polyprotein made it possible to create a very promising vaccine, which has now reached the stage of testing in primates.

DNA vaccines against tuberculosis

For genetic or polynucleotide vaccination, a circular double-strand DNA of a bacterial plasmid is used in which the expression of the desired (embedded) gene is under the control of a strong viral promoter. Promising results were obtained in the study of DNA vaccines based on the Arg85 complex (three mycobacterial proteins with a molecular weight of 30-32 kDa). Attempts are made to enhance the immunogenicity of DNA vaccines by combining into one molecule antigenic sequences and genes that modulate the immune response.

[28], [29], [30], [31], [32], [33], [34], [35],

Conjugated synthetic vaccines against tuberculosis

Vaccines of this type are based on the use of synthetic immunogens (enhancing the immune response) and proteogenic antigens of pathogens (including mycobacteria). Such attempts (relatively successful) have already been made.

Summarizing the foregoing, it should be noted that the search for a new anti-tuberculosis vaccine has brought to despair more than one generation of enthusiastic researchers. However, the importance of the problem for health, as well as the emergence of new genetic tools do not allow to postpone its decision in the long box.

[36], [37], [38], [39], [40], [41]