Tuberculosis prophylaxis (BCG vaccination)

Tuberculosis is a social and medical problem, therefore, to prevent tuberculosis, a range of social and medical measures are carried out.

Socially oriented measures 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 (anti-epidemic work, timely detection and treatment of patients), as well as to prevent tuberculosis (vaccination, chemoprophylaxis). They involve an impact on all links of the epidemic process - the source of mycobacterium tuberculosis, the conditions of spread and transmission of infection, human susceptibility to pathogens.

This approach allows us to coordinate various preventive measures and to distinguish between social, sanitary and specific prevention of tuberculosis.

Specific prevention of tuberculosis is aimed at increasing the body's resistance to the tuberculosis pathogen and is focused on a specific individual who is subject to aggression from mycobacteria. The resistance of a healthy person to tuberculosis infection can be increased by immunization - vaccination. Another way to increase the body's resistance to the action of pathogens involves the use of chemotherapy drugs that have a detrimental effect on mycobacteria.

To reduce the severity of the tuberculosis problem, international health authorities have identified detection and immunization against tuberculosis as the most important components of the tuberculosis control program. BCG vaccination has gained recognition in many countries. It is mandatory in 64 countries and officially recommended in 118 countries. This vaccination has been administered to 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.

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Tuberculosis prevention: BCG vaccination

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

Live mycobacteria of the BCG-1 strain, multiplying in the body of the vaccinated person, contribute to the development of long-term specific immunity to tuberculosis. Vaccine-induced immunity

BCG is formed approximately 6 weeks after immunization. The mechanism of protection after vaccination against tuberculosis consists of suppressing the hematogenous spread of bacteria from the site of primary infection, which reduces the risk of developing the disease and reactivation of the process. The domestic BCG substrain (BCG-1 Russia) occupies an average position in residual virulence among other substrains with high immunogenicity. This means that with high protective properties, the vaccine prepared from the domestic substrain has low reactogenicity, causing no more than 0.06% of post-vaccination lymphadenitis.

The main theses by which the BCG and BCG-M vaccine preparations are controlled

• Specific harmlessness. The avirulent Russian strain BCG-1, like other substrains, has some stable residual virulence, sufficient to ensure the reproduction of BCG mycobacteria in the body of the vaccinated person. However, checking the preparation according to this test ensures constant monitoring of the absence of a tendency to increase the virulence of the strain and the prevention of accidental entry of a virulent strain of mycobacteria into production.
• Absence of foreign microflora. The BCG vaccine production technology does not provide for the use of a preservative, so the possibility of contamination of the drug must be monitored especially carefully.
• Total bacterial count. This test is an important indicator of the standard of the preparation. Insufficient bacterial count may result in low intensity of anti-tuberculosis immunity, while excessive count may result in undesirable post-vaccination complications.
• The number of viable bacteria in the preparation (specific activity of the vaccine). A decrease in the number of viable individuals in the preparation entails a violation of the ratio of the number of live and killed bacteria, which leads to an insufficient protective effect of the vaccine. An increase in the number of viable cells may cause an increase in the frequency of complications from the introduction of the vaccine.
• Dispersion. The BCG vaccine after dissolution has the form 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 persons. Therefore, the dispersion index should be no less than 1.5.
• Thermal stability. The BCG vaccine is quite thermally stable. When stored in a thermostat for 28 days, at least 30% of viable BCG individuals are preserved. This test allows us to confirm that, provided the preparation is stored correctly, the vaccine will retain its original viability throughout the entire expiration date indicated on the label.
• Solubility: When solvent is added to the ampoule, the vaccine should dissolve within 1 minute.
• Availability of vacuum. The vaccine is in an ampoule under vacuum. According to the instructions for use of the drug, the personnel performing the vaccination must check the integrity of the ampoule and the condition of the tablet, and also be able to open the ampoule correctly.

The national control body - the Federal State Scientific Institution State Research Institute for Standardization and Control of Medical and Biological Preparations named after L.A. Tarasevich (FSBI GISK) - controls each series of vaccines by individual tests, as well as selectively about 10% of series by all tests. All of the above is intended to ensure the high quality of domestic BCG and BCG-M vaccines.

Release form: in vacuum-sealed ampoules containing 0.5 or 1.0 mg of BCG (10 or 20 doses, respectively) and 0.5 mg of BCG-M (20 doses) complete with a solvent (0.9% sodium chloride solution) of 1.0 or 2.0 ml per ampoule for BCG vaccine, respectively, and 2.0 ml per ampoule for 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 exceeding 8 ^° C. The shelf life of BCG vaccines is 2 years and BCG-M - 1 year.

The vaccination dose of BCG vaccine contains 0.05 mg of the drug (500,000-1,500,000 viable bacteria) in 0.1 ml of solvent. The vaccination dose of BCG-M vaccine contains 0.025 mg of the drug (500,000-750,000 viable bacteria).

BCG vaccination: indications

Primary vaccination is carried out on healthy full-term newborns on the 3rd-7th day of life.

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

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

The second revaccination of children is carried out at the age of 14 (for students in grades 9 and teenagers in secondary specialized educational institutions in the first year of study).

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Indications for the use of BCG-M vaccines:

• in the maternity hospital, one day before discharge home - premature newborns weighing 2000-2500 g upon restoration of the initial body weight;
• in departments for nursing premature newborns before discharge from the hospital home - children weighing 2300 g or more;
• in children's clinics - children who were not vaccinated in the maternity hospital due to medical contraindications and who are subject to vaccination due to the removal of contraindications;
• in areas with a satisfactory epidemiological situation for tuberculosis - all newborns; in areas with tuberculosis incidence up to 80 per 100 thousand population, by decision of local health authorities - all newborns.

BCG vaccination: contraindications

Contraindications to BCG and BCG-M vaccination in newborns:

• 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, moderate to severe;
  • severe damage to the nervous system with pronounced neurological symptoms;
  • generalized skin lesions;
• primary immunodeficiency;
• malignant neoplasms;
• generalized BCG infection detected in other children in the family;
• HIV infection:
  • in a child with clinical manifestations of secondary diseases;
  • in the mother of the newborn, if she did not receive antiretroviral therapy during pregnancy.

Children who are diverted from vaccinations in the maternity hospital are given a gentle vaccination with BCG-M 1-6 months after recovery. When immunosuppressants and radiation therapy are prescribed, the vaccination is given 12 months after the end of treatment.

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

Persons temporarily exempted from vaccinations should be taken under observation and registered and vaccinated after full recovery or removal of contraindications. In each individual case not included in this list, immunization against tuberculosis is carried out with the permission of the relevant specialist doctor.

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BCG vaccination technique

Vaccination against tuberculosis is carried out by specially trained medical personnel of the maternity hospital, the department for nursing premature babies, the children's clinic or the feldsher-obstetric station.

Vaccination of newborns is carried out in the morning hours in a specially designated room after examination of children by a pediatrician. Vaccination at home is prohibited. In polyclinics, the selection of children to be vaccinated is preliminarily carried out by a doctor (paramedic) with mandatory thermometry on the day of vaccination, taking into account medical contraindications and anamnesis data, with mandatory clinical blood and urine tests. In order to avoid contamination, it is unacceptable to combine vaccination against tuberculosis with other parenteral manipulations, including blood sampling, on the same day. Failure to comply with the requirements for vaccination increases the risk of post-vaccination complications. Children who have not been vaccinated in the first days of life are vaccinated during the first two months in a children's polyclinic or other preventive institution without preliminary tuberculin diagnostics. Children over 2 months old require a preliminary Mantoux test with 2 TE before immunization. Children with a negative reaction to tuberculin are vaccinated (in the complete absence of infiltrate, hyperemia or in the presence of a prick reaction up to 1 mm). The interval between the Mantoux test and immunization should be at least 3 days (the day of recording the reaction to the Mantoux test) and no more than 2 weeks. Other preventive vaccinations can be carried out at an interval 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 solvent, the BCG-M vaccine - at a dose of 0.025 mg in 0.1 ml of solvent. Ampoules with the vaccine are carefully examined before opening.

The drug should not be used in the following cases:

• if there is no label on the ampoule or it is filled incorrectly;
• if the expiration date has passed;
• if there are cracks or notches on the ampoule;
• when physical properties change (wrinkling of the tablet, color change, etc.);
• if there are foreign inclusions or non-breakable flakes in the diluted preparation.

The dry vaccine is diluted immediately before use with a sterile 0.9% sodium chloride solution attached to the vaccine. The solvent must be transparent, colorless and free of foreign impurities. Since the vaccine in the ampoule is under vacuum, first wipe the neck and head of the ampoule with alcohol, file the glass and carefully break off the sealing place (head) with tweezers. Only after this can you file and break off the neck of the ampoule, wrapping the filed end in a sterile gauze napkin.

The required amount of 0.9% sodium chloride solution is transferred into the ampoule with the vaccine using a sterile syringe with a long needle. The vaccine should be completely dissolved within 1 minute after shaking two or three times. Sedimentation or formation of flakes that do not break up when shaken is unacceptable. The diluted vaccine must be protected from sunlight and daylight (black paper cylinder) and used immediately after dilution. For immunization, a separate disposable sterile syringe with a capacity of 1.0 ml with tightly fitted 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 vaccination, 0.2 ml (2 doses) of the diluted vaccine is drawn up with a sterile syringe, then 0.1 ml of the vaccine is released through the needle into a cotton swab to displace the air and bring the syringe plunger to the desired graduation - 0.1 ml. It is unacceptable 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 medical personnel with live mycobacteria.

The vaccine is administered strictly intradermally at the border of the upper and middle thirds of the outer surface of the left shoulder after preliminary treatment of the skin with a 70% ethyl alcohol solution. The needle is inserted with the cut upwards into the superficial layer of the skin. First, a small amount of the vaccine is administered to make sure that the needle has entered precisely intradermally, and then the entire dose of the drug (0.1 ml in total). Subcutaneous administration of the drug is unacceptable, since this will form a cold abscess. With the correct injection technique, a whitish papule of at least 7-8 mm is formed, usually disappearing after 15-20 minutes. It is prohibited to apply a bandage or treat the injection site with iodine or other disinfectant solutions.

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

In exceptional cases, the diluted vaccine may be used under strict sterility conditions and protection from sunlight and daylight for 2 hours. Unused vaccine is destroyed by boiling or immersion in a disinfectant solution (5% chloramine solution).

BCG Vaccination: Reaction to Vaccine Administration

At the site of intradermal administration of the BCG and BCG-M vaccines, a specific reaction develops in the form of an infiltrate 5-10 mm in diameter with a small nodule in the center and the formation of a smallpox-type crust. In some cases, a pustule appears. Sometimes, a small necrosis with a slight serous discharge appears in the center of the infiltrate.

In newborns, a normal vaccination reaction appears after 4-6 weeks. In revaccinated children, a 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 treat the reaction site, and parents should be warned about this. The reaction is subject to reverse development within 2-3 months, sometimes even longer. In 90-95% of vaccinated children, a superficial scar up to 10 mm in diameter is formed at the vaccination site. Vaccinated children are monitored by doctors and nurses of the general health care network, who should check the vaccination reaction 1, 3 and 12 months after immunization and record its size and the nature of local changes (papule, pustule with crust formation, with or without discharge, scar, pigmentation, etc.).

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BCG Vaccination: Prospects for the Development of New Tuberculosis Vaccines

The classic tuberculosis vaccine BCG, still used in many countries today, is a live attenuated strain of M. bovis. When BCG is administered, the immune system is confronted with an extremely complex set of antigens, which determines both its advantages and disadvantages. On the one hand, whole-cell vaccines are very often immunogenic and contain their own immunostimulatory molecules integrated into the membranes. 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 in such vaccines compete for presenting cells, and immunodominant antigens do not always induce maximum protection or their expression is transient. In addition, there is always a possibility that a complex mixture may contain immunosuppressive elements or molecules.

The opposite spectrum of problems arises when using subunit vaccines. On the one hand, the number of antigens in a vaccine can be reduced to a limited set of molecules that are important for the induction of protective immunity and are constantly expressed by the pathogen. On the other hand, the simplicity of the structure of 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 side effects from vaccination. The limited number of potential T-cell epitopes dictates the need for careful testing of vaccine components for the ability to induce a response in a heterogeneous population.

In a certain sense, an alternative to subunit vaccines are the so-called DNA vaccines, which use a polynucleotide sequence encoding a microbial antigen instead of a microbial antigen. The advantages of this type of vaccine include their comparative safety, simplicity and cheapness of production and administration (the so-called "genetic gun" allows one to do without a syringe for vaccination), as well as stability in the body. The disadvantages, however, are partly common with subunit vaccines - weak immunogenicity and a limited number of antigenic determinants.

Among the main directions of searching for new whole-cell vaccines, the following seem to be the most developed.

1. Modified BCG vaccines. Among the many hypotheses explaining the failure of the BCG vaccine to protect the adult population from tuberculosis, three based on immunological data can be distinguished:
   • BCG lacks important “protective” antigens; indeed, at least two gene clusters (RD1, RD2) that are absent in BCG have been identified in the genome of virulent M. bovis and in clinical isolates of M. tuberculosis;
   • BCG contains "suppressive" antigens that prevent the development of protection; thus, using a model of mouse tuberculosis, the staff of the Central Research Institute of Tuberculosis of the Russian Academy of Medical Sciences, in close cooperation with the group of Professor D. Young from the Royal Medical University (London), showed that the introduction of a gene of a protein with a molecular weight of 19 kDa, common to M. tuberculosis and BCG, which is absent in fast-growing mycobacterial strains, into M. vaccae or M. smegmatis leads to a weakening of the vaccine effectiveness of these mycobacteria;
   • BCG is unable to stimulate the “correct” combination of T-lymphocyte subpopulations required to provide protection (both CD4 ⁺ and CD8 ⁺ T-cells). It stimulates predominantly CD4 ⁺ T-cells.
2. Live attenuated strains of M. tuberculosis. The ideology of this approach is based on the assumption that the antigen composition of the vaccine strain should match the composition of the pathogen as closely as possible. Thus, the mutant M. tuberculosis strain H37Rv (mc23026), lacking the lysA gene and, accordingly, unable to grow in the absence of an exogenous source of lysine, in a model on germ-free C57BL/6 mice creates a level of protection comparable to BCG.
3. Live vaccines of non-mycobacterial origin. The potential of such vectors as Vaccinia, aroA viruses, Salmonella mutants and some others is being actively explored.
4. Naturally attenuated mycobacteria. The possibilities of using a number of naturally attenuated environmental mycobacteria, such as M. vaccae, M. microti, M. habana, as therapeutic or prophylactic vaccines are being studied.

In accordance with the above, a strategy for creating new BCG-based vaccines is being developed. First, these are attempts to supplement the BCG genome with M. tuberculosis genes from the RD1 or RD2 regions. However, it is necessary to take into account the possibility of restoring the virulence of the vaccine strain. Second, it is possible to remove the "suppressive" sequences from the BCG genome, creating so-called knockout strains for this gene. Third, methods are being developed to overcome the "rigid" distribution of antigens delivered by the BCG vaccine to certain cellular structures by creating a recombinant vaccine expressing the genes of proteins - cytolysins. An interesting idea in this regard was implemented by K. Demangel et al. (1998), who used BCG-loaded dendritic cells to immunize mice against tuberculosis.

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Subunit vaccines against tuberculosis

At present, the most promising approach in terms of constructing new anti-tuberculosis subunit vaccines is the use of secreted proteins of mycobacteria (with adjuvants), which is well associated with the greater effectiveness of live vaccine preparations compared to killed ones. Such studies have yielded encouraging results. Thus, by screening immunodominant epitopes of mycobacterial proteins using T cells from healthy PPD-positive donors, it was possible to isolate a number of protective antigens. Combining these epitopes into a polyprotein made it possible to create a very promising vaccine, which has now reached the stage of testing on primates.

DNA vaccines against tuberculosis

For genetic or polynucleotide vaccination, a circular double-stranded DNA of a bacterial plasmid is used, in which the expression of the desired (integrated) gene is under the control of a strong viral promoter. Encouraging results have been obtained in studying DNA vaccines based on the Ag85 complex (three mycobacterial proteins with a molecular weight of 30-32 kDa). Attempts are being made to enhance the immunogenicity of DNA vaccines by combining antigen sequences and genes that modulate the immune response into one molecule.

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Conjugate synthetic vaccines against tuberculosis

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

In conclusion, it should be noted that the search for a new anti-tuberculosis vaccine has driven more than one generation of enthusiastic researchers to despair. However, the importance of the problem for public health, as well as the emergence of new genetic tools, do not allow us to put off its solution for a long time.

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