Vaccination against tuberculosis

Tuberculosis is a major problem in the world, with 24,000 people falling ill and 7,000 dying every day. Vaccination against tuberculosis is included in the WHO Expanded Program on Immunization; it is administered in more than 200 countries, with over 150 countries administering it in the first days after a child’s birth. Revaccination is administered in 59 countries. A number of developed countries with low (10 per 100,000) tuberculosis incidence (USA, Canada, Italy, Spain, Germany) vaccinate only in risk groups.

The incidence of tuberculosis in Russia increased from 34 in 1991 to 85.4 per 100,000 in 2002, in 2004-2007 it decreased slightly and is in the range of 70-74 per 100,000. The incidence of children aged 0-14 has changed little in recent years (14-15 per 100,000), among all those sick with tuberculosis they make up 3-4%, and in children there is often overdiagnosis due to the so-called minor forms. The incidence of 15-17 year olds is higher, in 2007 it was 18.69 per 100,000. Naturally, in the conditions of Russia, mass vaccination against tuberculosis is necessary; vaccination of only children of social risk groups and contacts, as is the case in the USA, Germany and other countries with low incidence of tuberculosis, is not yet acceptable for our conditions, although, taking into account the frequency of BCG osteitis, it is advisable to transfer the vaccination in more prosperous areas to an older age.

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Indications for vaccination against tuberculosis

Vaccination is carried out on practically healthy newborns with the BCG-M vaccine at the age of 3-7 days. The BCG vaccine is used in newborns in the subjects of the Russian Federation with incidence rates above 80 per 100 thousand population, as well as in the presence of tuberculosis patients in the environment.

BCG vaccines registered in Russia

Vaccine	Content	Dosage
BCG - live lyophilized tuberculosis vaccine, Microgen, Russia	1 dose - 0.05 mg in 0.1 ml of solvent (0.5-1.5 million viable cells)	Ampoules 0.5 or 1.0 mg (10 or 20 doses), solvent - saline solution 1.0 or 2.0 ml
BCG-M - live lyophilized tuberculosis vaccine with a reduced number of microbial cells, Microgen, Russia	1 vaccination dose - 0.025 mg in 0.1 ml of solvent (0.5-0.75 viable cells, i.e. with a lower limit, like BCG)	Ampoules of 0.5 mg vaccine (20 doses), solvent (0.9% sodium chloride solution) 2.0 ml.

Newborns with contraindications are treated in neonatal pathology departments (stage 2), where they should be vaccinated before discharge, which will ensure a high level of coverage and reduce the number of children vaccinated in the clinic. Children not vaccinated in the neonatal period should be vaccinated within 1-6 months of life, children over 2 months are vaccinated if the Mantoux test result is negative.

Revaccination is performed on tuberculin-negative children aged 7 and 14 years who are not infected with tuberculosis. With tuberculosis incidence rates below 40 per 100,000 population, revaccination against tuberculosis at age 14 is performed on tuberculin-negative children who were not vaccinated at age 7.

The experience of V.A. Aksenova in the Moscow region showed the legitimacy of revaccination not at 7, but at 14 years. Vaccination of a newborn leads to a long-term (up to 10 years or more) preservation of immunity with post-vaccination or infraallergy with subsequent development of more pronounced sensitivity to tuberculin. Postponing revaccination until the age of 14 does not increase the incidence of tuberculosis in children and adolescents in regions with a satisfactory epidemiological situation. Refusal of revaccination at 7 years reduces the number and severity of positive Mantoux reactions, which facilitates the detection of infection, reducing the number of diagnostic errors by 4 times.

Characteristics of the tuberculosis vaccine

The BCG vaccine contains both live cells and cells that die during production. The BCG-M vaccine has a higher proportion of live cells, which allows for a lower dose to achieve a satisfactory result and a minimum of undesirable reactions. Both vaccines are from the M.bovis substrain - BCG (BCG-1 Russia), which has high immunogenicity and medium residual virulence. Both BCG preparations meet WHO requirements. Storage and transportation conditions: the preparations are stored at a temperature not exceeding 8° C. The shelf life of the BCG vaccine is 2 years, BCG-M - 1 year.

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Method of administration of tuberculosis vaccine and dosage

BCG and BCG-M vaccines are administered intravenously in a dose of 0.1 ml, which is obtained by transferring the vaccine into an ampoule using a sterile syringe with a long needle. The vaccine forms a suspension within 1 minute after shaking 2-3 times, it is protected from light (black paper cylinder) and used immediately.

Before each set, the vaccine is thoroughly mixed with a syringe 2-3 times. For one vaccination, 0.2 ml (2 doses) is drawn up with a sterile syringe, then 0.1 ml of the vaccine is released through a needle into a cotton swab to displace air and bring the syringe plunger to the desired graduation - 0.1 ml. One syringe can only be used to administer the vaccine to one child. It is prohibited to use syringes and needles with an expired shelf life and needle-free injectors. The vaccine is administered strictly intradermally at the border of the upper and middle third of the outer surface of the left shoulder after treatment with 70% alcohol. Bandages and treatment of the injection site with iodine and other disinfectants are prohibited.

Effectiveness of the tuberculosis vaccine

Mycobacteria of the BCG-1 strain, multiplying in the body of the vaccinated person, create long-term immunity to tuberculosis 6-8 weeks after immunization, providing protection against generalized forms of primary tuberculosis, but not protecting against the disease in case of close contact with the bacillus excretor and not preventing the development of secondary forms of tuberculosis. Vaccination reduces the infection rate of contacts. The prophylactic effectiveness of vaccination of newborns is 70-85%, almost completely protecting against disseminated tuberculosis and tuberculous meningitis. A 60-year observation of a high-risk group for tuberculosis (Indians and Eskimos in the USA) showed a 52% decrease in the incidence of vaccinated people over the entire period compared to those who received a placebo (66 and 132 per 100,000 person-years). More advanced vaccines, including those from M. hominis, are being developed.

Contraindications to the use of the tuberculosis vaccine

Contraindication to BCG vaccination is prematurity (as well as intrauterine hypotrophy of 3-4 degrees) - body weight at birth less than 2500 g. The use of BCG-M vaccine is permissible starting from a weight of 2000 g. Premature babies are vaccinated when the initial body weight is restored - the day before discharge from the maternity hospital (3rd stage department). In newborns, exemption from BCG is usually associated with purulent-septic disease, hemolytic disease, severe CNS lesions.

Contraindication to vaccination - primary immunodeficiency - it should be remembered if other children in the family had a generalized form of BCGitis or death from an unclear cause (probability of immunodeficiency). WHO does not recommend vaccinating children of HIV-infected mothers before their HIV status is determined (although it does recommend such practice in regions with high tuberculosis infection rates when it is impossible to identify HIV-infected children). Although perinatally infected HIV children remain immunocompetent for a long time and the vaccination process proceeds normally, if they develop AIDS, generalized BCGitis may develop. Moreover, during chemotherapy of HIV-infected children, 15-25% develop "inflammatory syndrome of immune reconstitution" with multiple granulomatous foci.

It is important to avoid subjective approaches to the exclusion of newborns from BCG and to organize vaccinations at the second stage of nursing, since it is among unvaccinated children (there are only 2-4%) that the majority of severe forms of tuberculosis are registered and up to 70-80% of all deaths.

Contraindications for revaccination are:

1. Immunodeficiency states, malignant blood diseases and neoplasms. When prescribing immunosuppressants and radiation therapy, vaccination is carried out no earlier than 12 months after the end of treatment.
2. Active or past tuberculosis, mycobacterial infection.
3. Positive and questionable Mantoux reaction with 2 TE PPD-L.
4. Complicated reactions to a previous administration of the BCG vaccine (keloid scars, lymphadenitis, etc.).

In the presence of an acute or exacerbation of a chronic disease, vaccination is carried out 1 month after its end. In case of contact with an infectious patient, vaccinations are carried out after the quarantine period (or the maximum incubation period).

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Reaction to the introduction of the tuberculosis vaccine and complications

Reactions

At the site of intradermal administration of BCG and BCG-M, an infiltrate of 5-10 mm in size develops with a nodule in the center and a smallpox-type crust, sometimes a pustule or small necrosis with scanty serous discharge. In newborns, the reaction appears after 4-6 weeks; after revaccination, sometimes already in the 1st week. The reverse development occurs within 2-4 months, sometimes longer; 90-95% of those vaccinated have a scar of 3-10 mm in size.

Complications

Complications are divided into 4 categories:

1. Local lesions (subcutaneous infiltrates, cold abscesses, ulcers) and regional lymphadenitis.
2. Persistent and disseminated BCG infection without a fatal outcome (lupus, osteitis, etc.).
3. Disseminated BCG infection, a generalized lesion with a fatal outcome, which is observed in congenital immunodeficiency.
4. Post-BCG syndrome (manifestations of a disease that occurs shortly after BCG vaccination, mainly of an allergic nature: erythema nodosum, annular granuloma, rashes, etc.).

Among all post-vaccination complications in Russia, the majority are associated with BCG, their number is about 300 cases per year (0.05 - 0.08% of those vaccinated).

The decrease in the indicator compared to 1995 occurred against the background of the introduction of a new registration method, as evidenced by the increase in the number of complications in 1998-2000.

Among children with local complications, there are 3 times more BCG-vaccinated than BCG-M-vaccinated, which indicates the greater reactogenicity of the former (although there is no precise data on the proportion of those vaccinated with different vaccines), which served as the basis for the transition to the use of BCG-M for vaccinating newborns.

Complication rate per 100,000 in 1995 and 2002-2003.

Complication	Vaccination		Revaccination
	1995	2002-03	1995	2002-03
Lymphadenitis	19.6	16.7	2.9	1.8
Infiltrate	2.0	0.2	1,1	0.3
Cold abscess	7.8	7.3	3.9	3.2
Ulcer	1.0	0.3	2.5	0.7
Keloid, scar	0.2	0,1	0.6	0.2
Osteitis	0,1	3.2	-	-
Generalized BCG-itis	-	0.2	-	-
All	30.9	28.1	10.9	6.1

Only 68% of children with complications from those vaccinated for the first time were vaccinated in the maternity hospital, 15% - in the polyclinic, although only 3% of children are vaccinated there. Obviously, this is due to less experience with intradermal injections among nurses at polyclinics; the risk of complications in specially trained personnel is 4 times lower than in those who have not undergone training. The disproportionately large number of children with complications vaccinated in the polyclinic dictates the need for maximum coverage of children with vaccination before discharge from the maternity hospital or neonatal care department.

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Clinical forms of post-vaccination complications

Ulcer - a defect of the skin and subcutaneous tissue at the site of vaccine administration measuring 10-30 mm, the edges are undermined. Ulcers are rarely (2.7%) considered a serious complication. Ulcers are more often reported during revaccination, BCG-M practically does not cause ulcers.

Infiltrate of 15-30 mm or more in size, there may be ulceration in its center, often with enlargement of regional lymph nodes. And this complication is rarely recorded (1.5%), every third child with infiltrate was vaccinated in the clinic.

Cold abscess (scrofuloderma) is a painless formation with fluctuation without skin changes, often with enlarged axillary lymph nodes, rarely with a fistula. In the non-fistulous form, 76% were children under 1 year old, 16% - 5-7 years old, 8% - 13-14 years old. Only 60% of infants were vaccinated in the maternity hospital, 40% - in the clinic.

Lymphadenitis - occurs mainly in young children. The enlargement of the lymph nodes is painless, more than 10 mm (abroad only more than 15 mm are taken into account); a size of 20-40 mm was observed in 17% of children. Their consistency is initially soft, later dense. The skin above them is unchanged or pinkish. The process can be accompanied by caseation with a breakthrough of caseous masses to the outside and the formation of a fistula. 80% of children were vaccinated in the maternity hospital, 10% - in the clinic, 2.4% - in the hospital, 4% - at school. The proportion of those vaccinated with the BCG vaccine - 84% - was significantly higher than among children with infiltrates and abscesses. Localization: in 87% - left-sided axillary, 5% - supra-, rarely - subclavian nodes on the left, in the cervical and right axillary.

Fistulous forms of lymphadenitis were observed only in children under 1 year of age after vaccination. 90% of children were vaccinated in the maternity hospital, 10% in the clinic, and 90% with the BCG vaccine.

Keloid scar is a tumor-like formation at the site of vaccine administration, rising above the skin level. Unlike a scar during the normal course of the vaccination process, a keloid has a cartilaginous consistency with clearly visible capillaries and a smooth, glossy surface from pale pink, pink with a bluish tint, to brownish; sometimes accompanied by itching. They make up 1.5% of the total number of complications, 3/4 of them after the 2nd and only 1/4 after the 1st revaccination.

Osteitis is an isolated foci in bone tissue, most often located in the femur, humerus, sternum, and ribs.

Although to prove the connection between osteitis and BCG it is necessary to obtain a mycobacterium culture and type it. The Order of the Ministry of Health and Social Development of the Russian Federation No. 109 of March 21, 2003 determines that "if it is impossible to verify the causative agent M. bovis BCG, the diagnosis of post-vaccination complication is established on the basis of a comprehensive examination (clinical, radiological, laboratory)". A practical criterion that allows one to reasonably assume the post-vaccination etiology of the bone process is the limitation of the lesion in a child aged from 6 months to 1-2 years, who does not have other tuberculosis lesions. This approach is quite justified, since infection with tuberculosis at this age is accompanied by the development of generalized and / or pulmonary forms of the disease, and bone lesions, if they occur, are multiple (Spina ventosa). Until recently, many cases of BCG osteitis in Russia were registered as bone tuberculosis, which allowed them to be treated free of charge; therefore, the report of 132 cases of osteitis over 7 years should be compared with the number of cases of "isolated bone tuberculosis" in children aged 1-2 years. The need to diagnose bone tuberculosis instead of BCG osteitis disappeared due to the publication of the Order of the Ministry of Health of the Russian Federation dated 21.03.2003 No. 109, which most likely led to an increase in the registration of BCG osteitis, the share of which among all complications reached 10%.

In 2002-03, 63 cases of osteitis were registered, and during the same years, 163 cases of isolated bone tuberculosis in children under 2 years of age were identified, i.e., in total, we can talk about 226 cases. During these years, 2.7 million newborns were vaccinated, so that when converted to the number of primary vaccinated, the frequency was 9.7 per 100,000.

According to foreign sources, the frequency of osteitis and non-lethal disseminated forms after BCG vaccination has a very wide range, according to WHO - from 1:3,000-1:100 million, a smaller range is also indicated - 0.37-1.28 per 1 million vaccinated. Our data on the frequency of osteitis are comparable only with the data published at the time in Sweden (1.2-19.0 per 100 thousand vaccinated), the Czech Republic (3.7) and Finland (6.4-36.9), which served as the basis for the cancellation of BCG vaccination there; in Chile, with an osteitis frequency of 3.2 per 100,000, vaccination of newborns was not stopped.

Osteitis cases were observed mainly in children under 1 year of age. Most children were vaccinated in the maternity hospital (98%). 85% of patients received the BCG vaccine, 15% received the BCG-M vaccine. Surgical treatment was required in 94% of children.

During immunological examination (Institute of Immunology of the Ministry of Health and Social Development of the Russian Federation) of 9 children with osteitis, chronic granulomatous disease (CGD) was detected in 1 child, and deficiency of interferon-γ production was detected in 4 children. The remaining children had less severe disturbances in the interferon-γ system: inhibition factors, impaired receptor activity, IL-12 receptor defect, and deficiency of surface molecules involved in the response to PHA. These defects are known to be detected in generalized complications of BCG, and their carriers are characterized by increased susceptibility to mycobacterial infections. Therefore, there is no reason to associate these complications with defects in vaccination technique, with the combination of tuberculosis and hepatitis B vaccinations in newborns, and, especially, with the quality of the vaccine (cases of osteitis are isolated and occur when using different series of vaccines).

Generalized BCG-itis is the most severe complication of BCG vaccination, occurring in newborns with defects in cellular immunity. Foreign authors cite the frequency of generalized BCG-itis as 0.06 - 1.56 per 1 million vaccinated.

Over 6 years, 4 such complications have been registered in Russia (0.2% of their total number). During this period, about 8 million newborns received primary vaccination, so the frequency of generalized BCG-itis was about 1 per 1 million vaccinations.

Most often, children are diagnosed with chronic granulomatous disease, less often hyper IgM syndrome, total combined immunodeficiency (1 child successfully underwent bone marrow transplantation). Boys accounted for 89%, which is natural, since chronic granulomatous disease has X-linked heredity. All children were under 1 year of age. Children were most often vaccinated in the maternity hospital with BCG or BCG-M vaccines.

The possible interaction of BCG and hepatitis B vaccines when administered in the neonatal period has been discussed for a number of years. Most experts, based on domestic and foreign data, have rejected the possibility of an unfavorable result of such a combination, which is not supported by facts. This position was confirmed by Order No. 673 of October 30, 2007.

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