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Canadian Immunization Guide
Seventh Edition - 2006
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Part 4
Active Immunizing Agents
Bacille Calmette-Guérin (BCG) Vaccine
Tuberculosis (TB), a communicable bacterial disease caused by Mycobacterium tuberculosis, results in diverse clinical manifestations, including pneumonia, meningitis, osteomyelitis and disseminated infection. Latent infection that reactivates later in life can also occur. BCG vaccine, derived from an attenuated strain of living bovine tubercle bacillus, is one of the mostly widely used vaccines in the world and is currently given at or soon after birth to children in over 100 countries to minimize the potential for serious forms of TB disease.
Since the publication of the 2002 Canadian Immunization Guide, in which BCG vaccine was recommended for infants and children in groups with rates of new infection in excess of 1% per year, case review of adverse events associated with BCG vaccine has raised concerns that routine neonatal vaccination in First Nations and Inuit communities could be associated with unacceptable health risks. The National Advisory Committee on Immunization (NACI) subsequently revised its recommendation for usage of BCG vaccine in 2004 (see Recommended Usage).
Epidemiology
The reported incidence of TB in Canada has been in significant decline since a peak in the early 1940s (Figure 1). In 2003, 1,630 cases of TB were reported, representing an incidence rate of 5.1 per 100,000. In that year 4.8% of cases (78/1630) were < 15 years of age, and the corresponding age-specific incidence of these cases was 1.3 per 100,000 (Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada [PHAC], Ottawa).
TB is a leading cause of morbidity and mortality worldwide. There is growing global concern about the emergence of drug-resistant strains, which are threatening to make TB incurable again; moreover, the resurgence of the disease is being accelerated by the spread of human immunodeficiency virus (HIV). In 1993, the World Health Organization (WHO) declared tuberculosis to be a "global emergency".
The distribution of risk for TB disease in the Canadian population has changed over recent decades. The Canadian-born non-Aboriginal population is generally at low risk, as TB now occurs in certain geographic areas and demographic groups that can be considered "high risk groups". These include homeless persons and illicit drug users, immigrants from areas with a high incidence of infectious TB, and Canadian-born Aboriginal peoples.
TB control measures include 1) early identification of people with active (infectious) disease and treatment of each case until cured using directly observed therapy (DOT); 2) treatment of latent TB infection in those who are recently infected or are otherwise at high risk to progress from infection to disease; (3) infection prevention and control measures in health care facilities and other institutions to prevent nosocomial/institutional spread; and (4) BCG vaccination of selected population groups to prevent serious complications of infection.
Preparations approved for use in Canada
This chapter will deal only with vaccines that are currently marketed in Canada:
- BCG Vaccine (bacillus Calmette-Guérin vaccine, freeze-dried), Sanofi Pasteur Ltd.
BCG vaccine is made from a culture of an attenuated strain of living bovine tubercle bacillus (bacille Calmette-Guérin). It is supplied in a multidose vial as a freeze-dried product, which is reconstituted with a supplied diluent of sterile phosphate-buffered saline.
Efficacy and immunogenicity
Although there are many BCG vaccines available in the world, all are derived from the original strain. These vaccines may vary in immunogenicity, efficacy and reactogenicity. No laboratory markers exist that correlate with protection against TB infection or disease. As well, neither the presence nor the size of the tuberculin skin test reaction predicts protection. The efficacy of BCG vaccine is estimated from prospective clinical trials and retrospective case-control studies. Although clinical trials have demonstrated conflicting results with regard to estimating BCG vaccine efficacy, meta-analytic reviews have estimated the vaccine efficacy to be 51% (95% confidence interval [CI] 30%-66%) in preventing any TB disease. In newborns the protective effect of BCG vaccine against TB compared with that in unvaccinated children is estimated at 74% (95% CI 62%-83%) and 64% (95% CI 30%-82%) for meningitis, and up to 78% (95% CI 58%-88%) for disseminated disease.
The protective effect of immunization increases with increased distance from the equator. The significance of this finding is unclear at present. Many factors have been considered to explain variations among studies, including BCG strain, infection with non-tuberculous mycobacteria, climate, storage of vaccine, vitamin D intake, sunlight exposure, and population genetics. BCG strain differences were not an independent risk factor in the meta-analyses.
BCG vaccine does not provide permanent or absolute protection against TB. The disease should be considered as a possible diagnosis in any vaccinee who presents with a suggestive history, or signs or symptoms of TB, regardless of immunization history.
Lyophilized preparations of BCG for intravesical use in the treatment of primary and relapsed carcinoma in situ of the urinary bladder are formulated at a much higher strength and must not be used for TB vaccination purposes.
Recommended usage
Because BCG immunization usually results in a significant (positive) tuberculin skin test, the benefits gained by immunization must be carefully weighed against the potential loss of the tuberculin test as a primary tool to identify infection with M. tuberculosis. In Canada, TB rates are relatively low, and the tuberculin skin test (Mantoux 5 tuberculin units of purified protein derivative) has become increasingly useful as an epidemiologic, case-finding and latent TB infection diagnostic tool. BCG should be given only to people with a non-significant (negative) tuberculin skin test. Infants < 6 weeks of age do not need to be tuberculin tested before receiving BCG vaccine, since reactivity does not develop before this age. BCG immunization will not prevent the development of active TB in individuals who are already infected with M. tuberculosis.
NACI does not recommend routine use of BCG vaccine in any Canadian population. However, in the following settings, consideration of local TB epidemiology and access to diagnostic services may lead to the decision to offer BCG vaccine:
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BCG vaccine may be considered for infants in First Nations and Inuit communities or infants residing among groups of persons with an average annual rate of smear-positive pulmonary TB greater than 15 per 100,000 population (all ages) during the previous 3 years, or infants residing in populations with an annual risk of TB infection greater than 0.1%, if early identification and treatment of TB infection are not available. Human immunodeficiency virus (HIV) antibody testing in the mother of the child should be negative, and there should be no evidence or known risk factors for immunodeficiency in the child being vaccinated, including no family history of immunodeficiency. This rate of smear-positive pulmonary TB, 15 per 100,000, is the same rate as that recommended by the Canadian Tuberculosis Committee and the PHAC for designating geographic areas outside Canada as having a high incidence of infectious TB. It is approximately five times higher than the general Canadian smear-positive pulmonary TB rate as estimated by the WHO. For information on international smear-positive pulmonary TB incidence rates, refer to http://www.phac-aspc.gc.ca/tbpc-latb/.
The annual risk of TB infection quoted above, of > 0.1%, is the incidence below which the International Union Against Tuberculosis and Lung Disease recommends that selective discontinuation of BCG vaccination programs be considered. If BCG vaccination is currently offered to all infants in a community that does not meet one of the above criteria, the vaccination program should be discontinued as soon as a program of early detection and treatment of latent TB infection can be implemented.
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Individuals, including health care workers and laboratory workers, repeatedly exposed to persons with untreated, inadequately treated or drug-resistant active TB or tubercle bacilli in conditions where protective measures against infection are not feasible (although primary treatment of the source, removal from the source or prophylaxis of the exposed person is generally preferred) may benefit from BCG vaccine. Consultation with a TB and/or infectious disease expert is recommended.
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BCG vaccine may be considered for travelers planning extended stays in areas of high TB incidence, particularly when a program of serial tuberculin skin testing and appropriate chemotherapy is not possible or where the prevalence of drug resistance, particularly multidrug-resistant (MDR) TB, is high. This decision should be made in consultation with an infectious disease or travel medicine specialist. Those planning to live for more than 12 months in a high prevalence area may opt for skin testing on an annual basis or 8-12 weeks after returning home. Preventive therapy according to current guidelines should be considered if tuberculin skin test conversion occurs. Factors that favour the BCG option might include poor access to repeat skin testing, personal preference against taking isoniazid (INH), contraindications to taking INH such as liver disease or previous intolerance to INH, and the limited number of treatment options if infected with an MDR strain. The efficacy of BCG vaccine in adults is uncertain. Travelers with medical conditions, particularly HIV infection, that may be associated with an increased risk of progression of latent TB infection to active disease should carefully weigh, with their physician, the risk of travel to a high-incidence area in determining the most appropriate means of prevention.
Schedule and dosage
The recommended dose is 0.05 mL (0.05 mg) in infants < 12 months of age. In persons > 12 months of age the dose is 0.1 mL (0.1 mg). Instructions in the manufacturer's product insert for suspending and administering vaccine should always be followed.
Route of administration
BCG vaccine is given as a single intradermal injection over the deltoid muscle of the arm. It is administered in a 1.0 mL syringe with a 26-gauge needle, the bevel facing upwards.
Booster doses and re-immunization
Re-immunization with BCG is not recommended. Tuberculin skin testing should not be used as a method to determine whether previously administered BCG immunization was effective.
Serologic testing
There is no indication for pre- or post-immunization serology.
Storage requirements
Before reconstitution, BCG vaccine should be kept in a refrigerator at +2º to +8º C. The vaccine is reconstituted by introducing the supplied diluent into the vaccine vial using aseptic technique. Detailed instructions for maintaining aseptic technique while handling the multidose vial are provided in the product insert. Reconstituted product must be maintained at +2º to +8º C and used within 8 hours or discarded. Neither freeze-dried nor reconstituted vaccine should be exposed to direct or indirect sunlight, and exposure to artificial light should be minimized.
Simultaneous administration with other vaccines
BCG should not be given within 4 weeks after administration of any live vaccine, since these vaccines are known to suppress the immune response, resulting in lowered immunogenicity. Live vaccines (e.g., MMR) may be given simultaneously with BCG, administered at a different site. Simultaneous administration of the inactivated vaccines against diphtheria, pertussis, tetanus and polio does not interfere with the immune response to BCG vaccine, therefore these vaccines may be given at the same time at a different site.
Adverse reactions
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.
The usual response to (intradermal) administration of BCG vaccine is the development of erythema and either a papule or ulceration, followed by a scar at the immunization site.
Most reactions are generally mild and do not require treatment. Adverse reactions are more common in young vaccinees (infants versus older children) and are frequently related to improper technique in administration (mainly improper dilution). Reactions may include persistent or spreading skin ulceration at the immunization site, regional lymphadenopathy and keloid formation.
Moderately severe reactions, such as marked lymphadenitis or suppurative adenitis, occur in 0.2 to 4.0 per 1,000 vaccinees. Rates of adverse reactions appear to vary with the strain of vaccine, dose and method of immunization, and the age of the recipient. A review of published and unpublished data, including a survey sponsored by the International Union Against Tuberculosis and Lung Disease, recorded 10,371 complications following almost 1.5 billion BCG vaccinations in adults and children. The most serious complication of BCG vaccination was disseminated BCG infection, which occurred in 3.0 per 1 million recipients. In that review dissemination was fatal in 0.02 per 1 million vaccine recipients and occurred in children who had had primary immunodeficiencies.
A review of adverse events associated with BCG vaccine in Canada was conducted by the PHAC's Advisory Committee on Causality Assessment (ACCA) after case reports of disseminated BCG infection had been identified by the IMPACT (Immunization Monitoring Program ACTive) system of hospital-based surveillance. IMPACT identified 21 BCG vaccine-related adverse events between 1993 and 2002, which were reviewed by ACCA. Fifteen of these were designated as serious (patient died or was in hospital for 3 or more days), consisting of six cases of disseminated BCG disease (five in First Nations and Inuit children, all of whom subsequently died), two cases of osteomyelitis, five abscesses and two cases of adenitis. In assessing causality, 14 of the 21 cases were deemed "very likely-certainly" associated with the vaccine (including the six disseminated cases), five were probably associated with the vaccine, one was possibly associated with the vaccine and one could not be classified. An additional fatal case of disseminated BCG was identified in 2003 and assessed by ACCA as "very likely-certainly" associated with the vaccine.
Contraindications and precautions
BCG immunization is contraindicated in persons with immune deficiency diseases, including congenital immunodeficiency, HIV infection, altered immune status due to malignant disease, and impaired immune function secondary to treatment with corticosteroids, chemotherapeutic agents or radiation. Extensive skin disease or burns are also contraindications. BCG is contraindicated for individuals with a positive tuberculin skin test, although immunization of tuberculin reactors has frequently occurred without incident. Before a newborn is vaccinated with BCG vaccine the mother must be known to be HIV negative, and there should be no family history of immunodeficiency. Clues that an inherited immunodeficiency may be present in a family include a history of neonatal or infant deaths in the immediate or extended family. Immunization of pregnant women should preferably be deferred until after delivery, although harmful effects on the fetus have not been observed. The vaccine should not be administered to individuals receiving drugs with anti tuberculous activity, since these agents may be active against the vaccine strain.
Other considerations
When interpreting tuberculin skin test results, there are at least three considerations: 1) size of the reaction; 2) predictive value of a positive test based on the relative likelihood of true-positive and false-positive reactions; and 3) risk of development of active TB. The following is based on the Canadian Tuberculosis Standards, produced by the Canadian Lung Association/ Canadian Thoracic Society and PHAC (2006 edition; in press).
Previous BCG vaccination may be the cause of a false-positive result. Vaccine may have been received by several population groups, including immigrants from many European countries and most developing countries. In Canada, many Aboriginal Canadians and persons born in Quebec and Newfoundland and Labrador from the 1940s until the late 1970s were vaccinated. For information on current and historical BCG vaccine usage in Canada by province/territory, refer to <http://www.phac-aspc.gc.ca/tbpc-latb>.
Studies conducted in Canada and in several other countries reveal that if BCG vaccine is received in infancy (the first year of life), it is very unlikely to cause tuberculin skin test reactions of 10 mm or more in persons aged ≥ 5 years. Therefore, a history of BCG immunization received in infancy can be ignored in all persons in this age range when interpreting a tuberculin skin test result of 10 mm or greater. If the BCG immunization was received between the ages of 1 and 5 years, persistently positive tuberculin skin test reactions will be seen in 10% to 15% of subjects even 20 to 25 years later. Among subjects vaccinated at the age of ≥ 6 years, up to 40% will have persistent positive reactions. BCG-related reactions may be as large as 25 mm or even greater. Therefore, if BCG immunization was received after the first year of life, it can be an important cause of false-positive tuberculin skin test reactions, particularly in populations in which the expected prevalence of TB infection (i.e., true positive reactions) is less than 10%.
In summary, BCG immunization can be ignored as a cause of a positive tuberculin skin test under the following conditions:
- BCG vaccine was given during infancy, and the person tested is now aged ≥ 5 years;
- the person is from a group with a high prevalence of TB infection (true positives), e.g., close contacts of an infectious TB case, Aboriginal Canadians from a high-risk community, immigrants from countries with a high incidence of TB;
- the person has a high risk of progression to disease if infected (refer to Canadian Tuberculosis Standards for further details).
BCG should be considered the likely cause of a positive tuberculin skin test if BCG vaccine was given after 12 months of age AND there has been no known exposure to an active TB case or other risk factors AND the person is either Canadian-born non-Aboriginal OR an immigrant from a country with low TB incidence (e.g., Western Europe, USA, etc.).
Selected references
Brewer TF, Colditz GA. Relationship between bacille Calmette-Guérin (BCG) strains and the efficacy of BCG vaccine in the prevention of tuberculosis. Clinical Infectious Diseases 1995;20(1):126-35.
Canadian Lung Association/Canadian Thoracic Society, Public Health Agency of Canada. Canadian tuberculosis standards, 6th edition. Ottawa (Canada): Canadian Lung Association and Government of Canada; in press.
Ciesielski SD. BCG vaccination and the PPD test: what the clinician needs to know. Journal of Family Practice 1995;40(1):76-80.
Colditz GA, Berkey CS, Mosteller F et al. The efficacy of bacillus Calmette-Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics 1995;96:29-35.
Colditz GA, Brewer TF, Berkey CS et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. Journal of the American Medical Association 1994;271(9):698-702.
Deeks SL, Clark M, Scheifele D et al. Serious adverse events associated with bacille Calmette-Guérin vaccine in Canada. Pediatric Infectious Disease 2005;24(6):538-41.
Fine PE. Bacille Calmette-Guérin vaccines: a rough guide. Clinical Infectious Diseases 1995;20(1):11-14.
Houston S, Fanning A, Soskolne CL et al. The effectiveness of bacillus Calmette-Guérin (BCG) vaccination against tuberculosis: a case-control study in Treaty Indians, Alberta, Canada. American Journal of Epidemiology 1990;131(2):340-48.
Lotte A, Wasz-Hockert O, Poisson N et al. BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Advances in Tuberculosis Research 1984;21;107-93.
National Advisory Committee on Immunization. Statement on Bacille Calmette-Guérin (BCG) vaccine. Canada Communicable Disease Report 2004;30(ACS-5):1-12.
O'Brien KL, Ruff AJ, Louis MA et al. Bacille Calmette-Guérin complications in children born to HIV-1 infected women with a review of the literature. Pediatrics 1995;95(3):414-18.
Pabst HF, Godel J, Grace M et al. Effect of breast-feeding on immune response to BCG vaccination. Lancet 1989;1(8633):295-97.
World Health Organization. Global tuberculosis programme and global programme on vaccines. Statement on BCG revaccination for the prevention of tuberculosis. Weekly Epidemiological Record 1995;70(32):229-31.
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