ARCHIVED - Statement on Bacille Calmette Guérin (BCG) Vaccine
Canada Communicable Disease Report
An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)*
Volume 30 • ACS-5, 1 December 2004
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering or using the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the conflict of interest policy, including yearly declaration of potential conflict of interest.
Bacille Calmette-Guérin (BCG) vaccine is one of the most 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(1). In Canada, targeted newborn BCG immunization programs exist in some First Nations and Inuit communities and the vaccine is offered to individuals in certain high-risk settings. Since the preparation of the 2002 Canadian Immunization Guide, in which vaccine was recommended for infants and children in groups with rates of new infection in excess of 1% per year, careful review of adverse events associated with BCG vaccine has raised concerns that routine neonatal immunization in First Nations children could be associated with unacceptable health risks. In this statement, NACI reviews the indications for BCG vaccine in Canada in the light of current epidemiology and understanding of adverse events associated with the vaccine.
Tuberculosis (TB) is estimated to result in 8.3 million new cases and almost 2 million deaths worldwide annually, making it the second leading cause of death globally from an infectious disease(2). There is growing concern about the emergence of multidrug-resistant strains, which threaten to make TB much more difficult to cure, and about resurgence of disease being accelerated by the spread of HIV. In 1993, the World Health Organization (WHO) declared TB to be a "global emergency".
In Canada, the reported incidence of TB has been in significant decline since a peak in the early 1940s (Figure 1). In 2002, 1,634 cases of TB were reported representing an incidence rate of 5.2 per 100,000. In that year 5.7 % (93/1,634) of cases were < 15 years of age and the corresponding incidence of these cases was 1.6 per 100,000 (Centre for Infectious Disease Prevention and Control, Ottawa: Health Canada, 2004.)
Figure 1. Tuberculosis incidence and mortality rate - Canada: 1924-2002
The distribution of risk for TB disease among the Canadian population has changed over recent decades. The Canadian-born non-aboriginal population is at low risk of TB; in Canada in 2002 the rate of disease was 1 case per 100,000. TB now occurs in certain geographic areas and demographic groups that can be considered "high-risk groups." These include the homeless and substance abusers, immigrants from areas with a high prevalence of TB and Canadian-born Aboriginal Peoples.
In the 2001 Canadian census, foreign-born persons represented 19% of the Canadian population. In 2002, persons of foreign birth accounted for 67% of all reported TB cases in Canada. Reported rates varied by region but were highest among those from the WHO Africa region (53.5/100,000). Over 75% of foreign-born cases were reported from metropolitan areas in British Columbia, Ontario, and Quebec (Health Canada, Tuberculosis Prevention and Control, 2003).
Canadian-born Aboriginal Peoples, including Status Indians, non-Status Indians, Metis and Inuit, represented 3% of the overall population but accounted for 15% of the national disease burden in 2002. The majority of cases in Manitoba, Saskatchewan, the Northwest Territories, and Nunavut were of Aboriginal origin. While the overall risk for TB has decreased among Status Indians living on-reserve (i.e. First Nations communities) from 80 cases per 100,000 persons in 1990 to 30 per 100,000 in 2000, the risk is not uniform. Between 1997 and 2000, 38% of TB cases in Canadian-born Aboriginal persons were reported from only 10 communities. In northern Saskatchewan, for example, the rate of TB in 2002 for Status Indians living on-reserve remained elevated at 117 per 100,000(3). The incidence of TB among Inuit persons continues to be high. In 2002, it was 71.1 per 100,000.
Among the Aboriginal population, TB disease is more often reported in the younger age groups (21.7% of all reported cases are < 14 years of age compared to 7% among Canadian-born non-Aboriginals and 2% among the foreign born). The incidence of the more serious forms of disease, such as meningeal and miliary TB in children < 10 years of age, is shown in Figure 2.
Figure 2. Meningeal and miliary tuberculosis among Canadian-born Aboriginal children (0-9 years of age) in Canada: 1970-2002
*Accurate population data not available prior to 1991.
Denominator: Canadian-born Aboriginal children < 10 years of age.
Source: Indian and Northern Affairs Canada.
Background: Role of BCG vaccine in the TB control and elimination strategy
Control of TB in a population requires a multidimensional approach whose major emphasis is to minimize risk of transmission by the early identification of people with active infectious disease and the treatment of each case until cured using directly observed therapy (DOTS)(4). Secondly, preventive treatment for those with latent infection but without active disease should be given, when appropriate, to prevent progression to active TB disease. This preventive treatment is also known as treatment of latent TB infection (LTBI) or TB prophylaxis. Infection control measures should be used in health care facilities and other institutions to prevent nosocomial/institutional spread. Finally, BCG vaccination of selected population groups is used to prevent serious complications of infection.
Immunization with BCG is thought to reduce hematogenous spread of Mycobacterium tuberculosis from the site of primary infection. If it occurs, hematogenous spread may result in serious disease, such as miliary TB and TB meningitis(5). This decrease in risk of serious disease is important for young children since they are at increased risk of progression to active disease. Infected children < 12 months have a 43% risk of progression to active disease, 1-to 5-year olds have a 24% risk and adolescents, a 15% risk(6).
BCG is used in TB control programs primarily to prevent serious complications of infection (e.g. meningitis, military disease) in persons with undiagnosed disease who do not have access to early identification and treatment or where TB control programs have been tried and not been successful. The WHO's Expanded Programme on Immunization recommends that BCG vaccine be given as a single dose as soon as possible after birth in all populations at high risk.
In 1992, Health Canada's First Nations and Inuit Health Branch (FNIHB) released its Tuberculosis Elimination Strategy in partnership with the Assembly of First Nations. The goal of this strategy is to eliminate the disease from Aboriginal peoples in Canada by reducing incidence to below 1 per 100,000 among the First Nations on-reserve population. As part of a comprehensive public health approach, the strategy includes offering BCG vaccine to newborn First Nations infants, particularly those living on-reserve, on a routine basis(4). Vaccine coverage currently varies widely from no immunization to 80% of newborns in different communities.
As TB rates have fallen many countries have discontinued routine BCG programs(7) because of their high cost: benefit ratio, adverse reactions associated with BCG immunization or because such programs have hindered investigation of TB transmission through tuberculin skin testing. In Canada newborn BCG vaccination of First Nations' infants has been discontinued in the Atlantic provinces and is being phased out in the Pacific region. The International Union Against Tuberculosis and Lung Disease developed guidelines to assist low prevalence countries in decision making(8). These criteria include the following:
The average annual notification rate of sputum smear-positive pulmonary TB should be 5 cases/100,000 population or less during the previous 3 years; OR
The average annual notification rate of TB meningitis in children < 5 years of age should be less than 1 case per 10 million general population over the previous 5 years; OR
The average annual risk of TB infection should be 0.1% or less.
Review of adverse reactions and safety, including events reported from Canadian First Nations communities
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. Reactions may include persistent or spreading skin ulceration, inflammatory adenitis and keloid formation. Regional lymphadenopathy may occur. Moderately severe reactions, such as marked lymphadenitis or suppurative adenitis, occur in 0.2 to 4.0 per 1,000 vaccines. Rates of adverse reactions appear to vary with the strain of vaccine, dose and method of immunization, and the age of the recipient(7). Adverse reactions are more common in young vaccinees (infants versus older children) and are frequently related to improper technique in administration (mainly improper dilution).
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(9). The most serious complication of BCG vaccination was disseminated BCG infection, which occurred in three per million recipients. In that review, dissemination was fatal in 0.02 per million vaccine recipients due to primary immunodeficiencies. The risk for developing serious adverse events varies by country.
A review of adverse events associated with BCG vaccine in Canada has recently been completed by the Agency's Advisory Committee on Causality Assessment (ACCA) subsequent to case reports of disseminated BCG infection identified by the IMPACT (Immunization Monitoring Program-Active) system of hospital-based surveillance(10, 11). IMPACT identified 21 BCG vaccine-related adverse events between 1993 and 2002, which were reviewed by ACCA; 15 of these were designated as serious (patient died or was in hospital for 3 or more days). The serious cases were 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.
Health Canada's First Nations and Inuit Health Branch (FNIHB) has also reviewed its data on adverse event rates for BCG in First Nations children on-reserve and calculated estimates of the incidence of adverse events(12). The period 1996-2000 was chosen for the FNIHB analysis because data on doses of BCG administered to First Nations children on-reserve are available for that period (n = 4,622 doses). This denominator is likely an underestimate since it does not capture all the doses administered by non-FNIHB providers, such as hospitals and other health care providers. The estimates of selected adverse event rates associated with BCG vaccine use in First Nations children compared to estimated global rates taken from the medical literature(9,13-16) are seen in the Table 1. The range of estimates for adenitis and osteitis encompass the global estimates and can be interpreted as evidence that the rates of these complications in First Nations children are consistent with global rates. By contrast, the rate of disseminated BCG in First Nations children is much greater than the highest global estimate (1.56/million doses)(17), which suggests that Canadian First Nations children are at higher risk for this complication of BCG vaccine than children in other parts of the world. Since disseminated BCG infection is a known complication of the vaccine in immunocompromised persons(18-19), the high rate suggests that immunodeficiency states may be more common in First Nations children. The risk of disseminated BCG infection should be considered in evaluating the risks and benefits of routine infant BCG immunization in Canada.
Adverse event (AE)
Absolute number of AE
Canadian First Nations on-reserve AE/million doses BCG (95% CI)
Global estimates of AE/million doses BCG(9,13-16)
1.7 - 72.9
0.19 - 1.56
Preparations approved for immunization
The only vaccine approved for use in Canada is BCG Vaccine (freeze-dried) (Aventis Pasteur Ltd.). BCG vaccine is made from a culture of an attenuated strain of living bovine tubercle bacillus (bacille Calmette-Guerin). It is supplied in a multidose vial as a freeze-dried product, which is reconstituted with a supplied diluent of sterile phosphate-buffered saline.
Storage and handling
Before reconstitution, BCG vaccine should be kept in a refrigerator at +2° to +8° 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 monograph. Reconstituted product must be maintained at +2° to +8° 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.
Route of administration and dosage
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 with the bevel facing upwards. The recommended dose is 0.05 mL (0.05 mg) in children < 12 months of age. In persons > 12 months of age the dose is 0.1mL (0.1 mg).
Efficacy and immunogenicity
No laboratory markers exist that correlate with protection against TB infection or disease. As well, neither the presence nor size of the TB skin test predicts immunity to disease(20). The efficacy of BCG vaccine is thus estimated from prospective clinical trials and retrospective case-control studies. Since many of these studies were performed decades ago, they often do not meet current methodologic standards. One large review of 1,264 publications describing BCG studies in newborns found that only 27 met strict criteria for methodology and minimum potential bias(21).
Studies have been done in different populations, with different age groups, disease surveillance criteria and vaccine strains. Although clinical trials have demonstrated conflicting results with regard to estimating BCG vaccine efficacy, reviews have estimated vaccine efficacy at up to 50% for preventing any TB disease, 64% for meningitis and up to 80% for disseminated disease in infants(21).
TB should always be suspected as a possible diagnosis by the clinician if a compatible history exists, regardless of immunization history.
Booster doses and reimmunization
Reimmunization with BCG is not recommended. There is no evidence that reimmunization with BCG confers additional protection; large studies in school children suggests it confers no protection(22,23). The WHO does not recommend reimmunization on the basis of absence of evidence of protection or lack of protection(24). Of note, tuberculin skin testing is not recommended as a method to evaluate immunogenicity because neither presence nor size of the skin reaction correlates with protection from TB, nor does it discriminate between M. tuberculosis infection and previous BCG immunization.
Administration with other vaccines
BCG must not be given within 4 weeks of the administration of any live vaccine because such vaccines may suppress the immune response resulting in lowered immunogenicity. Simultaneous administration of the inactivated vaccines against diphtheria, pertussis, tetanus and polio does not interfere with the immune response to BCG vaccine(5) and, therefore, these inactivated vaccines may be administered at the same time in a different site.
BCG vaccine is approved for the prevention of tuberculosis disease individuals who are repeatedly exposed to untreated or inadequately treated active TB; communities or groups of persons with high rates of infection, including First Nations, Metis and Inuit children in which other control measures have proven ineffective; health care workers at considerable risk of exposure to unrecognized infectious pulmonary TB or who handle tubercle bacilli or potentially infectious specimens in a laboratory; and for newborn infants whose mothers have infectious TB at the time of delivery (although isoniazid (INH) prophylaxis is preferred to avoid the necessary separation of mother and infant when BCG vaccine is used), if the mother's strain of TB is INH-resistant or if compliance with a program of INH prophylaxis cannot be assured.
NACI recommends that BCG vaccine no longer be routinely offered to infants in First Nations and Inuit communities. In each community, health authorities should consider local TB epidemiology and access to diagnostic services in deciding whether the advantage of immunization in preventing serious outcomes of infection (but not infection itself) is outweighed by the risk of disseminated BCG disease if that child has undiagnosed immunodeficiency.
NACI recommends BCG vaccine as follows:
In infants in First Nations and Inuit communities or groups of persons with an average annual rate of smear-positive pulmonary TB greater than 15 per 100,000 (all ages) population during the previous 3 years OR with an annual risk of TB infection > 0.1% if early identification and treatment of TB infection is not available. 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. This rate of smear-positive pulmonary TB, 15 per 100,000, is the same rate recommended by the Canadian Tuberculosis Committee and Health Canada for designating geographic areas outside Canada with a high prevalence of infectious TB. It is approximately five times higher than the general Canadian smear-positive pulmonary TB rate as estimated by the WHO(25). The annual risk of TB infection quoted above is that recommended by the International Union Against Tuberculosis and Lung Disease for selective discontinuation of BCG vaccination programs(8). 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.
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. Consultation with a TB and/or infectious disease expert is recommended.
Travellers planning extended stays in areas of high TB prevalence, particularly where a program of serial tuberculin skin testing and appropriate chemotherapy is not possible or where drug resistance to prophylactic regimens is high. This decision should be made in consultation with an infectious disease or travel medicine specialist.
BCG vaccination is contraindicated for people 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 irradiation. Specialist consultation should be sought if there is a family history of immunodeficiency, and careful benefit-risk assessment made before vaccinating. Extensive skin disease or burns are also contraindications. Although no adverse events in the fetus are known, immunization of pregnant women is not recommended. Individuals with a positive tuberculin skin test should not be immunized.
Public health issues, limitations of knowledge and areas for future study
BCG vaccine is intended only to prevent serious consequences of unrecognized infection in young children when TB identification and control programs are suboptimal. The ultimate goal of the TB elimination strategy developed by Health Canada's FNIHB in 1992 is to reduce the incidence of TB cases in First Nations on-reserve population to less than 1/100,000 by 2010. The main components of this effort should continue unabated: case identification and treatment, contact tracing and directly observed treatment, prophylaxis, surveillance , research, education and training.
Research on the resource requirements and health impacts of withdrawal of BCG vaccine should be undertaken and program discontinuation should be replaced with enhanced alternative TB prevention programs in First Nations and Inuit communities at high, medium and low risk of TB.
Given the higher than globally estimated rate of adverse events with BCG vaccine in First Nations children, research into the incidence and nature of immunodeficiency disorders is being done by FNIHB to determine if these are more common among First Nations children than in other populations.
Addendum by the First Nations and Inuit Health Branch, Health Canada
In April 2003, Health Canada's FNIHB held a meeting with representation from First Nations communities, First Nations and Inuit organizations, professional and scientific bodies (including an ethicist), and implicated territorial and provincial public health representatives to discuss the approach to dealing with BCG use on reserve within the context of an overall TB program for First Nations on reserves. The advice given to FNIHB by participants at this meeting was to approach the issue of BCG vaccine program changes cautiously and with much communication and engagement at the local level with the affected First Nations communities. First Nations stakeholders at that meeting were very clear in their advice not to quickly discontinue the BCG vaccination program in any community at high risk for TB outbreaks until there are adequate and reliable TB control program elements available at the community level to replace BCG. FNIHB has been pursuing discussion and engagement on a First Nations community level on the topic of BCG, and some communities have begun the process of discontinuing BCG vaccine and replacing it with alternative TB control program options.
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Members: Dr. M. Naus (Chairperson), Dr. T. Tam (Executive Secretary), Dr. I. Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. M.-N. Primeau, Dr. B. Tan, Dr. B. Warshawsky, A. Zierler.
Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. L. Chapman (CDC), Dr. A. Gruslin (SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. A. McCarthy (AMMI Canada), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS), Dr. D. Scheifele (CAIRE).
Ex-Officio Representatives: Dr. S. Deeks (CIDPC), Dr. A. Klein and Dr. H. Rode (BREC), Dr. M. Lem (FNIHB), Dr. M. Tepper (DND).
This statement was prepared by Dr. Joanne Langley with assistance from Dr. Edward Ellis, Dr. Shelley Deeks and the Health Canada First Nations and Inuit Health Branch. It was approved by NACI.
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