Background
Methods
Search strategy
Inclusion Criteria | Exclusion Criteria |
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Publication Timeframe and Language | |
• Studies published after 1988 • Studies published in English or French | • Studies published before 1988 • Studies in languages other than English or French |
Study Population | |
• Taking place among a high-risk group in a low TB-burden country o Low-burden countries are defined as those with less than 100 TB cases per million population [21]. | • Not taking place among a high-risk group in a low TB-burden country (or, if including both low and high-burden countries, not stratifying results by burden level). o Countries excluded in the initial search were those on the current list of high-TB-burden countries provided by the WHO [22] (see Additional file 1). o Further countries were excluded during abstract screening if they did not meet the WHO’s low incidence cut-off of less than 100 TB cases per million population after consultation of the WHO TB database [23]. • Studies taking place in other contexts considered not relevant to BCG vaccination considerations in the Canadian Indigenous setting, (e.g. studies taking place only among immune-compromised subjects) |
Study Design | |
• Epidemiological studies • Case studies • Public health policy reviews or reports | • Animal, ex-vivo, molecular biology or non-clinical studies • Editorials, commentaries, conference abstracts, or outdated policy reports for countries for which newer versions were already included in the review |
Reported Outcomes | |
• Studies providing information on BCG vaccination policies, and specifically, information regarding: o Effectiveness of BCG in the target population o Possible harms of vaccination o Possible harms / implications of discontinuation of vaccination | • Studies not relating to BCG vaccination for TB (e.g. studies on TB screening or diagnosis) • Studies on novel vaccine development • Studies not providing information on BCG vaccination policies, and specifically, information regarding: o Effectiveness of BCG in the target population o Possible harms of vaccination o Possible harms / implications of discontinuation of vaccination • Studies on vaccination policy of healthcare personnel |
Data collection and synthesis
Risk of Bias assessment
Results
Study characteristics
Overview of vaccination policies by TB incidence in included study countries
Country | #S | Prior Vaccination Policies | Current Vaccination Policy b | As of (Year) | Age at Vaccination | Currently Targeted Risk Groups (TRG) | Nat. TB Inc. a c | TB Inc. a in TRG | |
---|---|---|---|---|---|---|---|---|---|
UAE d | 1 | Mass vaccination | No change - Mass vaccination | NA | At birth | NA | 0.7 | NA | Low number of adverse events suggests vaccine is safe and current policy of mass vaccination is acceptable [28]. |
USA d | 3 | Targeted | No change - Targeted | NA | NR | Children residing in contexts in which risk of TB infection is high (detailed cut-offs unspecified) | 2.9 | NR | Mass vaccination remains unnecessary [29]. Regarding high-risk groups, BCG vaccination among the homeless has been shown to be effective [30], and the protective efficacy of the vaccine among Native American communities has been shown to persist up to 50–60 years post-vaccination, suggesting a long-term benefit of vaccination among this risk group [8]. |
Finland | 2 | Mass vaccination | Targeted | 2006 | At birth (and previously, re-vaccination at school age) | • Children of immigrant families from high-incidence countries, • Children living with relatives with TB • Children staying in high-incidence countries for a prolonged period • Children whose families request BCG • Children from high-incidence countries who have not yet entered school. | 4.3 | NR | In Finland, most TB cases are among seniors (65 or older) and the Indigenous population (rather than among immigrants, as is the case in many other European countries). However, recommended target groups remain immigrant and other at-risk children (see targeted risk groups) [31]. Before routine vaccination was discontinued in 2004, it was emphasized that the following criteria (set by the International union against TB and lung disease) should be met before discontinuation: • Strong established TB control program • Knowledge of impact of HIV prevalence in the population on TB transmission • Incidence of smear-positive TB no more than 5 / 100,000 in the past 3 years, or • Less than 1 case per 10,000,000 of TB meningitis in children under 5 in the last 5 years, or • Annual risk of TB 0.1% or less [32]. |
Czech Republic | 2 | Mass vaccination | Targeted | 2010 | Between birth and 6 weeks of age (and previously, re-vaccination at 11 years) | Newborns from high-risk families | 4.7 | NR | Although TB incidence increased in the region where mass vaccination was stopped [10], risk of infection was low, so re-introduction of mass vaccination was not deemed necessary [11]. Overcrowded living conditions were associated with a higher risk of infection, which is also a relevant consideration in the Canadian Indigenous context, however, no specific risk groups or criteria for targeted vaccination were identified, except neonates from families at “high risk” of infection [11]. |
Canada | 3 | Routine vaccination among Indigenous communities | Targeted (see currently targeted risk groups) | 2003–2005 (Varies by community) | Within 1 year of birth | • Infants in some Indigenous Communities, • Infants in populations with an annual risk of TB infection > 0.1% | 4.8 | 26.6 | As recommended by the National Advisory Committee on Immunizations, vaccination should continue in: • Infants in First Nations and Inuit communities with an average annual rate of smear-positive pulmonary TB greater than 15 per 100,000 population in the past 3 years, or • Infants residing in populations with an annual risk of TB infection greater than 0.1% [33]. Where vaccination is withdrawn, it should be ascertained that a strong surveillance system is in place before withdrawal [19]. |
Netherlands | 2 | Targeted vaccination of children with parents from endemic countries | Targeted | 2005 | NR | Children with one or both parents born in a country with TB incidence > 50/100000 (as per WHO estimate) | 5.2 | NR | Issues of incomplete coverage (39% of at-risk children not vaccinated in a 2014 study) suggest that further cases could be prevented through stricter adherence to vaccination of high-risk children. Specifically, the continuation of targeted vaccination in new-borns of parents from TB endemic countries (WHO-estimated incidence > 50 /100.000 population) is recommended [14]. |
Norway d | 2 | Mass vaccination | Targeted | 2009 | At birth | Newborns with parents from high prevalence countries | 5.6 | NR | Targeted vaccination of high-risk groups recommended over universal vaccination due to high number of vaccinations needed to prevent one case in low-risk groups [34]. Due to concerns of incomplete coverage of risk groups after discontinuation of universal vaccination policy, improvements are needed in the identification of children considered high risk [35]. |
Australia | 3 | Mass vaccination | Targeted | Mid-1980s | Previously at school age, currently at birth | • Newborns in high-incidence Aboriginal and Torres Strait Islander communities • Newborns in families with leprosy, • Newborns and children otherwise at risk (e.g. those who will be travelling to high TB prevalence countries | 5.7 | Foreign-born pop.: 15.5–21.0 (1992–2012) Aboriginal pop.: 5.9 (2008) | |
Denmark | 4 | Mass vaccination | Targeted | 1986 | At birth | • Children traveling to endemic countries • Children with a family history of TB | 5.8 | NR | |
Ireland d | 1 | Mass vaccination (in some regions) | No change - Mass vaccination in some regions | NA | At birth (and previously, re-vaccination at 11–12 years) | NA | 6.8 | NA | A 1997 study in Ireland showed the number of vaccinations needed to prevent one case had decreased over time, suggesting that continuing the policy of routine neonatal BCG vaccination is beneficial [42], however, this policy may need to be updated based on the current situation. |
Sweden | 3 | Mass vaccination | Targeted | 1975 | At 6 months - 1 year (and previously, re-vaccination at 7 years) | High risk infants, i.e. those with: • Family history of TB, • Close contact to TB case • Parents from endemic countries • Plans to travel to endemic countries [43] | 7.4 | NR | Targeted vaccination of high-risk groups should continue, however, the age at vaccination should be postponed from at birth to 6 months of age, to allow the detection of immune-compromising conditions prior to vaccination (thereby avoiding serious adverse events) [44]. |
France | 6 | Mass vaccination | Targeted | 2007 | Before hospital discharge or entry into daycare | • Children with parents from endemic countries • Children with a family history of TB | 7.6 | NR | No significant difference in incidence of TB meningitis before and after the changes in vaccination policy, suggesting that targeted screening is sufficient for TB control. However, given the possibility of incomplete coverage of high-risk children after suspension of mass vaccination, surveillance efforts should be strengthened [12]. |
Egypt d | 1 | Mass vaccination | No change - Mass vaccination | NA | At birth | NA | 8.6 | NA | Routine vaccination at birth continues to be considered beneficial (based on the significant correlation of BCG vaccine coverage with reduced TB incidence and TB-associated mortality) [45]. |
Saudi Arabia d | 1 | Mass vaccination | No change - Mass vaccination | NA | At birth | NA | 9.3 | NA | Routine vaccination continues, however, given the change of strains used for vaccination (from Pasteur 1173 P2 and Tokyo 172–1 to the Danish 1331 strain in 2005), more detailed population-based studies are recommended before the introduction of new strains in the future, with particular attention to the prevalence of host risk factors that contraindicate vaccination, such as immunodeficiency [9]. |
UK | 6 | Mass vaccination | Targeted | 2005 | At birth in at-risk neonates and opportunistically in older children [46] (previously at 12–13 years) | Children from high-risk families (see recommendations for details) | 9.4 | NR | Re-introduction of routine vaccination is not recommended [13]. Instead, targeted vaccination is recommended among the following groups: • Infants attending primary care organisations with a high incidence of TB, • Infants in low-incidence communities meeting the following criteria:– those born in an area with a high incidence of TB, or– those with one or more parents or grandparents who were born in a high-incidence country (> 40 cases per 100,000 per year), or– those with a family history of TB in the past 5 years. • Children younger than 16 who also meet these risk criteria should be opportunistically vaccinated [47]. |
BCG vaccine efficacy and effect of vaccination policies on TB incidence
Study Characteristics | Study Outcomes | Policy Recommendations | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ref, Year | CTR | ST | Study Pop | Current / prior BCG policy (cov) a | New policy (cov) a | Int description b | Cont description | N (int) | N (cont) | TB Incidence and Vaccine Efficacy | Risk groups for Targeted Vaccination | Observations and General Recommendations | ||
TB Inc. (cont) n/N | TB Inc. (int) n/N | % Efficacy (95%CI) | ||||||||||||
[48], 1990 | Can | CC | Alberta indigenous communities (Treaty Indians) | All Treaty Indians in Alberta are given BCG vaccination at birth since 1948 | Cases - TB | No TB | 160 | 314 | 57 (23.4–75.3) | Indigenous population | Vaccination in this population should continue until incidence rates fall (cut-off not specified) (as benefits in this high-incidence community outweigh risks and costs), however, vaccination at an older age (instead of at birth) warrants consideration given the finding of higher protection among those vaccinated after 6 months of age (63% efficacy after 6 months of age, 42% before 6 months). Diagnosis and treatment should be strengthened as control measures. | |||
[11], 1994 | Czh | CS | Non-BCG vaccinated children | Mass BCG vaccination in all newborns (discontinued in 3 regions of the country in 1986) | Vaccination only in high-risk infants | Non-vaccinated | NA | 184,648 | NA | LTBI: 283/184648 | Unspecified high-risk infants | Risk of infection was low, so re-introduction of mass vaccination is not necessary. Overcrowded living conditions were associated with a higher risk of infection (also relevant to Canadian Indigenous context). | ||
[10], 1993 | Czh | QE | Czech children | Mass vaccination | Discontinuation of mass vaccination in one region in 1986 | Region of ceased vaccination | Regions of continued mass vaccination | 148,560 | 600,195 | 31/148560 (not vaccinated) | 24/600195 (vaccinated) | 80% | Although incidence increased in the region where mass vaccination was stopped, mass vaccination found to be obsolete due to the small number of children that were not vaccinated developing TB. The cessation of mass vaccination is additionally beneficial due to the restoration of the utility of the TST as a screening tool. Implications of Withdrawal: 25.6 cases could have been prevented through continuation of mass vaccination in the region where it was stopped. | |
[12], 2015 | Fr | CS | French Children | Mass vaccination until 2007 | Vaccination in high risk groups | Children in Ile-de-France (all vaccinated, as all considered high risk) | Children in other regions of France where mass vaccination was ceased | Regions where only at-risk children are vaccinated: 2000–2005:0.30, 2006–2011: 0.47 | Ile-de-France (all considered at risk, all vaccinated): 2000–2005: 1.14, 2006–2011: 0.29 per million | There was no significant difference in incidence of TB meningitis before and after the changes in policy, suggesting that targeted screening is sufficient for TB control, however, given the possibility of incomplete coverage of high-risk children after suspension of mass vaccination, surveillance efforts should continue. | ||||
[49], 2011 | Fr | QE | General French population | Universal BCG vaccination (47%) | Lower coverage due to de-commercialisation of vaccine | 2008 coverage (lower) | 2006 vaccination coverage (higher) | 82 cases (in children under 3) | 105 cases (in children under 3) | Implications of withdrawal: Increase in number of cases reported in 2008 (low vaccine coverage) compared to 2006, where vaccine coverage was higher - although it is unclear whether this change indicates an actual increase in transmission, or rather is the result of improved surveillance | ||||
[50], 1994 | Fr | RC | General French population | Routine vaccination at birth (80% in children under 5 in 1990) | 70 cases of TB meningitis in total population (1.2 per million inhabitants (95% CI: 0.9–1.5), 6 in under 5 age group | 87.5% (30–98) | Routine BCG vaccination continues to play an important role in TB control in France, and should be maintained unless the risk of infection continuous to reduce. | |||||||
[42], 1997 | Ire | QE | Children (15 or younger) in Ireland | Dependent on area (see int/cont description) (38% in 1986 to 35% in 1991) | Areas with neonatal BCG vaccination | Areas without neonatal BCG vaccination | children < 15, 1986 and 91: 751813, 680,269 | 269,350, 282,489 | 1986: 14.1/100000, 1991: 13.4/100000 | 1986: 4.9/100000, 1991: 3.4/100000 | In areas with vs. without neonatal BCG vaccination: IRR = 1.92 (95% CI = 1.47–2.40) p = 1.5 × 10–5 in 1986; and IRR = 2.12 (95% CI 1.75–2.58), p = 1.0 × 10–7 in 1991 | Neonates | TB incidence in areas without a policy of neonatal BCG was significantly higher than areas where neonates were vaccinated. As the number of vaccinations needed to prevent one case decreased over time (1986: 646, 1991: 551), this suggests that continuing the policy of neonatal BCG vaccination is beneficial. Also, based on the WHO’s recommendations that routine vaccination of newborns should not be continued until: • The average incidence is < 5 cases per 100,000 per year in three successive years, − • The annual risk of tuberculosis infection is ≤0.1%, • A 10% decrease in tuberculosis annually for a period of 10 years is observed • Or the incidence of childhood tuberculosis meningitis is < 1 case per 10 million per year which was not yet the case in Ireland at the time of the study. | |
[51], 2009 | LIC | M | General population in LIC | A common reason for the discontinuation of mass vaccination programs has been the trade-off between vaccinating and being able to effectively detect LTBI, with most low-incidence countries having suspended mass vaccination and focusing instead on the accurate identification and subsequent prophylaxis of LTBI, however, according to this model, low-incidence countries do not detect and treat LTBI at rates high enough to benefit from the cessation of mass vaccination programs. (Note that the model assumed that LTBI in previously vaccinated individuals is completely undetectable, regardless of time since vaccination, and thus represents a conservative estimate of the benefit of mass vaccination). Based on US life expectancy, incidence and cure rate data, mass vaccination begins to become beneficial at a vaccine efficacy of 50%. (Given that many of the studies included in the current review report higher efficacies in their populations, this modeling study suggests that mass vaccination continues to be beneficial in a low-incidence country context). | ||||||||||
[52], 2008 | LIIC | M | Children in LIIC | Universal vaccination was found to be beneficial in settings with a prevalence of approx. 30 sputum smear positive cases per 100,000. If prevalence is below 5 per 100,000, a universal vaccination strategy may not be beneficial due to high incidence of adverse events per case prevented. Note that the model assumes 100% BCG coverage and a vaccine efficacy of 80% against both meningitis and miliaryTB. | ||||||||||
[34], 2009 | Nor | QE | Native-born (non-immigrant) population < 30 years old | Vaccinates all 12–14 year olds. | NA | Vaccination policies in Sweden, Finland and Denmark | Norwegian vaccination policy | Py: Nor: 16, 567, 951 | Py: Swe: 29, 851, 794 Den: 18, 042, 696 Fin: 18, 353, 224 | Per100 000 py: (95%CI) Nor: 0.45 (0.36–0.57) | Swe: 0.56 (0.48–0.65) Den 1.41 (1.24–1.59) Fin: 0.65 (0.54–0.78) IRR: Fin vs. Swe: 0.45 (95%CI 0.22–0.94) | 61–64 (Norwegian 15–29-year-olds) 67–71 (after adjustment for coverage) Average annual # of prevented cases 1.9–2.2. | Children with origins in high-incidence countries or travelling to high-incidence countries | Protective effect of BCG vaccination of newborns in Finland, and adolescent vaccination in Norway among persons at low risk of TB, however, a high number of vaccinations (21699–25,125) were needed to prevent one TB case among the low-risk population. The Norwegian Ministry of Health therefore decided in 2009 to discontinue vaccination among low-risk groups but continue it among high-risk groups. |
[43], 2006 | Swe | RC | Swedish population | Routine vaccination of newborns until 1975 (discontinued due to high incidence of bcg osteitis (more than 95% before 1975) | Targeted, in high-risk groups < 2% in 1976–1980, and 16% post 1980. (88% of targeted risk groups)) | Born before 1974 (routine vaccination) | Born after 1974 (targeted vaccination) | For the birth cohort born in 1975 and followed up to 2004: 0.5/100,000py (227 cases) (6.4 per 100,000 in 2005) | 85% in 1969–74 | High risk infants include those with - Family history of TB, - Close contact of TB case- Origin from endemic countries (whether born in Sweden or not), − Planned travel to endemic countries | An increased incidence of TB in the mostly non-BCG vaccinated cohorts born after 1975 was observed vs those born during routine vaccination period (1969 to 1974). In addition, the recommended age at vaccination was recommended to be increased from at birth to 6 months in 1994, to avoid vaccinating newborns who may later develop immune-deficiencies. | |||
[13], 1991 | UK | RC | Population of Oxfordshire, UK | Routine vaccination of 13 year olds in schools, until 1981 | Cessation of routine vaccination | 4 cases since 1981, of children who had not been routinely vaccinated at school. All four had other risk factors apart from being unvaccinated. | Neonates of African, Asian, Central and South American and Middle Eastern origin, those with a family history of tuberculosis, contacts of TB cases, children newly immigrating from or travelling to endemic countries. | Given the continued decline in cases from 1973 to 89, (94 vs. 24 cases), does not recommend re-introduction of universal vaccination, but seeing as the 4 cases all had other risk factors, recommends improvement in identification and subsequent vaccination of at-risk groups | ||||||
[53], 1991 | UK | CC | Asian Children living in England | (51 and 64% in cases and controls, respectively) | Cases - TB | No TB | 111 | 555 | 49 (14–62) | Children originating in endemic countries (or whose parents originate in these countries) | Continued vaccination of high-risk children, e.g. those originating in endemic countries. As the incidence in this group is decreasing, this policy may be reviewed in the future. | |||
[54], 1989 | UK | M | UK general population | Universal vaccination through school programs at age 14 (75–80%) | Gradual increase in vaccinations needed to prevent one case: 5800 in 1994, 9300 in 1999 (as risk of infection also decreased: 1:17000 to 1:26000). Implications of withdrawal: If universal vaccination were stopped in 1991, case notifications would increase by 80, and 50 if stopped in 1996. (These new infections would mainly be in the 15–29 year old age group and would comprise existing as well as new sources of infection in the community) | |||||||||
[55], 2018 | USA, Can, Grn | PC | Canadian, American and Greenland Indigenous populations | Mass vaccination of infants in some study years, but discontinued in others. (Greenland, Eeyou Istchee, Nunavik, and Nunavut: at least 80%; First Nations population of Alberta: 50–60%) | Decrease in annual TB incidence attributed to population-based BCG vaccination: −10% (95% CI −5 to −15) (adjusted for infant mortality and crowded housing) | Indigenous populations | Population-based vaccination was significantly associated with a decrease in TB incidence. This remained true when adjustment was made for improvements in overall health and socioeconomic status over the years of the study. This therefore suggests that population-level vaccination in high-risk groups (rather than vaccination based on individual risk factors) may be beneficial in the Indigenous community context. Implications of withdrawal: Cessation of population-based vaccination in Indigenous communities may have led to exacerbation of TB incidence in these populations (e.g. Greenland) | |||||||
[8], 2004 | USA | QE | Native American (and Alaskan) Indigenous population | BCG vaccinated | Placebo | 1483 | 1309 | 66/1309 (138 / 100,000 py) | 36/1483 (66/100000 py) | 52 (27–69) | Indigenous populations | Vaccine efficacy persisted for 50–60 years, suggesting long-term utility of vaccination | ||
[30], 2001 | USA | M | Homeless individuals | Vaccination | No vaccination | 2 million | NA | Homeless population | Vaccination resulted in a 15.4% decline in TB cases among the chronically homeless and a 21.5% decline among the transiently homeless. Vaccination of 10% of the chronically homeless population led to a 10% decrease in TB cases and 2.4% decrease in TB-associated deaths over 10 years. Targeted BCG vaccination among the homeless HIV negative population is most beneficial if treatment for LTBI is available to those who have been vaccinated |
BCG-associated adverse events and non-specific effects
Study Characteristics | Study Outcomes | Policy Recommendations | ||||||||||||
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Ref, Year | CTR | ST | Study Pop | Current / pior BCG policy (cov) a | New policy (cov) a | Int description b | Cont description | N (int) | N (cont) | BCG-related adverse events | Target population / risk group | General Recommendations | ||
Event or Measure | Inc cont n/N | Inc Int n/N | ||||||||||||
[37], 2016 | Aus | CS | Australian children aged < 7 years | Targeted Vaccination (see risk groups) | Unregistered vaccine | Registered vaccine | Any AE (most commonly reported AEs: abscess (31%), injection site reaction (27%), lymphadenopathy/ lymphadenitis (17%) | 87/100000 in 2009 | 201/100000 in 2014 | Children < 5 at high risk (traveling to high-incidence countries (annual incidence 40 or more / 100,000) and aboriginal people | Surveillance of AEs during the use of unregistered vaccines due to shortages is important. Use of unregistered products may result in increased AEs. | |||
[38], 2017 | Aus | CS | Australian Children | Targeted Vaccination (see risk groups) | Unregistered vaccine (2012 onwards) | Registered vaccine (2001) | 11,145 doses | 8740 doses | Any AE | 2/8740 (rate per 100,000 doses: 22.9 (0–54.6)) | 20/11145 (rate per 100,000 doses: 179.5 (100.9–258.0) | Need to monitor AEs, particular when unregistered vaccines are used. | ||
[10], 1993 | Czh | QE | Czech children | Until 1986, mass vaccination of infants born in a particular region of the country (in other regions, mass vaccination continues) | Region of ceased vaccination | Regions of continued mass vaccination | 148,560 | 600,195 | Osteomyelitis BCGitis | 8 cases, 2 cases | (See Table 3) | |||
[40], 2013 | Den | CC | Danish general population | Routine BCG vaccination | Routine BCG vaccination ceased in 1985 | With IBD | No IBD | 474 | 5672 | IBD (CD or UC) | Hazard ratio: 0.95 (95%CI: 0.75–1.1) | There was no significant effect of BCG on IBD overall (p = 0.14) (although being vaccinated with BCG early, before 4 months of age, was associated with a lower risk of IBD than not being vaccinated: HR =0.44 (95% CI, 0.21–0.96). BCG is safe for continued use regarding risk of IBD. | ||
[59], 2016 | Den | RCT | Infants (from birth to 13 months) | No routine vaccination of newborns | BCG vaccination within 7 days of birth | No BCG | 2129 | 2133 | Parent-reported early childhood infections | 336/2099 | 291/2113 (IRR = 0.87 (95% confidence interval (CI): 0.72 to 1.05)) | No significant non-specific public health benefit of vaccination (in terms of preventing non-TB infections) | ||
[39], 2016b | Den | RCT | Infants | No routine vaccination of newborns | BCG vaccination within 7 days of birth | No BCG | 1779 | 1674 | Effect on child psychomotor development (Ages and Stages Questionnaire mean Score (SD)) | 179.9 (53.6) | 178.2 (52.4) mean difference: −0.7 (BCG vs. control, 95%CI-3.7 to 2.4), p = 0.67 | No significant negative effects of BCG on psychomotor development in infants was found | ||
[41], 2016 | Den | RCT | Newborns in Denmark | No routine vaccination of newborns | BCG Vaccination within 7 days of birth | No BCG | 2118 | NR | Supparative LA Regional LA | 10 cases 13 cases | Few AEs and no fatalities linked to BCG | |||
[60], 2010 | Fr | O | French children admitted to the emergency department | Mass vaccination of newborns (or children before entry into daycare) | Targeted vaccination in high-risk groups at birth or within the first month of life (116/157 (73.9%)) | Total: 224 | Children: - Born in TB endemic countries or with at least one parent from an endemic country, - Traveling to TB endemic countries, - Having familial TB cases or being in contact with TB cases, - Living in precarious or overcrowded housing - Of low-socioeconomic status, − Residing in the ile-de-France or Guyane regions | 41 infants falling into at least one of the risk categories were not vaccinated under the new (targeted) vaccination program. This indicates that through targeted vaccination of high-risk groups only, a proportion of children at risk may be missed, and that therefore, the discontinuation of universal vaccination needs to be accompanied by the strengthening of prevention, surveillance, and screening efforts | ||||||
[14], 2014 | Ne | CS | Dutch Children | - Newborn children with a parent born in a TB endemic country (TB incidence > 50 per 100,000 population. 2) - Immigrant children < 12 years, with no evidence of prior vaccination | 39% of TB patients eligible for targeted vaccination (see target groups) had not been vaccinated, suggesting that further cases could have been prevented through stricter adherence to vaccination of high-risk children. Specifically, the continuation of targeted vaccination in new-borns of parents from TB endemic countries (WHO-estimated incidence > 50 /100.000 population) is recommended. | |||||||||
[61], 2008 | Ne | RCT | Newborns with a family history of allergic disease (asthma, allergicrhinitis, eczema or food allergy) | BCG given at 6 weeks and repeated if BCG scar absent and TST negative at four months | Placebo | 61 | 54 | Asthma attack Medication use for eczema | 8/54 (15%) 23/54 (43%) | 11/61 (18%) RR: 1.22 (0.5–2.8) p value: ns 15/61 (25%) RR: 0.58 (0.3–1.0) p value = 0.04 | BCG may be beneficial in reducing allergic disease, however, there was no significant difference in occurrence of asthma, although there was significantly lower medication use for eczema in the BCG group. Larger studies are needed however in order to confirm the effect of BCG on allergic disease. | |||
[35], 2016 | Nor | CS | Norwegian Children | Universal vaccination of children aged 13–15 until 2009 | Targeted vaccination shortly after birth of children with at least one parent born in a country with high burden of TB (83.60%) | Total: 240,484 | Children of parents from high-burden countries. | This study found that coverage of BCG vaccination, which was targeted, was lower than coverage of vaccines that are offered under a universal vaccination program, and suggests that improvements in the identification of children eligible for vaccination is needed, including the appropriate informing of healthcare professionals regarding the new guidelines. | ||||||
[9], 2014 | S. Ar | CS | Children diagnosed with BCG lymphadenitis | Mandatory BCG vaccination since 1968, mainly using Pasteur 1173 P2 and Tokyo 172–1. (98%) | Introduction of Danish 1331 strain in 2005 | BCG-associated Lymphadenitis | 42 cases, 41 of which received the Danish strain (and 1 the Tokyo strain). | NR | More comprehensive population-based studies before the introduction of a new vaccine strain, with particular attention to the prevalence of host risk factors that contraindicate vaccination, such as immunodeficiency. | |||||
[44], 1993 | Swe | RC | Children < 6 years of age who were vaccinated | Vaccination of high-risk infants at birth (following cessation of routine vaccination in 1975) | Vaccination of high-risk infants at six months of age (7% (1979 to 1983),14% (1984 to 1990)) | Total: 139000 | Any AE Of these, the most common AE was Lymph node abscess: Disseminated BCG infection | 268/139000 (I .9 per 1000 vaccinated children) 115/139000 4/139000 (3 of which had SCID). | High-risk infants | Targeted vaccination of high-risk groups should continue, however, the age should be moved from at birth to 6 months of age, to allow the detection of immune-compromising conditions prior to vaccination, to avoid serious AEs. | ||||
[62], 1995 | Swe | RC | Children under 15 | Routine vaccination of newborns until 1975 (95%) | Targeted vaccination of high-risk groups (post-1975) (2% prior t0 1980. Between 10 and 15% following 1980) | BCG vaccinated | BCG non-vaccinated | Atypical mycobacterial disease (incidence in children younger than 5) | 26.8 per 100,000 | 4.6 per 100,000 | High-risk infants | BCG vaccination may protect against atypical mycobacterial disease | ||
[28], 1990 | UAE | CS | Full term infants vaccinated at birth | Routine vaccination at birth | Total: 387 | Sterile Abscesses at vaccination site (without lymphadenopathy) | 3/387 | Current vaccine is safe. |
General recommendations in reviews and policy reports
Study Characteristics | Reported Adverse Events | Recommendations | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Ref, Year | CTR | National TB incidence (at the time of study) | Study Pop | Current / prior BCG policy | New policy | Event | Inc Cont n/N | Inc Int n/N | Target population / risk group | Observations and General Recommendations |
[19], 2006 | Canada | Canadian Indigenous communities | Vaccination remains in some Indigenous communities only (discontinued in others since 2004) | Disseminated BCG infection | 7 cases from 1993 to 2003 (6 fatal) in First Nations communities across Canada (all had an underlying immunodeficiency) | Communities with: - Average annual rate of smear positive pulmonary TB > 15/100000 in previous 3 years, or - Annual risk of TB infection > 0.1%, - Average annual notification rate of paediatric TB meningitis is > 1/10 million in children under 5 in the last 5 years | Should not be withdrawn in communities who continue to have high TB incidence. Consider withdrawal for low-risk communities. Readiness for withdrawal requires an effective surveillance system for monitoring of subsequent incident cases. Implications of withdrawal: As of 2006, 5 communities in the Sioux Look out zone met the criteria for high-risk (see left), and would thus be at risk for further TB transmission if BCG is withdrawn. | |||
[64], 1994 | UK | NR | General UK population | Routine vaccination in school programs | - Healthcare and prison staff, - Children of immigrants from high-prevalence countries, - Child or young adult contacts of active TB cases identified via contact tracing, - Babies of mothers with pulmonary TB | Routine vaccination of 10–14 year olds in schools (policy to be reviewed in 1995. In addition, vaccination of healthcare and prison staff, children of immigrants from high-prevalence countries, and child or young adult contacts of active TB cases. Babies of mothers with pulmonary TB should be vaccinated in the case of a negative TST six weeks after chemoprophylaxis. | ||||
[29], 1995 | USA | US General population | NR | Routine vaccination is not recommended in the US. The primary strategy for TB control focuses on the identification and treatment of active cases, and the second priority is the identification of LTBI. BCG Vaccination should be considered among children with negative TSTs if they are in contact with an active TB case. | ||||||
[65], 2006 | France | Routine vaccination before entry into day-care | Selective vaccination of high-risk groups begun in 2004 | BCGitis | Approx. 12 cases in total in France per year | At 50% efficacy for preventing all forms of TB in children under 15, 320 additional cases of childhood TB would occur if routine vaccination is stopped, however, 240 of these can be prevented by selective vaccination of only 15% of the child population, which would therefore also prevent 85% of BCG associated adverse events, and 11 of the 12 cases of BCGitis per year. Selective vaccination is therefore recommended, but caution is advised to ensure appropriate coverage of target populations. Revaccination: Not recommended (no evidence of efficacy) | ||||
[66], 2012 | Australia | 5.28 and 5.95 cases per 100,000 population in 2005–2009 | General population of Australia | Selective vaccination of high-risk groups | - Aboriginal and Torres Strait Islander neonates in communities with a high incidence of TB; - Neonates and children 5 years of age and under who will be travelling to or living in countries or areas with a high prevalence of TB for extended periods; - Neonates born to parents with leprosy or a family history of leprosy. | Most TB cases (80–90%) are among immigrants from high-prevalence countries. Selective vaccination is therefore used. Vaccination is recommended for:1. Aboriginal and Torres Strait Islander neonates in communities with a high incidence of TB;2. Neonates and children 5 years of age and under who will be travelling to or living in countries or areas with a high prevalence of TB for extended periods;3. Neonates born to parents with leprosy or a family history of leprosy. BCG vaccination may be considered in Children over 5 years of age who will be travelling to or living in countries or areas with a high prevalenceof TB for extended periods; Revaccination: Not recommended | ||||
[47], 1996 | UK | High-incidence communities in the UK | NR | Selective vaccination in high-incidence communities (over 40 cases per 100,000) as well as of immigrants from endemic areas may be of interest, although this is more difficult to implement effectively, as a universal vaccination program would reduce the number of eligible people missed | ||||||
[33], 2011 | Canada | 4.8/100,000 | Canadian First nations population | Routine vaccination discontinued in Alberta, Saskatchewan, Quebec and some Ontario First Nations communities (Moose Factory and Thunder Bay Zones) between 2003 and 2005. | Disseminated BCG infection | 6 cases between 1993 and 2003 (estimated rate: 205 cases per million doses) | - Infants in First Nations and Inuit communities or infants in communities with an average annual rate of smear-positive pulmonary TB greater than 15 per 100,000 population in the past 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.) | The 2011 Report found no increase in TB meningitis or miliary TB since the discontinuation of routine vaccination. However, due to the small population sizes of first nations communities, incidence rates easily fluctuate above or below the National Advisory Committee on Immunisation (NACI) cut-offs (see left) and therefore perhaps make these of limited use in determining appropriate vaccination policy. | ||
[45], 2014 | Egypt | 34 cases to 17 cases per 100,000 population (1992–2011) | General Egyptian population | Routine vaccination at birth (1992: 92%, 2006: 99%) | There was a significant correlation between vaccine coverage and TB incidence, prevalence, TB-associated mortality, and TB associated under five mortality in 1992–2011: (R, p value): 0.74 < 0.0001, 0.86 < 0.0001, 0.86 < 0.0001, 0.77 < 0.0001. Current routine vaccination therefore remains effective. | |||||
[31], 2006 | Finland | 6.6/100000 in 2004 | General Finnish population | Routine vaccination at birth (98%) | Targeted vaccination among high-risk groups (planned to begin 2008) | BCG osteitis | 2 cases in 2002 | 6 cases in 2003 | - Children of immigrant families from high-incidence countries - Children of Finnish-born parents with a family history of TB - Children of families planning to stay for a prolonged period in a high-incidence country - Upon request by the parent | In Finland, most TB cases are among seniors (65 or older) and the Indigenous population (rather than among immigrants, as is the case in many other European countries). |
[46], 2007 | UK | Vaccination of all secondary school children | Targeted BCG vaccination both in neonates and opportunistically in older children | - Infants attending primary care in areas with a high incidence of TB Infants who: - Were born in an area with a high incidence of tuberculosis, or - Have one or more parents or grandparents who were bornin a high-incidence country (> 40 cases per 100,000 per year), or - Have a family history of tuberculosis in the past 5 years. Children younger than 16 who also meet these risk criteria should be opportunistically vaccinated. | See target groups | |||||
[32], 1994 | Finland | Finnish General population | NR (50–80%) | Necessities before discontinuation (International union against TB and lung disease): - Strong, established TB control program for TB case data over past 5 years, - Knowledge of the impact of HIV prevalence in the population on TB transmission - Incidence of smear-positive TB no more than 5 / 100,000 in past 3 years, or - < 1 per 10,000,000 cases of TB meningitis in children under 5 in the last 5 years, or - Annual risk of TB 0.1% or less. Implications of withdrawal: discontinuation of mass vaccination resulted in an increase of TB in Sweden1 and in former Czechoslovakia Revaccination: Not recommended | ||||||
[6], 2001 | Global | Varied | Varied | International Union against Tuberculosis and LungDisease recommends that a country should only move from universal to targeted vaccination if: - An efficient system of case notification is established- The average annual notification rate of smear-positive pulmonary tuberculosis is < 5 per 100,000;or - The average annual notification rate of TB meningitis in children aged < 5 years is < 1 per 10 million population over the previous 5 years, or the average annual risk of TB infection is < 0.1% Revaccination: Not recommended |
Risk of Bias assessment
Discussion
Summary of evidence
Criteria a | Criteria met (yes = 1, no/unclear = 0, NA = not applicable) | |||
---|---|---|---|---|
Study (Author, Year) | ||||
Manissero, 2008 | Sutherland, 1989 | Brewer, 2001 | Gerberry, 2009 | |
Model Structure: | ||||
Inputs and outputs relevant to decision-making | 1 | 1 | 1 | 1 |
Structure consistent with the theory of the disease | 1 | 1 | 1 | 1 |
Structure is simple but includes essential elements for vaccine policy decision-making (and any simplifications are justified) | 1 | 1 | 1 | 1 |
Heterogeneity in the modelled population accounted for by stratifying by groups that have different outcome probabilities or costs | 1 | 0 | 1 | 1 |
Time horizon of the model sufficient to detect important (and clinically meaningful) differences in long-term health and cost outcomes | 0 | 1 | 1 | 0 |
For Markov models / health state transition models: | ||||
Health states appropriately defined, relevant subdivisions of health states included | NA | NA | 1 | 1 |
Where relevant, transition probabilities take into account clinical history | NA | NA | 1 | 1 |
Choice of cycle length justified | NA | NA | 0 | 0 |
Data Identification: | ||||
Systematic reviews of the literature conducted on key model inputs | 0 | 0 | 1 | 0 |
Ranges provided in base-case estimates of all input parameters for which sensitivity analyses were done | NA | NA | 1 | 1 |
Data based on expert opinion, if used, are derived via formal methods, e.g. Delphi | NA | NA | NA | NA |
Attempts to obtain new data prior to modeling have been considered | 1 | 1 | 1 | 1 |
Data Incorporation and Modeling: | ||||
Modeling methods follow accepted methods of biostatistics and epidemiology | 1 | 1 | 1 | 1 |
Included sensitivity analyses of key parameters | 0 | 0 | 1 | 1 |
Model validation: | ||||
Model subjected to internal testing through input of extreme values (or equal values for replication testing) | 1 | 0 | 0 | 1 |
Calibration data, where available, should be from sources independent of those used to estimate inputs | 1 | 0 | 0 | 1 |
Source code available for peer-review | 0 | 0 | 0 | 0 |
Model based on the best evidence available at the time | 1 | 1 | 1 | 1 |