Table 4 Secondary Outcomes: Adverse Events and other Outcomes under the Evaluated Prior and Current Vaccination Policies, by Country

[37], 2016

Aus

CS

Australian children aged < 7 years

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

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

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)

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

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)

No significant negative effects of BCG on psychomotor development in infants was found

[41], 2016

Den

RCT

Newborns in Denmark

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%)

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))

Any AE

Of these,

the most common AE was Lymph node abscess:

Disseminated BCG infection

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

Sterile Abscesses at vaccination site (without lymphadenopathy)

3/387

Current vaccine is safe.