Research
Effect of BCG vaccination against Mycobacterium tuberculosisinfection in children: systematic review and meta-analysis

BMJ 2014;349:g4643

Abstract
Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon ? release assays (IGRA) in children.

Design Systematic review and meta-analysis.
Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts.
Setting Community congregate settings and households.

Inclusion criteria
Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon ? release assays.

Data extraction
Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis.

Results
The primary analysis included 14 studies and 3855 participants.
The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon ? release assays (ELISpot or QuantiFERON).

Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77).

Conclusions
BCG protects against M tuberculosis infection as well as progression from infection to disease.

Introduction
BCG vaccine has been the subject of numerous efficacy trials and epidemiological studies conducted over several decades.
These trials indicate that BCG has 60-80% protective efficacy against severe forms of tuberculosis in children, particularly meningitis, and its efficacy against pulmonary diseases varies geographically.
BCG does not seem to protect against disease when it is given to people already infected or sensitised to environmental mycobacteria, which could explain the geographical variation.

Until recently it was not possible to establish whether the protective effect of BCG vaccination against disease was from its action in preventing acquisition of infection or limited to prevention of progression from infection to clinical disease.

The scarcity of evidence on whether the vaccine is effective against Mycobacterium tuberculosis infection was because of limitations of the tuberculin skin test. This test cannot distinguish a positive response caused by M tuberculosis infection from that caused by BCG vaccination or non-tuberculous mycobacterial infection.

The recently developed T cell based interferon ? release assays (IGRA) can detect M tuberculosis infection and discriminate this from previous BCG vaccination and most non-tuberculous mycobacterial infections, allowing investigation of whether BCG protects against M tuberculosis infection.

If BCG is found to protect against infection, it will have key implications for its use in current immunisation programmes as well as in the future development of new improved tuberculosis vaccines.

In this systematic review we examined the evidence for the protective effect of BCG against M tuberculosisinfection, as opposed to against disease, in settings where children can be presumed to have been exposed to M tuberculosis.
This therefore assesses the degree to which BCG vaccination before exposure is associated with a subsequent negative result on an interferon ? release assay.

We also looked at factors that could alter the measured protective effect of BCG: latitude, the recommended age of vaccination in the area where the study was conducted, type of assay, and study quality. When there was sufficient information, we determined protection against early progression from infection to disease during screening.

G Mohan.