Rationale The heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure.
Methods We updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context.
Main results Of 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings with longer follow-up showed no protection, sometimes with higher case rates in the vaccinated than the controls in the later follow-up period.
Conclusions The most plausible explanatory hypothesis for these results is that BCG protects against TB that results from exposure shortly after vaccination. However, we found no evidence of protection when exposure occurs later from vaccination, which would be of greater importance in trials in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection observed for many years thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines with repeated exposure to Mycobacterium tuberculosis or other pathogens.
- clinical epidemiology
- respiratory infection
Data availability statement
Data are available in a public, open access repository. Stata code for meta-analysis, and the data and Python V.3.6 code for generating figures 2 and 3 are available at https://github.com/jtrauer/bcg_tb_context_review.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Contributors JMT designed the study. AK and JMT designed and performed the literature search. AK, JMT, RR and BMW contributed to data extraction and analysis. JMT wrote the first draft and all authors contributed to producing the final text of the manuscript.
Funding JMT is a recipient of an Early Career Fellowship from the Australian National Health and Medical Research Council (APP1142638).
Disclaimer The authors acknowledge that the article title for reference Bettag et al, 1964 may cause offence and would like to note that 'mentally retarded' is not an acceptable terminology but is one that was used during the time of the publication.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.