Abstract
Background The variable efficacy observed in studies of BCG vaccination is incompletely explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure. We investigated heterogeneity in BCG vaccination in the context of participant demography, diagnostic approach and TB-related epidemiological context.
Methods We updated previous systematic reviews of the effectiveness of BCG vaccination to 31st December 2018. We employed an identical search strategy and inclusion/exclusion criteria to past reviews, but reclassified several studies and developed an alternative classification system.
Results Of 21 included trials, those recruiting neonates and children aged under five were consistent in demonstrating considerable protection 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 is that BCG protects against TB that results from exposure shortly after vaccination. However, risk is equivalent or increased when exposure occurs later from vaccination, a phenomenon which is predominantly observed in adults in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines due to repeated exposure to M. tuberculosis or other pathogens.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Protocols
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=119676
Funding Statement
No specific funding was received for this project. James Trauer is a recipient of an Early Career Fellowship from the Australian National Health and Medical Research Council (APP1142638).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
No applicable.
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Footnotes
Funding No specific funding was received for this project. James Trauer is a recipient of an Early Career Fellowship from the Australian National Health and Medical Research Council (APP1142638).
Data Availability
As indicated in the manuscript, all code and new data are available at the link below.