ABSTRACT
Background:
Bacille Calmette-Guérin (
BCG)
vaccination has off-target (non-specific) effects that are associated with
protection against unrelated
infections and decreased all-cause
mortality in
infants. We aimed to determine whether
BCG vaccination prevents febrile and
respiratory infections in
adults.
Methods:
This randomised controlled phase 3 trial was done in 36
healthcare centres in
Australia,
Brazil, the
Netherlands,
Spain, and the
United Kingdom.
Healthcare workers were randomised to receive
BCG-
Denmark (single 0.1 ml
intradermal injection) or no
BCG in a 11 ratio using a web-based
procedure, stratified by stage, site, age, and presence of co-
morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified
secondary outcome) using the
intention-to-treat (ITT)
population. This trial is registered with ClinicalTrials.gov, NCT04327206.
Findings:
Between March 30, 2020, and April 1, 2021, 6828
healthcare workers were randomised to
BCG-
Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated
risk of ≥1 episode of febrile or respiratory illness was 66.8% in the
BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the
control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated
risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the
BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the
control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a
similar number of episodes of illness,
pneumonia, and hospitalisation. There were three deaths, all in the
control group. There were no
safety concerns following
BCG vaccination.
Interpretation:
In contrast to the beneficial off-target effects reported following neonatal
BCG in
infants, a small increased
risk of symptomatic febrile or respiratory illness was observed in the 12 months following
BCG vaccination in
adults. There was no evidence of a difference in the
risk of severe
disease.
Funding:
Bill & Melinda Gates
Foundation, Minderoo
Foundation, Sarah and Lachlan Murdoch, the Royal
Children's
Hospital Foundation,
Health Services Union NSW, the Peter Sowerby
Foundation, SA
Health, the
Insurance Advisernet
Foundation, the NAB
Foundation, the Calvert-Jones
Foundation, the Modara Pines Charitable
Foundation, the UHG
Foundation Pty Ltd, Epworth
Healthcare, the National
Health and
Medical Research Council, the Swiss National
Science Foundation and individual
donors.