BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial

Abstract

Background Trials done in infants with low birthweight in west Africa suggest that BCG vaccination reduces all-cause mortality in the neonatal period, probably because of heterologous protection against non-tuberculous infections. This study investigated whether BCG alters all-cause infectious disease morbidity in healthy infants in a different high-mortality setting, and explored whether the changes are mediated via trained innate immunity.Methods This was an investigator-blind, randomised, controlled trial done at one hospital in Entebbe, Uganda. Infants who were born unwell (ie, those who were not well enough to be discharged directly home from the labour ward because they required medical intervention), with major congenital malformations, to mothers with HIV, into families with known or suspected tuberculosis, or for whom cord blood samples could not be taken, were excluded from the study. Any other infant well enough to be discharged directly from the labour ward was eligible for inclusion, with no limitation on gestational age or birthweight. Participants were recruited at birth and randomly assigned (1:1) to receive standard dose BCG 1331 (BCG-Danish) on the day of birth or at age 6 weeks (computer-generated randomisation, block sizes of 24, stratified by sex). Investigators and clinicians were masked to group assignment; parents were not masked. Participants were clinically followed up to age 10 weeks and contributed blood samples to one of three immunological substudies. The primary clinical outcome was physician-diagnosed non-tuberculous infectious disease incidence. Primary immunological outcomes were histone trimethylation at the promoter region of TNF, IL6, and IL1B; ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation; and transferrin saturation and hepcidin levels. All outcomes were analysed in the modified intention-to-treat population of all randomly assigned participants except those whose for whom consent was withdrawn. This trial is registered with the International Standard Randomised Controlled Trial Number registry (#59683017).

Parental Bacillus Calmette-Guérin vaccine scars decrease infant mortality in the first six weeks of life: A retrospective cohort study

“…Bacillus Calmette-Guérin (BCG) and other live attenuated vaccines have been associated with beneficial non-specific effects (NSEs); they increase child survival by protecting against unrelated infections [1] , [2] , [3] , [4] . In a meta-analysis of three trials from 2017, BCG-at-birth vs. the usual delayed-BCG to low-weight (LW) infants reduced neonatal all-cause mortality by 38% (95% CI, 17% to 54%) and infant mortality by 16% (0% to 29%) [2] .…”

Antituberculosis BCG vaccination: more reasons for varying innate and adaptive immune responses

“…More recently, the possibility that BCG may produce protection against heterologous, nontuberculous, infectious disease has been recognized. Trials have shown that BCG has protective effects against morbidity and mortality from unrelated infections in neonates and young children, in countries with high infectious disease burden (4,5), corroborating epidemiological studies associating BCG with reductions in sepsis and lower respiratory tract infections in children (6,7). Mechanistic studies suggest that this heterologous protection afforded by BCG may result, at least in part, from the induction of nonspecific innate immune memory via epigenetic reprogramming of myeloid cells (8).…”

“…The finding by Koeken and de Bree et al (13) of sex-differential effects of BCG on systemic inflammation is also important. Earlier trials in Guinea-Bissau, where BCG was given to low-birth weight infants, showed greater nonspecific benefits in males compared with females (4), and a similar effect has been observed in East Africa (5). A metaanalysis of more than 3,000 COVID-19 patients in China showed that males had a higher rate of disease progression than females (16), so a more marked effect of BCG on inflammation might substantially benefit males.…”

Using cross-species vaccination approaches to counter emerging infectious diseases

“…BCG was developed through close collaboration between medical and veterinary practitioners more than 100 years ago 19 , and the extensive experience of its use in humans is now informing vaccination strategies to control tuberculosis in cattle 20 . A recent study found that BCG vaccination in humans also confers protection against other non-tuberculous infections in early childhood 21 ; we are aware of no studies of non-specific effects of BCG vaccination in cattle, but this clearly warrants investigation. Edward Jenner’s observation that milkmaids exposed to the cowpox virus were protected against smallpox is perhaps the earliest example of exploiting pathogen relatedness for vaccine development and was the basis of the vaccine that was used for eradication of smallpox 22 .…”