BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates
BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial - PubMed (nih.gov)
Sarah Prentice 1, Beatrice Nassanga 2, Emily L Webb 3, Florence Akello 2, Fred Kiwudhu 2, Hellen Akurut 2, Alison M Elliott 4, Rob J W Arts 5, Mihai G Netea 6, Hazel M Dockrell 7, Stephen Cose 8, Delayed BCG Study Team Collaborators, Affiliations expand
Free PMC article
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).
Findings: Between Sept 25, 2014, and July 31, 2015, 560 participants were enrolled and randomly assigned to receive BCG at birth (n=280) or age 6 weeks (n=280). 12 participants assigned to receive BCG at birth and 11 participants assigned to receive BCG at age 6 weeks were withdrawn from the study by their parents shortly after randomisation and were not included in analyses. During the first 6 weeks of life before the infants in the delayed vaccination group received BCG vaccination, physician-diagnosed non-tuberculous infectious disease incidence was lower in infants in the BCG at birth group than in the delayed group (98 presentations in the BCG at birth group vs 129 in the delayed BCG group; hazard ratio [HR] 0·71 [95% CI 0·53-0·95], p=0·023). After BCG in the delayed group (ie, during the age 6-10 weeks follow-up), there was no significant difference in non-tuberculous infectious disease incidence between the groups (88 presentations vs 76 presentations; HR 1·10 [0·87-1·40], p=0·62). BCG at birth inhibited the increase in histone trimethylation at the TNF promoter in peripheral blood mononuclear cells occurring in the first 6 weeks of life. H3K4me3 geometric mean fold-increases were 3·1 times lower at the TNF promoter (p=0·018), 2·5 times lower at the IL6 promoter (p=0·20), and 3·1 times lower at the IL1B promoter (p=0·082) and H3K9me3 geometric mean fold-increases were 8·9 times lower at the TNF promoter (p=0·0046), 1·2 times lower at the IL6 promoter (p=0·75), and 4·6 times lower at the IL1B promoter (p=0·068), in BCG-vaccinated (BCG at birth group) versus BCG-naive (delayed BCG group) infants. No clear effect of BCG on ex-vivo production of TNF, IL-6, IL-1β, IL-10, and IFNγ after heterologous stimulation, or transferrin saturation and hepcidin concentration, was detected (geometric mean ratios between 0·68 and 1·68; p≥0·038 for all comparisons).
Interpretation: BCG vaccination protects against non-tuberculous infectious disease during the neonatal period, in addition to having tuberculosis-specific effects. Prioritisation of BCG on the first day of life in high-mortality settings might have significant public-health benefits through reductions in all-cause infectious morbidity and mortality.
Funding: Wellcome Trust.
Translations: For the Luganda and Swahili translations of the abstract see Supplementary Materials section.
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Figures Figure 1 Trial profile Trial profiles for… Figure 2 Cumulative hazard of physician-diagnosed, non-tuberculous… Figure 3 Comparison of fold changes in…
BCG: new life for a centenarian vaccine.Aaby P, Benn CS.Lancet Infect Dis. 2021 Jul;21(7):897-898. doi: 10.1016/S1473-3099(20)30714-3. Epub 2021 Feb 17.PMID: 33609459 No abstract available.
Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial.Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, Geldenhuys H, Shenje J, Luabeya AKK, Murillo I, Doce J, Aguilo N, Marinova D, Puentes E, Rodríguez E, Gonzalo-Asensio J, Fritzell B, Thole J, Martin C, Scriba TJ, Hatherill M; MTBVAC Clinical Trial Team.Lancet Respir Med. 2019 Sep;7(9):757-770. doi: 10.1016/S2213-2600(19)30251-6. Epub 2019 Aug 12.PMID: 31416768 Clinical Trial.
Investigating the non-specific effects of BCG vaccination on the innate immune system in Ugandan neonates: study protocol for a randomised controlled trial.Prentice S, Webb EL, Dockrell HM, Kaleebu P, Elliott AM, Cose S.Trials. 2015 Apr 11;16:149. doi: 10.1186/s13063-015-0682-5.PMID: 25872925 Free PMC article. Clinical Trial.
BCG revaccination of health workers in Brazil to improve innate immune responses against COVID-19: A structured summary of a study protocol for a randomised controlled trial.Junqueira-Kipnis AP, Dos Anjos LRB, Barbosa LCS, da Costa AC, Borges KCM, Cardoso ADRO, Ribeiro KM, Rosa SBA, Souza CC, das Neves RC, Saraiva G, da Silva SM, Silveira EA, Rabahi MF, Conte MB, Kipnis A.Trials. 2020 Oct 26;21(1):881. doi: 10.1186/s13063-020-04822-0.PMID: 33106170 Free PMC article. Clinical Trial.
BCG vaccination in India and tuberculosis in children: newer facets.Udani PM.Indian J Pediatr. 1994 Sep-Oct;61(5):451-62. doi: 10.1007/BF02751703.PMID: 7744445 Review.
Bacillus Calmette-Guérin vaccination at birth: Effects on early childhood infections, growth, and development.Kjærgaard J.Dan Med J. 2016 Nov;63(11):B5304.PMID: 27808041 Review.
Ortega Páez E, Esparza Olcina MJ. La BCG proporciona beneficios adicionales en entornos de alta morbimortalidad neonatal. Evid Pediatr. 2021;17:45.