{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:56:21Z","timestamp":1753890981196,"version":"3.41.2"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold>The immunogenicity of BCG vaccination in infants differs between populations. We hypothesized that prenatal exposure to mycobacterial antigens might explain the differences in immune responses to BCG seen in other studies of infants in Africa and the United Kingdom (UK) and we explored this in birth cohorts in Uganda and the UK.<\/jats:p><jats:p><jats:bold>Materials and Methods:<\/jats:bold>Blood samples were obtained from BCG-immunized infants of mothers with (<jats:italic>n<\/jats:italic>= 110) and without (<jats:italic>n<\/jats:italic>= 121) latent<jats:italic>Mycobacterium tuberculosis<\/jats:italic>infection (LTBI) in Uganda and BCG-immunized infants of mothers without LTBI (<jats:italic>n<\/jats:italic>= 25) in the UK at 10 and 52 weeks after birth. Cytokine and chemokine responses to PPD were measured to assess responses to BCG immunization, and to ESAT6\/CFP10 to assess exposure to or infection with<jats:italic>M. tuberculosis<\/jats:italic>or non-tuberculous mycobacteria (NTM) in 6-day whole blood culture supernatants by a 17-plex Luminex assay. Median responses were compared between Ugandan infants (together, and separated by maternal LTBI status) and UK infants.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold>The IFN-\u03b3 response to BCG vaccination was similar between Ugandan and UK infants at 10 and 52 weeks. At week 52, TNF production was marginally higher in Ugandan infants, but after adjusting for multiple comparisons this difference was not significant. At weeks 10 and 52, stimulation of blood with ESAT6\/CFP10 produced significantly higher IFN-\u03b3, TNF, IL-12p40, IL-1\u03b1, IL-1\u03b2, IL-1Ra, IP-10, MIP-1\u03b1, MIP-1\u03b2, and GM-CSF in Ugandan compared to UK infants. Stimulation of blood with ESAT6\/CFP10 produced significantly higher amounts of IL-8 (<jats:italic>p<\/jats:italic>= 0.0001), IL-10 (<jats:italic>p<\/jats:italic>= 0.0022), and IL-13 (<jats:italic>p<\/jats:italic>= 0.0020) in the UK than in Ugandan infants of mothers without LTBI at week 10, but not at week 52.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold>Immune responses to mycobacterial antigens following BCG immunization are similar for PPD, but differ for ESAT6\/CFP10, between infants in Uganda and the UK. Neither maternal LTBI nor infant exposure to or infection with mycobacteria impacts the response to BCG. The observed global differences in immune response to BCG immunization are likely to be due to other causes.<\/jats:p>","DOI":"10.3389\/fimmu.2021.637114","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T05:42:22Z","timestamp":1616132542000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune Responses Following BCG Immunization of Infants in Uganda and United Kingdom Are Similar for Purified Protein Derivative but Differ for Secretory Proteins of Mycobacterium tuberculosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Patrice A.","family":"Mawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mateusz","family":"Hasso-Agopsowicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence","family":"Lubyayi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Nabakooza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjorie","family":"Nakibuule","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rose","family":"Blitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Dun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abha","family":"Govind","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pontiano","family":"Kaleebu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily L.","family":"Webb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison M.","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hazel M.","family":"Dockrell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Cose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven G.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S64","DOI":"10.1086\/314072","article-title":"Preventing tuberculosis with bacillus Calmette-Guerin vaccine: a meta-analysis of the literature","volume":"31","author":"Brewer","year":"2000","journal-title":"Clin Infect Dis"},{"key":"B2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1542\/peds.96.1.29","article-title":"The efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature","volume":"96","author":"Colditz","year":"1995","journal-title":"Pediatrics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/S0140-6736(95)92348-9","volume":"346","year":"1995","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1093\/clinids\/20.4.982","article-title":"Geographic latitude and the efficacy of bacillus Calmette-Guerin vaccine","volume":"20","author":"Wilson","year":"1995","journal-title":"Clin Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.vaccine.2010.10.047","article-title":"Effects of maternal and infant co-infections, and of maternal immunisation, on the infant response to BCG and tetanus immunisation","volume":"29","author":"Elliott","year":"2010","journal-title":"Vaccine"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1093\/infdis\/162.5.1043","article-title":"Measles incidence, vaccine efficacy, and mortality in two urban African areas with high vaccination coverage","volume":"162","author":"Aaby","year":"1990","journal-title":"J Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e37535","DOI":"10.1371\/journal.pone.0037535","article-title":"A comparative analysis of polyfunctional T cells and secreted cytokines induced by Bacille Calmette-Guerin immunisation in children and adults","volume":"7","author":"Ritz","year":"2012","journal-title":"PLoS ONE"},{"key":"B8","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.4049\/jimmunol.163.4.2249","article-title":"Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination","volume":"163","author":"Marchant","year":"1999","journal-title":"J Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1098\/rstb.2014.0137","article-title":"The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette-Guerin immunization","volume":"370","author":"Mawa","year":"2015","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1164\/rccm.200912-1862OC","article-title":"CD4 and CD8 T-cell responses to mycobacterial antigens in African children","volume":"182","author":"Tena-Coki","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1086\/597069","article-title":"Population differences in immune responses to Bacille Calmette-Guerin vaccination in infancy","volume":"199","author":"Lalor","year":"2009","journal-title":"J Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1016\/j.vaccine.2009.11.004","article-title":"Complex cytokine profiles induced by BCG vaccination in UK infants","volume":"28","author":"Lalor","year":"2010","journal-title":"Vaccine"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1093\/infdis\/jir515","article-title":"BCG vaccination induces different cytokine profiles following infant BCG vaccination in the UK and Malawi","volume":"204","author":"Lalor","year":"2011","journal-title":"J Infect Dis"},{"key":"B14","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/1471-2334-14-184","article-title":"Factors affecting immunogenicity of BCG in infants, a study in Malawi, The Gambia and the UK","volume":"14","author":"Hur","year":"2014","journal-title":"BMC Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e14066","DOI":"10.1371\/journal.pone.0014066","article-title":"A longitudinal study of BCG vaccination in early childhood: the development of innate and adaptive immune responses","volume":"5","author":"Djuardi","year":"2010","journal-title":"PLoS ONE"},{"key":"B16","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.vaccine.2016.11.079","article-title":"Maternal BCG scar is associated with increased infant proinflammatory immune responses","volume":"35","author":"Mawa","year":"2017","journal-title":"Vaccine"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e00929","DOI":"10.3389\/fimmu.2020.00929","article-title":"Maternal latent Mycobacterium tuberculosis does not affect the infant immune response following BCG at birth: an observational longitudinal study in Uganda","volume":"11","author":"Lubyayi","year":"2020","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e9699","DOI":"10.1371\/journal.pone.0009699","article-title":"Influence of maternal gestational treatment with mycobacterial antigens on postnatal immunity in an experimental murine model","volume":"5","author":"Rahman","year":"2010","journal-title":"PLoS ONE"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1084\/jem.20091473","article-title":"Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway","volume":"208","author":"Potian","year":"2011","journal-title":"J Exp Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e93429","DOI":"10.1371\/journal.pone.0093429","article-title":"The effect of maternal helminth infection on maternal and neonatal immune function and immunity to tuberculosis","volume":"9","author":"Gebreegziabiher","year":"2014","journal-title":"PLoS ONE"},{"key":"B21","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1111\/j.1365-3083.1992.tb02878.x","article-title":"Immune responses during human schistosomiasis mansoni. XVIII. Immunologic status of pregnant women and their neonates","volume":"35","author":"Novato-Silva","year":"1992","journal-title":"Scand J Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2861","DOI":"10.1084\/jem.20092469","volume":"206","year":"2009","journal-title":"J Exp Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1016\/S0140-6736(02)08353-8","article-title":"BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies","volume":"359","author":"Black","year":"2002","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1093\/infdis\/jit570","article-title":"Distinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants","volume":"209","author":"Lutwama","year":"2014","journal-title":"J Infect Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.4049\/jimmunol.1000552","article-title":"Delaying bacillus Calmette-Guerin vaccination from birth to 4 1\/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age","volume":"185","author":"Burl","year":"2010","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1086\/322042","article-title":"Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi","volume":"184","author":"Black","year":"2001","journal-title":"J Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1016\/j.vaccine.2012.01.053","article-title":"The influence of BCG vaccine strain on mycobacteria-specific and non-specific immune responses in a prospective cohort of infants in Uganda","volume":"30","author":"Anderson","year":"2012","journal-title":"Vaccine"},{"key":"B28","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.cell.2016.09.024","article-title":"Genetic adaptation and neandertal admixture shaped the immune system of human populations","volume":"167","author":"Quach","year":"2016","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e00084","DOI":"10.1128\/CMR.00084-18","article-title":"Factors that influence the immune response to vaccination","volume":"32","author":"Zimmermann","year":"2019","journal-title":"Clin Microbiol Rev"},{"key":"B30","doi-asserted-by":"publisher","first-page":"5865","DOI":"10.1128\/JB.00683-09","article-title":"Region of difference 1 in nontuberculous Mycobacterium species adds a phylogenetic and taxonomical character","volume":"191","author":"van Ingen","year":"2009","journal-title":"J Bacteriol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/1471-2334-13-88","article-title":"Species and genotypic diversity of non-tuberculous mycobacteria isolated from children investigated for pulmonary tuberculosis in rural Uganda","volume":"13","author":"Asiimwe","year":"2013","journal-title":"BMC Infect Dis"},{"key":"B32","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1038\/19546","article-title":"MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions","volume":"398","author":"Gerszten","year":"1999","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/S1359-6101(97)00022-1","article-title":"Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF\/MCP-1), chemokines essentially involved in inflammatory and immune reactions","volume":"9","author":"Mukaida","year":"1998","journal-title":"Cytokine Growth Factor Rev"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1038\/nm.3670","article-title":"Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants","volume":"20","author":"Gibbons","year":"2014","journal-title":"Nat Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"327","DOI":"10.2174\/156652407780598557","article-title":"Th2 cytokines in susceptibility to tuberculosis","volume":"7","author":"Rook","year":"2007","journal-title":"Curr Mol Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.immuni.2010.05.007","article-title":"Alternative activation of macrophages: mechanism and functions","volume":"32","author":"Gordon","year":"2010","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1084\/jem.174.6.1549","article-title":"Macrophage deactivation by interleukin 10","volume":"174","author":"Bogdan","year":"1991","journal-title":"J Exp Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1165\/rcmb.2010-0319OC","article-title":"IL-10 blocks phagosome maturation in mycobacterium tuberculosis-infected human macrophages","volume":"45","author":"O'Leary","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1111\/j.1365-2249.2006.03288.x","article-title":"Mycobacterium bovis bacillus Calmette-Guerin (BCG) induces human CC- and CXC-chemokines in vitro and in vivo","volume":"147","author":"Luo","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1172\/JCI117788","article-title":"Monocyte chemotactic protein-1 (MCP-1),\u22122, and\u22123 are chemotactic for human T lymphocytes","volume":"95","author":"Taub","year":"1995","journal-title":"J Clin Invest"},{"key":"B41","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1016\/j.vaccine.2016.09.002","article-title":"Polyfunctional CD4 T-cells correlate with in vitro mycobacterial growth inhibition following Mycobacterium bovis BCG-vaccination of infants","volume":"34","author":"Smith","year":"2016","journal-title":"Vaccine"},{"key":"B42","doi-asserted-by":"publisher","first-page":"5488","DOI":"10.1016\/j.vaccine.2009.06.103","article-title":"Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response","volume":"27","author":"Kagina","year":"2009","journal-title":"Vaccine"},{"key":"B43","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12916-016-0617-3","article-title":"Human newborn bacille Calmette-Guerin vaccination and risk of tuberculosis disease: a case-control study","volume":"14","author":"Fletcher","year":"2016","journal-title":"BMC Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"644","DOI":"10.3389\/fimmu.2017.00644","article-title":"Whole blood profiling of bacillus calmette-guerin-induced trained innate immunity in infants identifies epidermal growth factor, IL-6, platelet-derived growth factor-AB\/BB, and natural killer cell activation","volume":"8","author":"Smith","year":"2017","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3791","DOI":"10.4049\/jimmunol.1602000","article-title":"Innate control of adaptive immunity: beyond the three-signal paradigm","volume":"198","author":"Jain","year":"2017","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.chom.2011.04.006","article-title":"Trained immunity: a memory for innate host defense","volume":"9","author":"Netea","year":"2011","journal-title":"Cell Host Microbe"},{"key":"B47","doi-asserted-by":"publisher","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B48","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12916-016-0685-4","article-title":"The potential impact of BCG vaccine supply shortages on global paediatric tuberculosis mortality","volume":"14","author":"Harris","year":"2016","journal-title":"BMC Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.637114\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T12:40:28Z","timestamp":1698064828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.637114\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,19]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2021.637114"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.637114","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2021,3,19]]},"article-number":"637114"}}