Maternal Latent Mycobacterium tuberculosis Does Not Affect the Infant Immune Response Following BCG at Birth: An Observational Longitudinal Study in Uganda

Abstract

Background: BCG has low efficacy in tropical countries. We hypothesized that maternal latent Mycobacterium tuberculosis (M.tb) infection (LTBI) results in fetal tolerance to mycobacterial antigens and impaired responses to BCG immunization. Methods: We enrolled 132 LTBI-positive and 150 LTBI-negative mothers and their babies in Entebbe, Uganda. Infants were BCG-immunized at birth. Cord blood and samples at weeks 1, 4, 6, 10, 14, 24, and 52 were analyzed for cytokine/chemokine responses to M.tb antigens by Luminex 17-plex assay in 6-day whole blood cultures and antibody responses by ELISA. Of the 17 Luminex analytes, seven (IL-2, IL-5, IL-10, IL-13, IL-17A, TNF, and IFN-γ) were included in the main analysis as they were considered most likely to represent T cell responses. Immune sensitization was defined as a detectable cord blood cytokine response to PPD for any of the seven cytokines. Patterns of cytokine and antibody responses were compared between infants of mothers with and without LTBI using linear mixed models adjusting for confounders. Results: Most infants (73%) were sensitized in utero to M.tb antigens, with no overall difference seen between infants born to mothers with or without LTBI. Patterns of post-BCG cytokine and antibody responses to mycobacterial antigens were similar between the two infant groups. Conclusions: Our data do not support the hypothesis that maternal LTBI results in an impaired response to BCG immunization, in Ugandan infants. BCG vaccination at or shortly after birth is likely to be beneficial to all infants, irrespective of maternal LTBI status.

Protection against mycobacterial infection: A case-control study of mycobacterial immune responses in pairs of Gambian children with discordant infection status despite matched TB exposure

“…There was also no difference in IL-2, IFN-γ, TNF-α, and/or IL- 17-expressing subsets of CD4, CD8 and γδ T-cells between IGRA+ and IGRA- South African adults following 12 h of BCG stimulation, nor correlations with MTB growth in a cross-sectional study [48] . Cytokine responses to MTB antigens of samples from babies born to mothers with or without LTBI also do not differ [57] .…”

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

“…The ESAT6/CFP10-expressing NTM such as M. szulgai (30) have previously been identified in Ugandan infants and adolescents where the overall prevalence of NTM in infants from rural Uganda investigated for pulmonary tuberculosis was 3.7% (31). We were interested in whether the differences observed for overall median responses to mycobacterial antigens between Ugandan and UK infants were influenced by maternal LTBI exposure of Ugandan infants, though we recently demonstrated that, in Uganda, maternal LTBI does not influence infant responses to BCG immunization (17). Similarly, in this analysis we did not find differences in the immune response between infants of mothers with and without a LTBI for most cytokines except for IL-10, IL-13, and IL-8 responses to ESAT6/CFP10 stimulation that were higher in UK infants than in Ugandan infants of mothers without LTBI, at 10 weeks.…”

“…Between June 2014 and October 2016, healthy Ugandan mothers and their infants were recruited at Entebbe General Hospital as part of a larger study to investigate the impact of maternal LTBI on the infant response to BCG immunization ( 17 ).…”

“…Women positive on both tests were considered LTBI-positive; those negative on both tests were considered LTBI-negative; those with indeterminate and inconsistent results were excluded. LTBI-positive mothers were examined for active tuberculosis by symptoms, sputum examination (if available), and chest x-ray and there were no cases of active TB disease detected in mothers and their infants during the study period, and data available on the subjects has been reported ( 17 ).…”

“…The profile of immune response to BCG immunization seen in infants from Malawi may be similar to other settings in sub-Saharan Africa where the protective efficacy of BCG is low. We aimed to explore whether prenatal exposure to mycobacterial antigens explained the Africa-UK differences to any extent using samples obtained from a study that investigated the impact of maternal latent M. tuberculosis infection (LTBI) on the infant response to BCG immunization ( 17 ). In murine studies, mycobacterial antigens have been shown to cross the placenta following gestational treatment with mycobacterial antigens ( 18 ).…”