Neonatal BCG Vaccination Reduces Interferon-γ Responsiveness to Heterologous Pathogens in Infants From a Randomized Controlled Trial

Bridget Freyne, Nicole L Messina, Susan Donath, Susie Germano, Rhian Bonnici, Kaya Gardiner, Dan Casalaz, Roy M Robins-Browne, Mihai G Netea, Katie L Flanagan, Toby Kollmann, Nigel Curtis, Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group, Veronica Abruzzo, Katie Allen, Clare Morrison, Anne-Louise Ponsonby, Peter Vuillermin, Bridget Freyne, Nicole L Messina, Susan Donath, Susie Germano, Rhian Bonnici, Kaya Gardiner, Dan Casalaz, Roy M Robins-Browne, Mihai G Netea, Katie L Flanagan, Toby Kollmann, Nigel Curtis, Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group, Veronica Abruzzo, Katie Allen, Clare Morrison, Anne-Louise Ponsonby, Peter Vuillermin

Abstract

Background: BCG vaccination has beneficial nonspecific (heterologous) effects that protect against nonmycobacterial infections. We have previously reported that BCG vaccination at birth alters in vitro cytokine responses to heterologous stimulants in the neonatal period. This study investigated heterologous responses in 167 infants in the same trial 7 months after randomization.

Methods: A whole-blood assay was used to interrogate in vitro cytokine responses to heterologous stimulants (killed pathogens) and Toll-like receptor (TLR) ligands.

Results: Compared to BCG-naive infants, BCG-vaccinated infants had increased production of interferon gamma (IFN-γ) and monokine induced by gamma interferon (MIG) (CXCL9) in response to mycobacterial stimulation and decreased production of IFN-γ in response to heterologous stimulation and TLR ligands. Reduced IFN-γ responses were attributable to a decrease in the proportion of infants who mounted a detectable IFN-γ response. BCG-vaccinated infants also had increased production of MIG (CXCL9) and interleukin-8 (IL-8), and decreased production of IL-10, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, the pattern of which varied by stimulant. IL-1Ra responses following TLR1/2 (Pam3CYSK4) stimulation were increased in BCG-vaccinated infants. Both sex and maternal BCG vaccination status influenced the effect of neonatal BCG vaccination.

Conclusions: BCG vaccination leads to changes in IFN-γ responsiveness to heterologous stimulation. BCG-induced changes in other cytokine responses to heterologous stimulation vary by pathogen.

Keywords: BCG; heterologous; immunization; infants; innate immunity; nonspecific effects.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Flow diagram showing participant inclusion. Table shows number of individual stimulations done for each stimulant. Abbreviations: LPS, lipopolysaccharide; PEPG, peptidoglycan; TLR, Toll-like receptor.
Figure 2.
Figure 2.
The effect of neonatal BCG vaccination vs no BCG vaccination on cytokine responses to heterologous stimulants. Significant results P < .05 are depicted in black. Geometric mean ratio > 1.0 indicates that cytokine levels were higher in BCG-vaccinated infants compared with BCG-naive infants. Data that were not normally distributed were analyzed using quantile regression and differences in medians (95% confidence intervals). As this only applied to interferon gamma (IFN-γ), to aid interpretation, all IFN-γ analyses are displayed on stand-alone axes irrespective of the type of analysis done. Abbreviations: CI, confidence interval; GMR, geometric mean ratio; IFN, interferon; IL, interleukin; IP, interferon-gamma induced protein; LPS, lipopolysaccharide; MCP, monocyte chemoattractant protein; MIF, macrophage migration inhibitory factor; MIG, monokine induced by gamma interferon; MIP, macrophage inflammatory protein; PEPG, peptidoglycan; TNF, tumor necrosis factor.
Figure 3.
Figure 3.
Proportion of BCG-vaccinated and BCG-naive participants with production of interferon gamma (IFN-γ) in response to heterologous stimulation (“responders”) (Fisher exact test). Data for R848 are not included as IFN-γ responses were above the lower limit of detection for all participants.
Figure 4.
Figure 4.
Subgroup analysis for the effect of infant sex and maternal BCG vaccination on in vitro cytokine responses. Interleukin 6 (A), interleukin 1β (B), and remaining cytokine/stimulant pairs (C) with a significant interaction between sex and BCG vaccination. Geometric mean ratios (GMRs) and 95% confidence intervals (CIs) are shown for the effect of infant BCG vaccination on all study participants (i), girls (ii), and boys (iii). D, Cytokine/stimulant pairs with a significant interaction between maternal BCG vaccination and BCG vaccination. GMRs and 95% CIs are shown for the effect of infant BCG vaccination on all study participants (i), infants whose mothers were BCG-vaccinated (ii), and infants whose mothers were BCG naive (iii). GMR > 1 indicates that cytokine production is higher in BCG-vaccinated infants. Abbreviations: CI, confidence interval; GMR, geometric mean ratio; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MIG, monokine induced by gamma interferon; MIP, macrophage inflammatory protein; PEPG, peptidoglycan; TNF, tumor necrosis factor.

References

    1. Higgins JP, Soares-Weiser K, López-López JA, et al. . Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016; 355:i5170.
    1. Pollard AJ, Finn A, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child 2017; 102:1077–81.
    1. Aaby P, Roth A, Ravn H, et al. . Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011; 204:245–52.
    1. Biering-Sørensen S, Aaby P, Napirna BM, et al. . Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J 2012; 31:306–8.
    1. Hollm-Delgado MG, Stuart EA, Black RE. Acute lower respiratory infection among bacille Calmette-Guérin (BCG)-vaccinated children. Pediatrics 2014; 133:e73–81.
    1. de Castro MJ, Pardo-Seco J, Martinón-Torres F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin Infect Dis 2015; 60:1611–9.
    1. Thøstesen LM, Kjaergaard J, Pihl GT, et al. . Neonatal BCG vaccination and atopic dermatitis before 13 months of age: a randomized clinical trial. Allergy 2018; 73:498–504.
    1. Berendsen MLT, Oland CB, Bles P, et al. . Maternal priming: bacillus Calmette-Guerin (BCG) vaccine scarring in mothers enhances the survival of their child with a BCG vaccine scar. J Pediatric Infect Dis Soc 2019. doi:10.1093/jpids/piy142.
    1. Kjærgaard J, Birk NM, Nissen TN, et al. . Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial. Pediatr Res 2016; 80:681–5.
    1. Kandasamy R, Voysey M, McQuaid F, et al. . Non-specific immunological effects of selected routine childhood immunisations: systematic review. BMJ 2016; 355:i5225.
    1. Freyne B, Donath S, Germano S, et al. . Neonatal BCG vaccination influences cytokine responses to Toll-like receptor ligands and heterologous antigens. J Infect Dis 2018; 217:1798–808.
    1. Kleinnijenhuis J, Quintin J, Preijers F, et al. . Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 2014; 6:152–8.
    1. Lalor MK, Floyd S, Gorak-Stolinska P, et al. . BCG vaccination induces different cytokine profiles following infant BCG vaccination in the UK and Malawi. J Infect Dis 2011; 204:1075–85.
    1. Lalor MK, Smith SG, Floyd S, et al. . Complex cytokine profiles induced by BCG vaccination in UK infants. Vaccine 2010; 28:1635–41.
    1. Flanagan KL, van Crevel R, Curtis N, Shann F, Levy O; Optimmunize Network Heterologous (“nonspecific”) and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clin Infect Dis 2013; 57:283–9.
    1. Messina NL, Gardiner K, Donath S, et al. . Study protocol for the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial to determine the non-specific effects of neonatal BCG vaccination in a low-mortality setting. BMJ Open 2019; 9:e032844.
    1. Burl S, Adetifa UJ, Cox M, et al. . Delaying bacillus Calmette-Guérin vaccination from birth to 4 ½ months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol 2010; 185:2620–8.
    1. Corral-Fernández NE, Cortez-Espinosa N, Salgado-Bustamante M, et al. . Induction of transcription factors, miRNAs and cytokines involved in T lymphocyte differentiation in BCG-vaccinated subjects. Mol Immunol 2016; 77:44–51.
    1. van den Biggelaar AH, Prescott SL, Roponen M, et al. . Neonatal innate cytokine responses to BCG controlling T-cell development vary between populations. J Allergy Clin Immunol 2009; 124:544–50, 50.e1–2.
    1. Zufferey C, Germano S, Dutta B, Ritz N, Curtis N. The contribution of non-conventional T cells and NK cells in the mycobacterial-specific IFNγ response in bacille Calmette-Guérin (BCG)-immunized infants. PLoS One 2013; 8:e77334.
    1. Nissen TN, Birk NM, Blok BA, et al. . Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial. Eur J Clin Microbiol Infect Dis 2018; 37:29–41.
    1. Smith SG, Kleinnijenhuis J, Netea MG, Dockrell HM. Whole blood profiling of bacillus Calmette-Guérin-induced trained innate immunity in infants identifies epidermal growth factor, IL-6, platelet-derived growth factor-AB/BB, and natural killer cell activation. Front Immunol 2017; 8:644.
    1. Joosten SA, van Meijgaarden KE, Arend SM, et al. . Mycobacterial growth inhibition is associated with trained innate immunity. J Clin Invest 2018; 128:1837–51.
    1. Djuardi Y, Sartono E, Wibowo H, Supali T, Yazdanbakhsh M. A longitudinal study of BCG vaccination in early childhood: the development of innate and adaptive immune responses. PLoS One 2010; 5:e14066.
    1. Finan C, Ota MO, Marchant A, Newport MJ. Natural variation in immune responses to neonatal Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccination in a cohort of Gambian infants. PLoS One 2008; 3:e3485.
    1. Newport MJ, Goetghebuer T, Weiss HA, Whittle H, Siegrist CA, Marchant A; MRC Gambia Twin Study Group Genetic regulation of immune responses to vaccines in early life. Genes Immun 2004; 5:122–9.
    1. Boer MC, Prins C, van Meijgaarden KE, van Dissel JT, Ottenhoff TH, Joosten SA. Mycobacterium bovis BCG vaccination induces divergent proinflammatory or regulatory T cell responses in adults. Clin Vaccine Immunol 2015; 22:778–88.
    1. Fletcher HA, Filali-Mouhim A, Nemes E, et al. . BCG Study Team Human newborn bacille Calmette-Guérin vaccination and risk of tuberculosis disease: a case-control study. BMC Med 2016; 14:76.
    1. Walk J, de Bree LCJ, Graumans W, et al. . Outcomes of controlled human malaria infection after BCG vaccination. Nat Commun 2019; 10:874.
    1. Bohrer AC, Tocheny C, Assmann M, Ganusov VV, Mayer-Barber KD. Cutting Edge: IL-1R1 mediates host resistance to Mycobacterium tuberculosis by trans-protection of infected cells. J Immunol 2018; 201:1645–50.
    1. Mayer-Barber KD, Andrade BB, Oland SD, et al. . Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 2014; 511:99–103.
    1. Arts RJW, Moorlag S, Novakovic B, et al. . BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 2018; 23:89–100.e5.
    1. Koeken VACM, Verrall AJ, Netea MG, Hill PC, van Crevel R. Trained innate immunity and resistance to Mycobacterium tuberculosis infection. Clin Microbiol Infect 2019; 25:1468–72.
    1. Moorlag SJCFM, Röring RJ, Joosten LAB, Netea MG. The role of the interleukin-1 family in trained immunity. Immunol Rev 2018; 281:28–39.
    1. Biering-Sørensen S, Jensen KJ, Monterio I, Ravn H, Aaby P, Benn CS. Rapid protective effects of early BCG on neonatal mortality among low birth weight boys: observations from randomized trials. J Infect Dis 2018; 217:759–66.
    1. Mawa PA, Webb EL, Filali-Mouhim A, et al. . Maternal BCG scar is associated with increased infant proinflammatory immune responses. Vaccine 2017; 35:273–82.
    1. Stensballe LG, Ravn H, Birk NM, et al. . BCG vaccination at birth and rate of hospitalization for infection until 15 months of age in Danish children: a randomized clinical multicenter trial. J Pediatr Infect Dis Soc 2019; 8:213–20.
    1. Weir RE, Black GF, Nazareth B, et al. . The influence of previous exposure to environmental mycobacteria on the interferon-gamma response to bacille Calmette-Guérin vaccination in southern England and northern Malawi. Clin Exp Immunol 2006; 146:390–9.

Source: PubMed

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