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URL: https://pubmed.ncbi.nlm.nih.gov/29415180/

⇱ Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens - PubMed

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Abstract

Background: BCG vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain, but long-term modulation of the innate immune response (trained immunity) may be involved.

Methods: Whole-blood specimens, collected 7 days after randomization from 212 neonates enrolled in a randomized trial of neonatal BCG vaccination, were stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses.

Results: BCG-vaccinated infants had increased production of interleukin 6 (IL-6) in unstimulated samples and decreased production of interleukin 1 receptor antagonist, IL-6, and IL-10 and the chemokines macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1) following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination.

Conclusions: Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterized by decreased antiinflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine whether there is an association between these findings and the beneficial nonspecific (heterologous) effects of BCG vaccine on all-cause mortality.

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Figures

👁 Figure 1.
Figure 1.
Flow chart of eligible participants and relevant exclusions. Table shows number of individual stimulations done for each antigen. C. albicans, Candida albicans; GBS, group B streptococcus; E. coli, Escherichia coli; H. influenzae, Haemophilus influenzae type B; L. monocytogenes, Listeria monocytogenes; LPS, lipopolysaccharide; M. tuberculosis, Mycobacterium tuberculosis; Pam3CSK4, (S)-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4OH, trihydrochloride; PEPG, peptidoglycan; R848, resiquimod; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae serotype 15C.
👁 Figure 2.
Figure 2.
The effect of BCG vaccination on cytokine expression. Significant results P < .05 are depicted in pale gray. A geometric mean ratio (GMR) of >1.0 indicates cytokine levels were higher in BCG-vaccinated infants, compared with BCG-naïve infants. C. albicans, Candida albicans; CI, confidence interval; E. coli, Escherichia coli; GBS, group B streptococcus; H. influenzae, Haemophilus influenzae type B; IFN-γ, interferon γ; IL-1RA, interleukin 1 receptor antagonist; IL-1β, interleukin 1β; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; L. monocytogenes, Listeria monocytogenes; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein 1/CCL2; MIF, macrophage migration inhibitory factor; MIG, monokine induced by interferon γ/CXCL9; MIP-1 α/β, macrophage inflammatory protein 1 CCL3/CCL4; M. tuberculosis, Mycobacterium tuberculosis; Pam3CSK4, (S)-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4OH, trihydrochloride; PEPG, peptidoglycan; R848, resiquimod; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae serotype 15C; TNF-α, tumor necrosis factor α.
👁 Figure 3.
Figure 3.
Interaction and subgroup analysis for the effect of sex on BCG vaccination. Macrophage migration inhibitory factor (MIF) production for cytokine/stimulant pairs where a significant interaction between sex and BCG vaccination was seen are shown for all participants (left), BCG-vaccinated females versus BCG-naïve females (middle), and BCG-vaccinated males versus BCG-naïve males. CI, confidence interval; GMR, geometric mean ratio; H. influenzae, Haemophilus influenzae type B; L. monocytogenes, Listeria monocytogenes; M. tuberculosis, Mycobacterium tuberculosis; Pam3CSK4, (S)-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4OH, trihydrochloride; R848, resiquimod; S. pneumoniae, Streptococcus pneumoniae serotype 15C.
👁 Figure 4.
Figure 4.
Interaction and subgroup analysis for the effect of maternal BCG vaccination status on neonatal BCG vaccination. Cytokine responses for cytokine/stimulant pairs where a significant interaction between maternal BCG vaccination status and neonatal BCG vaccination was seen are shown for all participants (left), in participants whose mothers were vaccinated with BCG (BCG-vaccinated infants vs BCG-naïve infants; middle), and participants whose mothers were not vaccinated with BCG (BCG-vaccinated infants vs BCG-naïve infants; right). CI, confidence interval; GMR, geometric mean ratio; H. influenzae, Haemophilus influenzae type B; IFN-γ, interferon γ; IL-1β, interleukin 1β; MIG, monokine induced by interferon γ/CXCL9; MIP-1α, macrophage inflammatory protein 1α CCL3; Pam3CSK4, (S)-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4OH, trihydrochloride; PEPG, peptidoglycan; S. pneumoniae, Streptococcus pneumoniae serotype 15C.
👁 Figure 5.
Figure 5.
Effect of the timing of BCG on the overall effect of BCG shown by the primary analysis. Cytokine responses for cytokine/stimulant pairs where a significant effect of BCG vaccination was seen are shown for all participants (top), for infants who received BCG < 48 hours of birth (early) vs controls (bottom left), for participants who received BCG ≥48 hours from birth (late) vs controls (bottom right). C. albicans, Candida albicans; CI, confidence interval; GMR, geometric mean ratio; E. coli, Escherichia coli; IL-1RA, interleukin 1 receptor antagonist; IL-10, interleukin 10; L. monocytogenes, Listeria monocytogenes; MCP-1, monocyte chemoattractant protein 1/CCL2; MIP-1 α/β, macrophage inflammatory protein 1 (CCL3/CCL4); PEPG, peptidoglycan; R848, resiquimod; S. pneumoniae, Streptococcus pneumoniae serotype 15C.

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