Search

ABSTRACT Background Objective Methods Results Conclusions and Clinical Relevance The beneficial off‐target effects of Bacille Calmette–Guérin (BCG) vaccination potentially include protection against allergy.In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants.In this randomised controlled trial, 1272 neonates were allocated to BCG‐Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3‐monthly online questionnaires and oral food challenges. Data were analysed by intention‐to‐treat using binary regression. Clinicaltrials.gov (NCT01906853).Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI −1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI −3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration).Neonatal BCG‐Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life. [ABSTRACT FROM AUTHOR]

Background Antibiotic exposure increases antimicrobial resistance and has also been associated with long-term harms, including allergies, inflammatory diseases and weight gain. We assessed antibiotic exposure in the first 2 years of life in Australian children, the factors influencing this and its appropriateness. Methods Data from 1201 participants in the MIS BAIR randomized controlled trial were used. Multivariable logistic regression was used to identify factors associated with antibiotic exposure. Results At 1 and 2 years of age, exposure to at least one course of antibiotics was 43% and 67%, with the highest first antibiotic prescription rate between 9 and 18 months. Amoxicillin was the most frequently used antibiotic (59%), followed by cefalexin (7%). The most common diagnoses for which antibiotics were prescribed were respiratory tract infections from 0 to 6 months of age and otitis media from 6 to 12 months. Factors associated with antibiotic exposure from 0 to 12 months of age were delivery by Caesarean section (adjusted odd-ratio (aOR) 1.5, 95%CI 1.1–1.9), birth in winter (aOR 1.7, 95%CI 1.2–2.4), maternal antibiotic exposure during the last trimester of pregnancy (aOR 1.6, 95%CI 1.1–2.3), cessation of breastfeeding by 6 months of age (aOR 1.5, 95%CI 1.1–2.0) and day-care attendance (aOR 1.4, 95%CI 1.1–1.8). Based on parent-reported questionnaires, 27% of infants were treated in the first year of life for conditions unlikely to need antibiotic treatment. Conclusion At least two-thirds of children were prescribed antibiotics in the first 2 years of life, and more than a quarter of these exposures may have been unnecessary. [ABSTRACT FROM AUTHOR]

BCG vaccination has beneficial off-target ("nonspecific") effects on nonmycobacterial infections. On this premise, trials set out to investigate whether BCG provides off-target protection against coronavirus disease 2019 (COVID-19). A literature search identified 11 randomized "BCG COVID-19" trials, with conflicting results. These trials and the differences in their study design are discussed using the PICOT (participants, intervention, control, outcome, and timing) framework to highlight the factors that likely explain their inconsistent findings. These include participant age, sex and comorbid conditions, BCG vaccination strain and dose, outcome measure and duration of follow-up. Understanding how to control these factors to best exploit BCG's off-target effects will be important in designing future trials and intervention strategies. [ABSTRACT FROM AUTHOR]

Background and objectives: Because of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using samples from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS‐CoV‐2. Conclusions: The immunomodulatory signature of BCG's off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette‐Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off‐target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. Methods: Randomized controlled trial with 1272 infants allocated to receive BCG‐Denmark or no BCG at birth. The primary outcome was the 12‐month incidence of eczema based on 3‐monthly questionnaires. Eczema was also assessed at a 12‐month clinic visit. ClinicalTrial.gov: NCT01906853. Results: The 12‐month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) −4.3%, 95% CI −9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12‐month visit (aRD −3.5%, 95% CI −8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD −3.3, 95% CI −9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD −3.0%, 95% CI −8.8% to 2.7%). In 344 high‐risk infants (two atopic parents), the 12‐month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD −11.5%, 95% CI −21.9% to −1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). Conclusion: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high‐risk infants. A single dose of BCG‐Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette-Guérin (BCG) vaccination has beneficial off-target effects that may include protecting against non-mycobacterial infectious diseases. We aimed to determine whether neonatal BCG vaccination reduces lower respiratory tract infections (LRTI) in infants in the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) trial.Methods: In this investigator-blinded trial, neonates in Australia were randomized to receive BCG-Denmark vaccination or no BCG at birth. Episodes of LRTI were determined by symptoms reported in parent-completed, 3-month questionnaires over the first year of life. Data were analyzed by intention-to-treat using binary regression.Results: A total of 1272 neonates were randomized to the BCG vaccination (n = 637) or control (n = 635) group. The proportion of participants with an episode of LRTI in the first year of life among BCG-vaccinated infants was 54.8% compared to 58.0% in the control group, resulting in a risk difference of -3.2 (95% confidence interval, -9.0 to 2.6) after multiple imputation. There was no interaction observed between the primary outcome and sex, maternal BCG, or the other prespecified effect modifiers.Conclusions: Based on the findings of this trial, there is insufficient evidence to support the use of neonatal BCG vaccination to prevent LRTI in the first year of life in high-income settings. [ABSTRACT FROM AUTHOR]

The influence of genetic variability on human immune responses has major implications for the understanding of disease mechanisms and host-pathogen interactions. Bacillus Calmette-Guérin (BCG) vaccine, which is given globally to protect against tuberculosis, has high variability in its protective efficacy against mycobacteria and its beneficial off-target (heterologous) effects. Single nucleotide polymorphisms (SNPs) are major cause of genetic variation and have been strongly associated with susceptibility to tuberculosis and outcomes following BCG immunotherapy for cancer. This review discusses the contribution of SNPs to the variability in mycobacterial-specific and off-target BCG responses, and the implications for this on development of novel TB vaccines and strategies to harness the beneficial off-target effects of BCG. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents the authors' reply to comments on their article on BGC vaccination to reduce the Covid-19 impact on healthcare workers in 2023. It states that there is danger in flawed medical studies, and that the effect of BCG vaccination could not be determined on the current definition of severe disease. Also noted is the importance of considering modifying factors in interpreting the outcomes of vaccine trials.

Focus of Presentation Statistical methods for causal mediation analysis are useful for understanding the pathways by which a certain treatment or exposure impacts health outcomes. Existing methods necessitate modelling of the distribution of the mediators, which quickly becomes infeasible when mediators are high-dimensional (e.g. biomarkers). We propose novel data-adaptive methods for estimating the indirect effect of a randomised treatment that acts via a pathway represented by a high-dimensional set of measurements. This work was motivated by the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial investigating the effect of neonatal tuberculosis vaccination on clinical allergy and infection outcomes, and its mechanisms of action. Findings The proposed methods are doubly robust, which allows us to achieve (uniformly) valid statistical inference, even when machine learning algorithms are used for the two required models. We illustrate these in the context of the MIS BAIR study, investigating the mediating role of immune pathways represented by a high-dimensional vector of cytokine responses under various stimulants. We confirm adequate performance of the proposed methods in an extensive simulation study. Conclusions/Implications The proposed methods provide a feasible and flexible analytic strategy for examining high-dimensional mediators in randomised controlled trials. Key messages Data-adaptive methods for mediation analysis are desirable in the context of high-dimensional mediators, such as biomarkers. We propose novel doubly robust methods, which enable valid statistical inference when using machine learning algorithms for estimation. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 1 (Stat1) mediates anti-viral responses and cytokine-driven anti-proliferative, apoptotic and immunomodulatory activities. As de-regulated Stat1 function can affect tumour progression we sought to elucidate the effects of tumour cell-intrinsic Stat1 expression on immunosurveillance. Knockout of Stat1 enhanced the development of sarcomas induced by the chemical carcinogen 3-methylcholanthrene (MCA). Growth of transplanted MCA-induced Stat1−/− sarcomas was suppressed in wild-type mice compared to growth in Stat1−/− and immunocompromised recipients. Co-depletion of NK and CD8+ T cells from wild-type mice facilitated Stat1-deficient tumour growth whereas depletion of CD4+ T cells and CD8+ T cells did not. In vitro and in vivo analysis of the tumours implicated a role for NK cell-mediated, perforin-dependent killing of Stat1-deficient tumours. Interestingly, restoration of Stat1 expression in Stat1−/− tumours resulted in diminished involvement of NK cells and increased contribution of CD8+ T cells in anti-tumour responses. Therefore, Stat1 expression within tumour cells modulated anti-tumour immune responses by altering the dominant immune effector cell involvement from NK cells to CD8+ T cells in the absence or presence of Stat1 respectively. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) were discovered as cytokines induced during and protecting from viral infection. They have been documented to play essential roles in numerous physiological processes beyond antiviral and antimicrobial defense, including immunomodulation, cell cycle regulation, cell survival, and cell differentiation. Recent data have also uncovered a potentially darker side to IFN, including roles in inflammatory diseases, such as autoimmunity and diabetes. IFN can have effects in the absence of acute infection, highlighting a physiologic role for constitutive IFN. Type I IFNs are constitutively produced at vanishingly low quantities and yet exert profound effects, mediated in part through modulation of signaling intermediates required for responses to diverse cytokines. We review evidence for a yin-yang of IFN function through its role in modulating crosstalk between multiple cytokines by both feedforward and feedback regulation of common signaling intermediates and postulate a homeostatic role for IFN through tonic signaling in the absence of acute infection. [Copyright &y& Elsevier]

Autocrine priming of cells by small quantities of constitutively produced type I interferon (IFN) is a well-known phenomenon. In the absence of type I IFN priming, cells display attenuated responses to other cytokines, such as anti-viral protection in response to IFNc. This phenomenon was proposed to be because IFNa/b receptor1 (IFNAR1) is a component of the IFNc receptor (IFNGR), but our new data are more consistent with a previously proposed model indicating that regulated expression of STAT1 may also play a critical role in the priming process. Initially, we noticed that DNA binding activity of STAT1 was attenuated in c-Jun-/- fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun-/- fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFNb, as it was inhibited by antibodies to IFNAR1, or when IFNb expression was knocked down in wild-type cells. IFNAR1-/- fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFNc. The lack of priming in IFNAR1-/- fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFNγ and restored the ability of IFNγ to induce protective anti-viral immunity. This study provides a comprehensive description of the molecular events involved in priming by type I IFN. Adding to the previous working model that proposed an interaction between type I and II IFN receptors, our work and that of others demonstrates that type I IFN primes IFNc-mediated immune responses by regulating expression of STAT1. This may also explain how type I IFN can additionally prime cells to respond to a range of other cytokines that use STAT1 (e.g., IL-6, M-CSF, IL-10) and suggests a potential mechanism for the changing levels of STAT1 expression observed during viral infection. [ABSTRACT FROM AUTHOR]

Autocrine priming of cells by small quantities of constitutively produced type I interferon (IFN) is a well-known phenomenon. In the absence of type I IFN priming, cells display attenuated responses to other cytokines, such as anti-viral protection in response to IFNc. This phenomenon was proposed to be because IFNa/b receptor1 (IFNAR1) is a component of the IFNc receptor (IFNGR), but our new data are more consistent with a previously proposed model indicating that regulated expression of STAT1 may also play a critical role in the priming process. Initially, we noticed that DNA binding activity of STAT1 was attenuated in c-Jun-/- fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun-/- fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFNb, as it was inhibited by antibodies to IFNAR1, or when IFNb expression was knocked down in wild-type cells. IFNAR1-/- fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFNc. The lack of priming in IFNAR1-/- fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFNc and restored the ability of IFNc to induce protective anti-viral immunity. This study provides a comprehensive description of the molecular events involved in priming by type I IFN. Adding to the previous working model that proposed an interaction between type I and II IFN receptors, our work and that of others demonstrates that type I IFN primes IFNc-mediated immune responses by regulating expression of STAT1. This may also explain how type I IFN can additionally prime cells to respond to a range of other cytokines that use STAT1 (e.g., IL-6, M-CSF, IL-10) and suggests a potential mechanism for the changing levels of STAT1 expression observed during viral infection. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) are a family of immunoregulatory cytokines with important roles in anti-viral and anti-tumor responses. Type I and II IFNs bind distinct receptors and are associated with different stages of the immune response. There is however, considerable crosstalk between these two cytokines with enhancement of IFNγ responses following IFNα/β priming and loss of IFNα/β receptor (IFNAR) resulting in diminished IFNγ responses. In this study, we sought to define the mechanism of crosstalk between the type I and II IFNs. Our previous reports demonstrated reduced expression of the canonically activated transcription factor signal transducer and activator of transcription (STAT)1, in cells lacking the IFNAR α chain (IFNAR1). Therefore, we used microarray analysis to determine whether reconstitution of STAT1 in IFNAR1-deficient cells was sufficient to restore IFNγ responses. We identified several biological pathways, including the MHC class I antigen presentation pathway, in which STAT1 reconstitution was able to significantly rescue IFNγ-mediated gene regulation inIfnar1−/−cells. Notably, we also found that in addition to low basal expression of STAT1, cells lacking the IFNAR1 also had aberrant expression of multiple other transcription factors and signaling intermediaries. The studies described herein demonstrate that basal and regulated expression of signaling intermediaries is a mechanism for crosstalk between cytokines including type I and II IFNs. [ABSTRACT FROM PUBLISHER]

Introduction: The early-life intestinal microbiome plays a crucial role in the development and regulation of the immune system. Perturbations in its composition during this critical period have been linked to the development of allergic diseases. Objective: This study aimed to investigate the association between the composition of the early-life intestinal microbiome and the presence of eczema in the first year of life using shotgun metagenomic sequencing and functional analyses (metabolic pathways). Methods: Stool samples from 393 healthy term infants collected at 1 week of age were analyzed with shotgun metagenomic sequencing. Environmental and clinical data were prospectively collected using 3-monthly validated questionnaires. Participants were clinically assessed during study visits at 12 months of age. Eczema was diagnosed by the UK diagnostic tool and by a research nurse. Data analysis was stratified by delivery mode. Results: Eczema was diagnosed in 16.4% (60/366) of participants by nurse diagnosis. Infants born by cesarean section (CS) with nurse-diagnosed eczema had a higher relative abundance of Escherichia, Shigella, Enterobacter, and Citrobacter and a lower relative abundance of Veillonella than CS-born infants without eczema. In addition, CS-born infants without eczema had a higher abundance of genes involved in lactic fermentation. Vaginally born infants with eczema had a higher relative abundance of Bacteroides and a lower abundance of Streptococcus. [ABSTRACT FROM AUTHOR]

Background: With the emergence of novel vaccines and new applications for older vaccines, co-administration is increasingly likely. The immunomodulatory effects of BCG could theoretically alter the reactogenicity of co-administered vaccines. Using active surveillance in a randomised controlled trial, we aimed to determine whether co-administration of BCG vaccination changes the safety profile of influenza vaccination. Methods: Participants who received influenza vaccine alone (Influenza group) were compared with those who also received BCG-Denmark vaccine in the contralateral arm (Influenza+BCG group). Data on the influenza vaccination site were collected using serial questionnaires and active follow-up for 3 months post vaccination. Results: Of 1351 participants in the Influenza+BCG group and 1418 participants in the Influenza group, 2615 (94%) provided influenza vaccine safety data. There was no significant difference in the proportion of participants with any local adverse reaction between the Influenza+BCG group and the Influenza group (918/1293 [71.0%] versus (906/1322 [68.5%], p = 0.17). The proportion of participants reporting any pain, erythema and tenderness at the influenza vaccination site were similar in both groups. Swelling was less frequent (81/1293 [6.3%] versus 119/1322 (9.0%), p = 0.01) and the maximal diameter of erythema was smaller (mean 1.8 cm [SD 2.0] versus 3.0 cm [SD 2.5], p<0.001) in the Influenza+BCG group. Sixteen participants reported serious adverse events: 9 participants in the Influenza+BCG group and 7 in the Influenza group. Conclusions: Adverse events following influenza vaccination are not increased when BCG is co-administered. [ABSTRACT FROM AUTHOR]

• BCG vaccination reduced IFN-γ and MCP-1 responses to heterologous stimulants. • HBV vaccination alone did not alter heterologous cytokine responses. • Males overall produced more IFN-γ and TNF-α compared with females. • HBV co-administration influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner. Bacille Calmette-Guérin (BCG) and hepatitis B (HBV) vaccines are frequently given concomitantly at birth. Neonatal BCG vaccination induces off-target immunological effects. Whether HBV vaccine has immunomodulatory effects is unknown. As off-target effects might vary when vaccines are given simultaneously, this randomised controlled trial aimed to evaluate the influence of neonatal vaccination with BCG and/or HBV on heterologous immune responses. A total of 185 neonates in Australia were randomised to receive either neonatal BCG-Denmark vaccine, HBV vaccine, both (BCG + HBV group), or none (No vaccine group). In-vitro responses to heterologous stimulants were assessed 7 days after vaccination. The influence of (i) randomisation group and (ii) sex on interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-α) responses was analysed using linear regression. Overall, BCG vaccination alone or with HBV co-administration reduced IFN-γ and MCP-1 responses to heterologous stimulants. HBV vaccination alone did not alter heterologous cytokine responses. In general, males produced more IFN-γ and TNF-α than females. We observed a sex-differential effect in relation to the influence of HBV co-administration on the effect of BCG on heterologous responses. Compared with males in the No vaccine group, males in the BCG + HBV group had lower IFN-γ and MCP-1 responses. In contrast, compared with females in the No vaccine group, females in the BCG group had higher IFN-γ response and lower MCP-1 responses. Neonatal BCG vaccination resulted in lower cytokine responses to unrelated pathogens. HBV co-administration did not have a significant impact on responses overall but influenced the heterologous effects of neonatal BCG vaccination in a sex-differential manner. [ABSTRACT FROM AUTHOR]

The NF-κB signal transduction pathway is best known as a major regulator of innate and adaptive immune responses, yet there is a growing appreciation of its importance in immune cell development, particularly of T lineage cells. In this Review, we discuss how the temporal regulation of NF-κB controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokine and growth factor signals. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin vaccine (BCG), one of the most widely used vaccines, does not only provide protection against tuberculosis and other mycobacterial infections, but also has non-specific (heterologous) immunomodulatory effects. In participants in a randomised trial, we investigated the effect of neonatal BCG immunisation on antibody responses to routine infant vaccines given in the first year of life. Antibodies against antigens in the diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib), and the 13-valent pneumococcal conjugate vaccines were measured in 91 (45 BCG-vaccinated, 46 BCG-naïve) infants one month after, and in 310 (169 BCG-vaccinated, 141 BCG-naïve) infants seven months after immunisation at 6 weeks, 4 and 6 months of age. In addition, antibodies against meningococcus C, Hib , measles, mumps, and rubella were measured in 147 (78 BCG-vaccinated, 69 BCG-naïve) infants one month after immunisation at 12 months of age. The seroprotection rates for each vaccine and the geometric mean concentrations (GMC) of antibodies were compared in BCG-vaccinated and BCG-naïve infants. At 7 months of age, seroprotection rates were high in both BCG-vaccinated and BCG-naïve infants. At 13 months of age, seroprotection rates were lower than at 7 months of age, particularly for pertussis and a number of pneumococcal antigens, with generally higher rates for the latter in BCG-vaccinated infants. Although not statistically significant, antibody responses in BCG-vaccinated infants were consistently higher against diphtheria, tetanus, and pneumococcal antigens at both 7 and 13 months of age, and against measles and mumps at 13 months of age, but were lower against Hib one month after immunisation at both 7 and 13 months of age. The immunomodulatory effect of BCG on antibody responses to heterologous vaccines adds to the evidence that BCG immunisation at birth has broad heterologous effects on the infant immune system. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]