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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]

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: 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]

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]

• 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]