Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial.

BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: 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). RESULTS: 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). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

Prevention of infant eczema by neonatal Bacillus Calmette-Guérin vaccination: The MIS BAIR randomized controlled trial.

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.

Neonatal Bacille Calmette-Guérin Vaccination and Infections in the First Year of Life: The MIS BAIR Randomized Controlled Trial.

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.

Use of a paediatric advice line for parents of infants recruited to a randomised controlled trial.

BACKGROUND: This study aims to describe the use of a paediatric advice line (PAL) provided to parents whose infants were recruited to a large randomised controlled trial (RCT), including the number and types of medical concerns addressed, seasonal variability and call outcomes. Additionally, sociodemographic characteristics of the parents and children of those parents who used the PAL are compared with those who did not. METHODS: Prospective cohort of 1246 children nested in the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) RCT. All MIS BAIR participants were offered access to the PAL. Data were collected over the initial 2 years of a 5-year follow-up. Data were analysed using χ2 tests, and ORs were calculated using multiple logistic regression. RESULTS: The PAL was used by 230 (18.5%) participants, who made a total of 586 calls during the 2-year study period. The reasons for calling the PAL were dermatological (24%); gastrointestinal (18%); disturbances in feeding, sleeping and crying (14%); respiratory (7%); and developmental/neurological (6%). Analysis revealed that those who used the PAL were more likely to be first-time parents (OR 1.4, 95% CI 1.1 to 1.9) and mothers who hold a university degree (OR 3.3, 95% CI 1.3 to 8.4). PAL costs were minimal and comprised 15 clinicians with paediatric experience. CONCLUSIONS: A cost-effective PAL service for clinical trial participants was used appropriately by parents for relatively minor concerns and may have a role in trials to promote participant engagement and reduce demand for other health services.

Discordance Between Diagnosis Tools for Assessing Eczema in Infants: A Challenge for Intervention Trials.

BACKGROUND: There is no standardized definition for infant eczema, and various tools have been used across studies, precluding direct comparison. OBJECTIVE: The aim of the study was to assess and to compare the accuracy of diagnostic tools for infant eczema using the extensive data collected in Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), an eczema prevention trial. METHODS: Eczema incidence was assessed by 3 questionnaire-based measures: modified UK diagnostic tool, parent-reported medically diagnosed eczema, and parent-reported use of topical corticosteroids. Agreement between the definitions was quantified using κ coefficient. Eczema severity was assessed by 3-monthly Patient-Oriented Eczema Measure (POEM) scores and a SCORing Atopic Dermatitis (SCORAD) clinical assessment at a 12-month visit (ClinicalTrial.gov: NCT01906853). RESULTS: Among the 538 participants fulfilling at least 1 of the 3 questionnaire-based eczema definitions, only 197 participants (37%) met all 3 definitions. Agreement between the definitions was poor with κ coefficients ranging from -0.11 to 0.62. The most frequently reported symptoms were generally dry skin (483/538, 90%) and pruritus (400/538, 74%). The face (352/538, 65%) and the trunk (306/538, 57%) were more frequently affected than the creases (257/538, 48%). Participants fulfilling all 3 questionnaire-based definitions of eczema were more likely to have higher severity scores and earlier onset of symptoms. CONCLUSIONS: There is poor agreement between currently available tools for assessing infant eczema.

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial).

INTRODUCTION: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19. METHODS AND ANALYSIS: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections. ETHICS AND DISSEMINATION: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

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.

INTRODUCTION: BCG vaccination reduces all-cause infant mortality in high-mortality settings by more than can be attributed to protection against tuberculosis. This is proposed to result from non-specific protection against non-vaccine targeted ('off-target') infections. There is also evidence that BCG protects against allergic diseases. METHODS AND ANALYSIS: The Melbourne Infant Study: BCG for Allergy and Infection Reduction is a phase III multicentre, single-blinded, randomised controlled trial. A total of 1438 healthy neonates will be randomised to receive either BCG vaccination or no BCG vaccination in the first 10 days of life. Measures of allergy, eczema, infection and asthma will be obtained from parent-completed questionnaires 3 monthly in the first year and 6 monthly from 1 to 5 years of age, and clinical assessments at 1 and 5 years of age. Biological samples will also be collected for future immunological studies. ANALYSIS PRIMARY OUTCOME: The proportion of participants with measures of allergy and infection (atopic sensitisation, eczema, lower respiratory tract infection) at 1 and 5 years of age, and asthma at 5 years of age. SECONDARY OUTCOMES: (1) the proportion of participants with additional measures of allergy, eczema, asthma and infections; (2) medication use for eczema and asthma; (3) the severity and age of onset of eczema and asthma; (4) the number of episodes of infection; (5) hospitalisations for infections and (6) laboratory measures of immune responses. ETHICS AND DISSEMINATION: This trial has ethical and governance approval from Mercy Health Human Research Ethics Committee (HREC, No. R12-28) and Royal Children's Hospital HREC (No. 33025) with additional governance approval from Barwon Health and St John of God, Geelong, Victoria. Results of this trial will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT01906853.

Normal foetal kidney volume in offspring of women treated for gestational diabetes.

AIMS: The worldwide prevalence of gestational diabetes mellitus (GDM) is increasing. Studies in rodent models indicate that hyperglycaemia during pregnancy alters kidney development, yet few studies have examined if this is so in humans. The objective of this study was to evaluate the association of treated GDM with foetal kidney size. MATERIALS AND METHODS: Participants were recruited from an Australian tertiary hospital, and clinical data were collected from women without GDM and women diagnosed and treated for GDM and their offspring. Participants underwent an obstetric ultrasound at 32-34 weeks gestation for foetal biometry and foetal kidney volume measurement. RESULTS: Sixty-four non-GDM and 64 GDM women participated in the study. Thirty percent of GDM women were diagnosed with fasting hyperglycaemia, while 89% had an elevated 2-hour glucose level. Maternal age, weight and body mass index were similar in women with and without GDM. Estimated foetal weight, foetal kidney dimensions, total foetal kidney volume and birth weight were similar in offspring of women with and without GDM. CONCLUSIONS: We conclude that a period of mild hyperglycaemia prior to diagnosis of GDM and treatment initiation, which coincides with a period of rapid nephron formation and kidney growth, does not alter kidney size at 32-34 weeks gestation.