Melbourne Infant Study - Bacille Calmette Guérin (BCG) for Allergy & Infection Reduction (MIS BAIR)

A Randomised, Controlled Trial to Determine if BCG Immunisation at Birth Reduces Allergy and Infection in Infants

1. To determine if BCG immunisation at birth, compared to no BCG immunisation, leads to a reduction in measures of allergy and infection in the first 12 months of life.
2. To evaluate the immunological mechanisms underlying the non-specific effects of BCG by comparing markers of immunity between the BCG and non-BCG groups.

Study Overview

• Status: Active, not recruiting
• Conditions: Respiratory Tract Infections; Allergy; Eczema
• Intervention / Treatment: Biological: BCG

Detailed Description

There has been a dramatic rise in allergic diseases worldwide since the 1980s. Asthma rates increased first, followed by eczema, allergic rhinitis and, more recently, food allergy - especially in infants and young children. In Australia, the prevalence of allergic disease is particularly high: up to 30% of children are affected, and eczema and asthma are among the most common chronic diseases of childhood.

Preventing allergic disease by an immunomodulatory intervention early in life would be a major advance with significant implications for individual health and public health resources. Bacillus Calmette-Guérin (BCG) immunisation is a potential intervention with an established safety profile. This vaccine has powerful non-specific effects on the cellular immune response that potentially prime host immunity away from an allergic pathway. Observational data and one small randomised controlled trial (RCT) suggest that BCG immunisation at birth leads to a substantial reduction in allergic disease - however, there is an absence of level 1 evidence.

• Study Type: Interventional
• Enrollment (Actual): 1272
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Mercy Hospital for Women
    • Melbourne, Victoria, Australia, 3052
      • Royal Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 week (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

• Less than 10 days old;
• English speaking mother;
• An informed consent form must be signed and dated by their parent(s) or legally acceptable representative after the nature of the study has been explained and prior to any study assessments/procedures;
• The infant's mother has screened negative for HIV during this pregnancy;
• Born no earlier than eight weeks before estimated date of delivery;
• Birth weight >1500g.
• The legal guardian expects to be able to complete four online/phone questionnaires over the infant's first 12 months of life and for the infant to be available for skin prick testing at RCH between 12-16 months of age.

Exclusion criteria:

• Any indication for BCG immunisation in the first 12 months of life including:

  • likely travel to a high tuberculosis (TB) incidence country in the first year of life.
  • Aboriginal and Torres Strait Islander babies living in parts of Australia where the incidence of TB is higher
  • newborn babies, if either parent has leprosy or a family history of leprosy
  • newborn in contact with a patient with TB.
• Known or suspected HIV infection
• Treatment with corticosteroids or other immunosuppressive therapy, including monoclonal antibodies against tumour necrosis factor-alpha (TNF-alpha) (e.g. infliximab, etanercept, adalimumab).
• Born to a mother treated with bDMARDS (e.g. TNF-alpha blocking monoclonal antibodies) in the 3rd trimester;
• Congenital cellular immunodeficiencies including specific deficiencies of the interferon gamma pathway;
• Malignancies involving bone marrow or lymphoid systems;
• Serious underlying illness including severe malnutrition;
• Medically unstable;
• Generalised septic skin disease and skin conditions such as eczema, dermatitis and psoriasis;
• Significant febrile illness;
• Mother immunosuppressed;
• Family history of immunodeficiency;
• Consanguineous parents;
• Multiple births more than twins.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No BCG
Experimental: BCG; Mycobacterium bovis BCG (Bacille Calmette Guérin) vaccine, Danish Strain 1331	Biological: BCG; Other Names: Statens Serum Institute BCG vaccine; Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331; BCG Denmark; BCG vaccine - Denmark strain

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atopic sensitisation measured by skin prick test (SPT)	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to one or more of a panel of food and aeroallergens	1 year of age
Atopic sensitisation measured by skin prick test (SPT)	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to one or more of a panel of food and aeroallergens	5 years of age
Lower respiratory tract infection (LRTI)	Measured by parent report	0-12 months
Lower respiratory tract infection (LRTI) hospital admissions	Proportion of participants with ≥1 hospital admission for LRTI reported by parent	0-5 years of age
Eczema ever	Proportion of participants with eczema measured by Williams' UK diagnostic criteria using parental report of symptoms	0-12 months
Eczema ever	Proportion of participants with eczema measured by Williams' UK diagnostic criteria using parental report of symptoms	0-5 years of age
Current asthma	Using ISAAC definitions	5 years of age
Asthma ever	Using ISAAC definitions	5 years of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atopic sensitisation measured by SPT using a more stringent cut-off	Proportion of participants with a positive SPT defined as wheal diameter ≥3 mm greater than negative control at 15 min to one or more of a panel of food allergens and aeroallergens	1 year of age
Atopic sensitisation measured by SPT using a more stringent cut-off	Proportion of participants with a positive SPT defined as wheal diameter ≥3 mm greater than negative control at 15 min to one or more of a panel of food allergens and aeroallergens	5 years of age
Atopic sensitisation to multiple allergens measured by SPT	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to two or more of a panel of food allergens and aeroallergens	1 year of age
Atopic sensitisation to multiple allergens measured by SPT	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to two or more of a panel of food allergens and aeroallergens	5 years of age
Parent report of food allergy	Proportion of participants with an allergic reaction to any food reported by parent	0-12 months of age
Parent report of food allergy	Proportion of participants with an allergic reaction to any food reported by parent	0-5 years of age
Egg sensitisation	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to egg allergen	1 year of age
Egg sensitisation	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to egg allergen	5 years of age
Atopic wheeze	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to one or more of a panel of food and aeroallergens together with parent-reported wheeze	1 year of age
Atopic wheeze	Proportion of participants with a positive SPT defined as wheal diameter ≥2 mm greater than negative control at 15 min to one or more of a panel of food and aeroallergens together with parent-reported wheeze	5 years of age
Lower respiratory tract infection (LRTI)	Proportion of participants with ≥1 episode of LRTI, by parental report	Prior to first Diphtheria, Tetanus, Pertussis (DTP) vaccination
Lower respiratory tract infection (LRTI)	Proportion of participants with ≥1 episode of LRTI, by parental report	0-5 years of age
Rate of lower respiratory tract infection (LRTI)	Number of clinical episodes of LRTI, by parental report	0-12 months
Rate of lower respiratory tract infection (LRTI)	Number of clinical episodes of LRTI, by parental report	Prior to first DTP vaccination
Rate of lower respiratory tract infection (LRTI)	Number of clinical episodes of LRTI, by parental report	0-5 years of age
Infections	Hospital admissions for any infection by parental report	0-12 months
Infections	Hospital admissions for any infection by parental report	Prior to first DTP vaccination
Infections	Hospital admissions for any infection by parental report	0-5 years of age
Hospitalisation for respiratory tract infection (RTI)	Proportion of participants with ≥1 hospital admission for a RTI, by parent report	0-12 months of age
Hospitalisation for respiratory tract infection (RTI)	Proportion of participants with ≥1 hospital admission for a RTI, by parent report	Prior to first DTP vaccination
Hospitalisation for respiratory tract infection (RTI)	Proportion of participants with ≥1 hospital admission for a RTI, by parent report	0-5 years of age
Rate of any infection	Number of clinical episodes of where an infant had symptoms of: wheeze, rattle/rattly chest, fever, runny/blocked nose, cough, or diarrhoea (with vomiting), by parent report	0-12 months of age
Rate of any infection	Number of clinical episodes of where an infant had symptoms of: wheeze, rattle/rattly chest, fever, runny/blocked nose, cough, or diarrhoea (with vomiting), by parent report	Prior to first DTP vaccination
Rate of upper respiratory tract infection (URTI)	Number of clinical episodes of upper respiratory tract infections, by parent report	0-12 months of age
Rate of upper respiratory tract infection (URTI)	Number of clinical episodes of upper respiratory tract infections, by parent report	Prior to first DTP vaccination
Rate of fever	Number of clinical episodes of fever, by parent report	0-12 months of age
Rate of fever	Number of clinical episodes of fever, by parent report	Prior to first DTP vaccination
Diarrhoea	Proportion of participants with ≥1 episodes of diarrhoea	0-12 months of age
Diarrhoea	Proportion of participants with ≥1 episodes of diarrhoea	Prior to first DTP vaccination
Rash with fever	Proportion of participants with ≥1 episodes of rash with fever	0-12 months of age
Rash with fever	Proportion of participants with ≥1 episodes of rash with fever	Prior to first DTP vaccination
Eczema ever	Proportion of participants with eczema measured by a combined eczema measure	0-12 months of age
Eczema ever	Proportion of participants with eczema measured by a combined eczema measure	0-5 years of age
Eczema	Proportion of clinician-diagnosed eczema, by parental report	0-12 months
Eczema	Proportion of clinician-diagnosed eczema, by parental report	0-5 years of age
Eczema onset	Age of onset of eczema, by parental report	0-12 months
Eczema onset	Age of onset of eczema, by parental report	0-5 years of age
Eczema severity	Measured by parental report (POEM score)	0-12 months
Eczema severity	Measured by clinical assessment (SCORAD)	0-12 months
Eczema severity	Eczema medication use, by parental report	0-12 months
Eczema severity	Measured by parental report (POEM score)	0-5 years of age
Eczema severity	Measured by clinical assessment (SCORAD)	0-5 years of age
Eczema severity	Eczema medication use, by parental report	0-5 years of age
Asthma severity	Measured by asthma control test (ACT), by parental/participant report	4 years of age
Asthma severity	Measured by asthma control test (ACT), by parental/participant report	5 years of age
Asthma severity	Hospital admissions for asthma, by parental report	2-5 years of age
Laboratory measures of the immune response		Time Frame: 0-5 years of age
Clinical food allergy	Proportion of participants with challenge-proven food allergy OR convincing history of food allergy in participants with a SPT wheal diameter ≥2 mm greater than negative control at 15 min to one or more of a panel of food allergens	1 year of age
Clinical food allergy	Proportion of participants with challenge-proven food allergy OR convincing history of food allergy in participants with a SPT wheal diameter ≥2 mm greater than negative control at 15 min to one or more of a panel of food allergens	5 years of age
Egg allergy	Proportion of participants with a challenge-proven egg allergy OR convincing history of egg allergy in participants with a SPT wheal diameter ≥2 mm greater than negative control at 15 min to egg	1 year of age
Egg allergy	Proportion of participants with a challenge-proven egg allergy OR convincing history of egg allergy in participants with a SPT wheal diameter ≥2 mm greater than negative control at 15 min to egg	5 years of age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of sex on the non-specific effects BCG	Sub-group analysis	0-12 months and 0-5 years of age
Effect of maternal BCG on the non-specific effects BCG	Sub-group analysis	0-12 months and 0-5 years of age
Effect of presence or absence BCG scar on the non-specific effects of BCG	Sub-group analysis	0-12 months and 0-5 years of age
Effect of timing of BCG administration on the non-specific effects BCG	Sub-group analysis	0-12 months and 0-5 years of age
Effect of mode of delivery on the non-specific effects BCG	Sub-group analysis	0-12 months and 0-5 years of age
Effect of family history of allergy on the allergy and eczema outcomes	Sub-group analysis	0-12 months and 0-5 years of age
Effect of season of birth on the non-specific effects BCG	Sub-group analysis	0-12 months and 0-5 years of age
Effect of hepatitis B vaccine timing birth on the non-specific effects BCG	Sub-group analysis	0-12 months and 0-5 years of age
Meta-analysis	Joint meta-analysis with data from the Danish Calmette study (NCT01694108)	36 months
Morbidity	Hospital admissions for any reason by parental report	0-12 months of age
Morbidity	Hospital admissions for any reason by parental report	0-5 years of age

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Royal Children's Hospital; University of Melbourne; Mercy Hospital for Women, Australia
• Investigators: Principal Investigator: Prof Nigel Curtis, MBBS DCH DTM&H MRCP FRCPCH PhD, Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne

Publications and helpful links

General Publications

• Pittet LF, Messina NL, Gardiner K, Freyne B, Abruzzo V, Morrison C, Vuillermin P, Allen KJ, Ponsonby AL, Robins-Browne R, Shann F, Flanagan KL, Donath S, Casalaz D, Phillips R, Curtis N. Discordance Between Diagnosis Tools for Assessing Eczema in Infants: A Challenge for Intervention Trials. Dermatitis. 2022 May-Jun 01;33(3):207-214. doi: 10.1097/DER.0000000000000842. Epub 2022 Feb 16.
• Pittet LF, Messina NL, Gardiner K, Freyne B, Abruzzo V, Francis KL, Morrison C, Zufferey C, Vuillermin P, Allen KJ, Ponsonby AL, Robins-Browne R, Shann F, Flanagan KL, Phillips R, Donath S, Casalaz D, Curtis N. Prevention of infant eczema by neonatal Bacillus Calmette-Guerin vaccination: The MIS BAIR randomized controlled trial. Allergy. 2022 Mar;77(3):956-965. doi: 10.1111/all.15022. Epub 2021 Aug 9.
• Cirovic B, de Bree LCJ, Groh L, Blok BA, Chan J, van der Velden WJFM, Bremmers MEJ, van Crevel R, Handler K, Picelli S, Schulte-Schrepping J, Klee K, Oosting M, Koeken VACM, van Ingen J, Li Y, Benn CS, Schultze JL, Joosten LAB, Curtis N, Netea MG, Schlitzer A. BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment. Cell Host Microbe. 2020 Aug 12;28(2):322-334.e5. doi: 10.1016/j.chom.2020.05.014. Epub 2020 Jun 15.
• Messina NL, Gardiner K, Donath S, Flanagan K, Ponsonby AL, Shann F, Robins-Browne R, Freyne B, Abruzzo V, Morison C, Cox L, Germano S, Zufferey C, Zimmermann P, Allen KJ, Vuillermin P, South M, Casalaz D, Curtis N. 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 Dec 15;9(12):e032844. doi: 10.1136/bmjopen-2019-032844.
• Zimmermann P, Perrett KP, van der Klis FR, Curtis N. The immunomodulatory effects of measles-mumps-rubella vaccination on persistence of heterologous vaccine responses. Immunol Cell Biol. 2019 Jul;97(6):577-585. doi: 10.1111/imcb.12246. Epub 2019 Mar 28.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: July 21, 2013
• First Submitted That Met QC Criteria: July 21, 2013
• First Posted (Estimated): July 24, 2013

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Infection; Allergy; Children; Vaccine; Immunity; Infants; BCG; Immune response; Bacille Calmette Guérin
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Disease Attributes; Hypersensitivity; Infections; Communicable Diseases; Respiratory Tract Infections; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; Vaccines; BCG Vaccine
• Other Study ID Numbers: BCG12/01; 1051228 (Other Grant/Funding Number: National Health and Medical Research Council (NHMRC))