- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01906853
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
- 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.
- 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
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
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
Accepts Healthy Volunteers
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
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
No Intervention: No BCG
|
|
Experimental: BCG
Mycobacterium bovis BCG (Bacille Calmette Guérin) vaccine, Danish Strain 1331
|
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Atopic sensitisation measured by skin prick test (SPT)
Time Frame: 1 year of age
|
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)
Time Frame: 5 years of age
|
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)
Time Frame: 0-12 months
|
Measured by parent report
|
0-12 months
|
Lower respiratory tract infection (LRTI) hospital admissions
Time Frame: 0-5 years of age
|
Proportion of participants with ≥1 hospital admission for LRTI reported by parent
|
0-5 years of age
|
Eczema ever
Time Frame: 0-12 months
|
Proportion of participants with eczema measured by Williams' UK diagnostic criteria using parental report of symptoms
|
0-12 months
|
Eczema ever
Time Frame: 0-5 years of age
|
Proportion of participants with eczema measured by Williams' UK diagnostic criteria using parental report of symptoms
|
0-5 years of age
|
Current asthma
Time Frame: 5 years of age
|
Using ISAAC definitions
|
5 years of age
|
Asthma ever
Time Frame: 5 years of age
|
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
Time Frame: 1 year of age
|
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
Time Frame: 5 years of age
|
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
Time Frame: 1 year of age
|
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
Time Frame: 5 years of age
|
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
Time Frame: 0-12 months of age
|
Proportion of participants with an allergic reaction to any food reported by parent
|
0-12 months of age
|
Parent report of food allergy
Time Frame: 0-5 years of age
|
Proportion of participants with an allergic reaction to any food reported by parent
|
0-5 years of age
|
Egg sensitisation
Time Frame: 1 year of age
|
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
Time Frame: 5 years of age
|
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
Time Frame: 1 year of age
|
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
Time Frame: 5 years of age
|
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)
Time Frame: Prior to first Diphtheria, Tetanus, Pertussis (DTP) vaccination
|
Proportion of participants with ≥1 episode of LRTI, by parental report
|
Prior to first Diphtheria, Tetanus, Pertussis (DTP) vaccination
|
Lower respiratory tract infection (LRTI)
Time Frame: 0-5 years of age
|
Proportion of participants with ≥1 episode of LRTI, by parental report
|
0-5 years of age
|
Rate of lower respiratory tract infection (LRTI)
Time Frame: 0-12 months
|
Number of clinical episodes of LRTI, by parental report
|
0-12 months
|
Rate of lower respiratory tract infection (LRTI)
Time Frame: Prior to first DTP vaccination
|
Number of clinical episodes of LRTI, by parental report
|
Prior to first DTP vaccination
|
Rate of lower respiratory tract infection (LRTI)
Time Frame: 0-5 years of age
|
Number of clinical episodes of LRTI, by parental report
|
0-5 years of age
|
Infections
Time Frame: 0-12 months
|
Hospital admissions for any infection by parental report
|
0-12 months
|
Infections
Time Frame: Prior to first DTP vaccination
|
Hospital admissions for any infection by parental report
|
Prior to first DTP vaccination
|
Infections
Time Frame: 0-5 years of age
|
Hospital admissions for any infection by parental report
|
0-5 years of age
|
Hospitalisation for respiratory tract infection (RTI)
Time Frame: 0-12 months of age
|
Proportion of participants with ≥1 hospital admission for a RTI, by parent report
|
0-12 months of age
|
Hospitalisation for respiratory tract infection (RTI)
Time Frame: Prior to first DTP vaccination
|
Proportion of participants with ≥1 hospital admission for a RTI, by parent report
|
Prior to first DTP vaccination
|
Hospitalisation for respiratory tract infection (RTI)
Time Frame: 0-5 years of age
|
Proportion of participants with ≥1 hospital admission for a RTI, by parent report
|
0-5 years of age
|
Rate of any infection
Time Frame: 0-12 months of age
|
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
Time Frame: Prior to first DTP vaccination
|
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)
Time Frame: 0-12 months of age
|
Number of clinical episodes of upper respiratory tract infections, by parent report
|
0-12 months of age
|
Rate of upper respiratory tract infection (URTI)
Time Frame: Prior to first DTP vaccination
|
Number of clinical episodes of upper respiratory tract infections, by parent report
|
Prior to first DTP vaccination
|
Rate of fever
Time Frame: 0-12 months of age
|
Number of clinical episodes of fever, by parent report
|
0-12 months of age
|
Rate of fever
Time Frame: Prior to first DTP vaccination
|
Number of clinical episodes of fever, by parent report
|
Prior to first DTP vaccination
|
Diarrhoea
Time Frame: 0-12 months of age
|
Proportion of participants with ≥1 episodes of diarrhoea
|
0-12 months of age
|
Diarrhoea
Time Frame: Prior to first DTP vaccination
|
Proportion of participants with ≥1 episodes of diarrhoea
|
Prior to first DTP vaccination
|
Rash with fever
Time Frame: 0-12 months of age
|
Proportion of participants with ≥1 episodes of rash with fever
|
0-12 months of age
|
Rash with fever
Time Frame: Prior to first DTP vaccination
|
Proportion of participants with ≥1 episodes of rash with fever
|
Prior to first DTP vaccination
|
Eczema ever
Time Frame: 0-12 months of age
|
Proportion of participants with eczema measured by a combined eczema measure
|
0-12 months of age
|
Eczema ever
Time Frame: 0-5 years of age
|
Proportion of participants with eczema measured by a combined eczema measure
|
0-5 years of age
|
Eczema
Time Frame: 0-12 months
|
Proportion of clinician-diagnosed eczema, by parental report
|
0-12 months
|
Eczema
Time Frame: 0-5 years of age
|
Proportion of clinician-diagnosed eczema, by parental report
|
0-5 years of age
|
Eczema onset
Time Frame: 0-12 months
|
Age of onset of eczema, by parental report
|
0-12 months
|
Eczema onset
Time Frame: 0-5 years of age
|
Age of onset of eczema, by parental report
|
0-5 years of age
|
Eczema severity
Time Frame: 0-12 months
|
Measured by parental report (POEM score)
|
0-12 months
|
Eczema severity
Time Frame: 0-12 months
|
Measured by clinical assessment (SCORAD)
|
0-12 months
|
Eczema severity
Time Frame: 0-12 months
|
Eczema medication use, by parental report
|
0-12 months
|
Eczema severity
Time Frame: 0-5 years of age
|
Measured by parental report (POEM score)
|
0-5 years of age
|
Eczema severity
Time Frame: 0-5 years of age
|
Measured by clinical assessment (SCORAD)
|
0-5 years of age
|
Eczema severity
Time Frame: 0-5 years of age
|
Eczema medication use, by parental report
|
0-5 years of age
|
Asthma severity
Time Frame: 4 years of age
|
Measured by asthma control test (ACT), by parental/participant report
|
4 years of age
|
Asthma severity
Time Frame: 5 years of age
|
Measured by asthma control test (ACT), by parental/participant report
|
5 years of age
|
Asthma severity
Time Frame: 2-5 years of age
|
Hospital admissions for asthma, by parental report
|
2-5 years of age
|
Laboratory measures of the immune response
Time Frame: Time Frame: 0-5 years of age
|
Time Frame: 0-5 years of age
|
|
Clinical food allergy
Time Frame: 1 year of age
|
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
Time Frame: 5 years of age
|
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
Time Frame: 1 year of age
|
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
Time Frame: 5 years of age
|
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
Time Frame: 0-12 months and 0-5 years of age
|
Sub-group analysis
|
0-12 months and 0-5 years of age
|
Effect of maternal BCG on the non-specific effects BCG
Time Frame: 0-12 months and 0-5 years of age
|
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
Time Frame: 0-12 months and 0-5 years of age
|
Sub-group analysis
|
0-12 months and 0-5 years of age
|
Effect of timing of BCG administration on the non-specific effects BCG
Time Frame: 0-12 months and 0-5 years of age
|
Sub-group analysis
|
0-12 months and 0-5 years of age
|
Effect of mode of delivery on the non-specific effects BCG
Time Frame: 0-12 months and 0-5 years of age
|
Sub-group analysis
|
0-12 months and 0-5 years of age
|
Effect of family history of allergy on the allergy and eczema outcomes
Time Frame: 0-12 months and 0-5 years of age
|
Sub-group analysis
|
0-12 months and 0-5 years of age
|
Effect of season of birth on the non-specific effects BCG
Time Frame: 0-12 months and 0-5 years of age
|
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
Time Frame: 0-12 months and 0-5 years of age
|
Sub-group analysis
|
0-12 months and 0-5 years of age
|
Meta-analysis
Time Frame: 36 months
|
Joint meta-analysis with data from the Danish Calmette study (NCT01694108)
|
36 months
|
Morbidity
Time Frame: 0-12 months of age
|
Hospital admissions for any reason by parental report
|
0-12 months of age
|
Morbidity
Time Frame: 0-5 years of age
|
Hospital admissions for any reason by parental report
|
0-5 years of age
|
Collaborators and Investigators
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
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- BCG12/01
- 1051228 (Other Grant/Funding Number: National Health and Medical Research Council (NHMRC))
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