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| ID | Type | Description | Link |
|---|---|---|---|
| 1051228 | Other Grant/Funding Number | National Health and Medical Research Council (NHMRC) |
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| Name | Class |
|---|---|
| Royal Children's Hospital | OTHER |
| Mercy Hospital for Women, Australia | OTHER |
| University of Melbourne | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| No BCG | No Intervention | No BCG | |
| BCG | Experimental | Mycobacterium bovis BCG (Bacille Calmette Guérin) vaccine, Danish Strain 1331 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BCG | Biological |
|
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| 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 |
Inclusion criteria:
Exclusion criteria:
Any indication for BCG immunisation in the first 12 months of life including:
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.
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| Name | Affiliation | Role |
|---|---|---|
| Prof Nigel Curtis, MBBS DCH DTM&H MRCP FRCPCH PhD | Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mercy Hospital for Women | Heidelberg | Victoria | 3084 | Australia | ||
| Royal Children's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41047269 | Derived | Khazaei Y, Kodikara S, Butler CA, Messina NL, Le Cao KA, Dashper SG, Silva MJ. Development and validation of diagnostic and prognostic prediction tools for dental caries in young children through prospective and cross-sectional observational studies: a protocol. BMJ Open. 2025 Oct 5;15(10):e105145. doi: 10.1136/bmjopen-2025-105145. | |
| 40464744 |
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| ID | Term |
|---|---|
| D006967 | Hypersensitivity |
| D004485 | Eczema |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
| D003872 | Dermatitis |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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| ID | Term |
|---|---|
| D001500 | BCG Vaccine |
| ID | Term |
|---|---|
| D032581 | Tuberculosis Vaccines |
| D001428 | Bacterial Vaccines |
| D014612 | Vaccines |
| D001688 | Biological Products |
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| Asthma ever |
Using ISAAC definitions |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Melbourne |
| Victoria |
| 3052 |
| Australia |
| Pittet LF, Forbes EK, Donath S, Francis KL, Gardiner K, Flanagan KL, Ponsonby AL, Robins-Browne R, Shann F, South M, Vuillermin P, Casalaz D, Curtis N, Messina NL; Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group. Neonatal BCG vaccination to prevent asthma: Results from the MIS BAIR randomized controlled trial. Pediatr Allergy Immunol. 2025 Jun;36(6):e70110. doi: 10.1111/pai.70110. |
| 39004434 | Derived | Messina NL, Gardiner K, Pittet LF, Forbes EK, Francis KL, Freyne B, Zufferey C, Abruzzo V, Morison C, Turner H, Allen KJ, Flanagan KL, Ponsonby AL, Robins-Browne R, Shann F, Vuillermin P, Donath S, Casalaz D, Curtis N; Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group. Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial. Clin Exp Allergy. 2024 Sep;54(9):682-693. doi: 10.1111/cea.14537. Epub 2024 Jul 14. |
| 35170523 | Derived | 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. |
| 34309859 | Derived | 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. |
| 32544459 | Derived | 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. |
| 31843845 | Derived | 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. |
| 30791143 | Derived | 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. |
| D017443 |
| Skin Diseases, Eczematous |
| D012140 | Respiratory Tract Diseases |
| D045424 |
| Complex Mixtures |