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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Allergy, Eczema, Respiratory Tract Infections

Intervention / Treatment
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* Biological: BCG


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 10 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No BCG<br>No BCG | |
| Experimental: BCG<br>Mycobacterium bovis BCG (Bacille Calmette Guérin) vaccine, Danish Strain 1331 | Biological: BCG<br> <br> * Other names: Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331;|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG, Bacille Calmette Guérin, Allergy, Immunity, Immune response, Vaccine, Infants, Children, Infection