Allergy, Eczema, Respiratory Tract Infections
Conditions
Keywords
BCG, Bacille Calmette Guérin, Allergy, Immunity, Immune response, Vaccine, Infants, Children, Infection
Brief summary
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.
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.
Interventions
BIOLOGICALBCG
Sponsors
Royal Children's Hospital
Mercy Hospital for Women, Australia
University of Melbourne
Murdoch Childrens Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 10 Days
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lower respiratory tract infection (LRTI) hospital admissions | 0-5 years of age | Proportion of participants with ≥1 hospital admission for LRTI reported by parent |
| Asthma ever | 5 years of age | Using ISAAC definitions |
| Current asthma | 5 years of age | Using ISAAC definitions |
| Lower respiratory tract infection (LRTI) | 0-12 months | Measured by parent report |
| Atopic sensitisation measured by skin prick test (SPT) | 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 |
| Eczema ever | 0-12 months | Proportion of participants with eczema measured by Williams' UK diagnostic criteria using parental report of symptoms |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Infections | 0-12 months | Hospital admissions for any infection by parental report |
| Rate of upper respiratory tract infection (URTI) | 0-12 months of age | Number of clinical episodes of upper respiratory tract infections, by parent report |
| Rate of fever | 0-12 months of age | Number of clinical episodes of fever, by parent report |
| Diarrhoea | 0-12 months of age | Proportion of participants with ≥1 episodes of diarrhoea |
| Rash with fever | 0-12 months of age | Proportion of participants with ≥1 episodes of rash with fever |
| Eczema ever | 0-12 months of age | Proportion of participants with eczema measured by a combined eczema measure |
| Eczema | 0-12 months | Proportion of clinician-diagnosed eczema, by parental report |
| Eczema onset | 0-12 months | Age of onset of eczema, by parental report |
| Eczema severity | 0-12 months | Measured by parental report (POEM score) |
| Asthma severity | 4 years of age | Measured by asthma control test (ACT), by parental/participant report |
| Laboratory measures of the immune response | Time Frame: 0-5 years of age | — |
| Clinical food allergy | 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 |
| Atopic sensitisation measured by SPT using a more stringent cut-off | 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 |
| Atopic sensitisation to multiple allergens measured by SPT | 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 |
| Parent report of food allergy | 0-12 months of age | Proportion of participants with an allergic reaction to any food reported by parent |
| Egg sensitisation | 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 |
| Egg allergy | 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 |
| Atopic wheeze | 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 |
| Lower respiratory tract infection (LRTI) | Prior to first Diphtheria, Tetanus, Pertussis (DTP) vaccination | Proportion of participants with ≥1 episode of LRTI, by parental report |
| Rate of lower respiratory tract infection (LRTI) | 0-12 months | Number of clinical episodes of LRTI, by parental report |
| Hospitalisation for respiratory tract infection (RTI) | 0-12 months of age | Proportion of participants with ≥1 hospital admission for a RTI, by parent report |
| Rate of any infection | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Effect of family history of allergy on the allergy and eczema outcomes | 0-12 months and 0-5 years of age | Sub-group analysis |
| Effect of season of birth on the non-specific effects BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
| Effect of sex on the non-specific effects BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
| Morbidity | 0-12 months of age | Hospital admissions for any reason by parental report |
| Meta-analysis | 36 months | Joint meta-analysis with data from the Danish Calmette study (NCT01694108) |
| Effect of hepatitis B vaccine timing birth on the non-specific effects BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
| Effect of mode of delivery on the non-specific effects BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
| Effect of timing of BCG administration on the non-specific effects BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
| Effect of presence or absence BCG scar on the non-specific effects of BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
| Effect of maternal BCG on the non-specific effects BCG | 0-12 months and 0-5 years of age | Sub-group analysis |
Countries
Australia
Outcome results
None listed