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

Overview

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.

Full Title of Study: “A Randomised, Controlled Trial to Determine if BCG Immunisation at Birth Reduces Allergy and Infection in Infants”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: June 30, 2024

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

  • Biological: BCG

Arms, Groups and Cohorts

  • No Intervention: No BCG
    • No BCG
  • Experimental: BCG
    • Mycobacterium bovis BCG (Bacille Calmette Guérin) vaccine, Danish Strain 1331

Clinical Trial Outcome Measures

Primary Measures

  • 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
  • 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
  • Lower respiratory tract infection (LRTI)
    • Time Frame: 0-12 months
    • Measured by parent report
  • 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
  • Eczema ever
    • Time Frame: 0-12 months
    • Proportion of participants with eczema measured by Williams’ UK diagnostic criteria using parental report of symptoms
  • 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
  • Current asthma
    • Time Frame: 5 years of age
    • Using ISAAC definitions
  • Asthma ever
    • Time Frame: 5 years of age
    • Using ISAAC definitions

Secondary Measures

  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Lower respiratory tract infection (LRTI)
    • Time Frame: 0-5 years of age
    • Proportion of participants with ≥1 episode of LRTI, by parental report
  • Rate of lower respiratory tract infection (LRTI)
    • Time Frame: 0-12 months
    • Number of clinical episodes of LRTI, by parental report
  • Rate of lower respiratory tract infection (LRTI)
    • Time Frame: Prior to first DTP vaccination
    • Number of clinical episodes of LRTI, by parental report
  • Rate of lower respiratory tract infection (LRTI)
    • Time Frame: 0-5 years of age
    • Number of clinical episodes of LRTI, by parental report
  • Infections
    • Time Frame: 0-12 months
    • Hospital admissions for any infection by parental report
  • Infections
    • Time Frame: Prior to first DTP vaccination
    • Hospital admissions for any infection by parental report
  • Infections
    • Time Frame: 0-5 years of age
    • Hospital admissions for any infection by parental report
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Rate of fever
    • Time Frame: 0-12 months of age
    • Number of clinical episodes of fever, by parent report
  • Rate of fever
    • Time Frame: Prior to first DTP vaccination
    • Number of clinical episodes of fever, by parent report
  • Diarrhoea
    • Time Frame: 0-12 months of age
    • Proportion of participants with ≥1 episodes of diarrhoea
  • Diarrhoea
    • Time Frame: Prior to first DTP vaccination
    • Proportion of participants with ≥1 episodes of diarrhoea
  • Rash with fever
    • Time Frame: 0-12 months of age
    • Proportion of participants with ≥1 episodes of rash with fever
  • Rash with fever
    • Time Frame: Prior to first DTP vaccination
    • Proportion of participants with ≥1 episodes of rash with fever
  • Eczema ever
    • Time Frame: 0-12 months of age
    • Proportion of participants with eczema measured by a combined eczema measure
  • Eczema ever
    • Time Frame: 0-5 years of age
    • Proportion of participants with eczema measured by a combined eczema measure
  • Eczema
    • Time Frame: 0-12 months
    • Proportion of clinician-diagnosed eczema, by parental report
  • Eczema
    • Time Frame: 0-5 years of age
    • Proportion of clinician-diagnosed eczema, by parental report
  • Eczema onset
    • Time Frame: 0-12 months
    • Age of onset of eczema, by parental report
  • Eczema onset
    • Time Frame: 0-5 years of age
    • Age of onset of eczema, by parental report
  • Eczema severity
    • Time Frame: 0-12 months
    • Measured by parental report (POEM score)
  • Eczema severity
    • Time Frame: 0-12 months
    • Measured by clinical assessment (SCORAD)
  • Eczema severity
    • Time Frame: 0-12 months
    • Eczema medication use, by parental report
  • Eczema severity
    • Time Frame: 0-5 years of age
    • Measured by parental report (POEM score)
  • Eczema severity
    • Time Frame: 0-5 years of age
    • Measured by clinical assessment (SCORAD)
  • Eczema severity
    • Time Frame: 0-5 years of age
    • Eczema medication use, by parental report
  • Asthma severity
    • Time Frame: 4 years of age
    • Measured by asthma control test (ACT), by parental/participant report
  • Asthma severity
    • Time Frame: 5 years of age
    • Measured by asthma control test (ACT), by parental/participant report
  • Asthma severity
    • Time Frame: 2-5 years of age
    • Hospital admissions for asthma, by parental report
  • Laboratory measures of the immune response
    • Time Frame: Time Frame: 0-5 years of age

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 10 Days

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Murdoch Childrens Research Institute
  • Collaborator
    • Royal Children’s Hospital
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Prof Nigel Curtis, MBBS DCH DTM&H MRCP FRCPCH PhD, Principal Investigator, Murdoch Children’s Research Institute, Royal Children’s Hospital, University of Melbourne

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