Clinical trial NCT01906853: Melbourne Infant Study - Bacille Calmette Guérin (BCG) for Allergy & Infection Reduction
Official title: A Randomised, Controlled Trial to Determine if BCG Immunisation at Birth Reduces Allergy and Infection in Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Allergy
Eczema
Respiratory Tract Infections
Keywords: BCG
Bacille Calmette Guérin
Allergy
Immunity
Immune response
Vaccine
Infants
Children
Infection
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
Collaborators: name: Royal Children's Hospital
name: Mercy Hospital for Women, Australia
name: University of Melbourne
First posted: 2013-07-24
Enrollment: 1272
Sex: ALL
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Atopic sensitisation measured by skin prick test (SPT)
timeFrame: 1 year of age
measure: Atopic sensitisation measured by skin prick test (SPT)
timeFrame: 5 years of age
measure: Lower respiratory tract infection (LRTI)
timeFrame: 0-12 months
measure: Lower respiratory tract infection (LRTI) hospital admissions
timeFrame: 0-5 years of age
measure: Eczema ever
timeFrame: 0-12 months
measure: Eczema ever
timeFrame: 0-5 years of age
measure: Current asthma
timeFrame: 5 years of age
measure: Asthma ever
timeFrame: 5 years of age
Secondary outcomes:
measure: Clinical food allergy
timeFrame: 1 year of age
measure: Clinical food allergy
timeFrame: 5 years of age
measure: Atopic sensitisation measured by SPT using a more stringent cut-off
timeFrame: 1 year of age
measure: Atopic sensitisation measured by SPT using a more stringent cut-off
timeFrame: 5 years of age
measure: Atopic sensitisation to multiple allergens measured by SPT
timeFrame: 1 year of age
measure: Atopic sensitisation to multiple allergens measured by SPT
timeFrame: 5 years of age
measure: Parent report of food allergy
timeFrame: 0-12 months of age
measure: Parent report of food allergy
timeFrame: 0-5 years of age
measure: Egg sensitisation
timeFrame: 1 year of age
measure: Egg sensitisation
timeFrame: 5 years of age
measure: Egg allergy
timeFrame: 1 year of age
measure: Egg allergy
timeFrame: 5 years of age
measure: Atopic wheeze
timeFrame: 1 year of age
measure: Atopic wheeze
timeFrame: 5 years of age
measure: Lower respiratory tract infection (LRTI)
timeFrame: Prior to first Diphtheria, Tetanus, Pertussis (DTP) vaccination
measure: Lower respiratory tract infection (LRTI)
timeFrame: 0-5 years of age
measure: Rate of lower respiratory tract infection (LRTI)
timeFrame: 0-12 months
measure: Rate of lower respiratory tract infection (LRTI)
timeFrame: Prior to first DTP vaccination
measure: Rate of lower respiratory tract infection (LRTI)
timeFrame: 0-5 years of age
measure: Infections
timeFrame: 0-12 months
measure: Infections
timeFrame: Prior to first DTP vaccination
measure: Infections
timeFrame: 0-5 years of age
measure: Hospitalisation for respiratory tract infection (RTI)
timeFrame: 0-12 months of age
measure: Hospitalisation for respiratory tract infection (RTI)
timeFrame: Prior to first DTP vaccination
measure: Hospitalisation for respiratory tract infection (RTI)
timeFrame: 0-5 years of age
measure: Rate of any infection
timeFrame: 0-12 months of age
measure: Rate of any infection
timeFrame: Prior to first DTP vaccination
measure: Rate of upper respiratory tract infection (URTI)
timeFrame: 0-12 months of age
measure: Rate of upper respiratory tract infection (URTI)
timeFrame: Prior to first DTP vaccination
measure: Rate of fever
timeFrame: 0-12 months of age
measure: Rate of fever
timeFrame: Prior to first DTP vaccination
measure: Diarrhoea
timeFrame: 0-12 months of age
measure: Diarrhoea
timeFrame: Prior to first DTP vaccination
measure: Rash with fever
timeFrame: 0-12 months of age
measure: Rash with fever
timeFrame: Prior to first DTP vaccination
measure: Eczema ever
timeFrame: 0-12 months of age
measure: Eczema ever
timeFrame: 0-5 years of age
measure: Eczema
timeFrame: 0-12 months
measure: Eczema
timeFrame: 0-5 years of age
measure: Eczema onset
timeFrame: 0-12 months
measure: Eczema onset
timeFrame: 0-5 years of age
measure: Eczema severity
timeFrame: 0-12 months
measure: Eczema severity
timeFrame: 0-12 months
measure: Eczema severity
timeFrame: 0-12 months
measure: Eczema severity
timeFrame: 0-5 years of age
measure: Eczema severity
timeFrame: 0-5 years of age
measure: Eczema severity
timeFrame: 0-5 years of age
measure: Asthma severity
timeFrame: 4 years of age
measure: Asthma severity
timeFrame: 5 years of age
measure: Asthma severity
timeFrame: 2-5 years of age
measure: Laboratory measures of the immune response
timeFrame: Time Frame: 0-5 years of age
Other outcomes:
measure: Effect of sex on the non-specific effects BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of maternal BCG on the non-specific effects BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of presence or absence BCG scar on the non-specific effects of BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of timing of BCG administration on the non-specific effects BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of mode of delivery on the non-specific effects BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of family history of allergy on the allergy and eczema outcomes
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of season of birth on the non-specific effects BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Effect of hepatitis B vaccine timing birth on the non-specific effects BCG
timeFrame: 0-12 months and 0-5 years of age
measure: Meta-analysis
timeFrame: 36 months
measure: Morbidity
timeFrame: 0-12 months of age
measure: Morbidity
timeFrame: 0-5 years of age
Locations:
city: Heidelberg
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Melbourne
country: Australia
facility: Royal Children's Hospital
state: Victoria
Study officials:
affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne
name: Prof Nigel Curtis, MBBS DCH DTM&H MRCP FRCPCH PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.