WP3

An RCT of BCG at birth and childhood morbidity in Danish children 

Hypotheses

 BCG at birth reduces:

  1. Hospitalizations during infancy by 20%
  2. The development of eczema by 40%

Background

 For about 30 years the incidence of atopic diseases like eczema, wheezing, asthma and hay fever has increased in high-income countries. BCG vaccine is administered at birth in ≥ 100 countries to protect against tuberculosis (TB). In Denmark, due to the low TB incidence BCG was withdrawn in 1982. BCG causes a strong immunologic stimulation resulting in an interferon gamma (IFN-γ) response51. IFN-γ counter-balances the T-helper-cell-2 (TH2) response found in atopic individuals52. In an RCT, neonatal BCG reduced neonatal mortality by 45% in Bissau1. One small RCT from Holland found that BCG decreased the incidence of eczema by 40%53. We aim to conduct the first large RCT to explore the clinical potential of the NSEs of BCG in a high-income population.

Study design

 The study will be conducted at the three hospitals Rigshospitalet, Hvidovre and Sygehus Lillebælt, which have a total of 15,000 deliveries/year. Parents who will give birth in 2012 will receive an information letter and be offered inclusion during the 3rd trimester of pregnancy. Children randomized to BCG will receive intradermal BCG within 7 days of birth. Control children will receive no vaccine since there is no suitable placebo. Exclusion criteria: Any sign of disease at birth, born before gestational age 32 weeks, birth weight<1000g, known congenital disease, anomaly or malformation, mothers with immune deficiency/HIV/AIDS. At age 3 and 13 months, a telephone-interview will be conducted to ascertain the child’s anthropometric status, general practitioner (GP) visits, and hospital admissions. All children are also invited for a clinical examination.

Outcomes and sample size

 The main outcomes hospitalization and eczema, as well as the secondary outcomes cause-specific hospitalizations, wheeze, growth and use of antibiotics, will be ascertained based on the interviews and the clinical examination supplemented by data from the Danish National Patient Registry (DNPR) and the National Register of Medicinal Product Statistics (NRMPS). A subgroup will be included in an immunological study (WP8). In Denmark, >20% are hospitalized in infancy and 5% develop eczema. We need 3972 infants to detect a 20% reduction in admissions, and 4230 infants to detect a 40% protection against eczema. Hence, we aim to enroll 4500 infants. If only 1/3 of the expected 15,000 births are enrolled, enrolment can be completed in one year.

Deliverables

 An estimate of the effect of providing BCG at birth on the incidence of

  1. hospitalizations
  2. eczema

Implications

Finding a beneficial effect will strengthen the general acceptability of NSEs, since the effect would be unrelated to prevention of TB.

Ethics

 The RCT is approved by the Danish Data Protection Board (DDPD), the DNCBRE, and the Danish Medicines Agency. It will be monitored by the Good Clinical Practice Units in Region Hovedstaden and Syddanmark.

PhD students

 A total of 5 PhD students will be involved in WP3.

Rigshospitalet: 
 
The PhD student will be responsible for the inclusion and follow up of children in the study with help from a research nurse. The PhD project will address the effect of early BCG vaccine on morbidity and mortality among children with low birth weight (based on all children with low birth weight included in all three inclusion sites). The PhD student will be supervised by Gorm Greisen, Lone Graff Stensballe and Peter Aaby.

Hvidovre Hospital:
 
The two PhD students will be responsible for the inclusion and follow up of children in the study. One PhD project will address the effect of early BCG vaccine on hematological parameters, including the white blood cell distribution and the antibody response to other vaccines (A). One PhD project will address the effect of early BCG vaccination on in vitro cytokine response and thymus size (B). The PhD students will be supervised by Ole Pryds, Lone Graff Stensballe and Christine Stabell Benn (A) and Dorthe Jeppesen, Lone Graff Stensballe and Christine Stabell Benn (B).

Sygehus Lillebælt:
 The two PhD students will be responsible for the inclusion and follow up of children in the study. One PhD project will address the effect of early BCG vaccine on atopic disease (C). One PhD project will address the attitude of Danish parents towards vaccinations including their response to the side effects of BCG vaccination (D). The PhD students will be supervised by Poul-Erik Kofoed and Lone Graff Stensballe as well as another supervisor from Sygehus Lillebælt.

Common for all PhD students:
 The PhD students' academic focus will continuously be evaluated by CVIVA's steering committee.

Research results will be published in leading international journals and in conference proceedings, and in all cases, the Center and the Danish National Research Foundation be thanked for support.

The aim is that the PhD students will spend long periods at the Center, for example in connection with the statistical analysis of data. The PhD students will also participate in all key meetings and activities of the Center and contribute to the Center's general activities.