Delayed BCG Study (DBS): determining whether BCG vaccination might protect infants against non-tuberculous invasive infectious disease by stimulating the innate immune system

Conditions

All cause infectious disease Infections and Infestations

Sarah Prentice, Zephyrian Kamushaaga, Stephen Nash, Alison M. Elliott, Hazel M. Dockrell et al. (6 authors)

Vaccine2018-04-118 citations

10.1016/j.vaccine.2018.03.026

Investigating the non-specific effects of BCG vaccination on the innate immune system in Ugandan neonates: study protocol for a randomised controlled trial.

Prentice S, Webb EL, Dockrell HM, Kaleebu P, Elliott AM, Cose S.

2015-04-119 citations

10.1186/s13063-015-0682-5

Interventions

Current interventions as of 25/06/2020: 560 Ugandan babies will be randomly assigned to receive BCG-Danish 0.05 ml intradermal to the right deltoid on either the day of birth or at six

Eligibility

Sex/Gender

All

Inclusion criteria

Inclusion criteria: Neonates born to women delivering in Entebbe Grade B or Kisubi hospitals will be eligible for inclusion if: 1. Mother consents for participation 2. They reside in the study catchment areas 3. Mothers are HIV negative (based on records available from antenatal care received during this pregnancy) 4. The birth was sufficiently uncomplicated to allow the neonate to be discharged directly home from hospital with no infant admission or treatment for complications 5. The neonate is of a gestational age and birth weight to allow discharge directly home from hospital (no requirement for supplemental oxygen or feeding)

Exclusion criteria

Exclusion criteria: Neonates will be excluded from the study if: 1. Cord blood is not obtained 2. They have major congenital malformations 3. The infant is clinically unwell, as judged by a midwife 4. Known maternal tuberculosis (TB) or active TB within the family (based on direct questioning of mother during recruitment) 5. Maternal or family member positive for any TB screening symptoms: 5.1. Cough > 2 weeks 5.2. Recent haemoptysis 5.3. >3 kg weight loss in past month 5.4. Recurrent fevers/chills or night sweats for the past 3 days or more

Design outcomes

Primary

Measure	Time frame
Current primary outcome measure as of 25/06/2020: This study will be divided into three separate immunological sub-studies with their own primary outcome measures: Sub-study 1: Pro-inflammatory Cytokine Analysis IL-1ß, IL-6, TNF-a and IFN-? cytokine levels following in vitro stimulation with S. aureus, S. pneumoniae, E. coli, Poly I:C and C. albicans (measured by ELISA): 1. Up to 1 week post-birth intervention 2. Immediately prior to first dose of primary immunisations (6 weeks post-birth intervention) 3. Up to 1 week post-6-week intervention 4. Immediately prior to second dose of primary immunisations (4 weeks post-6-week intervention) Sub-study 2: Inflammatory Iron Status Hepcidin levels (measured by ELISA) and transferrin saturation (measured using the Cobas-Integra automated analyser): 1. Up to 1 week post-birth intervention 2. Up to 1 week post first dose of primary interventions 3. Up to 1 week post-6-week intervention 4. Up to 1 week post second dose of primary interventions Sub-study 3: Monocyte Epigenetic Modification Tri-methylation of histone-3, lysine-4 at the promoter regions of pro-inflammatory cytokines in monocytes (measured by chromatin immunoprecipitation): 1. Up to 1 week post-birth intervention 2. Immediately prior to first dose of primary immunisations (6 weeks post-birth intervention) Combined Studies - Clinical Illness Events 1. Physician-diagnosed Infectious Disease Previous primary outcome measure: This study will be divided into three separate immunological sub-studies with their own primary outcome measures: Sub-study 1: Pro-inflammatory Cytokine Analysis IL-1ß, IL-6, TNF-	—

Measure

Time frame

Current primary outcome measure as of 25/06/2020: This study will be divided into three separate immunological sub-studies with their own primary outcome measures: Sub-study 1: Pro-inflammatory Cytokine Analysis IL-1ß, IL-6, TNF-a and IFN-? cytokine levels following in vitro stimulation with S. aureus, S. pneumoniae, E. coli, Poly I:C and C. albicans (measured by ELISA): 1. Up to 1 week post-birth intervention 2. Immediately prior to first dose of primary immunisations (6 weeks post-birth intervention) 3. Up to 1 week post-6-week intervention 4. Immediately prior to second dose of primary immunisations (4 weeks post-6-week intervention) Sub-study 2: Inflammatory Iron Status Hepcidin levels (measured by ELISA) and transferrin saturation (measured using the Cobas-Integra automated analyser): 1. Up to 1 week post-birth intervention 2. Up to 1 week post first dose of primary interventions 3. Up to 1 week post-6-week intervention 4. Up to 1 week post second dose of primary interventions Sub-study 3: Monocyte Epigenetic Modification Tri-methylation of histone-3, lysine-4 at the promoter regions of pro-inflammatory cytokines in monocytes (measured by chromatin immunoprecipitation): 1. Up to 1 week post-birth intervention 2. Immediately prior to first dose of primary immunisations (6 weeks post-birth intervention) Combined Studies - Clinical Illness Events 1. Physician-diagnosed Infectious Disease Previous primary outcome measure: This study will be divided into three separate immunological sub-studies with their own primary outcome measures: Sub-study 1: Pro-inflammatory Cytokine Analysis IL-1ß, IL-6, TNF-

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Secondary

Measure	Time frame
Current secondary outcome measures as of 25/06/2020: 1. Parent-reported invasive infectious disease 2. Blood culture positive invasive infectious disease 3. Death Secondary outcomes will be collected up to 10 weeks of age. They will be measured via a combination of: 1. Questionnaires asking for parental recall of illness episodes, administered every time the participant is seen in the research clinic (this will be for the two blood samples and for all routine immunisations up to 10 weeks of age) 2. Physician case report forms, completed any time a child is seen in the clinic or the hospital during their participation in the study. Previous secondary outcome measures: All children in the study will be clinically followed up, providing combined secondary outcome measures: 1. Physician-diagnosed invasive infectious disease 2. Parent-reported invasive infectious disease 3. Blood culture positive invasive infectious disease 4. Death Secondary outcomes will be collected up to 10 weeks of age. They will be measured via a combination of: 1. Questionnaires asking for parental recall of illness episodes, administered every time the participant is seen in the research clinic (this will be for the two blood samples and for all routine immunisations up to 10 weeks of age) 2. Physician case report forms, completed any time a child is seen in the clinic or the hospital during their participation in the study.	—

Measure

Time frame

Current secondary outcome measures as of 25/06/2020: 1. Parent-reported invasive infectious disease 2. Blood culture positive invasive infectious disease 3. Death Secondary outcomes will be collected up to 10 weeks of age. They will be measured via a combination of: 1. Questionnaires asking for parental recall of illness episodes, administered every time the participant is seen in the research clinic (this will be for the two blood samples and for all routine immunisations up to 10 weeks of age) 2. Physician case report forms, completed any time a child is seen in the clinic or the hospital during their participation in the study. Previous secondary outcome measures: All children in the study will be clinically followed up, providing combined secondary outcome measures: 1. Physician-diagnosed invasive infectious disease 2. Parent-reported invasive infectious disease 3. Blood culture positive invasive infectious disease 4. Death Secondary outcomes will be collected up to 10 weeks of age. They will be measured via a combination of: 1. Questionnaires asking for parental recall of illness episodes, administered every time the participant is seen in the research clinic (this will be for the two blood samples and for all routine immunisations up to 10 weeks of age) 2. Physician case report forms, completed any time a child is seen in the clinic or the hospital during their participation in the study.

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Countries

Uganda

Outcome results

None listed