Can BCG Vaccination at First Health-facility Contact Reduce Early Infant Mortality?

NCT04658680 | Active Not Recruiting Phase 4 DMC

• 1 other identifier: 062/CNES/INASA/2020
• Study Type: interventional
• Target: 22,800
• Locations: 1 country
• Sites: 1

Brief Summary

Bacillus Calmette-Guérin (BCG) vaccination is recommended at birth to protect against tuberculosis (TB) in countries with high TB burden. BCG is supplied in multidose vials with limited durability after reconstitution. In Guinea-Bissau, this has led to a practice of only opening a BCG vial at specific days, and only if sufficient children are present. Therefore, BCG vaccination is frequently delayed. Accumulating evidence indicates that BCG has beneficial effects on survival beyond the specific protection against tuberculosis, so called non-specific effects (NSEs). The hypothesis of this study is that increasing the availability of BCG and vaccinating children at the first health-facility contact can reduce early infant non-accidental mortality by 25%. In a cluster-randomised crossover trial, 23 health facilities (HFs) in three rural regions in Guinea-Bissau will be randomised to either continue with current practice (typically BCG vaccination once a week if a sufficient number of children are present for vaccination); or to offer additional BCG vaccines to make BCG available every day and open a vial of BCG if there is just one eligible child present. All children born in the three regions and registered during the study period, will be eligible for inclusion into the trial 1 day after birth. If consent is given by the mother, the child will be followed until day 42 after birth, when other vaccines are scheduled to be given. The primary outcome will be non-accidental mortality, secondary outcomes are non-accidental hospital admissions, non-accidental neonatal mortality and cost-effectiveness of making BCG available at the first health-facility contact.

Conditions

Infant Mortality; BCG

Keywords

Non-specific effects of vaccines

Outcome Measures

Primary Outcomes (1)

• Odds ratio of non-accidental early infant mortality

  The primary analysis of early infant non-accidental mortality will be assessed in an intention-to-treat (TT) analysis. Logistic regression models with generalised estimating equation (GEE) correction for village cluster will be used. Furthermore, an assessment of whether the effect of the intervention on the primary outcome is modified by the following potential effect modifiers, will be carried out: Sex, maternal BCG scar (yes/no), season of birth (dry/rainy), strain of BCG.

  From 1 day after birth to 42 days after birth

Secondary Outcomes (3)

• Odds ratio of non-accidental neonatal mortality

  From 1 day after birth to 28 days after birth

• Odds ratio of severe morbidity

  From 1 day after birth to 42 days after birth

• Incremental cost-effectiveness ratio per death averted by making BCG available at the first health facility contact

  From 1 day after birth to 42 days after birth

Study Arms (2)

BCG available at first health facility contact

EXPERIMENTAL

Infants living in catchment areas of HFs randomized to opening of BCG vial if just 1 eligible child is present.

Drug: BCG vaccination at first health facility contact

Usual availability of BCG at health facilities

NO INTERVENTION

Infants living in catchment areas of HFs randomized to BCG availability according to the per usual restricted vial opening policy aiming at reducing vaccine wastage. This entails that BCG vaccination is commonly only available on specific predefined days where a BCG vial will only be opened if several children are present.

Interventions

BCG vaccination at first health facility contact DRUG

Intradermal injection at first health facility contact: 0.05 ml dose Mycobacterium bovis BCG live attenuated vaccine in the left deltoid region. The strain supplied by the national vaccination programme is provided through UNICEF. Different strains are used interchangeably. The additional BCG vaccines provided through this study will be procured by the Bandim Health Project. Vaccines will be from the WHO list of prequalified vaccines and the same strain will be used in intervention and control health centres.

BCG available at first health facility contact

Eligibility Criteria

• Age: 1 Day - 42 Days
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• All children registered during pregnancy in Oio, Biombo or Farim by CHWs or the BHP HDSS

You may not qualify if:

• Children, who have died within 1 day after birth
• Children born outside Oio, Biombo and Farim health regions

Sponsors & Collaborators

• Bandim Health Project: lead
• University of Southern Denmark: collaborator

Study Sites (1)

Bandim Health Project

Bissau, Guinea-Bissau

Location

Related Publications (14)

• World Health Organization. BCG vaccine: WHO position paper, February 2018 - Recommendations. Vaccine. 2018 Jun 7;36(24):3408-3410. doi: 10.1016/j.vaccine.2018.03.009. Epub 2018 Mar 30.

  PMID: 29609965 BACKGROUND

• Thysen SM, Byberg S, Pedersen M, Rodrigues A, Ravn H, Martins C, Benn CS, Aaby P, Fisker AB. BCG coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study. BMC Public Health. 2014 Oct 4;14:1037. doi: 10.1186/1471-2458-14-1037.

  PMID: 25282475 BACKGROUND

• Kagone M, Ye M, Nebie E, Sie A, Schoeps A, Becher H, Muller O, Fisker AB. Vaccination coverage and factors associated with adherence to the vaccination schedule in young children of a rural area in Burkina Faso. Glob Health Action. 2017;10(1):1399749. doi: 10.1080/16549716.2017.1399749.

  PMID: 29185899 BACKGROUND

• Wallace AS, Willis F, Nwaze E, Dieng B, Sipilanyambe N, Daniels D, Abanida E, Gasasira A, Mahmud M, Ryman TK. Vaccine wastage in Nigeria: An assessment of wastage rates and related vaccinator knowledge, attitudes and practices. Vaccine. 2017 Dec 4;35(48 Pt B):6751-6758. doi: 10.1016/j.vaccine.2017.09.082. Epub 2017 Oct 21.

  PMID: 29066189 BACKGROUND

• Mutua, M.K., et al. Analysis of Fully Immunized Child (FIC), Associated Factors, Outcomes, and Impact Using Routinely Population Cohort Data 2001-2014. Report by the INDEPTH Network as a collaboration with GAVI 2015 18th April 2020 ]; Available from: http://www.indepth-network.org/sites/default/files/content/project_pages/files/Fully%20Immunized%20Child%20Report%20and%20Appendices.pdf.

  BACKGROUND

• Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, Lalli M, Bhutta Z, Barros AJ, Christian P, Mathers C, Cousens SN; Lancet Every Newborn Study Group. Every Newborn: progress, priorities, and potential beyond survival. Lancet. 2014 Jul 12;384(9938):189-205. doi: 10.1016/S0140-6736(14)60496-7. Epub 2014 May 19.

  PMID: 24853593 BACKGROUND

• Higgins JP, Soares-Weiser K, Lopez-Lopez JA, Kakourou A, Chaplin K, Christensen H, Martin NK, Sterne JA, Reingold AL. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016 Oct 13;355:i5170. doi: 10.1136/bmj.i5170.

  PMID: 27737834 BACKGROUND

• Roth A, Jensen H, Garly ML, Djana Q, Martins CL, Sodemann M, Rodrigues A, Aaby P. Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: community study from Guinea-Bissau. Pediatr Infect Dis J. 2004 Jun;23(6):544-50. doi: 10.1097/01.inf.0000129693.81082.a0.

  PMID: 15194836 BACKGROUND

• Biering-Sorensen S, Aaby P, Lund N, Monteiro I, Jensen KJ, Eriksen HB, Schaltz-Buchholzer F, Jorgensen ASP, Rodrigues A, Fisker AB, Benn CS. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis. 2017 Oct 1;65(7):1183-1190. doi: 10.1093/cid/cix525.

  PMID: 29579158 BACKGROUND

• Schaltz-Buchholzer F, Biering-Sorensen S, Lund N, Monteiro I, Umbasse P, Fisker AB, Andersen A, Rodrigues A, Aaby P, Benn CS. Early BCG Vaccination, Hospitalizations, and Hospital Deaths: Analysis of a Secondary Outcome in 3 Randomized Trials from Guinea-Bissau. J Infect Dis. 2019 Jan 29;219(4):624-632. doi: 10.1093/infdis/jiy544.

  PMID: 30239767 BACKGROUND

• Jayaraman K, Adhisivam B, Nallasivan S, Krishnan RG, Kamalarathnam C, Bharathi M, McSharry B, Namachivayam SP, Shann F, Boopalan SI, David P, Bhat BV. Two Randomized Trials of the Effect of the Russian Strain of Bacillus Calmette-Guerin Alone or With Oral Polio Vaccine on Neonatal Mortality in Infants Weighing <2000 g in India. Pediatr Infect Dis J. 2019 Feb;38(2):198-202. doi: 10.1097/INF.0000000000002198.

  PMID: 30256314 BACKGROUND

• Curtis N. BCG Vaccination and All-Cause Neonatal Mortality. Pediatr Infect Dis J. 2019 Feb;38(2):195-197. doi: 10.1097/INF.0000000000002230. No abstract available.

  PMID: 30640189 BACKGROUND

• Thysen SM, Benn CS, Gomes VF, Rudolf F, Wejse C, Roth A, Kallestrup P, Aaby P, Fisker A. Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study. BMJ Open. 2020 Feb 28;10(2):e035595. doi: 10.1136/bmjopen-2019-035595.

  PMID: 32114478 BACKGROUND

• Thysen SM, Moller Jensen A, Vedel JO, da Silva Borges I, Aaby P, Jensen AKG, Benn CS, Fisker AB. Can BCG vaccination at first health-facility contact reduce early infant mortality? Study protocol for a cluster-randomised trial (CS-BCG). BMJ Open. 2022 Nov 21;12(11):e063872. doi: 10.1136/bmjopen-2022-063872.

  PMID: 36410811 DERIVED

MeSH Terms

Conditions

Infant Death

Condition Hierarchy (Ancestors)

Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Ane B Fisker, MD, PhD

  Bandim Health Project and University of Southern Denmark

  PRINCIPAL INVESTIGATOR

• Andreas M Jensen, MSc

  Bandim Health Project and University of Southern Denmark

  PRINCIPAL INVESTIGATOR

• Julie O Vedel, MD

  Bandim Health Project and University of Southern Denmark

  PRINCIPAL INVESTIGATOR

• Sanne M Thysen, MD, PhD

  Bandim Health Project and Center for Clinical Research and Prevention, Hospital of Bispebjerg and Frederiksberg

  STUDY DIRECTOR

• Christine S Benn, MD,PhD,DMSc

  Bandim Health Project and University of Southern Denmark

  STUDY DIRECTOR

• Peter Aaby, DMSc

  Bandim Health Project

  STUDY DIRECTOR

• Aksel Jensen, MSc, PhD

  Department of Public Health, University of Copenhagen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants live in the catchment areas of one of 23 HFs. The HFs will be randomized to either BCG vaccination per usual practice or to extended BCG availability. The randomization of HFs will be crossed over after 12 months.

Study Record Dates

• First Submitted: November 19, 2020
• First Posted: December 8, 2020
• Study Start: February 25, 2021
• Primary Completion: March 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: February 11, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: After conclusion of the study period.
• Access Criteria: Data will be available on a collaborative basis. Please contact a.fisker@health.sdu.dk

Locations

GU (1)