BCG Revaccination With the Third Dose of Diphtheria-tetanus-pertussis Vaccine and Infant Mortality in Africa

NCT07005726 | Enrolling By Invitation Phase 4 DMC

• 1 other identifier: 003/CNES/INASA/2025
• Study Type: interventional
• Target: 6,000
• Locations: 1 country
• Sites: 1

Brief Summary

Studies in low-income countries show that vaccines can have important non-specific effects on other infections. Live BCG vaccine can train the immune system and reduce susceptibility to unrelated infections. In contrast, non-live diphtheria-tetanus-pertussis-containing (DTP) vaccine enhances susceptibility in females: DTP vs no DTP is associated with 2-fold higher mortality, and in DTP-vaccinated children, females have higher mortality than males. These effects are seen as long as a vaccine is the most recent vaccine. WHO recommends BCG at birth followed by three DTP vaccines. A metaanalysis based on observational studies has shown that co-administration of BCG+DTP is associated with lower mortality than BCG followed by DTP. The investigators will implement a randomised trial in urban Guinea-Bissau, including 6000 children, to test the hypothesis that an extra dose of BCG given with DTP3 (BCG2+DTP3 vs. DTP3) can:

• reduce death and hospital admissions by 25%
• reduce the F/M severe morbidity hazard ratio

Conditions

Infant Morbidity; Infant Mortality; Non-Specific Effects of Vaccines; BCG

Keywords

Non-specific-effects of vaccines; BCG; DTP; Infant mortality; Guinea-Bissau; Infant morbidity; Female survival; BCG revaccination

Outcome Measures

Primary Outcomes (1)

• Non-accidental servere morbidity

  Composite outcome of death and admissions. Obtained via active follow-up of participants by phone calls, home visits and at the hospital. Cox regression models will be used to compare severe morbidity for BCG2+DTP3 versus controls (DTP3). The comparison of BCG2+DTP3 vs DTP3 will also be analysed separately by sex

  Baseline to the age of measles vaccine (scheduled at 9 months, to be received by latest by 12 months. Children will be censored upon migration or death.

Secondary Outcomes (7)

• Female/Male servere morbidity ratio

  Baseline to the age of measles vaccine (scheduled at 9 months, to be received by latest by 12 months. Children will be censored upon migration or death.

• Non-accidental mortality

  Baseline to the age of measles vaccine (scheduled at 9 months, to be received by latest by 12 months. Children will be censored upon migration or death.

• Non-accidental morbidity

  Baseline to the age of measles vaccine (scheduled at 9 months, to be received by latest by 12 months. Children will be censored upon migration or death.

• Cause-specific deaths

  Baseline to the age of measles vaccine (scheduled at 9 months, to be received by latest by 12 months. Children will be censored upon migration or death.

• Cause-specific admissions

  Baseline to the age of measles vaccine (scheduled at 9 months, to be received by latest by 12 months. Children will be censored upon migration or death.

Study Arms (2)

BCG2+DTP3

EXPERIMENTAL

Infants aged 14-24 weeks will receive a second dose of BCG with the third dose of DTP.

Biological: BCG Vaccine

DTP3

NO INTERVENTION

Infants aged 14-24 weeks will as-per-usual receive a third dose of DTP.

Interventions

BCG Vaccine BIOLOGICAL

The WHO-prequalified BCG-Japan or BCG-Denmark

BCG2+DTP3

Eligibility Criteria

• Age: 14 Weeks - 24 Weeks
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Children, who are between 14 weeks and 24 weeks of age,
• Received DTP2 at least 4 weeks earlier and who are due to receive DTP3.

You may not qualify if:

• Children, who are ill and require hospitalization.
• Children with severe malformations
• Children, who had suppurative lymphadenitis after BCG1 (extremely rare)

Sponsors & Collaborators

• Bandim Health Project: lead
• University of Southern Denmark: collaborator
• Radboud University Medical Center: collaborator

Study Sites (1)

Bandim Health Project

Bissau, Guinea-Bissau

Location

Related Publications (6)

• Aaby P, Ravn H, Benn CS. The WHO Review of the Possible Nonspecific Effects of Diphtheria-Tetanus-Pertussis Vaccine. Pediatr Infect Dis J. 2016 Nov;35(11):1247-1257. doi: 10.1097/INF.0000000000001269.

  PMID: 27753772 BACKGROUND

• Aaby P, Nielsen J, Benn CS, Trape JF. Sex-differential and non-specific effects of routine vaccinations in a rural area with low vaccination coverage: an observational study from Senegal. Trans R Soc Trop Med Hyg. 2015 Jan;109(1):77-84. doi: 10.1093/trstmh/tru186.

  PMID: 25573112 BACKGROUND

• Hirve S, Bavdekar A, Juvekar S, Benn CS, Nielsen J, Aaby P. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine. 2012 Nov 26;30(50):7300-8. doi: 10.1016/j.vaccine.2012.09.035. Epub 2012 Sep 26.

  PMID: 23022401 BACKGROUND

• Aaby P, Andersen A, Ravn H, Zaman K. Co-administration of BCG and Diphtheria-tetanus-pertussis (DTP) Vaccinations May Reduce Infant Mortality More Than the WHO-schedule of BCG First and Then DTP. A Re-analysis of Demographic Surveillance Data From Rural Bangladesh. EBioMedicine. 2017 Aug;22:173-180. doi: 10.1016/j.ebiom.2017.07.012. Epub 2017 Jul 14.

  PMID: 28784413 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

• 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

Related Links

• Related Info

MeSH Terms

Conditions

Infant Death

Interventions

BCG Vaccine

Condition Hierarchy (Ancestors)

Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Officials

• Christine Stabell Benn, MD, PhD, DMSc

  Bandim Health Project and Danish Institute for Advanced Science, University of Southern Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: All follow-up will be masked as the intervention is not marked on the child's vaccination card.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 5, 2025
• First Posted: June 5, 2025
• Study Start: May 9, 2025
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): July 1, 2030
• Last Updated: June 12, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

GU (1)