Can earlier BCG vaccination reduce early infant mortality? Study protocol for a cluster randomised trial in Guinea-Bissau

Sanne M Thysen, Aksel Karl Georg Jensen, Amabelia Rodrigues, Igualdino da Silva Borges, Peter Aaby, Christine Benn, Ane Fisker, Sanne M Thysen, Aksel Karl Georg Jensen, Amabelia Rodrigues, Igualdino da Silva Borges, Peter Aaby, Christine Benn, Ane Fisker

Abstract

Introduction: The BCG vaccine is designed to protect against tuberculosis, but the vaccine may have broader effects. In 2014, the Strategic Advisory Group of Experts on Immunization reviewed the literature on non-specific effects of BCG, and concluded that the evidence was consistent with beneficial non-specific effects and requested further randomised trials.

Methods and analyses: Within the Bandim Health Project's urban and rural health and demographic surveillance systems, we will conduct a cluster-randomised trial in six suburban districts and 55 rural villages. Infants are enrolled at a home visit before 72 hours of life. In intervention clusters, children are vaccinated with BCG and oral polio vaccine (OPV). In control clusters, the caregivers are informed about vaccination opportunities. Using Cox-proportional hazards models, we will test whether BCG and OPV provided at a single home visit can reduce early infant mortality up to 60 days.The trial was initiated with a pilot study in Biombo region in June 2015. The trial was scaled up to full study including Oio and Cacheu regions in July 2016. The trial was expanded to include the urban study area in July 2017.

Ethics and dissemination: BCG vaccination is delayed in many low-income settings. WHO-recommended home visits are resource demanding and vaccines are not part of the recommendation. Utilising the home visits to provide BCG and OPV may provide countries with a further incentive to introduce a single home visit. In countries, where home visits are already in place, vaccines can easily be added to reduce early infant mortality. The trial is approved by the Guinean Ethical Committee (Reference number: 0016/CNES/INASA/2015) and the Danish Ethics Committee has given its consultative approval. The results of the trial will be published in international peer-reviewed journals.

Trial registration number: NCT02504203; Pre-results.

Keywords: BCG vaccine; Cluster randomised trial; Non-specific effects of vaccines; Oral polio vaccine.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Recommended vaccination schedule in Guinea-Bissau.

References

    1. WHO, UNICEF . WHO/Unicef joint statement: home visits for the newborn child: a strategy to improve survival, 2009.
    1. WHO Who recommendations on postnatal care of the mother and newborn, 2013. Available:
    1. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435–8. 10.1136/bmj.321.7274.1435
    1. Aaby P, Benn C, Nielsen J, et al. . Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open 2012;2:e000707 10.1136/bmjopen-2011-000707
    1. Aaby P, Ravn H, Roth A, et al. . Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child 2012;97:685–91. 10.1136/archdischild-2011-300646
    1. Aaby P, Roth A, Ravn H, et al. . Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245–52. 10.1093/infdis/jir240
    1. Biering-Sørensen S, Aaby P, Napirna BM, et al. . Small randomized trial among Low–birth-weight children receiving Bacillus Calmette-Guéerin vaccination at first health center contact. Pediatr Infect Dis J 2012;31:306–8. 10.1097/INF.0b013e3182458289
    1. Aaby P, Jensen H, Samb B, et al. . Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies. The Lancet 2003;361:2183–8. 10.1016/S0140-6736(03)13771-3
    1. Biering-Sørensen S, Aaby P, Lund N, et al. . Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial. Clin Infect Dis 2017;65:1183–90. 10.1093/cid/cix525
    1. Benn CS, Netea MG, Selin LK, et al. . A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol 2013;34:431–9. 10.1016/j.it.2013.04.004
    1. Hirve S, Bavdekar A, Juvekar S, et al. . Non-specific and sex-differential effects of vaccinations on child survival in rural Western India. Vaccine 2012;30:7300–8. 10.1016/j.vaccine.2012.09.035
    1. Aaby P, Kollmann TR, Benn CS. Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges. Nat Immunol 2014;15:895–9. 10.1038/ni.2961
    1. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? where? why? The Lancet 2005;365:891–900. 10.1016/S0140-6736(05)71048-5
    1. Shann F. Commentary: BCG vaccination halves neonatal mortality. Pediatr Infect Dis J 2012;31:308–9. 10.1097/INF.0b013e3182465be8
    1. Netea MG, Quintin J, van der Meer JWM. Trained immunity: a memory for innate host defense. Cell Host Microbe 2011;9:355–61. 10.1016/j.chom.2011.04.006
    1. Kleinnijenhuis J, Quintin J, Preijers F, et al. . Bacille Calmette-Guerin induces Nod2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 2012;109:17537–42. 10.1073/pnas.1202870109
    1. Jensen KJ, Larsen N, Biering-Sørensen S, et al. . Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J Infect Dis 2015;211:956–67. 10.1093/infdis/jiu508
    1. Thysen SM, Byberg S, Pedersen M, et al. . Bcg coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study. BMC Public Health 2014;14:1037 10.1186/1471-2458-14-1037
    1. Roth A, Gustafson P, Nhaga A, et al. . Bcg vaccination scar associated with better childhood survival in Guinea-Bissau. Int J Epidemiol 2005;34:540–7. 10.1093/ije/dyh392
    1. Roth A, Sodemann M, Jensen H, et al. . Tuberculin reaction, BCG scar, and lower female mortality. Epidemiology 2006;17:562–8. 10.1097/01.ede.0000231546.14749.ab
    1. Garly M-L, Martins CL, Balé C, et al. . Bcg scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Vaccine 2003;21:2782–90. 10.1016/s0264-410x(03)00181-6
    1. Roth A, Sodemann M, Jensen H, et al. . Vaccination technique, PPD reaction and BCG scarring in a cohort of children born in Guinea-Bissau 2000–2002. Vaccine 2005;23:3991–8. 10.1016/j.vaccine.2004.10.022
    1. Frankel H, Byberg S, Bjerregaard-Andersen M, et al. . Different effects of BCG strains - a natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau. Vaccine 2016;34:4586–93. 10.1016/j.vaccine.2016.07.022
    1. Funch KM, Thysen SM, Rodrigues A, et al. . Determinants of BCG scarification among children in rural Guinea-Bissau: a prospective cohort study. Hum Vaccin Immunother 2018;14:2434–42. 10.1080/21645515.2017.1421879
    1. Kagoné M, Ye M, Nébié E, et al. . 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;10:1399749 10.1080/16549716.2017.1399749
    1. Hanifi SMA, Das S, Rahman M. Bangladeshi neonates miss the potential benefits of early BCG vaccination. Int J Epidemiol 2018;47:348–9. 10.1093/ije/dyx223
    1. Wallace AS, Willis F, Nwaze E, et al. . Vaccine wastage in Nigeria: an assessment of wastage rates and related vaccinator knowledge, attitudes and practices. Vaccine 2017;35:6751–8. 10.1016/j.vaccine.2017.09.082
    1. Lund N, Andersen A, Hansen ASK, et al. . The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin Infect Dis 2015;61:1504–11. 10.1093/cid/civ617

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