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Original research
Seasonal variation in the non-specific effects of BCG vaccination on neonatal mortality: three randomised controlled trials in Guinea-Bissau
  1. Kristoffer Jarlov Jensen1,2,
  2. Sofie Biering-Sørensen1,
  3. Johan Ursing3,4,
  4. Poul-Erik Lund Kofoed5,6,
  5. Peter Aaby1,6,
  6. Christine Stabell Benn1,7
  1. 1Bandim Health Project, University of Southern Denmark, Copenhagen, Denmark
  2. 2Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
  3. 3Department of Infectious Diseases, Danderyd University Hospital, Stockholm, Sweden
  4. 4Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden
  5. 5Department of Pediatrics, Kolding Hospital, Kolding, Denmark
  6. 6Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau
  7. 7OPEN, Institute of Clinical Research, University of Southern Denmark, Odense, Syddanmark, Denmark
  1. Correspondence to Professor Christine Stabell Benn; CB{at}ssi.dk

Abstract

The BCG vaccine protects non-specifically against other diseases than tuberculosis. Three randomised controlled trials of early BCG in Guinea-Bissau found a 38% reduction in all-cause neonatal mortality. Little is known about the underlying mechanisms. In Guinea-Bissau, prevalent infectious diseases display distinct seasonality. Revisiting the three trials (>6500 infants) comparing early BCG versus no early BCG in low weight infants on all-cause neonatal mortality over 12 consecutive years, we explored the seasonal variation in BCG’s effect on mortality. In a subgroup of participants, adaptive and innate cytokine responses were measured 4 weeks after randomisation. Consistently over the course of the three trials and 12 years, the effect of BCG on all-cause neonatal mortality was particularly beneficial when administered in November to January, coincident with peaking malaria infections. During these months, BCG was also associated with stronger proinflammatory responses to heterologous challenge. Recent studies have suggested a protective effect of BCG against malaria. BCG may also ameliorate immune-compromising fatal effects of placental malaria in the newborn.

  • immunisation
  • maternal health
  • paediatrics
  • vaccines
  • malaria
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjgh-2019-001873

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    Footnotes

    • Handling editor Seye Abimbola

    • Contributors KJJ, SB-S, PA and CSB conceived and designed the BCG-related studies. JU and P-ELK carried out the malaria surveys. KJJ and SB-S analysed the data. KJJ wrote the first draft of the manuscript. All authors contributed to the final version of the manuscript.

    • Funding The randomised controlled trials of early BCG were supported by The European Research Council (starting grant ERC-2009-StG-243149); the Novo Nordisk Foundation (research professorship grant to PA); the Danish National Research Foundation (grant DNRF108 to the Research CenterCentre for Vitamins & Vaccines); and DANIDA, European Union FP7, and OPTIMUNISE (grant Health-F3-2011-261 375 to the Bandim Health Project). The immunological subgroup study was supported by Novo Nordisk Foundation and University of Southern Denmark; KJJ is supported by a grant from Novo Nordisk Foundation (grant NNF14OC0012169).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The BCG RCTs and the immunological substudy were approved by the National Committee on Health Ethics of the Ministry of Health in Guinea-Bissau; a consultative approval was obtained from the Danish National Committee on Biomedical Research Ethics. The BCG trials were registered with clinicaltrials.gov, numbers NCT00146302 (Trials I+II), NCT00625482 (Trial III).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available on reasonable request.

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