Parental Bacillus Calmette-Guérin vaccine scars decrease infant mortality in the first six weeks of life: A retrospective cohort study

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Abstract

Background

Live attenuated vaccines have been observed to have particularly beneficial effects for child survival when given in the presence of maternally transferred immunity (priming). We aimed to test this finding and furthermore explore the role of paternal priming.

Methods

In an exploratory, retrospective cohort study in 2017, parental Bacillus Calmette-Guérin (BCG) scars were assessed for infants from the Bandim Health Project (BHP) who had participated in a 2008–2013 trial of neonatal BCG vaccination. Parental scar effects on mortality were estimated from birth to 42 days, the age of the scheduled diphtheria-tetanus-pertussis (DTP) vaccination, in Cox proportional hazard models adjusted with Inverse Probability of Treatment Weighting.

Findings

For 66% (510/772) of main trial infants that were still registered in the BHP area, at least one parent was located. BCG scar prevalence was 77% (353/461) among mothers and 63% (137/219) among fathers. In the first six weeks of life, maternal scars were associated with a mortality reduction of 60% (95%CI, 4% to 83%) and paternal scars with 49% (-68% to 84%). The maternal scar association was most beneficial among infants that had received BCG vaccination at birth (73% (-1% to 93%)). Although priming was less evident for paternal scars, having two parents with scars reduced mortality by 89% (13% to 99%) compared with either one or none of the parents having a scar.

Interpretation

Parental BCG scars were associated with strongly increased early-life survival. These findings underline the importance of future studies into the subject of inherited non-specific immunity and parental priming.

Funding

Danish National Research Foundation; European Research Council; Novo Nordisk Foundation; University of Southern Denmark.

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Most cited references 37

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Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies

Peter C Austin, Elizabeth A. Stuart (2015)

The propensity score is defined as a subject's probability of treatment selection, conditional on observed baseline covariates. Weighting subjects by the inverse probability of treatment received creates a synthetic sample in which treatment assignment is independent of measured baseline covariates. Inverse probability of treatment weighting (IPTW) using the propensity score allows one to obtain unbiased estimates of average treatment effects. However, these estimates are only valid if there are no residual systematic differences in observed baseline characteristics between treated and control subjects in the sample weighted by the estimated inverse probability of treatment. We report on a systematic literature review, in which we found that the use of IPTW has increased rapidly in recent years, but that in the most recent year, a majority of studies did not formally examine whether weighting balanced measured covariates between treatment groups. We then proceed to describe a suite of quantitative and qualitative methods that allow one to assess whether measured baseline covariates are balanced between treatment groups in the weighted sample. The quantitative methods use the weighted standardized difference to compare means, prevalences, higher‐order moments, and interactions. The qualitative methods employ graphical methods to compare the distribution of continuous baseline covariates between treated and control subjects in the weighted sample. Finally, we illustrate the application of these methods in an empirical case study. We propose a formal set of balance diagnostics that contribute towards an evolving concept of ‘best practice’ when using IPTW to estimate causal treatment effects using observational data. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

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Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.

Johanneke Kleinnijenhuis, Jessica Quintin, Frank Preijers … (2012)

Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.

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BCG-induced trained immunity in NK cells: Role for non-specific protection to infection.

Johanneke Kleinnijenhuis, Jessica Quintin, Frank Preijers … (2014)

Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination. BCG vaccination of healthy volunteers increased proinflammatory cytokine production following ex vivo stimulation of NK cells with mycobacteria and other unrelated pathogens up until at least three months after vaccination. In addition, in a murine model of disseminated candidiasis, BCG vaccination led to an increased survival in SCID mice, which was partially dependent on NK cells. These findings suggest that NK cells may contribute to the non-specific (heterologous) beneficial effects of BCG vaccination.

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Author and article information

Contributors

MLT Berendsen

CS. Benn

Journal

Journal ID (nlm-ta): EClinicalMedicine

Journal ID (iso-abbrev): EClinicalMedicine

Title: EClinicalMedicine

Publisher: Elsevier

ISSN (Electronic): 2589-5370

Publication date PMC-release: 12 August 2021

Publication date Collection: September 2021

Publication date (Electronic): 12 August 2021

Volume: 39

Electronic Location Identifier: 101049

Affiliations

[a ]Bandim Health Project, Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark

[b ]Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau

[c ]Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands

[d ]Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kgs Lyngby, Denmark

[e ]Center for Clinical Research and Prevention, Frederiksberg Hospital, Frederiksberg, Denmark

[f ]Danish Institute for Advanced Study, University of Southern Denmark, Denmark

Author notes

[* ]Corresponding author at: Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands. Mike.Berendsen@ 123456radboudumc.nl

Article

Publisher Item ID: S2589-5370(21)00329-1 Publisher ID: 101049

DOI: 10.1016/j.eclinm.2021.101049

PMC ID: 8365433

PubMed ID: 34430834

SO-VID: b66d4f20-9b7a-4351-a9c3-e8b16240d4fd

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 17 March 2021

Date revision received : 30 June 2021

Date accepted : 13 July 2021

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Parental Bacillus Calmette-Guérin vaccine scars decrease infant mortality in the first six weeks of life: A retrospective cohort study

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Abstract

Background

Methods

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Funding

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Malaria vaccine development

Most cited references 37

Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies

Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.

BCG-induced trained immunity in NK cells: Role for non-specific protection to infection.

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Cited by 13

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