Development of BCG Scar and Subsequent Morbidity and Mortality in Rural Guinea-Bissau

Storgaard, Line Margrethe Hust; Rodrigues, Amabélia; Martins, Cesário; Nielsen, Bent; Ravn, Henrik; Benn, Christine Stabell; Aaby, Péter; Fisker, Ane Bærent

doi:10.1093/cid/civ452

Cited by 58 publications

(55 citation statements)

References 27 publications

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“…This highlights the needs of systematic HIV screening during pregnancy and access to early ART for infected children. The trend of lower mortality among children without BCG scar is consistent with previous studies reporting non-specific effects of BCG vaccination beyond the protecting effect against tuberculosis, that could be explained by the epigenetic modulations in monocytes and increased responsiveness against unrelated stimuli 17,18 . Comparative mortality data for the group of non-treated children admitted for presumptive TB are very scarce.…”

Section: A C C E P T E Dsupporting

confidence: 91%

Outcome of Children With Presumptive Tuberculosis in Mbarara, Rural Uganda

Bonnet¹,

Nansumba

Bastard³

et al. 2018

Pediatric Infectious Disease Journal

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Section: A C C E P T E Dsupporting

confidence: 91%

Outcome of Children With Presumptive Tuberculosis in Mbarara, Rural Uganda

Bonnet¹,

Nansumba

Bastard³

et al. 2018

Pediatric Infectious Disease Journal

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“…In our RCT of OPV0+BCG versus BCG only, the effect on infant mortality was particularly strong when OPV0 was given in the first days of life 10. Studies of BCG have likewise indicated that the beneficial effect is particularly good when administered early 32. Although the effect in the present analysis is different since it is generated by a subsequent early MV, it does suggest that OPV0 is capable of inducing strong immune training.…”

Section: Discussioncontrasting

confidence: 44%

Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine

et al. 2016

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BackgroundBCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV).MethodsDuring an RCT of 2 doses of MV at 4.5 and 9 months versus 1 dose of MV at 9 months of age, we experienced 2 natural experiments with OPV. We assessed whether these OPV experiments modified the effect of 2-dose MV in the MV trial.SettingMV RCT conducted in urban Guinea-Bissau 2003–2009.InterventionsNatural experiments with OPV due to missing vaccine and the implementation of OPV campaigns.Main outcome measureChanges in the mortality rate ratio (MRR) for 2-dose MV versus 1-dose MV.ResultsFirst, the MRR (2-dose/1-dose MV) overall was 0.70 (0.52 to 0.94), but the MRR was 1.04 (0.53 to 2.04) when OPV at birth (OPV0) was not given, suggesting that early priming with OPV was important for the effect of 2-dose MV. The effect of OPV0 depended on age of administration; the MRR (2-dose/1-dose MV) was 0.45 (0.29 to 0.71) for children receiving OPV0 in the first week of life, but 3.63 (0.87 to 15.2) for those receiving OPV0 after the first month of life (p=0.007, test of no interaction). Second, campaign-OPV may have reduced the difference between the randomisation groups since the MRR (2-dose/1-dose MV) was 0.60 (0.42 to 0.85) for children who had not received campaign-OPV before RCT-enrolment versus 0.72 (0.23 to 2.31) and 1.42 (0.70 to 2.90) for children who had received 1 or 2 doses of campaign-OPV-before-enrolment, respectively.ConclusionsBissau had no polio infection during this trial, so OPV0 and campaign-OPV may have NSEs since they modified the effect of 2-dose MV in an RCT. Different interventions may interact to a much larger effect than usually assumed.

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“…BCG scarring has been correlated with heterologous protective effects. A recent prospective study in rural Guinea-Bissau showed that children vaccinated with the BCG Moscow strain (also known as BCG Russia) who developed a scar had 26% lower mortality compared to children who did not develop a scar, mainly attributable to prevention of deaths from respiratory infections (mortality rate ratio [MRR] 0.2) (Storgaard et al, 2015). This correlation of BCG scarring and improved survival has been replicated over different time periods and with different BCG strains; however, scarification rates differ by BCG formulation.…”

Section: Examples Of Trained Immunity In Human Cohorts and Mechanistimentioning

confidence: 99%

“…However, the extent, mechanism and ontogeny of trained immunity in early life remain incompletely defined. Understanding how BCG-induced innate immune engagement, including BCG-induced enhancement of Th-polarizing cytokine production by antigen-presenting cells, varies by BCG strain and age is of basic and translational importance (Arts et al, 2015;Storgaard et al, 2015).…”

Section: Examples Of Trained Immunity In Human Cohorts and Mechanistimentioning

confidence: 99%

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

et al. 2020

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Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-Guérin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (∼50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces "heterologous" protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed "trained immunity." In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TBspecific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCG's innate immune activation, suggesting that aspects of BCG's effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines.

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Development of BCG Scar and Subsequent Morbidity and Mortality in Rural Guinea-Bissau

Abstract: Among BCG-vaccinated children in a setting with low scar prevalence, having a scar is associated with lower mortality and morbidity. BCG scar prevalence may be an important marker of vaccination program quality.

Cited by 58 publications

References 27 publications

Outcome of Children With Presumptive Tuberculosis in Mbarara, Rural Uganda

Outcome of Children With Presumptive Tuberculosis in Mbarara, Rural Uganda

Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

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