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Journal Article•DOI•

Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

Sofie Biering-Sørensen1, Peter Aaby, Najaaraq Lund1, Ivan Monteiro, Kristoffer Jarlov Jensen2, Kristoffer Jarlov Jensen1, Helle Brander Eriksen1, Frederik Schaltz-Buchholzer, Anne Sofie Pinstrup Jørgensen, Amabelia Rodrigues, Ane Bærent Fisker1, Christine Stabell Benn1 •
Statens Serum Institut1, Technical University of Denmark2
01 Oct 2017-Clinical Infectious Diseases (Oxford University Press)-Vol. 65, Iss: 7, pp 1183-1190
TL;DR: It is found that early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate.
Abstract: Background BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months. Conclusion Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration NCT00625482.

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Citations
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Journal Article•DOI•
Defining trained immunity and its role in health and disease

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Mihai G. Netea1, Mihai G. Netea2, Jorge Domínguez-Andrés1, Luis B. Barreiro3, Luis B. Barreiro4, Triantafyllos Chavakis5, Triantafyllos Chavakis6, Maziar Divangahi7, Maziar Divangahi8, Elaine Fuchs9, Leo A. B. Joosten1, Jos W. M. van der Meer1, Musa M. Mhlanga10, Musa M. Mhlanga11, Willem J. M. Mulder12, Willem J. M. Mulder13, Niels P. Riksen1, Andreas Schlitzer2, Joachim L. Schultze2, Christine Stabell Benn14, Joseph C. Sun15, Joseph C. Sun16, Ramnik J. Xavier17, Ramnik J. Xavier18, Eicke Latz19, Eicke Latz2, Eicke Latz20 •
Radboud University Nijmegen1, University of Bonn2, University of Chicago3, Université de Montréal4, University of Edinburgh5, Dresden University of Technology6, McGill University7, McGill University Health Centre8, Rockefeller University9, University of Cape Town10, Instituto de Medicina Molecular11, Eindhoven University of Technology12, Icahn School of Medicine at Mount Sinai13, University of Southern Denmark14, Memorial Sloan Kettering Cancer Center15, Cornell University16, Broad Institute17, Harvard University18, German Center for Neurodegenerative Diseases19, University of Massachusetts Medical School20
04 Mar 2020-Nature Reviews Immunology
TL;DR: A group of leaders in the field define ‘trained immunity’ as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.
Abstract: Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.

1,116 citations

Journal Article•DOI•
Obesity could shift severe COVID-19 disease to younger ages.

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David A. Kass1, Priya Duggal2, Oscar H. Cingolani1•
Johns Hopkins University School of Medicine1, Johns Hopkins University2
16 May 2020-The Lancet

358 citations

Journal Article•DOI•
Non-specific effects of BCG vaccine on viral infections

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Simone J.C.F.M. Moorlag1, Rob J.W. Arts1, R. van Crevel1, Mihai G. Netea1, Mihai G. Netea2 •
Radboud University Nijmegen1, University of Bonn2
01 Dec 2019-Clinical Microbiology and Infection
TL;DR: Evidence for non-specific protection induced by BCG vaccination against viral infections, possible mechanisms of action, and implications for vaccination policies and vaccine discovery are reviewed.

340 citations

Journal Article•DOI•
Considering BCG vaccination to reduce the impact of COVID-19.

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Nigel Curtis1, Nigel Curtis2, Annie Sparrow3, Tedros Adhanom Ghebreyesus, Mihai G. Netea4, Mihai G. Netea5 •
Royal Children's Hospital1, University of Melbourne2, Icahn School of Medicine at Mount Sinai3, Radboud University Nijmegen4, University of Bonn5
16 May 2020-The Lancet

279 citations

Journal Article•DOI•
BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment

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Branko Cirovic1, L. Charlotte J. de Bree2, L. Charlotte J. de Bree3, L. Charlotte J. de Bree4, Laszlo Groh3, Bas A. Blok2, Bas A. Blok4, Bas A. Blok3, Joyce Chan5, Walter J.F.M. van der Velden6, Manita E J Bremmers6, Reinout van Crevel3, Kristian Händler7, Simone Picelli7, Jonas Schulte-Schrepping1, Kathrin Klee1, Marije Oosting3, Valerie A. C. M. Koeken3, Jakko van Ingen6, Yang Li8, Yang Li3, Christine Stabell Benn2, Christine Stabell Benn4, Joachim L. Schultze1, Joachim L. Schultze7, Leo A. B. Joosten3, Nigel Curtis5, Mihai G. Netea3, Mihai G. Netea1, Andreas Schlitzer7, Andreas Schlitzer1 •
University of Bonn1, Statens Serum Institut2, Radboud University Nijmegen Medical Centre3, University of Southern Denmark4, Royal Children's Hospital5, Radboud University Nijmegen6, German Center for Neurodegenerative Diseases7, Hannover Medical School8
12 Aug 2020-Cell Host & Microbe
TL;DR: It is shown that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow.

218 citations

Cites background from "Early BCG-Denmark and Neonatal Mort..."

  • ...Among these vaccines, BCG has been shown to reduce neonatal mortality by 38% (17%–54%) in high infectious pressure environments (Aaby et al., 2011; Biering-Sørensen et al., 2017)....

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  • ...Epidemiological studies have shown that many vaccines, especially those employing attenuated live microorganisms, such as Bacille Calmette-Guérin (BCG), measles, or oral polio vaccine, lead to a decrease in overall childhood mortality that cannot be solely attributed to protection against the target disease alone (Aaby et al., 2011; Benn et al., 2013; Biering-Sørensen et al., 2017)....

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  • ...These effects on HSPCs are accompanied by a clinically relevant and significant increase in the number of neutrophils in infants vaccinated with BCG, constituting a part of the functional basis for the non-specific clinical effects of BCG vaccination (Biering-Sørensen et al., 2017; Zimmermann et al., 2018)....

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  • ...First, the demonstration of these effects of BCG vaccination in vivo at the level of human BM-resident HSPC provides the mechanistic explanation for the persistent effects of BCG vaccination on circulating innate immune cells and for themany epidemiological observations of beneficial non-specific effects of BCG years after vaccination (Biering-Sørensen et al., 2017; Rieckmann et al., 2017; Villumsen et al., 2009; Zimmermann et al., 2018)....

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References
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Journal Article•DOI•
New Ballard Score, expanded to include extremely premature infants.

[...]

Jeanne L. Ballard1, J. C. Khoury, K. Wedig, L. Wang, B. L. Eilers-Walsman, R. Lipp •
University of Cincinnati Academic Health Center1
01 Sep 1991-The Journal of Pediatrics
TL;DR: The Ballard Maturational Score was refined and expanded to achieve greater accuracy and to include extremely premature neonates and remains valid for the entire newborn infant population.

1,784 citations

"Early BCG-Denmark and Neonatal Mort..." refers methods in this paper

  • ...The infants enrolled at the national hospital were examined by a physician or a neonatal nurse, and Ballard score was used to assess gestational age [14]....

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Journal Article•DOI•
Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes

[...]

Johanneke Kleinnijenhuis1, Jessica Quintin, Frank Preijers1, Leo A. B. Joosten, Daniela C. Ifrim, Sadia Saeed2, Cor Jacobs, Joke van Loenhout, Dirk J. de Jong1, Hendrik G. Stunnenberg2, Ramnik J. Xavier3, Ramnik J. Xavier4, Jos W. M. van der Meer, Reinout van Crevel, Mihai G. Netea •
Radboud University Nijmegen Medical Centre1, Radboud University Nijmegen2, Harvard University3, Massachusetts Institute of Technology4
23 Oct 2012-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: It is shown that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led 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.
Abstract: 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-Guerin (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.

1,178 citations

Additional excerpts

  • ...Consistent with this, BCG vaccination of BCG-naive Dutch adults was found to increase innate immune responses to heterologous pathogens [31]....

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Journal Article•DOI•
Trained Immunity: A Memory for Innate Host Defense

[...]

Mihai G. Netea1, Jessica Quintin1, Jos W. M. van der Meer1•
Radboud University Nijmegen1
19 May 2011-Cell Host & Microbe
TL;DR: Understanding trained immunity will revolutionize the view of host defense and immunological memory, and could lead to defining a new class of vaccines and immunotherapies.

1,077 citations

"Early BCG-Denmark and Neonatal Mort..." refers background in this paper

  • ...BCG induced epigenetic reprogramming of monocytes, a phenomenon termed “trained innate immunity” [32]....

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Journal Article•DOI•
Genome plasticity of BCG and impact on vaccine efficacy.

[...]

Roland Brosch1, Stephen V. Gordon, Thierry Garnier, Karin Eiglmeier, Wafa Frigui, Philippe Valenti, Sandrine Dos Santos, Stephanie Duthoy, Céline Lacroix, Carmen Garcia-Pelayo, Jacqueline Inwald, Paul Golby, Javier Nunez Garcia, R. Glyn Hewinson, Marcel A. Behr, Michael A. Quail, Carol Churcher, Bart Barrell, Julian Parkhill, Stewart T. Cole •
Pasteur Institute1
27 Mar 2007-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: The combined findings suggest that early BCG vaccines may even be superior to the later ones that are more widely used, and that further amplification of the DU2 region is ongoing, even within vaccine preparations used to immunize humans.
Abstract: To understand the evolution, attenuation, and variable protective efficacy of bacillus Calmette-Guerin (BCG) vaccines, Mycobacterium bovis BCG Pasteur 1173P2 has been subjected to comparative genome and transcriptome analysis. The 4,374,522-bp genome contains 3,954 protein-coding genes, 58 of which are present in two copies as a result of two independent tandem duplications, DU1 and DU2. DU1 is restricted to BCG Pasteur, although four forms of DU2 exist; DU2-I is confined to early BCG vaccines, like BCG Japan, whereas DU2-III and DU2-IV occur in the late vaccines. The glycerol-3-phosphate dehydrogenase gene, glpD2, is one of only three genes common to all four DU2 variants, implying that BCG requires higher levels of this enzyme to grow on glycerol. Further amplification of the DU2 region is ongoing, even within vaccine preparations used to immunize humans. An evolutionary scheme for BCG vaccines was established by analyzing DU2 and other markers. Lesions in genes encoding sigma-factors and pleiotropic transcriptional regulators, like PhoR and Crp, were also uncovered in various BCG strains; together with gene amplification, these affect gene expression levels, immunogenicity, and, possibly, protection against tuberculosis. Furthermore, the combined findings suggest that early BCG vaccines may even be superior to the later ones that are more widely used.

545 citations

"Early BCG-Denmark and Neonatal Mort..." refers background in this paper

  • ...The BCG vaccine exists in several strains [17], with differences in immunogenicity [18–21] and genetics [20, 22]....

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Journal Article•DOI•
Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?

[...]

Peter Aaby1, Adam Roth2, Adam Roth3, Henrik Ravn3, Bitiguida Mutna Napirna, Amabelia Rodrigues1, Ida Maria Lisse, Lone Graff Stensballe3, Birgitte Rode Diness1, Karen Rokkedal Lausch1, Najaaraq Lund1, Sofie Biering-Sørensen1, Hilton Whittle, Christine Stabell Benn3, Christine Stabell Benn1 •
Bandim Health Project1, Lund University2, Statens Serum Institut3
15 Jul 2011-The Journal of Infectious Diseases
TL;DR: Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period, which could be important for public health because BCG is often delayed in low-income countries.
Abstract: Background. Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. Methods. In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. Results. Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. Conclusions. Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries. (Less)

476 citations

"Early BCG-Denmark and Neonatal Mort..." refers background or methods in this paper

  • ...We conducted a small RCT among infants receiving their first vaccination at the health centers from 2002 to 2004 (trial I) and a larger, mainly hospital-based, RCT from 2004 to 2008 (trial II) [7, 8]....

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  • ...20% in the control group in trial II [7]....

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  • ...Because the effect of BCG vaccine on neonatal mortality rates was smaller than hypothesized, we made explorative analyses of factors that could have affected the measured effect of BCG vaccination in the present and the previous trial [7] (Appendix 1)....

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  • ...These nonspecific effects have recently been confirmed in randomized controlled trials (RCTs) [7, 8]....

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  • ...When the mortality analyses of trial II were completed, they showed major reductions in neonatal mortality rates in both sexes [7]....

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