EDITORIAL COMMENTARY
BCG Modulates Neonatal Innate Immune Cytokine Production Tobias R. Kollmann Global Pediatric Infectious Disease Training Program (GpID)
(See the major article by Jensen et al on pages 956–67.)
Received 4 September 2014; accepted 5 September 2014; electronically published 9 September 2014. Correspondence: Tobias R. Kollmann, MD, Division of Infectious Disease, Department of Pediatrics, UBC, CFRI A5-147, 950 W 28th Ave, Vancouver, BC V5Z4H4, Canada ([email protected]). The Journal of Infectious Diseases® 2015;211:859–60 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu509
data in support of bacillus CalmetteGuérin (BCG) being such a highly effective, cheap, and easy to sustain solution to tackle neonatal infection. Jensen et al identify that neonatal administration of BCG can induce an altered cytokine response in LBW newborns of GuineaBissau. More specifically, they show that BCG alters the cytokine response to antigen-specific but also to nonspecific stimuli as well as at baseline, that is, in unstimulated samples. These data expand on this group’s previous finding that innate immune cytokine production in blood correlates with neonatal survival [4]. They now show that the type of innate cytokine change induced by neonatal BCG immunization could be expected to support enhanced Th-1 helper cell differentiation and/or be generally proinflammatory; and they conclude that a BCG-mediated “accelerated development of the neonatal innate immune system” may be partially responsible for the comprehensive protection against infectious mortality they had previously noted following neonatal BCG vaccination in Guinea-Bissau [5–7]. All live vaccines studied so far have been shown to reduce mortality more than can be explained by prevention of the targeted infection [8]. More specifically, the protective effect of BCG on neonatal survival, which has now been observed in several randomised trials in LBW infants, cannot be explained by reduction of the risk for infection with Mycobacterium tuberculosis
or active tuberculosis [5–7] but is instead believed to be due to nonspecific (ie, not only targeting M. tuberculosis) immunomodulation by BCG [8]. The topic is very timely given the recent World Health Organization’s (WHO) acknowledgement of nonspecific effects of vaccines and the WHO’s urgent call for more research on this topic to identify the underlying mechanisms [9]. With respect to mechanisms, the findings presented by Jensen et al are in agreement with data obtained in adults indicating prolonged alteration of innate immunity following BCG administration [10, 11], a novel concept summarized under the term “innate immune memory” [12, 13]. The Jensen et al article is, however, the first time that a change of innate immune status following BCG has been documented in the neonatal age group, in which the protective effect of BCG on mortality had previously been identified. This article thus adds a key piece of information to this highly relevant field. Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Lawn JE, Blencowe H, Oza S, et al. Every newborn: Progress, priorities, and potential beyond survival. Lancet 2014; 384:189–205.
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JID 2015:211 (15 March)
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Downloaded from http://jid.oxfordjournals.org/ at University of California, San Francisco on April 26, 2015
Infection causes 0.6 million of the total 2.9 million neonatal deaths every year and devastates the lives of millions more who initially survive; it mercilessly seeks out those weakened by premature delivery and/or low birth weight (LBW), an unfortunate combination too frequently encountered all over the world but particularly so in low-income countries [1]. Reduction of neonatal mortality over the last decade has been slower than that for maternal and child mortality but slowest in the highest burden countries of Africa [2]. Given the scale and the scope of this problem, any intervention even remotely effective would save millions of lives as well as billions of dollars; but given the uneven global distribution, with neonatal infections most severely affecting the poorest regions of the world, such intervention has to be cheap to initiate and easy to sustain [3]. The article “Heterologous immunological effects of early BCG vaccination in low-birth weight infants in Guinea-Bissau: A randomized-controlled trial” by Jensen et al in this issue of the Journal presents
2. Darmstadt GL, Kinney MV, Chopra M, et al. Who has been caring for the baby? Lancet 2014; 384:174–88. 3. Bhutta ZA, Black RE. Global maternal, newborn, and child health—so near and yet so far. N Engl J Med 2013; 369:2226–35. 4. Andersen A, Jensen KJ, Erikstrup C, et al. Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea-Bissau. PLoS One 2014; 9:e93562. 5. Roth A, Jensen H, Garly ML, et al. Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: Community study from Guinea-Bissau. Pediatr Infect Dis J 2004; 23:544–50. 6. Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-
7.
8.
9.
10.
birth-weight children: Beneficial nonspecific effects in the neonatal period? J Infect Dis 2011; 204:245–52. Biering-Sørensen S, Aaby P, Napirna BM, et al. Small randomized trial among lowbirth-weight children receiving bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J 2012; 31:306–8. Benn CS, Netea MG, Selin LK, Aaby P. A small jab—a big effect: Nonspecific immunomodulation by vaccines. Trends Immunol 2013; 34:431–9. WHO/SAGE, Meeting of the Strategic Advisory Group of Experts on immunization, April 2014—Conclusions and recommendations. Wkly Epidemiol Rec 2014; 89:221–36. Kleinnijenhuis J, Quintin J, Preijers F, et al. Long-lasting effects of BCG vaccination on
both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 2014; 6:152–8. 11. Kleinnijenhuis J, Quintin J, Preijers F, et al. Bacille Calmette-Guerin induces NOD2dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 2012; 109:17537–42. 12. Quintin J, Cheng SC, van der Meer JW, Netea MG. Innate immune memory: Towards a better understanding of host defense mechanisms. Curr Opin Immunol 2014; 29c:1–7. 13. Levy O, Netea MG. Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines. Pediatr Res 2014; 75:184–8.
Downloaded from http://jid.oxfordjournals.org/ at University of California, San Francisco on April 26, 2015
860
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JID 2015:211 (15 March)
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EDITORIAL COMMENTARY
BCG Modulates Neonatal Innate Immune Cytokine Production Tobias R. Kollmann Global Pediatric Infectious Disease Training Program (GpID)
(See the major article by Jensen et al on pages 956–67.)
Received 4 September 2014; accepted 5 September 2014; electronically published 9 September 2014. Correspondence: Tobias R. Kollmann, MD, Division of Infectious Disease, Department of Pediatrics, UBC, CFRI A5-147, 950 W 28th Ave, Vancouver, BC V5Z4H4, Canada ([email protected]). The Journal of Infectious Diseases® 2015;211:859–60 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiu509
data in support of bacillus CalmetteGuérin (BCG) being such a highly effective, cheap, and easy to sustain solution to tackle neonatal infection. Jensen et al identify that neonatal administration of BCG can induce an altered cytokine response in LBW newborns of GuineaBissau. More specifically, they show that BCG alters the cytokine response to antigen-specific but also to nonspecific stimuli as well as at baseline, that is, in unstimulated samples. These data expand on this group’s previous finding that innate immune cytokine production in blood correlates with neonatal survival [4]. They now show that the type of innate cytokine change induced by neonatal BCG immunization could be expected to support enhanced Th-1 helper cell differentiation and/or be generally proinflammatory; and they conclude that a BCG-mediated “accelerated development of the neonatal innate immune system” may be partially responsible for the comprehensive protection against infectious mortality they had previously noted following neonatal BCG vaccination in Guinea-Bissau [5–7]. All live vaccines studied so far have been shown to reduce mortality more than can be explained by prevention of the targeted infection [8]. More specifically, the protective effect of BCG on neonatal survival, which has now been observed in several randomised trials in LBW infants, cannot be explained by reduction of the risk for infection with Mycobacterium tuberculosis
or active tuberculosis [5–7] but is instead believed to be due to nonspecific (ie, not only targeting M. tuberculosis) immunomodulation by BCG [8]. The topic is very timely given the recent World Health Organization’s (WHO) acknowledgement of nonspecific effects of vaccines and the WHO’s urgent call for more research on this topic to identify the underlying mechanisms [9]. With respect to mechanisms, the findings presented by Jensen et al are in agreement with data obtained in adults indicating prolonged alteration of innate immunity following BCG administration [10, 11], a novel concept summarized under the term “innate immune memory” [12, 13]. The Jensen et al article is, however, the first time that a change of innate immune status following BCG has been documented in the neonatal age group, in which the protective effect of BCG on mortality had previously been identified. This article thus adds a key piece of information to this highly relevant field. Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Lawn JE, Blencowe H, Oza S, et al. Every newborn: Progress, priorities, and potential beyond survival. Lancet 2014; 384:189–205.
EDITORIAL COMMENTARY
•
JID 2015:211 (15 March)
•
859
Downloaded from http://jid.oxfordjournals.org/ at University of California, San Francisco on April 26, 2015
Infection causes 0.6 million of the total 2.9 million neonatal deaths every year and devastates the lives of millions more who initially survive; it mercilessly seeks out those weakened by premature delivery and/or low birth weight (LBW), an unfortunate combination too frequently encountered all over the world but particularly so in low-income countries [1]. Reduction of neonatal mortality over the last decade has been slower than that for maternal and child mortality but slowest in the highest burden countries of Africa [2]. Given the scale and the scope of this problem, any intervention even remotely effective would save millions of lives as well as billions of dollars; but given the uneven global distribution, with neonatal infections most severely affecting the poorest regions of the world, such intervention has to be cheap to initiate and easy to sustain [3]. The article “Heterologous immunological effects of early BCG vaccination in low-birth weight infants in Guinea-Bissau: A randomized-controlled trial” by Jensen et al in this issue of the Journal presents
2. Darmstadt GL, Kinney MV, Chopra M, et al. Who has been caring for the baby? Lancet 2014; 384:174–88. 3. Bhutta ZA, Black RE. Global maternal, newborn, and child health—so near and yet so far. N Engl J Med 2013; 369:2226–35. 4. Andersen A, Jensen KJ, Erikstrup C, et al. Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea-Bissau. PLoS One 2014; 9:e93562. 5. Roth A, Jensen H, Garly ML, et al. Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: Community study from Guinea-Bissau. Pediatr Infect Dis J 2004; 23:544–50. 6. Aaby P, Roth A, Ravn H, et al. Randomized trial of BCG vaccination at birth to low-
7.
8.
9.
10.
birth-weight children: Beneficial nonspecific effects in the neonatal period? J Infect Dis 2011; 204:245–52. Biering-Sørensen S, Aaby P, Napirna BM, et al. Small randomized trial among lowbirth-weight children receiving bacillus Calmette-Guerin vaccination at first health center contact. Pediatr Infect Dis J 2012; 31:306–8. Benn CS, Netea MG, Selin LK, Aaby P. A small jab—a big effect: Nonspecific immunomodulation by vaccines. Trends Immunol 2013; 34:431–9. WHO/SAGE, Meeting of the Strategic Advisory Group of Experts on immunization, April 2014—Conclusions and recommendations. Wkly Epidemiol Rec 2014; 89:221–36. Kleinnijenhuis J, Quintin J, Preijers F, et al. Long-lasting effects of BCG vaccination on
both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 2014; 6:152–8. 11. Kleinnijenhuis J, Quintin J, Preijers F, et al. Bacille Calmette-Guerin induces NOD2dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 2012; 109:17537–42. 12. Quintin J, Cheng SC, van der Meer JW, Netea MG. Innate immune memory: Towards a better understanding of host defense mechanisms. Curr Opin Immunol 2014; 29c:1–7. 13. Levy O, Netea MG. Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines. Pediatr Res 2014; 75:184–8.
Downloaded from http://jid.oxfordjournals.org/ at University of California, San Francisco on April 26, 2015
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JID 2015:211 (15 March)
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EDITORIAL COMMENTARY
