Gamma-irradiated bacille Calmette-Guérin vaccination does not modulate the innate immune response during experimental human endotoxemia in adult males

Linda A C Hamers, Matthijs Kox, Rob J W Arts, Bastiaan Blok, Jenneke Leentjens, Mihai G Netea, Peter Pickkers, Linda A C Hamers, Matthijs Kox, Rob J W Arts, Bastiaan Blok, Jenneke Leentjens, Mihai G Netea, Peter Pickkers

Abstract

Bacille Calmette-Guérin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humans in vivo during experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG (n = 10) or placebo (n = 10) and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess the in vivo immune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assess ex vivo immune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither this in vivo immune response, nor ex vivo leukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered with NCT02085590.

Figures

Figure 1
Figure 1
Experimental design. BCG: Bacille Calmette-Guérin; LPS: lipopolysaccharide.
Figure 2
Figure 2
Blood pressure, heart rate, and symptoms during experimental endotoxemia in subjects vaccinated with gamma-irradiated BCG or placebo. Data are expressed as mean ± SEM (n = 10 per group). P values calculated using repeated measures two-way analysis of variance (ANOVA, time and interaction terms). MAP: mean arterial pressure; HR: heart rate; bpm: beats/min.
Figure 3
Figure 3
Plasma cytokine concentrations in subjects vaccinated with gamma-irradiated BCG or placebo. In the panels (a–d), median values of proinflammatory cytokines TNF-α, IL-6, IL-8, and MCP-1 are depicted while in panels (e) and (f) median values of anti-inflammatory cytokines IL-10 and IL-1RA are shown (n = 10 per group). Panels (g–l) depict median ± interquartile range of area under curve (AUC) of the respective cytokines (n = 10 per group). P values calculated using Mann-Whitney U tests.
Figure 4
Figure 4
Production of IFN-gamma, TNF-α, and IL-1β by peripheral blood mononuclear cells stimulated ex vivo with Mycobacterium tuberculosis (MTB), LPS, Staphylococcus aureus (SA), and Candida albicans (CA) of subjects vaccinated with gamma-irradiated BCG or placebo. Data expressed as median and interquartile range of the fold change compared with day 1 (before vaccination) (n = 10 per group). P values calculated using repeated measures two-way analysis of variance (ANOVA, time and interaction terms) on log-transformed data. Day 6 was the endotoxemia experiment day.

References

    1. Boomer J. S., To K., Chang K. C., et al. Immunosuppression in patients who die of sepsis and multiple organ failure. The Journal of the American Medical Association. 2011;306(23):2594–2605. doi: 10.1001/jama.2011.1829.
    1. Hamers L., Kox M., Pickkers P. Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options. Minerva Anestesiologica. In press.
    1. Leentjens J., Kox M., van der Hoeven J. G., Netea M. G., Pickkers P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation time for a paradigm change? The American Journal of Respiratory and Critical Care Medicine. 2013;187(12):1287–1293. doi: 10.1164/rccm.201301-0036cp.
    1. Tulzo Y. L., Pangault C., Amiot L., et al. Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. American Journal of Respiratory and Critical Care Medicine. 2004;169(10):1144–1151. doi: 10.1164/rccm.200309-1329OC.
    1. Otto G. P., Sossdorf M., Claus R. A., et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Critical Care. 2011;15(4, article R183) doi: 10.1186/cc10332.
    1. Angus D. C., van der Poll T. Severe sepsis and septic shock. The New England Journal of Medicine. 2013;369(9):840–851. doi: 10.1056/nejmra1208623.
    1. Meisel C., Schefold J. C., Pschowski R., et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. American Journal of Respiratory and Critical Care Medicine. 2009;180(7):640–648. doi: 10.1164/rccm.200903-0363oc.
    1. Colditz G. A., Brewer T. F., Berkey C. S., et al. Efficacy of BCG vaccine in the prevention of tuberculosis: Meta-analysis of the published literature. The Journal of the American Medical Association. 1994;271(9):698–702. doi: 10.1001/jama.271.9.698.
    1. Levine M. I., Sackett M. F. Results of BCG immunization in New York City. The American Review of Tuberculosis. 1946;53:517–532.
    1. Rosenthal S. R., Loewinsohn E., Graham M. L., et al. BCG vaccination in tuberculous households. The American Review of Respiratory Disease. 1961;84:690–704.
    1. Breiman R. F., Streatfield P. K., Phelan M., Shifa N., Rashid M., Yunus M. Effect of infant immunisation on childhood mortality in rural Bangladesh: analysis of health and demographic surveillance data. The Lancet. 2004;364(9452):2204–2211. doi: 10.1016/s0140-6736(04)17593-4.
    1. Roth A., Jensen H., Garly M.-L., et al. Low birth weight infants and Calmette-Guérin bacillus vaccination at birth: community study from Guinea-Bissau. Pediatric Infectious Disease Journal. 2004;23(6):544–550. doi: 10.1097/01.inf.0000129693.81082.a0.
    1. Kristensen I., Aaby P., Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. British Medical Journal. 2000;321(7274):1435–1438. doi: 10.1136/bmj.321.7274.1435.
    1. Aaby P., Roth A., Ravn H., et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? The Journal of Infectious Diseases. 2011;204(2):245–252. doi: 10.1093/infdis/jir240.
    1. Biering-Sørensen S., Aaby P., Napirna B. M., et al. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guéerin vaccination at first health center contact. Pediatric Infectious Disease Journal. 2012;31(3):306–308. doi: 10.1097/INF.0b013e3182458289.
    1. Flanagan K. L., van Crevel R., Curtis N., Shann F., Levy O. Heterologous (‘nonspecific’) and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clinical Infectious Diseases. 2013;57(2):283–289. doi: 10.1093/cid/cit209.
    1. Kleinnijenhuis J., Quintin J., Preijers F., et al. Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(43):17537–17542. doi: 10.1073/pnas.1202870109.
    1. Netea M. G., van Crevel R. BCG-induced protection: effects on innate immune memory. Seminars in Immunology. 2014;26(6):512–517. doi: 10.1016/j.smim.2014.09.006.
    1. Quintin J., Cheng, S.-C., van der Meer J. W. M., Netea M. G. Innate immune memory: towards a better understanding of host defense mechanisms. Current Opinion in Immunology. 2014;29:1–7. doi: 10.1016/j.coi.2014.02.006.
    1. Saeed S., Quintin J., Kerstens H. H. D., et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204) doi: 10.1126/science.1251086.1251086
    1. Kleinnijenhuis J., Quintin J., Preijers F., et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. Journal of Innate Immunity. 2014;6(2):152–158. doi: 10.1159/000355628.
    1. Talbot E. A., Perkins M. D., Suva S. F. M., Frothingham R. Disseminated bacille Calmette-Guerin disease after vaccination: case report and review. Clinical Infectious Diseases. 1997;24(6):1139–1146. doi: 10.1086/513642.
    1. Dorresteijn M. J., Draisma A., van der Hoeven J. G., Pickkers P. Lipopolysaccharide-stimulated whole blood cytokine production does not predict the inflammatory response in human endotoxemia. Innate Immunity. 2010;16(4):248–253. doi: 10.1177/1753425909339923.
    1. Kox M., De Kleijn S., Pompe J. C., et al. Differential ex vivo and in vivo endotoxin tolerance kinetics following human endotoxemia. Critical Care Medicine. 2011;39(8):1866–1870. doi: 10.1097/CCM.0b013e3182190d5d.
    1. Bahador M., Cross A. S. Review: from therapy to experimental model: a hundred years of endotoxin administration to human subjects. Journal of Endotoxin Research. 2007;13(5):251–279. doi: 10.1177/0968051907085986.
    1. Kox M., van Eijk L. T., Zwaag J., et al. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(20):7379–7384. doi: 10.1073/pnas.1322174111.
    1. Jensen M. L., Dave S., van der Loeff M. S., et al. Vaccinia scars associated with improved survival among adults in rural Guinea-Bissau. PLoS ONE. 2006;1(1, article e101) doi: 10.1371/journal.pone.0000101.
    1. Roth A., Gustafson P., Nhaga A., et al. BCG vaccination scar associated with better childhood survival in Guinea-Bissau. International Journal of Epidemiology. 2005;34(3):540–547. doi: 10.1093/ije/dyh392.
    1. de Vos A. F., Pater J. M., van den Pangaart P. S., de Kruif M. D., van 't Veer C., van der Poll T. In vivo lipopolysaccharide exposure of human blood leukocytes induces cross-tolerance to multiple TLR ligands. Journal of Immunology. 2009;183(1):533–542. doi: 10.4049/jimmunol.0802189.
    1. Cox R. J., Brokstad K. A., Ogra P. Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines. Scandinavian Journal of Immunology. 2004;59(1):1–15. doi: 10.1111/j.0300-9475.2004.01382.x.
    1. Minassian A. M., Satti I., Poulton I. D., Meyer J., Hill A. V. S., McShane H. A human challenge model for Mycobacterium tuberculosis using Mycobacterium bovis bacille Calmette-Guérin. Journal of Infectious Diseases. 2012;205(7):1035–1042. doi: 10.1093/infdis/jis012.
    1. Sander L. E., Davis M. J., Boekschoten M. V., et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature. 2011;474(7351):385–392. doi: 10.1038/nature10072.
    1. van Eijk L. T., Dorresteijn M. J., Smits P., van der Hoeven J. G., Netea M. G., Pickkers P. Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers. Critical Care Medicine. 2007;35(6):1464–1469. doi: 10.1097/01.ccm.0000266534.14262.e8.
    1. Stensballe L. G., Nante E., Jensen I. P., et al. Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls: community based case-control study. Vaccine. 2005;23(10):1251–1257. doi: 10.1016/j.vaccine.2004.09.006.
    1. Aaby P., Jensen H., Rodrigues A., et al. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. International Journal of Epidemiology. 2004;33(2):367–373. doi: 10.1093/ije/dyh004.
    1. Murray C. J., Ortblad K. F., Guinovart C., et al. Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet. 2014;384(9947):1005–1070. doi: 10.1016/S0140-6736(14)60844-8.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren