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Volume 3 Supplement 1

ESICM LIVES 2015

Gamma-irradiated bacille calmette-guÉrin vaccination does not modulate the innate immune response during experimental human endotoxemia

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Introduction

Recent insights in sepsis pathology have led to the view that not the initial hyperinflammatory state, but rather a profoundly suppressed state of the immune system, also called immunoparalysis, accounts for the majority of sepsis-related deaths. Therefore, reconstitution of immunocompetence in sepsis is emerging as a promising therapeutic target to improve outcome. Bacille Calmette-Guérin (BCG) vaccine not only protects against tuberculosis, but exerts beneficial effects on other infectious diseases as well. These non-specific effects of BCG seem to be mediated by potentiation of adaptive immunity through heterologous effects, as well as epigenetic functional reprogramming of innate immune cells to an enhanced phenotype, a process described as 'trained immunity', which has been shown in vitro, ex vivo, and in animal models. Therefore, BCG-vaccination could represent a novel therapeutic option to treat sepsis-induced immunoparalysis, although its immunomodulatory effects in humans in vivo have not yet been investigated. Furthermore, the live BCG vaccine presents a potential risk of disseminated disease in immunoparalyzed patients, which can be circumvented by inactivating the vaccine through gamma-irradiation.

Objectives

To determine the effects of gamma-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia. Also, to determine the effects of gamma-irradiated BCG-vaccination on ex vivo responsiveness of leukocytes to various inflammatory stimuli.

Methods

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.

Results

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 neither modulated this in vivo immune response (Figure 1), nor ex vivo leukocyte responses at any time-point (Figure 2).

Figure 1
figure1

In the panels A and B, median values of pro-inflammatory cytokines TNF-α and Il-6 are depicted while in panel C median values of the anti-inflammatory cytokine IL-10 is shown (n = 10 per group). Panels D-F 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 2
figure2

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.

Conclusions

Gamma-irradiated BCG does not modulate the innate immune response in vivo in humans and is therefore unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis.

Grant Acknowledgment

M.G.N. was supported by a Vici grant of the Netherlands Organization for Scientific Research and an ERC Consolidator Grant (#310372).

Author information

Correspondence to LAC Hamers.

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Hamers, L., Kox, M., Arts, R. et al. Gamma-irradiated bacille calmette-guÉrin vaccination does not modulate the innate immune response during experimental human endotoxemia. ICMx 3, A419 (2015) doi:10.1186/2197-425X-3-S1-A419

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Keywords

  • Innate Immune Response
  • Innate Immune Cell
  • Promising Therapeutic Target
  • Grant Acknowledgment
  • Human Endotoxemia