Effects of BCG on Immune Response
Condition: Sepsis
MeSH terms: Sepsis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      In the present study, we want to investigate whether BCG-vaccination enhances the innate
      immune response in humans in vivo during (single) human endotoxemia.

      In a future experiment we will investigate whether BCG-vaccination can reverse the tolerant
      state observed upon a second LPS administration.

      Our goal is to ultimately translate our results into clinic applications to reverse for
      example sepsis-induced immunoparalysis.
    

Detailed description: 
      Sepsis is a major medical challenge associated with a high mortality rate. Release of
      pro-inflammatory mediators can result in hemodynamic instability, coagulation abnormalities
      and end-organ dysfunction. Previous strategies have aimed to treat sepsis by inhibition of
      pro-inflammatory mediators, however, most of these approaches have failed. This might be due
      to the fact that the majority of septic patients do not succumb to the initial
      pro-inflammatory "hit", but die at a later time-point in a pronounced immunosuppressive
      state. This so-called 'immunoparalysis', which renders patients extremely vulnerable to
      secondary infections, results from the triggering of counter-regulatory anti-inflammatory
      pathways along with the pro-inflammatory response, already starting in the beginning of
      sepsis. Immunoparalysis is increasingly being recognized as the overriding immune dysfunction
      during sepsis. As a consequence, reconstitution of immunocompetence is now emerging as a new
      and promising therapeutic target to improve outcome in sepsis patients.

      Bacille Calmette-Guérin (BCG) is one of the most commonly administered vaccines worldwide. In
      addition to protection against tuberculosis, evidence suggests that BCG immunization has a
      number of additional beneficial non-specific immunological effects, hereby protecting against
      infections with pathogens other than tuberculosis. The underlying immunologic mechanisms are
      not fully elucidated. Recently it was demonstrated that monocytes can be functionally
      reprogrammed to an enhanced and lasting phenotype after vaccination with BCG. Production of
      pro-inflammatory cytokines by monocytes isolated from volunteers after BCG vaccination, was
      found to be enhanced upon ex vivo stimulation with non-related pathogens, even months after
      BCG vaccination. The observed effects are proposed to be due to modulation of the innate
      immune system in a process called 'trained immunity'. Upon stimulation with a pathogen, the
      innate immune system becomes primed and is able to react faster and more efficient to a
      secondary (and non-related) stimulus, even months later. Monocyte "training" was shown to
      rely on epigenetic reprogramming, namely increased methylation of histone 3 at lysine 4
      (H3K4me3) at the level of cytokine and TLR4 gene promoter regions.

      Considering these potentiating effects of BCG on innate host defense, it could be a viable
      treatment option for sepsis-induced immunoparalysis. However, the effects of BCG vaccination
      on the innate immune response in humans have hitherto only been shown ex vivo. It has yet to
      be established whether these findings can be extrapolated to the human in vivo situation,
      because previous data from our group indicates that ex vivo measurements do not accurately
      reflect the in vivo situation. The human endotoxemia model, in which healthy volunteers
      receive lipopolysaccharide (LPS) derived from Escherichia coli, is widely used to study the
      effects of systemic inflammation in humans in vivo and is considered a safe and highly
      reproducible method to investigate the innate immune response. Furthermore, LPS
      administration results in a hyporesponsive state towards a second LPS administration called
      "endotoxin tolerance", which resembles sepsis-induced immunoparalysis, and can thus be used
      as a model to investigate therapeutic interventions to reverse this condition.

      The intended target group for this novel therapy, sepsis patients, are immunocompromised.
      Therefore, use of a live attenuated vaccine such as BCG could present a risk of disseminated
      mycobacterial infection. Therefore, we will use γ-irradiated (inactivated) BCG vaccine in
      this study. Recent, yet unpublished results of the group of Prof. Netea have shown that the
      effects of γ-irradiated BCG on monocyte training are comparable to those of the live vaccine.
      Furthermore, a study by the group of Prof. Netea (CMO 2013/319) with this type and dose of
      γ-irradiated BCG in healthy volunteers to study ex vivo responses has been previously
      approved by the ethics committee.

      Study design:

      A randomized double-blind placebo-controlled pilot study in healthy human volunteers during
      experimental endotoxemia.

      In this pilot study, we will enrol 20 subjects. On day 1, 10 subjects will receive
      γ-irradiated BCG-vaccination and 10 subjects will receive placebo. On day 6, all subjects
      will undergo experimental endotoxemia.
    

Intervention name(s): BCG vaccine; Lipopolysaccharide (LPS) E. Coli 1 ng/kg intravenously
Intervention type(s): Biological; Biological
Other intervention name(s): BCG vaccine SSI; Bacille Calmette-Guérin; RVG 17661; Lipopolysaccharide; LPS; Endotoxin derived from E. Coli
Intervention MeSH terms: Vaccines; BCG Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: BCG vaccine; Sepsis; Immunity