The Effects of Preceding LPS Administration on the Fluenz-induced Immune Response
Condition: Innate Immune Response; Immune Tolerance
Study type: Interventional

Summary: 
      To evaluate the bacterial-viral interactions between LPS and Fluenz as a model for sepsis
      (bacterial) and Influenza (viral) infections which are common and associated with high
      mortality rates in the ICU. To understand these interactions is important for the development
      of preventive and therapeutic interventions.
    

Detailed description: 
      The Influenza virus is known for its severe course of infection and systemic effects,
      associated with high mortality rates. Recent work has shown that influenza promotes
      susceptibility for secondary bacterial infections, thereby worsening the prognosis. While it
      has become clear that bacterial infections induce an immunosuppressed state in which the
      immune response against viral infections is attenuated1, it is unknown how a bacterial
      infection, such as in sepsis, influences the susceptibility and immune response to influenza.
      The sepsis-induced immunosuppressive state, called "immunoparalysis", may be a major
      contributor to this increased vulnerability. Because of the high mortality rates of both
      sepsis and influenza, it is of main importance to understand this interaction for the
      development of putative preventive and therapeutic interventions in ICU patients.

      Human endotoxemia represents a model of systemic inflammation, mimicking bacterial sepsis and
      subsequent development of immunoparalysis. The live, attenuated, quadrivalent influenza
      vaccine "Fluenz™" is registered in the European Union and can be used as a surrogate for an
      actual influenza infection. In this study, we want to investigate the effects of an
      endotoxemia challenge on the Fluenz™-induced inflammatory response to present unique in vivo
      data on mechanistic interactions of systemic LPS followed by mucosal Fluenz™, thereby
      providing clues regarding the increased vulnerability towards viral infections in septic
      patients and open up new avenues to investigate therapeutic measures to prevent this.
      Furthermore, it provides important implications regarding the safety and efficacy of the
      vaccine in (post)septic or immunocompromised patients.

      Objective: Our primary objective is to investigate the effects of endotoxin-induced systemic
      inflammation and subsequent development of endotoxin tolerance on the inflammatory response
      following Fluenz administration in vivo. To evaluate whether these effects involve local
      and/or systemic inflammation, symptoms, temperature and peak expiratory flow will be
      measured. Next, local inflammatory parameters are measured in nasal wash and systemic
      inflammatory parameters are measured in blood. Furthermore, we want to evaluate whether
      preceding endotoxemia influences the viral shedding of influenza in nasal wash. Also, changes
      in the mucosal microbiome, transcriptome and metabolome will be assessed. Finally,
      mitochondrial function and mental strength during human endotoxemia will be assessed.
    

Intervention name(s): Fluenz; placebo; LPS
Intervention type(s): Biological; Other; Other
Intervention description(s): intranasal inoculation with Fluenz
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Fluenz; innate immune response; endotoxin tolerance; priming