Immune Tolerance Clinical Trial
Official title:
The Effects of an Endotoxin Challenge on the Immune Response Elicited by a Subsequent Challenge With Fluenz in Healthy Volunteers, an Explorative Study
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.
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.
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