The Effects of Preceding LPS Administration on the Fluenz-induced Immune Response (LPS-Fluenz)
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|ClinicalTrials.gov Identifier: NCT02642237|
Recruitment Status : Completed
First Posted : December 30, 2015
Last Update Posted : April 17, 2018
|Condition or disease||Intervention/treatment||Phase|
|Innate Immune Response Immune Tolerance||Biological: Fluenz Other: placebo Other: LPS||Not Applicable|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||40 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|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|
|Actual Study Start Date :||December 2015|
|Actual Primary Completion Date :||January 2017|
|Actual Study Completion Date :||February 2018|
Healthy volunteers administered intravenously with endotoxin, followed by an intranasal inoculation with Fluenz, a live-attenuated influenza vaccin
intranasal inoculation with Fluenz
Placebo Comparator: Placebo-Fluenz
Healthy volunteers administered intravenously with placebo, followed by an intranasal inoculation with Fluenz, a live-attenuated influenza vaccin
intranasal inoculation with Fluenz
- IFN-gamma-inducible protein 10 (IP-10) in nasal wash [ Time Frame: 35 days ]the difference in concentrations of IP-10 in nasal wash between subjects in the placebo-Fluenz™ group and the LPS-Fluenz™ group.
- Cytokines in nasal wash [ Time Frame: 35 days ]cytokine concentration
- Influenza viral shedding in nasal wash [ Time Frame: 35 days ]Influenza viral shedding in nasal wash (both Influenza A and B subtypes).
- Leukocytes in nasal wash [ Time Frame: 35 days ]Leukocyte numbers and differentiation in nasal wash (NK-cells, neutrophils, monocytes, dendritic cells and lymphocytes
- Fluenz IgA [ Time Frame: 35 days ]hemagglutination inhibition assay in nasal wash (measured for all four subtypes) strains).
- Circulating leukocytes [ Time Frame: 35 days ]Circulating leukocyte counts and differentiation (NK-cells, neutrophils, monocytes, dendritic cells and lymphocytes)
- Plasma cytokines [ Time Frame: 35 days ]Various plasma cytokines
- Fluenz IgG [ Time Frame: 35 days ]hemagglutination inhibition assay in serum
- ex vivo cytokines [ Time Frame: 28 days ]Cytokine production by leukocytes ex vivo stimulated with various pathogens/stimuli.
- Questionnaire [ Time Frame: 35 days ]Local and systemic symptoms during human endotoxemia and after Fluenz
- Temperature [ Time Frame: 35 days ]tympanic temperature
- Blood pressure [ Time Frame: 35 days ]intra-arterial cannula
- spirometry [ Time Frame: 35 days ]Peak expiratory flow (PEF).
- sequence analysis [ Time Frame: 35 days ]mucosal microbiome
- sequence analysis [ Time Frame: 35 days ]Mucosal transcriptome
- sequence analysis [ Time Frame: 35 days ]Mucosal metabolome
- physiological parameter [ Time Frame: 35 days ]Mental strength scale
- Mitochondrial function [ Time Frame: 35 days ]Mitochondrial function analysis
- heart rate [ Time Frame: 35 days ]measured by ECG
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02642237
|Principal Investigator:||Peter Pickkers, Prof. Dr.||Radboud University|