Clinical trial NCT02642237: The Effects of Preceding LPS Administration on the Fluenz-induced Immune Response
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Innate Immune Response
Immune Tolerance
Keywords: Fluenz
innate immune response
endotoxin tolerance
priming
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2015-12-30
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Healthy

Exclusion Criteria:

* Pre-existent lung disease, including asthma, severe allergic rhinitis
* Use of any medication
* Current smoker or more than 5 pack-year history
* Use of recreational drugs within 21 days prior to start of the study
* Use of caffeine or alcohol within 1 day prior to start of the study
* Surgery or trauma with significant blood loss or blood donation within 3 months prior to start of the study
* Participation in another clinical trial within 3 months prior to start of the study
* Frequent nosebleeds
* Recent nasal or otologic surgery
* (suspected) influenza infection during the last year
* Clinically significant acute (febrile) illness or a common cold within four weeks prior to start of the study
* History of frequent vaso-vagal collapse or of orthostatic hypotension History, signs or symptoms of cardiovascular disease.
* History of allergic reaction to Fluenz™, eggs / gelatin / gentamicin
* History of Guillain-Barré Syndrome
* Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
* Hypertension (defined as Blood pressure (RR) systolic \> 160 or RR diastolic \> 90).
* Hypotension (defined as RR systolic \< 100 or RR diastolic \< 50).
* Renal impairment (defined as plasma creatinin \>120 μmol/l).
* Liver function abnormality: alkaline phosphatase\>230 U/L and/or Alanine-aminotransferase (ALT)\>90 units per Liter (U/L)
* C-reactive protein (CRP) \> 20 mg/L, white blood cell count (WBC) \> 12x109/L
* Vaccination with influenza this season
* Recent vaccination

Primary outcomes:
measure: Peak Levels of Interferon Gamma-induced Protein 10 (IP-10) in Nasal Wash Fluid
timeFrame: 35 days after FLuenz inoculation
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Radboud University Medical Center
name: Peter Pickkers, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: