The Effects of Preceding LPS Administration on the Fluenz-induced Immune Response (LPS-Fluenz)

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.

Study Overview

• Status: Completed
• Conditions: Innate Immune Response; Immune Tolerance
• Intervention / Treatment: Other: placebo; Biological: Fluenz; Other: LPS

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LPS-Fluenz; Healthy volunteers administered intravenously with endotoxin, followed by an intranasal inoculation with Fluenz, a live-attenuated influenza vaccin	Biological: Fluenz; intranasal inoculation with Fluenz; Other: LPS
Placebo Comparator: Placebo-Fluenz; Healthy volunteers administered intravenously with placebo, followed by an intranasal inoculation with Fluenz, a live-attenuated influenza vaccin	Other: placebo; Biological: Fluenz; intranasal inoculation with Fluenz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Levels of Interferon Gamma-induced Protein 10 (IP-10) in Nasal Wash Fluid	Interferon gamma-induced protein 10 is a marker of viral-induced inflammation. Higher levels indicate a more pronounced inflammatory response upon a viral infection.	35 days after FLuenz inoculation

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Peter Pickkers, Prof. Dr., Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: December 14, 2015
• First Submitted That Met QC Criteria: December 23, 2015
• First Posted (Estimate): December 30, 2015

Study Record Updates

• Last Update Posted (Actual): May 14, 2019
• Last Update Submitted That Met QC Criteria: May 6, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: priming; innate immune response; Fluenz; endotoxin tolerance
• Other Study ID Numbers: LPS-Fluenz