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

Immune Tolerance Clinical Trial

— LPS-Fluenz  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02642237
• Other study ID #: LPS-Fluenz
• Status: Completed
• Phase: N/A
• Start date: December 2015
• Est. completion date: February 2018

Study information

• Verified date: May 2019
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: February 2018
• Est. primary completion date: January 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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

Related Conditions & MeSH terms

• Immune Tolerance
• Innate Immune Response

Intervention

Biological:
• Fluenz
intranasal inoculation with Fluenz

Other:
• placebo

• LPS

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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