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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02642237
Recruitment Status : Completed
First Posted : December 30, 2015
Last Update Posted : April 17, 2018
Information provided by (Responsible Party):
Matthijs Kox, Radboud University

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.

Condition or disease Intervention/treatment Phase
Innate Immune Response Immune Tolerance Biological: Fluenz Other: placebo Other: LPS Not Applicable

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  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
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

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
Biological: Fluenz
intranasal inoculation with Fluenz

Other: placebo

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Cytokines in nasal wash [ Time Frame: 35 days ]
    cytokine concentration

  2. Influenza viral shedding in nasal wash [ Time Frame: 35 days ]
    Influenza viral shedding in nasal wash (both Influenza A and B subtypes).

  3. Leukocytes in nasal wash [ Time Frame: 35 days ]
    Leukocyte numbers and differentiation in nasal wash (NK-cells, neutrophils, monocytes, dendritic cells and lymphocytes

  4. Fluenz IgA [ Time Frame: 35 days ]
    hemagglutination inhibition assay in nasal wash (measured for all four subtypes) strains).

  5. Circulating leukocytes [ Time Frame: 35 days ]
    Circulating leukocyte counts and differentiation (NK-cells, neutrophils, monocytes, dendritic cells and lymphocytes)

  6. Plasma cytokines [ Time Frame: 35 days ]
    Various plasma cytokines

  7. Fluenz IgG [ Time Frame: 35 days ]
    hemagglutination inhibition assay in serum

  8. ex vivo cytokines [ Time Frame: 28 days ]
    Cytokine production by leukocytes ex vivo stimulated with various pathogens/stimuli.

  9. Questionnaire [ Time Frame: 35 days ]
    Local and systemic symptoms during human endotoxemia and after Fluenz

  10. Temperature [ Time Frame: 35 days ]
    tympanic temperature

  11. Blood pressure [ Time Frame: 35 days ]
    intra-arterial cannula

  12. spirometry [ Time Frame: 35 days ]
    Peak expiratory flow (PEF).

  13. sequence analysis [ Time Frame: 35 days ]
    mucosal microbiome

  14. sequence analysis [ Time Frame: 35 days ]
    Mucosal transcriptome

  15. sequence analysis [ Time Frame: 35 days ]
    Mucosal metabolome

  16. physiological parameter [ Time Frame: 35 days ]
    Mental strength scale

  17. Mitochondrial function [ Time Frame: 35 days ]
    Mitochondrial function analysis

  18. heart rate [ Time Frame: 35 days ]
    measured by ECG

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

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 identifier (NCT number): NCT02642237

Sponsors and Collaborators
Radboud University
Principal Investigator: Peter Pickkers, Prof. Dr. Radboud University

Responsible Party: Matthijs Kox, Principal investigator, Radboud University Identifier: NCT02642237     History of Changes
Other Study ID Numbers: LPS-Fluenz
First Posted: December 30, 2015    Key Record Dates
Last Update Posted: April 17, 2018
Last Verified: April 2018

Keywords provided by Matthijs Kox, Radboud University:
innate immune response
endotoxin tolerance