Innate Immune Response, Immune Tolerance
Conditions
Keywords
Fluenz, innate immune response, endotoxin tolerance, priming
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.
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 35 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Levels of Interferon Gamma-induced Protein 10 (IP-10) in Nasal Wash Fluid | 35 days after FLuenz inoculation | Interferon gamma-induced protein 10 is a marker of viral-induced inflammation. Higher levels indicate a more pronounced inflammatory response upon a viral infection. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LPS-Fluenz Healthy volunteers administered intravenously with endotoxin, followed by an intranasal inoculation with Fluenz, a live-attenuated influenza vaccin
Fluenz: intranasal inoculation with Fluenz
LPS | 15 |
| Placebo-Fluenz Healthy volunteers administered intravenously with placebo, followed by an intranasal inoculation with Fluenz, a live-attenuated influenza vaccin
Fluenz: intranasal inoculation with Fluenz
placebo | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Total | LPS-Fluenz | Placebo-Fluenz |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 15 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 15 Participants | 15 Participants |
| Region of Enrollment Netherlands | 30 participants | 15 participants | 15 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 15 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
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.
Time frame: 35 days after FLuenz inoculation
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LPS-Fluenz | Peak Levels of Interferon Gamma-induced Protein 10 (IP-10) in Nasal Wash Fluid | 2000 pg/mL |
| Placebo-Fluenz | Peak Levels of Interferon Gamma-induced Protein 10 (IP-10) in Nasal Wash Fluid | 1900 pg/mL |