Biomarkers Predicting Infectivity in an Experimental Human Influenza Model

Study Overview
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Brief Summary
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This study aims to test the hypothesis that gene transcriptional changes occur within 24 hours of virus exposure in the blood and nasal mucosa, and to identify early biomarker signatures that are predictive of higher viral shedding at the peak of disease

Detailed Description
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This study will systematically investigate the early pre-symptomatic period following exposure to influenza in humans. The data obtained will be essential for further understanding of the natural history of human antiviral responses, and will allow us to identify a panel of biomarkers that can predict which individuals will go on to more severe symptoms and higher viral shedding, so that treatments and other interventions can be made at an early stage.

Official Title
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Biomarkers Predicting Infectivity in an Experimental Human Influenza Model

Conditions
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Influenza A

Intervention / Treatment
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* Biological: Influenza A/California/04/09


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy persons aged 18 to 55 years, able to give informed consent Exclusion Criteria: Chronic respiratory disease (asthma, chronic obstructive pulmonary disease, rhinitis, sinusitis) in adulthood Inhaled bronchodilator or steroid use within the last 12 months Use of any medication or other product (prescription or over-the-counter) for symptoms of rhinitis or nasal congestion within the last 6 months Acute upper respiratory infection or sinusitis in the past 6 weeks Smoking in the past 6 months OR >5 pack-year lifetime history Subjects with allergic symptoms present at baseline Clinically relevant abnormality on chest X-ray Those in close domestic contact (i.e. sharing a household with, caring for, or daily face to face contact) with children under 3 years, the elderly (>65 years), immunosuppressed persons, or those with chronic respiratory disease Subjects with known or suspected immune deficiency Receipt of systemic glucocorticoids (in a dose ≥ 5 mg prednisone daily or equivalent) within one month, or any other cytotoxic or immunosuppressive drug within 6 months prior to challenge Known immunoglobulin A deficiency, immotile cilia syndrome, or Kartagener's syndrome History of frequent nose bleeds Any significant medical condition or prescribed drug deemed by the study doctor to make the participant unsuitable for the study Pregnant or breastfeeding women Positive urine drug screen Detectable baseline haemagglutination inhibition titres against influenza challenge strains History of hypersensitivity to eggs, egg proteins, gentamicin, gelatin or arginine, or with life-threatening reactions to previous influenza vaccinations All women of childbearing age will have a pregnancy test performed prior to virus inoculation to exclude pregnancy and be required to use contraception throughout the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Influenza A/California/04/2009<br>Participants will be inoculated with Influenza A/California/04/09 3.5x10(4) tissue culture infective dose 50% (TCID50) in 1 mL in Dulbecco's phosphate buffered saline (DPBS) delivered by intranasal drops. They will then be monitored as in-patients for 10 days with daily clinical assessment and blood and respiratory tract sampling. Following discharge, they will be followed up for up to 6 months post-inoculation. | Biological: Influenza A/California/04/09<br>* Good Manufacturing Practices-certified Influenza A/California/04/09 3.5x10(4) TCID50 in 1 mL in DPBS delivered by intranasal drops<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral load | Nasal wash viral load by quantitative polymerase chain reaction (qPCR) | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptoms | Self-reported upper and lower respiratory and systemic symptoms by diary card | 28 days | 
| Differentially expressed genes in blood | Differentially expressed genes analysed by RNA sequencing of whole blood | 9 months | 
| Differentially expressed genes in nasal curettage | Differentially expressed genes analysed by RNA sequencing of nasal curettage samples | 9 months | 
| Metabolomics in serum | Differentially expressed metabolites in serum by mass spectrometry | 9 months |