Influenza A H3N2
Conditions
Keywords
Influenza A H3N2
Brief summary
The aim of the study is to investigate disease in volunteers deliberately infected with influenza A(H3N2), including biological markers of inflammation and immune response, and changes in physiological parameters including heart rate, respiratory rate, physical activity, oxygen saturation and electrocardiographic data during the onset of influenza infection. Ultimately, this may lead to prediction of symptomatic disease at an earlier stage to allow more effective interventions. The experimental medicine study design will involve human influenza infection challenge, whereby volunteers will be inoculated with influenza virus and monitored in hospital for 10 days as they develop and get better from flu. Continuously-monitoring wearable physiological sensors will be given to the participants 7 days before this and worn continuously until the end of the flu infection.
Detailed description
Influenza ('flu') is one of the most common causes of severe lung infection. Seasonal flu affects between 10 and 46% of the population each year and causes around 12 deaths in every 100,000 people infected. Furthermore, new strains of flu viruses emerge unpredictably every few years, causing pandemics that spread rapidly across the world. Since currently available antiviral drugs and vaccines cannot prevent these outbreaks, it is essential to be able to identify flu infections at an early stage to enable rapid treatment of individuals and implementation of public health measures. The aim of the study is to investigate disease in volunteers deliberately infected with influenza A(H3N2), including biological markers of inflammation and immune response, and changes in physiological parameters including heart rate, respiratory rate, physical activity, oxygen saturation and electrocardiographic data during the onset of influenza infection. To achieve this, the investigators will recruit healthy volunteers and inoculate them with a flu virus, after which they will be observed in hospital while they develop a cold. Each volunteer will be given a number of devices that they will wear before and during infection. In addition, they will have blood and nasal samples taken to examine the way their immune system responds to infection. The resulting data will be analysed to see if the sensors data correlate with the onset of infection and these will be compared with measures of the immune response. Ultimately, the investigators anticipate that optimised sensor data from devices to be developed may be useful in rapidly detecting when someone is about to develop flu infection, so that they can quickly be treated and outbreaks may be identified at an early stage.
Interventions
DEVICELumee Oxygen Platform
Two sensors will be inserted (one in the skin fo the upper arm and one on the side of the chest). A wireless patch reader is placed on top of the skin over the area where the sensor has been placed to measure local oxygen content.
Sponsors
Duke University
RTI International
Defense Advanced Research Projects Agency
Imperial College London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Biological: Influenza A/Belgium/4217/2015 at a dose of 5x105 TCID50 in a volume of 0.5 milliliters via intranasal drops
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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 3 months * Acute upper respiratory infection (URI 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 * Any ECG abnormality deemed clinically significant. * 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 antibody 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. * Participants may only recruited if they have previously been involved in research if they have completed the earlier study and are beyond the washout period of any administered drugs or period of effect of any intervention that would cause interference for either study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of PCR-confirmed Influenza Infections | Baseline to day 28 | Nasal wash viral load by quantitative polymerase chain reaction (qPCR) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Algorithmic Detection of Heart Rate Abnormalities | Baseline to day 10 | Sensor data read-outs |
| Tissue Oxygen Levels | Baseline to day 10 | Sensor data read-outs |
| Participant-reported Total Symptom Score | Day 1, Day 3 and Day 10 | Cumulative daily symptom score derived from self-reported upper and lower respiratory and systemic symptoms by diary card using the modified Jackson's symptom scoring system. Eight symptoms were scored: nasal obstruction, nasal discharge, sore throat, sneezing, cough, malaise, headache, and chills. Each symptom was scored 0-3, where 0=absent, 1=mild, 2=moderate and 3=severe. The maximum daily score is 24 and minimum daily score is 0. |
Countries
United Kingdom
Participant flow
Recruitment details
20 healthy volunteers were enrolled in the study and followed up from the period 11th February 2020 to 17th May 2021. The study was suspended from March to August 2020 due to the global SARS-CoV-2 pandemic.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Influenza A Participants were inoculated with Influenza A/Belgium/4217/2015 at a dose of 5x10\^5 TCID50 in a volume of 0,5mL via intranasal drops. They were then monitored as in-patients for 10 days with daily clinical assessment and blood, respiratory tract sampling, and sensor monitoring. Following discharge, they were followed up for up to 6 months post-inoculation.
Lumee Oxygen Platform: Two sensors were inserted (one in the skin for the upper arm and one on the side of the chest). A wireless patch reader was placed on top of the skin over the area where the sensor was placed to measure local oxygen content. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Experimental: Influenza A |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Race/Ethnicity, Customized Ethnicity All other ethnic groups | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Asian or Asian British (Indian) | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Asian or Asian British (Pakistani) | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Black or Black British (African) | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Black or Black British (all other) | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Chinese | 1 Participants |
| Race/Ethnicity, Customized Ethnicity White (all other) | 4 Participants |
| Race/Ethnicity, Customized Ethnicity White British | 7 Participants |
| Race/Ethnicity, Customized Ethnicity White Irish | 2 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 9 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Number of PCR-confirmed Influenza Infections
Nasal wash viral load by quantitative polymerase chain reaction (qPCR)
Time frame: Baseline to day 28
Population: One participant who was PCR positive for the challenge agent also tested positive for Rhinovirus on Day 4 post-inoculation therefore this participant was excluded from all further analyses.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental: Influenza A | Number of PCR-confirmed Influenza Infections | PCR positive Influenza infection | 17 Participants |
| Experimental: Influenza A | Number of PCR-confirmed Influenza Infections | PCR negative Influenza infection | 3 Participants |
Secondary
Participant-reported Total Symptom Score
Cumulative daily symptom score derived from self-reported upper and lower respiratory and systemic symptoms by diary card using the modified Jackson's symptom scoring system. Eight symptoms were scored: nasal obstruction, nasal discharge, sore throat, sneezing, cough, malaise, headache, and chills. Each symptom was scored 0-3, where 0=absent, 1=mild, 2=moderate and 3=severe. The maximum daily score is 24 and minimum daily score is 0.
Time frame: Day 1, Day 3 and Day 10
Population: 13 of 16 PCR positive participants (1 participant was excluded from the analysis due to co-infection with Rhinovirus) developed influenza-like symptom following inoculation. The 3 remaining participants were asymptomatic with modified Jackson's symptom scoring system.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Influenza A | Participant-reported Total Symptom Score | Day 1 | 2.44 scores on a scale | Standard Deviation 2.76 |
| Experimental: Influenza A | Participant-reported Total Symptom Score | Day 3 (peak) | 11.50 scores on a scale | Standard Deviation 13.67 |
| Experimental: Influenza A | Participant-reported Total Symptom Score | Day 10 | 1.19 scores on a scale | Standard Deviation 2.69 |
Secondary
Time to Algorithmic Detection of Heart Rate Abnormalities
Sensor data read-outs
Time frame: Baseline to day 10
Population: All metrics were expressed as z-scores matched for physical activity level. Multivariate process control techniques were used to quantify the change in the multidimensional HRV parameter space relative to baseline and formulated an algorithm for the detection of the illness. 170 total days monitored. Mean parameter values were computed on 24hr increments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Influenza A | Time to Algorithmic Detection of Heart Rate Abnormalities | 52 hours post-inoculation | Standard Deviation 17 |
Secondary
Tissue Oxygen Levels
Sensor data read-outs
Time frame: Baseline to day 10
Population: Data collected with the Lumee devices per group (A, B, and D). Lumee devices were not used in Group C. LOI = Lumee Oxygen Index which is a measure proportional to micro-molar concentration of Oxygen in the interstitial fluid. The normal range for LOI is 10-52. A higher LOI corresponds to higher micro-molar concentration of Oxygen in the interstitial fluid.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Influenza A | Tissue Oxygen Levels | 12.6 LOI | Standard Deviation 8.8 |
| Group B | Tissue Oxygen Levels | 13.7 LOI | Standard Deviation 8.5 |
| Group D | Tissue Oxygen Levels | 12.5 LOI | Standard Deviation 6.8 |