Broadening Our Understanding of Early Versus Late Influenza Vaccine Effectiveness (BELIEVE)
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|ClinicalTrials.gov Identifier: NCT04570904|
Recruitment Status : Recruiting
First Posted : September 30, 2020
Last Update Posted : October 5, 2020
|First Submitted Date||September 24, 2020|
|First Posted Date||September 30, 2020|
|Last Update Posted Date||October 5, 2020|
|Actual Study Start Date||September 28, 2020|
|Estimated Primary Completion Date||May 30, 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures
||Difference in antibody titre [ Time Frame: Antibody titres to be analysed at the end of the study once all samples collected - estimated May 2021 ]
Difference in antibody titres at set time points during the 2020/21 influenza season in HCWs stratified by those who are vaccinated early and late
|Original Primary Outcome Measures||Same as current|
|Current Secondary Outcome Measures
|Original Secondary Outcome Measures||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title||Broadening Our Understanding of Early Versus Late Influenza Vaccine Effectiveness|
|Official Title||Broadening Our Understanding of Early Versus Late Influenza Vaccine|
This study uses a prospective cohort design to investigate if the seasonal influenza vaccine is equally effective when given early and late before the proceeding influenza season. All health care workers will be vaccinated for seasonal influenza either 3 months before or 1 month prior to the start of the influenza season. HCWs that consent to take part in the study will have 4 blood samples taken for an antibody check. The initial antibody checks will be done just prior to vaccination as well as 2 weeks after vaccination. Subsequent samples will be taken at the peak of influenza season and at the end of the influenza season.
HCWs that develop ILI during the course of the influenza season will be asked to complete a questionnaire and oropharyngeal self-swab. HCWs will also provide exhaled breath samples and wear a mask in order to evaluate novel non-invasive methods for diagnosis of influenza.
Influenza positive and negative inpatients identified through the University of Leicester's laboratory system will also be asked to provide breath samples to evaluate this technique for the diagnosis of influenza.
Recruitment, Screening and Eligibility Assessment
Potential participants (University Hospitals of Leicester NHS Trust, UHL staff) will be contacted by email to advertise and explain the study. The email will be part of the routine seasonal influenza vaccination emails which are sent out each year to remind UHL staff to be immunised. In addition, the investigators will advertise by posters in the high staff traffic areas, e.g. the restaurant, and our Occupational Health Team will assist with this advertising of the study. The investigators expect some Health care workers (HCWs) to become aware of the study through word of mouth.
The study will have two phases of recruitment. For the month of September for the 'early' vaccination group, and from mid-November to mid-December for the 'late' vaccination group - the exact timings may vary depending on when the inactivated influenza vaccines are received and the seasonality of the virus, as all recruitment will be completed prior to the start of the influenza season. Allocation to the two vaccination groups will not be randomised; it will be the HCWs decision if they would like to have the vaccination either early or late. There will be a limit of 200 HCWs recruited to each group.
Individuals who express an interest in taking part in the study will be given an information sheet either in person or via email. Following this the investigators will give them as long as they need to decide whether or not to participate in the study. If the individual agrees to participate, a member of the research team will screen and confirm eligibility. Participants will only be recruited if all criteria are satisfied. At this time arrangements will be made for staff members to attend an initial appointment at the Research Space at the LRI. Recruitment in the research area will comply with the current social distancing measures in place at UHL.
At this initial appointment the study will be explained to staff members in groups. A member of the research team will then seek written informed consent as detailed below from each HCW individually. If an individual has more questions about the study another study team member will be allowed to support and facilitate informed consent.
Recruitment of inpatients Clinicians on the acute medical wards will be notified prior to the start of the influenza season via email and posters, in clinical areas, of the study involving inpatients with (influenza like illness) ILI. University Hospitals of Leicester Virology department routinely call the clinical team of positive influenza cases in inpatients during the influenza season. When the clinical team then goes to explain this diagnosis to the patient they would also make them aware of the study and provide them with a participant information leaflet. Following this the investigators will give the patient as long as they need to decide whether or not to participate in the study. If the individual agrees to participate they will inform a member of the clinical team who will then notify the research team. A member of the research team will attend the ward to screen and confirm eligibility. Participants will only be recruited if all criteria are satisfied. Using laboratory results data, twenty inpatients with confirmed influenza-negative swabs will also be recruited in the same way, as a control group.
The following activities will be carried out at each visit and recorded in the CRF:
Visit 1: Baseline visit
Visit 2: 3 weeks after baseline visit (+ or - 7days)
It will be reiterated to the study participant that results of these swab results will be emailed and phoned through to them along with the latest occupational health advice. They will be advised to follow occupational health policy for ILI whilst awaiting the swab results, report sickness in the normal way and contact their GP if further medical advice regarding this current period of illness is needed.
The contents of the ILIef will be entered into the participants case report form (CRF), no personal information will be included. These details will be used in the interpretation of the viral sequencing and antibody titres, performed at WHO Melbourne.
If the study participant is at work when they develop ILI they will be asked to provide a breath sample and mask sample for the detection of influenza using novel methods prior to leaving work. Sampling materials will be brought to where the HCW is located but if this could not happen straight away then the HCW would be told to follow occupational health advice and go home. Specimens collected from these processes are detailed in section 8.7.
Inpatient breath sample Inpatients will be approached as per the usual UHL infection control policy. Only patients who have results available for a recent throat swab tested for common respiratory pathogens will be approached. COVID-19 positive wards will not be involved in recruitment instead inpatients with Influenza and other respiratory viruses will be recruited from COVID-19 negative wards. Patients who are confirmed influenza positive are usually managed in side rooms as per policy. In all cases, the patient will not be required to come into contact with the analysis equipment, as the breath capture and analytical processes are separate. Mask sampling will not be undertaken on patients who require oxygen therapy via a face mask. Once consented to the study one member of the research team will approach the patient with the masks, syringes and mouthpieces needed for breath sample collection. A repeat throat swab will also be taken at this time so accurate comparison can take place between the novel diagnostic methods and current practise. All three breath sampling methods, where possible, will be used. Once the samples have been collected they will be placed in a biological hazard bag and taken to the analysis machines. Swabs and mask samples will be transported to the virology Laboratory at Leicester Royal Infirmary for processing. The breath capture equipment (syringes and disposable mouth pieces) will be disposed of in the normal way for clinical waste. TD tubes and the Bio-VOC sampler will be double bagged and will be decontaminated. This is the only study visit required by inpatients and no further follow up is required.
Self-swabs The swabs will be delivered to the Department of Clinical Microbiology at University Hospitals of Leicester NHS Trust where they will be handled under Cat 2 (BSL-2) conditions. They will be vortexed, and swabs discarded leaving the inoculated virus transport medium (VTM). The VTM tubes will be tested on a standard diagnostic assay (routinely used for hospital patient testing) to check for the presence of influenza (as many different respiratory viruses can cause an 'influenza-like illness'). If influenza is detected, then an aliquot of this VTM will be sent to WHO Melbourne, along with the serum samples, for viral sequencing of influenza. VTM will be transported to the WHO laboratory under UN3733/Category B regulations.
VOC breath analysis All three analysis platforms will use the same basic collection approach. Participants will be asked to not to have eaten or drank anything at least 30 minutes before breath sampling. Prior to sampling swill their mouth with water which they can then swallow - and then provide three non-forced breath samples by exhaling into disposable mouthpieces for 3-5 seconds. Researchers will wear PPE dictated by local trust policy at UHL for collecting nasal and oral swabs. Disposable clinical gloves will be used for all procedures. The analytical devices will be kept on the ward or in a research area away from direct patient contact.
For GC-IMS analysis, the mouthpiece is attached to a 10cm long plastic tube. As the patient exhales into the tube, the researcher will draw a breath sample into a 5ml syringe part way down the tube.
The sample will then be injected from the syringe by the researcher into the BreathSpecTM GC-IMS device for analysis. Any infectious material contained within the sample will be destroyed by being heated to over 60°C as part of the analytical process.
The eNose uses a commercial CE marked breath capture unit, the Markes Bio-VOC. The unit holds 129ml of breath, comes sealed and only opened when ready to use, and is disposable. The user fits a cardboard mouthpiece to the unit prior to sampling. Once the patient has breathed into the unit the mouthpiece is removed and a syringe fitting is added, which connects to the eNose. The syringe is then depressed and the sample is analysed. Analysis time is under 5 minutes. The eNose machine will be decontaminated at the end of each day of use according to the manufacture's guidelines.
For GC-MS analysis, a further breath sample is again collected using the Markes Bio-VOC unit as above. Once the sample is collected it will be transferred onto a thermal desorption (TD) tube (typically 89mm x 6.4mm). The inner walls of the tube are coated with an absorbent layer to which breath chemicals adhere. The TD tube is placed at the end of the Bio-VOC unit and captured air is pushed through the tube. Once completed, the ends of the tubes are sealed with end caps. A validated decontamination process is then undertaken for the Bio-VOC sampler and TD tubes through a long / high heat cycle to ensure the virus is killed off. The decontaminated TD tubes will be kept in storage boxes in the research area of Leicester Royal Infirmary for transport to the University of Warwick for analysis and final disposal, as per a pre-defined Material Transfer Agreement.
The results of the GC-IMS analysis will be uploaded regularly from the BreathSpecTM onto a DataSync shared drive and downloaded by analysts at the University of Warwick. No identifiable data will be associated with this data, only a study number.
Mask sampling Mask sampling consists of participants wearing a modified face mask (flat surgical, duckbilled or FFP1) which contains up to 5 strips of 3D printed Polyvinyl alcohol (PVA) for up to 60 minutes whilst being observed by a member of the research team. The investigators will provide training, support and personal protective equipment to research staff obtaining samples and agree protocols for local processing. Prior to use masks are sterilised and kept in sealed sample bags, once worn they are placed back in these bags and sealed. They will be transported to the UHL Virology Laboratory in line with current Risk Assessments and Standard Operating procedures concerning transporting hazardous materials. Viral RNA will be extracted and quantified from the PVA strips within the masks using Real-Time quantitative PCR. The processing of the PVA strips requires them to be dissolved into water, from which the RNA virus is extracted and analysed using molecular methods. The masks and bags will be destroyed.
Serum testing and viral sequencing On each of the scheduled days requiring serum samples, the clotted blood will be stored at 2oC to 8oC and centrifuged within 24 hours at the Research Space, LRI. Sera will be stored in cryovials, with all cryovials labelled with the participant's study number, visit number and date of collection at the Research Space, LRI. Samples will be stored frozen at -80 oC until shipment. One set of cryovials will be sent to the WHO reference laboratory in Melbourne once all samples have been collected. The other set of cryovials will be stored as a safety measure in case of transport issues. With participant consent, any unused serum samples will be stored for future ethically approved research and shared with other research collaborators in other academic institutions and industry partners inside and outside of the UK for future research. Serum will be used for Hemagglutination inhibition and microneutralization assays and once all samples have been processed results will be sent back to the research team at Leicester.
Haemagglutination Inhibition (HAI) and Microneutralisation (MN) assays, together with influenza viral sequencing will be performed at the WHO Collaborating Centre for Reference and Research on Influenza (VIDRL), Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.
|Study Design||Observational Model: Cohort
Time Perspective: Prospective
|Target Follow-Up Duration||Not Provided|
|Biospecimen||Retention: Samples Without DNA
With participant consent, any unused serum samples will be stored for future ethically approved research and shared with other research collaborators in other academic institutions and industry partners inside and outside of the UK for future research.
|Sampling Method||Non-Probability Sample|
|Study Population||The study population will be composed of HCWs at University Hospitals of Leicester, that are eligible for the seasonal influenza vaccine A further study population will be composed of inpatients at the University Hospitals of Leicester presenting and / or admitted with Influenza like illness|
|Intervention||Biological: Influenza vaccination at different time points
All HCWs will receive the seasonal influenza vaccine but at two different time points.
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Original Estimated Enrollment||Same as current|
|Estimated Study Completion Date||September 1, 2022|
|Estimated Primary Completion Date||May 30, 2021 (Final data collection date for primary outcome measure)|
For Health care workers (HCWs)
|Ages||16 Years and older (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers||Yes|
|Listed Location Countries||United Kingdom|
|Removed Location Countries|
|Other Study ID Numbers||0787
IRAS ( Other Identifier: 284733 )
Sponsor Reference Number ( Other Identifier: UOL0787 )
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement||
|Responsible Party||University of Leicester|
|Study Sponsor||University of Leicester|
|PRS Account||University of Leicester|
|Verification Date||September 2020|