Title: Influenza Severity and Pathogenesis
Funder: Department of Health and Social Care

Abstract: In line with key PHE priorities for Influenza, the overarching goals of the Theme are improved national surveillance of severe illness to enhance preparedness and rapid response to novel outbreaks, and identification of host and viral factors associated with severe and fatal disease to improve risk-stratification. Aim 1: To improve responsiveness to upcoming influenza outbreaks (seasonal, epidemic or pandemic) 1. Short term a. To develop a collaborative team, including the HPRU-funded nursing, administrative and bio-informatics support staff, integrating with the goals of MOSAIC and PREPARE. This will link clinical front line to national influenza reference laboratory b. Establish formal links with adult and paediatric ICUs for patient recruitment (including Brompton ECMO centre). c. Establish formal links with NHS histopathology services for sample acquisition. d. Obtain ethics approval for extensive sampling from hospitalised patients with influenza-like illnesses (including host DNA, refined according to our MOSAIC & MERS experiences). 2. Medium term a. Improve speed and efficiency of collecting key information on case history and presentation, including vaccination status and underlying risk factors (in accordance with the Hine Report’s recommendations) b. Establish capability for real time analysis of the information gathered 3. Long term a. Introduce serial sampling of materials from the respiratory tract and peripheral blood in sentinel patients during influenza season, with real-time analysis using protocols developed as a result of experience gathered in MOSAIC/ISARIC www.prognosis.org/isaric Aim 2: To identify changes in viral genome over time that predict the risk of severe influenza 1. Short term a. Establish case-control sampling protocols and ethical approvals to acquire influenza isolates for comparing whole genome viral sequences from mild vs. severe/fatal cases 2. Medium term a. To systematically collect virus isolates from hospital cases b. To optimise near-patient real time whole genome sequencing of virus isolates during influenza seasons 3. Long term a. To identify changes that occur in the virus genome over time in community vs. hospitalised influenza cases that may be associated with mild or severe influenza, or with antiviral resistance Aim 3: To identify and validate biomarkers that correlate with and predict subsequent severity of disease Specific Research Theme HPRU 2013 Application Ref No: 10064 3 1. Short term a. To develop a panel of inflammatory mediators and gene expression signatures (from MOSAIC or elsewhere) that are associated with severe disease or adverse outcomes. b. To establish an adult volunteer human challenge model for influenza c. Recruit joint MD/PhD student to this project. 2. Medium term a. To validate a panel of inflammatory mediators and gene expression signatures (from MOSAIC or elsewhere) associated with enhanced disease in experimental infections. 3. Long term b. To integrate MOSAIC and experimental infection data to develop a predictive model of disease severity using a refined panel of biomarkers that can applied clinically. Aim 4: Improve interventions available for treatment of severe influenza 1. Short term a. Design of protocols for human monoclonal antibody & immunomodulatory interventions b. Collect data from severe cases during seasonal flu, analysed according to outcome c. Assessment of antivirals and other interventions given to patients admitted to ICHT ICUs 2. Long term a. Recruit severe cases of influenza for intervention studies (antivirals/response modifiers)


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: INFECTION