COPD-like airway inflammation during RSV infection of older volunteers: INFLAMMAGE
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
Based on extensive preclinical and clinical research, we hypothesise that RSV disease represents a dysregulated and over-exuberant inflammatory response to infection. Steroids have limited efficacy, and identification of druggable inflammatory pathways in severe RSV disease would be of great potential value. There are promising clinical assets ready for investigation, however, our ability to test novel therapeutics is limited by the currently available models of viral disease and clinical endpoints tied to disease processes. Observational studies of natural infection are constrained by sampling, timing and access. We therefore propose to extend the experimental human RSV infection studies established at Imperial College to investigate the pulmonary response to RSV infection in older adult non-smokers and smokers, with the development of novel clinical endpoints which can then be used to evaluate the possible impact of treatment with validated novel anti-inflammatory agents from GSK in human RSV disease and therefore in COPD.
Technical Summary
Overall, the aims of this project are to investigate the mechanisms of inflammation in older adult volunteers during respiratory viral infection in vivo and in vitro to develop novel clinical end-points and biomarkers that correlate with infection outcome. In addition to elucidating the pathways involved in steroid-resistant inflammation triggered by viral infection, the future option of treatment with a validated novel therapeutic will allow us to determine if either reducing viral-driven inflammation or directly reducing viral load improves clinical outcome. The early Parts of this project will generate data which will enable selection of an appropriate clinical therapeutic agent for investigation.
Organisations
Publications
Wiseman DJ
(2020)
Immunological and Inflammatory Biomarkers of Susceptibility and Severity in Adult Respiratory Syncytial Virus Infections.
in The Journal of infectious diseases
Thwaites RS
(2017)
Nasosorption as a Minimally Invasive Sampling Procedure: Mucosal Viral Load and Inflammation in Primary RSV Bronchiolitis.
in The Journal of infectious diseases
Thwaites RS
(2021)
Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19.
in Science immunology
Sullivan MK
(2022)
Acute kidney injury in patients hospitalized with COVID-19 from the ISARIC WHO CCP-UK Study: a prospective, multicentre cohort study.
in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Stewart A
(2022)
Pandemic, Epidemic, Endemic: B Cell Repertoire Analysis Reveals Unique Anti-Viral Responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus.
in Frontiers in immunology
Shi T
(2020)
Global and Regional Burden of Hospital Admissions for Pneumonia in Older Adults: A Systematic Review and Meta-Analysis.
in The Journal of infectious diseases
Shi T
(2020)
Global Disease Burden Estimates of Respiratory Syncytial Virus-Associated Acute Respiratory Infection in Older Adults in 2015: A Systematic Review and Meta-Analysis.
in The Journal of infectious diseases
Sagawe JS
(2024)
Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection.
in GeroScience
Park M
(2020)
COVID-19: Lessons from SARS and MERS
in European Journal of Immunology
Openshaw PJM
(2017)
RSV Takes Control of Neonatal Breg Cells: Two Hands on the Wheel.
in Immunity
Openshaw PJM
(2017)
Protective and Harmful Immunity to RSV Infection.
in Annual review of immunology
Mehta P
(2020)
Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities.
in The Lancet. Respiratory medicine
McGinley JP
(2022)
Clinical and Viral Factors Associated With Disease Severity and Subsequent Wheezing in Infants With Respiratory Syncytial Virus Infection.
in The Journal of infectious diseases
Mazur NI
(2018)
The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates.
in The Lancet. Infectious diseases
Marsall P
(2024)
Development and validation of a respiratory syncytial virus multiplex immunoassay.
in Infection
Marchant A
(2017)
Maternal immunisation: collaborating with mother nature.
in The Lancet. Infectious diseases
Lord JM
(2024)
Accelarated immune ageing is associated with COVID-19 disease severity.
in Immunity & ageing : I & A
Liew F
(2024)
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.
in Nature immunology
Heath P
(2017)
Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis
in The Lancet Infectious Diseases
| Description | BSI President |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | The British Society for Immunology (BSI) is the largest immunology society in Europe and the second largest in the world. We are a learned society representing the interests of members working in academia, clinical medicine, and industry. Our main objective is to promote and support excellence in research, scholarship and clinical practice in immunology for the benefit of human and animal health. |
| URL | https://immunology.org/resources-careers--education/policy-and-public-affairs/--bsi-resources-policy... |
| Description | Developing ethical frameworks for human challenge studies |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Membership of a guideline committee |
| Description | Member and Vice Chair NERVTAG |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Description | Vaccine Taskforce Human Challenge Board |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Description | A UK underpinning platform to study immunology and immunopathology of COVID-19:The UK Coronavirus Immunology Consortium |
| Amount | £6,552,119 (GBP) |
| Funding ID | MR/V028448/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 07/2020 |
| End | 08/2022 |
| Description | A first-in-human open label wild-type SARS-CoV-2 dose-finding human infection challenge study |
| Amount | £817,899 (GBP) |
| Organisation | Department for Business, Energy & Industrial Strategy |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2020 |
| End | 10/2023 |
| Description | ISARIC - Coronavirus Clinical Characterisation Consortium (ISARIC-4C) |
| Amount | £490,894,600 (GBP) |
| Funding ID | MC_PC_19059 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 09/2021 |
| Description | NIHR Imperial Biomedical Research Centre |
| Amount | £90,008,747 (GBP) |
| Organisation | Barts Health NHS Trust |
| Department | NIHR Biomedical Research Unit |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 03/2017 |
| End | 03/2022 |
| Description | Senior Investigator Award |
| Amount | £60,000 (GBP) |
| Organisation | National Institute for Health and Care Research |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 03/2021 |
| Description | Analysis Discussion with Investigators (monthly) |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | Analysis Discussion |
| Year(s) Of Engagement Activity | 2023 |
| Description | Finalising Data |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | This Grant is coming to the end of it's tenure. There are no additional meetings planned at the moment as the two teams are finalising data and starting to write. Future meetings will be more focussed on draft reviews and planned in due course. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Inflammage Monthly Meeting Calls |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | Monthly Meeting calls to discuss data |
| Year(s) Of Engagement Activity | 2023 |
| Description | Inflammage Transcriptomics Manuscript |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | Study group discussion with view to publishing a manuscript |
| Year(s) Of Engagement Activity | 2024 |
| Description | Inflammage Analysis Discussion Monthly |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Study participants or study members |
| Results and Impact | Status Updates with Questions and discussions with regard to the research |
| Year(s) Of Engagement Activity | 2024 |
| Description | Inflammage Data Analysis Meeting at Imperial College NHLI |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | For progress of trial • Update on RNA analysis (sample movement, timelines): ready to send off samples from different sites, waiting for purchase order. Chris asked about ingenuity pathway analysis (IPA), but the licences are expensive and restrictive. This might be done at GSK. • Update on biomarker analysis (timelines): Have viral load data coming soon. The competition ELISAs are underway. FACS is being done re pre-F and post-F reagents awaited for Bmem analysis. There is a lot of T cell data to be analysed. Panel 1 (activation markers) might be done by a student. Want a pre-F stable M37 antigen from NIH. A2 not so relevant. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Inflammage Review Data set & Manuscript Planning |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | • Team introductions - 5mins Reviewing the Inlammage Part B data set and start to scope out manuscript planning from the primary data set.• . Outputs from RNASeq analysis (led by Chris F, supported by team members) - 55mins • Review of final symptom and biomarker data sets (led by Stef & Pete) - 30mins • Discussion of next steps (any further analysis actions) - 15mins • Discussion on manuscript preparation (All) - 15mins |
| Year(s) Of Engagement Activity | 2023 |
| Description | Inflammage Review Data set & Manuscript Planning February 2024 |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Study participants or study members |
| Results and Impact | to review continued analysis of INFLAMMAGE with the aim to arrive at a manuscript structure (potentially two separate publications). Outcome was: • Additional in vitro experiments - comparison of young vs old ALIs (confocal staining combined with functional and infection data) - Action Jo • Complete MSD analysis of lung cytokine samples from both young and old populations - Action Stef • Comparison of young adult D7 with old adult D28 - Action Emilio • Comparison of baseline of infected vs uninfected to see if there is anything obviously different in groups - Action Emilio • Manuscript 1 (Action Pete to draft) - focus on younger adults data set; transcriptomics and inflammatory markers from lower airways. Focus on cilia observations as novel. Include ALI data with functional endpoints and CXCR3 antagonist. • Manuscript 2 (Action Imperial to identify lead author(s) ) - focus on comparison of younger vs adult; kinetics and differences together with impaired immune response. Include MSD data and in vitro ALI comparison. |
| Year(s) Of Engagement Activity | 2024 |
| Description | Interview with BBC Drive Time Hereford and Worcester |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Expert reaction to study looking at long-term symptoms after other acute respiratory infections (including the common cold) versus after COVID-19, as published in eClinicalMedicine* discussed on local radio with two others. Dr David Strain and Professor Paul Harrison |
| Year(s) Of Engagement Activity | 2023 |
| Description | Interview with Luke Hanrahan of the BBC |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | This was an interview with regard to an update on the HIC VAC video |
| Year(s) Of Engagement Activity | 2023 |
| Description | Meeting to finalise Manuscript |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | Paper 3 - Inflammaging of Elderly Adults Impacts Immune response to RSV Hypothesis: older adults have subdued/delayed immune responses in lower airway than young (to be refined) DEGs in elderly brushings & biopsies BL infected vs uninfected D7 vs BL infected D28 vs BL infected TBD: uninfected D7 vs BL; uninfected D28 vs BL; D7 infected vs uninfected; D28 infected vs uninfected GSEA on all of above Comparison of GSEA between older & young Do kinetics or size of transcriptomic responses differ? MSD bronchial SAM data to confirm Consider lower airway flow/ICS data here Your latest heatmaps are great, but as they convey so much data in one figure, I think alone people can struggle to grasp it all - despite your nice annotations. I think the above should help guide and orientate. The above list is the main request but if you have the opportunity, I had a few additional suggestions that I think might add to the paper. Firstly, heatmaps of "leading edge" transcripts of the most interesting/relevant GO terms results (for clarity, I mean the most important genes that determine the enriched GSEA GO term) could be useful to see to highlight some expected genes (especially if DEGs don't show much). |
| Year(s) Of Engagement Activity | 2024 |
| Description | Monthly Meeting June 2022 |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | Welcoming new team member for translational statistical support for analysis for up coming data sets. • Potential antibody binding assay - Monkia and Alex presented slides on their multiplex immunoassays for humoral immunity which were well received (I'll ask in an email to them for non-conf slides if possible). Briefly, assay capable of measuring endpoints from serum, plasma, saliva and nasal samples, and will detect multiple (up to 500) antibodies at the same time. Platform is semi-automated, accepting 96 or 384 well input, resulting in ~1500 samples per day. Have recently focused on SARS-CoV2 assay, which now detects ~40 antigens and is easily updated with emerging variants. Platform can differentiate between vaccine immunity and infection. Future work to prioritise RSV, influenza and measles assays including varus variants. For RSV the assay has been created with various antigens already, with excellent intra and inter assay performance, dilution linearity, freeze thaw tolerance and reproducibility over time. Team are looking for well characterised sample sets to increase validation of assay and increase our understanding of disease biology. INFLAMMAGE (and wider Imperial projects) have access to well characterised samples which could benefit development and disease understanding. Volume required is 5ul, but typically request 20ul of each sample. Assay development would benefit from expert insight into new antigens to add to the assay against different targets (including specific Memphis37 strain used in challenge studies). Imperial could also potentially provide access to sample from outside the INFLAMMAGE project. ALI Cultures,. Recruitment updates |
| Year(s) Of Engagement Activity | 2022 |
| Description | Monthly Meeting to discuss recruitment |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | 1. Recruit and challenge non-smokers only. This will be the quickest way to complete the clinical study as we almost have the numbers already lined up, but would mean not doing something we originally proposed. 2. We make a protocol amendment to allow enrolment of non-smokers and smokers/ex-smokers with any pack year history. We then enrol 9 non-smokers (giving a total of 12 bronchoscoped non-smokers) and 9 smokers of any type (with the clinical team prioritising those with more pack years). In the meantime, we carry on looking for smokers with 20 pack years (recognising that we may not find any suitable). The amendment is likely to take 4-6 weeks plus local approvals. The other issue will be whether we have sufficient power to show anything with these subgroups. The major finding would be that RSV challenge in smokers is well tolerated. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Outcome from Dec 2022 Monthly Meeting |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | • Clinical Close out - all samples held, all D28 completed, first batch of D180 also captured. Previously agreed to process for RNASeq to avoid delays to timelines. We have duplicate biopsy samples which could be re-run with final D180 samples to understand any batch effect. Duplicate brushings samples retained for ALI culture work. • RNA sample timelines - obtaining quote from Genewiz, can ship in Dec - quote will include timeslines (Pete - any update on this?) This enables comparison with existing Imperial data sets for rapid analysis. Malcolm to explore additional GSK support on data uploading and potential analysis. • Biomarker analysis plans - All samples ready for analysis, with a number of downstream assays planned to fully interrogate the study. All symptom and demographic data collected - to be completed' viral load, IgA ELISA, serum IgG, neutrophil endpoints, flow cytometry endpoints including B-cell response, T-cell panels, BAL/serum/nasal MSDs • Statistical support - Agreed Stef and Rachel would set up time early in 2023 on analysis plan - data overview and appropriate tools and approaches to analysis to make ready for interpretation and future journal submission. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Outcome from Monthly Meeting Call |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Study participants or study members |
| Results and Impact | Update on recruitment Feedback from RSV Meeting Posters for BSI meeting Antigen Work marking progress. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Podcast Zoom - International Federation on Ageing | Podcast to Raise Awareness of hMPV | Recording Session with Dr. Peter Openshaw |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Podcast to raise Awareness of hMPV for the International Federation on Ageing |
| Year(s) Of Engagement Activity | 2024 |