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.
Publications
Correia GDS
(2022)
1H NMR Signals from Urine Excreted Protein Are a Source of Bias in Probabilistic Quotient Normalization.
in Analytical chemistry
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
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
Park M
(2020)
COVID-19: Lessons from SARS and MERS
in European Journal of Immunology
Ascough S
(2022)
Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model.
in The lancet. Healthy longevity
Guvenel A
(2020)
Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection.
in The Journal of clinical investigation
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
| 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 | 08/2020 |
| End | 08/2021 |
| 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 | 10/2020 |
| 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 | 04/2017 |
| End | 03/2022 |
| Description | Senior Investigator Award |
| Amount | £60,000 (GBP) |
| Organisation | National Institute for Health Research |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2020 |
| End | 03/2021 |
| Description | EMINENT network |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | We will adopt a dual approach, studying RSV infection in naturally infected children and experimentally infected adult volunteers. We will identify aspects of the inflammatory and immunological signature that are common to both situations and those that are distinct. From the pathways identified, we will target drug intervention strategies that can be tested experimentally. The proposal is split into two main parts: The first objective will be to identify markers in the childhood disease that can subsequently be used to select endpoints which will be measured in an adult study: 1. A pilot clinical study measuring transcriptomic changes and mediator release will be conducted on samples taken from children admitted with RSV disease by obtaining blood, nasal scrapings, nasal adsorptive strip fluids, rhinoscope, bronchoscope and sputum samples as available. Similar samples will also be captured from adults infected with RSV. 2. Samples will be incubated in vitro with a select panel of inhibitors (PI3Ki, p38, CXCR2, CCR1 or other GSK clinically tested compounds) to deduce which pathway is most susceptible to inhibition, and is therefore optimal to progress into an intervention study in RSV infected adults. The second objective will be a drug intervention study driven by data obtained by the findings from the preclinical and clinical pilot work. 1. Symptomatic/ infected adults will be dosed with drug(s) (or placebo) for up to 7-days. Samples will be taken throughout the study period, with endpoints directed towards understanding the effects of drug intervention. Dosing with drug after onset of symptoms will mimic a clinically realistic clinical intervention scenario and early or delayed intervention will generate abundant translational data. 2. Subsequent clinical studies may test additional compounds, refine sensitive populations, or evaluate different dosing regimens. We envision that this work may also be of benefit to other patient groups with virally driven respiratory diseases, including patients with ARDS, interstitial pneumonitis, common colds, asthma, COPD, and pneumonia. This project could provide training opportunities for a PhD student and a clinical training fellow. |
| Collaborator Contribution | Objective: To establish a unique collaborative network between UK academic and GlaxoSmithKline (GSK) investigators with unprecedented access to GSK's extensive portfolio of advanced clinic-ready compounds and technology platforms to accelerate the understanding of disease mechanisms and the development of new therapeutic strategies for patients in under-served disease areas. Adopting a programmatic, milestone driven approach, the EMINENT network will work flexibly to characterise new innovative pathogenic mechanisms, new drug targets and biomarkers for patient stratification or predictive end points, and new treatment paradigms for prolonged remission or cure. Impacts of collaboration: Patient benefit The overall aim of the Network formed by this initiative is to collectively generate scientific advances and ultimately new therapeutic strategies for both rare and common diseases of high unmet medical need for which industry engagement has traditionally been poor. Projects supported through the EMINENT initiative will be selected to address key scientific questions to further our understanding of disease mechanism by maximally exploiting GSK's portfolio of marketed drugs, deprioritised compounds and compounds in active clinical development (live assets). The scientific focus will be centred on the three areas where there is optimal alignment between UK academia and GSK's UK Research and Development capabilities, and will ultimately lead to experimental medicine studies in humans to decipher new disease pathomechanisms. Each project will begin to develop a road-map for future investigation in these under-served disease areas, and thereby greatly increase the prospect that new therapeutic options are made available to patients within the shortest possible time-frame. Enhanced academic-industry partnerships in the UK This initiative is unique in that the named academic partners already have considerable experience in working successfully between themselves and with the industry partner. As well as enhancing this interaction, the initiative will enable an even greater depth of cross-institutional working and will be rested on the flexible sharing of resource and expertise across the academic centres. New training opportunities will also be provided for both early-career and established researchers within the Network, helping to build a legacy of enhanced expertise in translational and experimental human research. Each academic centre has a Biomedical Research Centre (BRC or Scottish equivalent) and, as part of this initiative, projects will be able to draw on the additional resource and expertise available through them. Importantly, there will also be a flow of knowledge back to the network and back to the BRCs. Information and new knowledge will flow freely throughout the network in the spirit of open-innovation so that new advances will be rapidly transferred from one disease area to the next and thereby maximise the impact of these discoveries for patient benefit. As such, it will pioneer a new model of partnership, which, if successful, could be replicated with other partners and in other areas of biomedicine. Training and capacity building This is a key deliverable for EMINENT. All project proposals will be required to demonstrate how early-career researchers will be engaged and supported as part of the proposed work plan. Building and enhancing UK expertise in experimental medicine will be a key output of the initiative with particular emphasis on the training of clinical fellows, PhD students and post-doctoral fellows in preclinical translational sciences and clinical trials. Cohesion across the network will be enabled in a number of ways: • PhD students and fellows will be assigned an off-campus supervisor/mentor, who will be based at another academic institution within the network. • Students will also be assigned an industry supervisor/mentor to encourage two-way flow of ideas between academia and industry. • We will instigate an inter-institutional post-doctoral mentoring scheme with the opportunity for all early career fellows to spend 3-6 month secondments at GSK in order to expose early-career researchers to the unique drug discovery environment at GSK. • All participants involved in this initiative will meet at least once a year by attending a two-day EMINENT symposium. As well as keynote presentations from industry and academic experts, the symposium will focus on communicating project progress and new scientific discoveries to the network via the submission of abstracts for oral and poster presentation, with prizes awarded for the best student/early career fellow presentation. • GSK scientists will also be strongly encouraged to undertake short-term secondments to an academic centre. Thus the established academic training already available within the participant academic organisations will be complemented by unique exposure to the pharmaceutical industry. The network formed between academic institutions will also provide invaluable opportunities for cross-fertilisation and capacity building across the network. Importantly, the added value of the academic network to training will also be provided by promoting the inter-institutional exchange of researchers in instances where this will benefit both the project aims and the future training and development of high calibre individuals. The training opportunities offered by EMINENT and its linked projects will be enhanced by linking with other established training networks, in particular the NIHR Infrastructure National Training Forum. Prof David Jones, the PI for the Newcastle Centre is Chair of this forum and is the National lead for Training in the NIHR Infrastructure Publication and dissemination of knowledge The EMINENT initiative is predicated on the understanding that new knowledge will be shared throughout the network in a spirit of openness and collaboration. All EMINENT PIs will attend bi-annual meetings to discuss the progress of current projects and emerging scientific data. One of these meetings will also be attended by junior researchers on the projects, providing an opportunity for them to present their work through poster presentations and short talks. These meetings will help foster the generation of new ideas and collaborations to enhance the success of the individual projects and the initiative as a whole. All data generated both pre-clinically and clinically will be submitted for publication in highly regarded peer reviewed journals and made available to the wider scientific community in full compliance with MRC publication and six months open-access policy (although allowing for statutory and regulatory commitments regarding clinical trials). This will maximise the potential for the new knowledge and increased disease understanding generated by the EMINENT initiative to benefit the global biomedical community and will greatly accelerate the development of novel therapeutic strategies for patients. |
| Impact | INFLAMMAGE Presentations: Preliminary findings from the elderly RSV challenge pilot study were presented as a poster at the RSVVW meeting in November 2019 by Stephanie Ascough. This is the foremost international RSV vaccines meeting and was well attended by both academic and industry stakeholders. The work was also highlighted at the meeting in Peter Openshaw's plenary talk. Dissemination of these findings enabled fruitful discussions with potential industry collaborators with an interest in accessing the model. Additionally, these findings fed into a successful recent EC IMI grant application on accelerating vaccine development, with the subtopic led by Dr Chiu due to incorporate the model to enable more accurate prediction of vaccine efficacy in the older adult population. |
| Start Year | 2019 |
| Description | EMINENT network |
| Organisation | University College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We will adopt a dual approach, studying RSV infection in naturally infected children and experimentally infected adult volunteers. We will identify aspects of the inflammatory and immunological signature that are common to both situations and those that are distinct. From the pathways identified, we will target drug intervention strategies that can be tested experimentally. The proposal is split into two main parts: The first objective will be to identify markers in the childhood disease that can subsequently be used to select endpoints which will be measured in an adult study: 1. A pilot clinical study measuring transcriptomic changes and mediator release will be conducted on samples taken from children admitted with RSV disease by obtaining blood, nasal scrapings, nasal adsorptive strip fluids, rhinoscope, bronchoscope and sputum samples as available. Similar samples will also be captured from adults infected with RSV. 2. Samples will be incubated in vitro with a select panel of inhibitors (PI3Ki, p38, CXCR2, CCR1 or other GSK clinically tested compounds) to deduce which pathway is most susceptible to inhibition, and is therefore optimal to progress into an intervention study in RSV infected adults. The second objective will be a drug intervention study driven by data obtained by the findings from the preclinical and clinical pilot work. 1. Symptomatic/ infected adults will be dosed with drug(s) (or placebo) for up to 7-days. Samples will be taken throughout the study period, with endpoints directed towards understanding the effects of drug intervention. Dosing with drug after onset of symptoms will mimic a clinically realistic clinical intervention scenario and early or delayed intervention will generate abundant translational data. 2. Subsequent clinical studies may test additional compounds, refine sensitive populations, or evaluate different dosing regimens. We envision that this work may also be of benefit to other patient groups with virally driven respiratory diseases, including patients with ARDS, interstitial pneumonitis, common colds, asthma, COPD, and pneumonia. This project could provide training opportunities for a PhD student and a clinical training fellow. |
| Collaborator Contribution | Objective: To establish a unique collaborative network between UK academic and GlaxoSmithKline (GSK) investigators with unprecedented access to GSK's extensive portfolio of advanced clinic-ready compounds and technology platforms to accelerate the understanding of disease mechanisms and the development of new therapeutic strategies for patients in under-served disease areas. Adopting a programmatic, milestone driven approach, the EMINENT network will work flexibly to characterise new innovative pathogenic mechanisms, new drug targets and biomarkers for patient stratification or predictive end points, and new treatment paradigms for prolonged remission or cure. Impacts of collaboration: Patient benefit The overall aim of the Network formed by this initiative is to collectively generate scientific advances and ultimately new therapeutic strategies for both rare and common diseases of high unmet medical need for which industry engagement has traditionally been poor. Projects supported through the EMINENT initiative will be selected to address key scientific questions to further our understanding of disease mechanism by maximally exploiting GSK's portfolio of marketed drugs, deprioritised compounds and compounds in active clinical development (live assets). The scientific focus will be centred on the three areas where there is optimal alignment between UK academia and GSK's UK Research and Development capabilities, and will ultimately lead to experimental medicine studies in humans to decipher new disease pathomechanisms. Each project will begin to develop a road-map for future investigation in these under-served disease areas, and thereby greatly increase the prospect that new therapeutic options are made available to patients within the shortest possible time-frame. Enhanced academic-industry partnerships in the UK This initiative is unique in that the named academic partners already have considerable experience in working successfully between themselves and with the industry partner. As well as enhancing this interaction, the initiative will enable an even greater depth of cross-institutional working and will be rested on the flexible sharing of resource and expertise across the academic centres. New training opportunities will also be provided for both early-career and established researchers within the Network, helping to build a legacy of enhanced expertise in translational and experimental human research. Each academic centre has a Biomedical Research Centre (BRC or Scottish equivalent) and, as part of this initiative, projects will be able to draw on the additional resource and expertise available through them. Importantly, there will also be a flow of knowledge back to the network and back to the BRCs. Information and new knowledge will flow freely throughout the network in the spirit of open-innovation so that new advances will be rapidly transferred from one disease area to the next and thereby maximise the impact of these discoveries for patient benefit. As such, it will pioneer a new model of partnership, which, if successful, could be replicated with other partners and in other areas of biomedicine. Training and capacity building This is a key deliverable for EMINENT. All project proposals will be required to demonstrate how early-career researchers will be engaged and supported as part of the proposed work plan. Building and enhancing UK expertise in experimental medicine will be a key output of the initiative with particular emphasis on the training of clinical fellows, PhD students and post-doctoral fellows in preclinical translational sciences and clinical trials. Cohesion across the network will be enabled in a number of ways: • PhD students and fellows will be assigned an off-campus supervisor/mentor, who will be based at another academic institution within the network. • Students will also be assigned an industry supervisor/mentor to encourage two-way flow of ideas between academia and industry. • We will instigate an inter-institutional post-doctoral mentoring scheme with the opportunity for all early career fellows to spend 3-6 month secondments at GSK in order to expose early-career researchers to the unique drug discovery environment at GSK. • All participants involved in this initiative will meet at least once a year by attending a two-day EMINENT symposium. As well as keynote presentations from industry and academic experts, the symposium will focus on communicating project progress and new scientific discoveries to the network via the submission of abstracts for oral and poster presentation, with prizes awarded for the best student/early career fellow presentation. • GSK scientists will also be strongly encouraged to undertake short-term secondments to an academic centre. Thus the established academic training already available within the participant academic organisations will be complemented by unique exposure to the pharmaceutical industry. The network formed between academic institutions will also provide invaluable opportunities for cross-fertilisation and capacity building across the network. Importantly, the added value of the academic network to training will also be provided by promoting the inter-institutional exchange of researchers in instances where this will benefit both the project aims and the future training and development of high calibre individuals. The training opportunities offered by EMINENT and its linked projects will be enhanced by linking with other established training networks, in particular the NIHR Infrastructure National Training Forum. Prof David Jones, the PI for the Newcastle Centre is Chair of this forum and is the National lead for Training in the NIHR Infrastructure Publication and dissemination of knowledge The EMINENT initiative is predicated on the understanding that new knowledge will be shared throughout the network in a spirit of openness and collaboration. All EMINENT PIs will attend bi-annual meetings to discuss the progress of current projects and emerging scientific data. One of these meetings will also be attended by junior researchers on the projects, providing an opportunity for them to present their work through poster presentations and short talks. These meetings will help foster the generation of new ideas and collaborations to enhance the success of the individual projects and the initiative as a whole. All data generated both pre-clinically and clinically will be submitted for publication in highly regarded peer reviewed journals and made available to the wider scientific community in full compliance with MRC publication and six months open-access policy (although allowing for statutory and regulatory commitments regarding clinical trials). This will maximise the potential for the new knowledge and increased disease understanding generated by the EMINENT initiative to benefit the global biomedical community and will greatly accelerate the development of novel therapeutic strategies for patients. |
| Impact | INFLAMMAGE Presentations: Preliminary findings from the elderly RSV challenge pilot study were presented as a poster at the RSVVW meeting in November 2019 by Stephanie Ascough. This is the foremost international RSV vaccines meeting and was well attended by both academic and industry stakeholders. The work was also highlighted at the meeting in Peter Openshaw's plenary talk. Dissemination of these findings enabled fruitful discussions with potential industry collaborators with an interest in accessing the model. Additionally, these findings fed into a successful recent EC IMI grant application on accelerating vaccine development, with the subtopic led by Dr Chiu due to incorporate the model to enable more accurate prediction of vaccine efficacy in the older adult population. |
| Start Year | 2019 |
| Description | EMINENT network |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We will adopt a dual approach, studying RSV infection in naturally infected children and experimentally infected adult volunteers. We will identify aspects of the inflammatory and immunological signature that are common to both situations and those that are distinct. From the pathways identified, we will target drug intervention strategies that can be tested experimentally. The proposal is split into two main parts: The first objective will be to identify markers in the childhood disease that can subsequently be used to select endpoints which will be measured in an adult study: 1. A pilot clinical study measuring transcriptomic changes and mediator release will be conducted on samples taken from children admitted with RSV disease by obtaining blood, nasal scrapings, nasal adsorptive strip fluids, rhinoscope, bronchoscope and sputum samples as available. Similar samples will also be captured from adults infected with RSV. 2. Samples will be incubated in vitro with a select panel of inhibitors (PI3Ki, p38, CXCR2, CCR1 or other GSK clinically tested compounds) to deduce which pathway is most susceptible to inhibition, and is therefore optimal to progress into an intervention study in RSV infected adults. The second objective will be a drug intervention study driven by data obtained by the findings from the preclinical and clinical pilot work. 1. Symptomatic/ infected adults will be dosed with drug(s) (or placebo) for up to 7-days. Samples will be taken throughout the study period, with endpoints directed towards understanding the effects of drug intervention. Dosing with drug after onset of symptoms will mimic a clinically realistic clinical intervention scenario and early or delayed intervention will generate abundant translational data. 2. Subsequent clinical studies may test additional compounds, refine sensitive populations, or evaluate different dosing regimens. We envision that this work may also be of benefit to other patient groups with virally driven respiratory diseases, including patients with ARDS, interstitial pneumonitis, common colds, asthma, COPD, and pneumonia. This project could provide training opportunities for a PhD student and a clinical training fellow. |
| Collaborator Contribution | Objective: To establish a unique collaborative network between UK academic and GlaxoSmithKline (GSK) investigators with unprecedented access to GSK's extensive portfolio of advanced clinic-ready compounds and technology platforms to accelerate the understanding of disease mechanisms and the development of new therapeutic strategies for patients in under-served disease areas. Adopting a programmatic, milestone driven approach, the EMINENT network will work flexibly to characterise new innovative pathogenic mechanisms, new drug targets and biomarkers for patient stratification or predictive end points, and new treatment paradigms for prolonged remission or cure. Impacts of collaboration: Patient benefit The overall aim of the Network formed by this initiative is to collectively generate scientific advances and ultimately new therapeutic strategies for both rare and common diseases of high unmet medical need for which industry engagement has traditionally been poor. Projects supported through the EMINENT initiative will be selected to address key scientific questions to further our understanding of disease mechanism by maximally exploiting GSK's portfolio of marketed drugs, deprioritised compounds and compounds in active clinical development (live assets). The scientific focus will be centred on the three areas where there is optimal alignment between UK academia and GSK's UK Research and Development capabilities, and will ultimately lead to experimental medicine studies in humans to decipher new disease pathomechanisms. Each project will begin to develop a road-map for future investigation in these under-served disease areas, and thereby greatly increase the prospect that new therapeutic options are made available to patients within the shortest possible time-frame. Enhanced academic-industry partnerships in the UK This initiative is unique in that the named academic partners already have considerable experience in working successfully between themselves and with the industry partner. As well as enhancing this interaction, the initiative will enable an even greater depth of cross-institutional working and will be rested on the flexible sharing of resource and expertise across the academic centres. New training opportunities will also be provided for both early-career and established researchers within the Network, helping to build a legacy of enhanced expertise in translational and experimental human research. Each academic centre has a Biomedical Research Centre (BRC or Scottish equivalent) and, as part of this initiative, projects will be able to draw on the additional resource and expertise available through them. Importantly, there will also be a flow of knowledge back to the network and back to the BRCs. Information and new knowledge will flow freely throughout the network in the spirit of open-innovation so that new advances will be rapidly transferred from one disease area to the next and thereby maximise the impact of these discoveries for patient benefit. As such, it will pioneer a new model of partnership, which, if successful, could be replicated with other partners and in other areas of biomedicine. Training and capacity building This is a key deliverable for EMINENT. All project proposals will be required to demonstrate how early-career researchers will be engaged and supported as part of the proposed work plan. Building and enhancing UK expertise in experimental medicine will be a key output of the initiative with particular emphasis on the training of clinical fellows, PhD students and post-doctoral fellows in preclinical translational sciences and clinical trials. Cohesion across the network will be enabled in a number of ways: • PhD students and fellows will be assigned an off-campus supervisor/mentor, who will be based at another academic institution within the network. • Students will also be assigned an industry supervisor/mentor to encourage two-way flow of ideas between academia and industry. • We will instigate an inter-institutional post-doctoral mentoring scheme with the opportunity for all early career fellows to spend 3-6 month secondments at GSK in order to expose early-career researchers to the unique drug discovery environment at GSK. • All participants involved in this initiative will meet at least once a year by attending a two-day EMINENT symposium. As well as keynote presentations from industry and academic experts, the symposium will focus on communicating project progress and new scientific discoveries to the network via the submission of abstracts for oral and poster presentation, with prizes awarded for the best student/early career fellow presentation. • GSK scientists will also be strongly encouraged to undertake short-term secondments to an academic centre. Thus the established academic training already available within the participant academic organisations will be complemented by unique exposure to the pharmaceutical industry. The network formed between academic institutions will also provide invaluable opportunities for cross-fertilisation and capacity building across the network. Importantly, the added value of the academic network to training will also be provided by promoting the inter-institutional exchange of researchers in instances where this will benefit both the project aims and the future training and development of high calibre individuals. The training opportunities offered by EMINENT and its linked projects will be enhanced by linking with other established training networks, in particular the NIHR Infrastructure National Training Forum. Prof David Jones, the PI for the Newcastle Centre is Chair of this forum and is the National lead for Training in the NIHR Infrastructure Publication and dissemination of knowledge The EMINENT initiative is predicated on the understanding that new knowledge will be shared throughout the network in a spirit of openness and collaboration. All EMINENT PIs will attend bi-annual meetings to discuss the progress of current projects and emerging scientific data. One of these meetings will also be attended by junior researchers on the projects, providing an opportunity for them to present their work through poster presentations and short talks. These meetings will help foster the generation of new ideas and collaborations to enhance the success of the individual projects and the initiative as a whole. All data generated both pre-clinically and clinically will be submitted for publication in highly regarded peer reviewed journals and made available to the wider scientific community in full compliance with MRC publication and six months open-access policy (although allowing for statutory and regulatory commitments regarding clinical trials). This will maximise the potential for the new knowledge and increased disease understanding generated by the EMINENT initiative to benefit the global biomedical community and will greatly accelerate the development of novel therapeutic strategies for patients. |
| Impact | INFLAMMAGE Presentations: Preliminary findings from the elderly RSV challenge pilot study were presented as a poster at the RSVVW meeting in November 2019 by Stephanie Ascough. This is the foremost international RSV vaccines meeting and was well attended by both academic and industry stakeholders. The work was also highlighted at the meeting in Peter Openshaw's plenary talk. Dissemination of these findings enabled fruitful discussions with potential industry collaborators with an interest in accessing the model. Additionally, these findings fed into a successful recent EC IMI grant application on accelerating vaccine development, with the subtopic led by Dr Chiu due to incorporate the model to enable more accurate prediction of vaccine efficacy in the older adult population. |
| Start Year | 2019 |
| Description | EMINENT network |
| Organisation | University of Glasgow |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We will adopt a dual approach, studying RSV infection in naturally infected children and experimentally infected adult volunteers. We will identify aspects of the inflammatory and immunological signature that are common to both situations and those that are distinct. From the pathways identified, we will target drug intervention strategies that can be tested experimentally. The proposal is split into two main parts: The first objective will be to identify markers in the childhood disease that can subsequently be used to select endpoints which will be measured in an adult study: 1. A pilot clinical study measuring transcriptomic changes and mediator release will be conducted on samples taken from children admitted with RSV disease by obtaining blood, nasal scrapings, nasal adsorptive strip fluids, rhinoscope, bronchoscope and sputum samples as available. Similar samples will also be captured from adults infected with RSV. 2. Samples will be incubated in vitro with a select panel of inhibitors (PI3Ki, p38, CXCR2, CCR1 or other GSK clinically tested compounds) to deduce which pathway is most susceptible to inhibition, and is therefore optimal to progress into an intervention study in RSV infected adults. The second objective will be a drug intervention study driven by data obtained by the findings from the preclinical and clinical pilot work. 1. Symptomatic/ infected adults will be dosed with drug(s) (or placebo) for up to 7-days. Samples will be taken throughout the study period, with endpoints directed towards understanding the effects of drug intervention. Dosing with drug after onset of symptoms will mimic a clinically realistic clinical intervention scenario and early or delayed intervention will generate abundant translational data. 2. Subsequent clinical studies may test additional compounds, refine sensitive populations, or evaluate different dosing regimens. We envision that this work may also be of benefit to other patient groups with virally driven respiratory diseases, including patients with ARDS, interstitial pneumonitis, common colds, asthma, COPD, and pneumonia. This project could provide training opportunities for a PhD student and a clinical training fellow. |
| Collaborator Contribution | Objective: To establish a unique collaborative network between UK academic and GlaxoSmithKline (GSK) investigators with unprecedented access to GSK's extensive portfolio of advanced clinic-ready compounds and technology platforms to accelerate the understanding of disease mechanisms and the development of new therapeutic strategies for patients in under-served disease areas. Adopting a programmatic, milestone driven approach, the EMINENT network will work flexibly to characterise new innovative pathogenic mechanisms, new drug targets and biomarkers for patient stratification or predictive end points, and new treatment paradigms for prolonged remission or cure. Impacts of collaboration: Patient benefit The overall aim of the Network formed by this initiative is to collectively generate scientific advances and ultimately new therapeutic strategies for both rare and common diseases of high unmet medical need for which industry engagement has traditionally been poor. Projects supported through the EMINENT initiative will be selected to address key scientific questions to further our understanding of disease mechanism by maximally exploiting GSK's portfolio of marketed drugs, deprioritised compounds and compounds in active clinical development (live assets). The scientific focus will be centred on the three areas where there is optimal alignment between UK academia and GSK's UK Research and Development capabilities, and will ultimately lead to experimental medicine studies in humans to decipher new disease pathomechanisms. Each project will begin to develop a road-map for future investigation in these under-served disease areas, and thereby greatly increase the prospect that new therapeutic options are made available to patients within the shortest possible time-frame. Enhanced academic-industry partnerships in the UK This initiative is unique in that the named academic partners already have considerable experience in working successfully between themselves and with the industry partner. As well as enhancing this interaction, the initiative will enable an even greater depth of cross-institutional working and will be rested on the flexible sharing of resource and expertise across the academic centres. New training opportunities will also be provided for both early-career and established researchers within the Network, helping to build a legacy of enhanced expertise in translational and experimental human research. Each academic centre has a Biomedical Research Centre (BRC or Scottish equivalent) and, as part of this initiative, projects will be able to draw on the additional resource and expertise available through them. Importantly, there will also be a flow of knowledge back to the network and back to the BRCs. Information and new knowledge will flow freely throughout the network in the spirit of open-innovation so that new advances will be rapidly transferred from one disease area to the next and thereby maximise the impact of these discoveries for patient benefit. As such, it will pioneer a new model of partnership, which, if successful, could be replicated with other partners and in other areas of biomedicine. Training and capacity building This is a key deliverable for EMINENT. All project proposals will be required to demonstrate how early-career researchers will be engaged and supported as part of the proposed work plan. Building and enhancing UK expertise in experimental medicine will be a key output of the initiative with particular emphasis on the training of clinical fellows, PhD students and post-doctoral fellows in preclinical translational sciences and clinical trials. Cohesion across the network will be enabled in a number of ways: • PhD students and fellows will be assigned an off-campus supervisor/mentor, who will be based at another academic institution within the network. • Students will also be assigned an industry supervisor/mentor to encourage two-way flow of ideas between academia and industry. • We will instigate an inter-institutional post-doctoral mentoring scheme with the opportunity for all early career fellows to spend 3-6 month secondments at GSK in order to expose early-career researchers to the unique drug discovery environment at GSK. • All participants involved in this initiative will meet at least once a year by attending a two-day EMINENT symposium. As well as keynote presentations from industry and academic experts, the symposium will focus on communicating project progress and new scientific discoveries to the network via the submission of abstracts for oral and poster presentation, with prizes awarded for the best student/early career fellow presentation. • GSK scientists will also be strongly encouraged to undertake short-term secondments to an academic centre. Thus the established academic training already available within the participant academic organisations will be complemented by unique exposure to the pharmaceutical industry. The network formed between academic institutions will also provide invaluable opportunities for cross-fertilisation and capacity building across the network. Importantly, the added value of the academic network to training will also be provided by promoting the inter-institutional exchange of researchers in instances where this will benefit both the project aims and the future training and development of high calibre individuals. The training opportunities offered by EMINENT and its linked projects will be enhanced by linking with other established training networks, in particular the NIHR Infrastructure National Training Forum. Prof David Jones, the PI for the Newcastle Centre is Chair of this forum and is the National lead for Training in the NIHR Infrastructure Publication and dissemination of knowledge The EMINENT initiative is predicated on the understanding that new knowledge will be shared throughout the network in a spirit of openness and collaboration. All EMINENT PIs will attend bi-annual meetings to discuss the progress of current projects and emerging scientific data. One of these meetings will also be attended by junior researchers on the projects, providing an opportunity for them to present their work through poster presentations and short talks. These meetings will help foster the generation of new ideas and collaborations to enhance the success of the individual projects and the initiative as a whole. All data generated both pre-clinically and clinically will be submitted for publication in highly regarded peer reviewed journals and made available to the wider scientific community in full compliance with MRC publication and six months open-access policy (although allowing for statutory and regulatory commitments regarding clinical trials). This will maximise the potential for the new knowledge and increased disease understanding generated by the EMINENT initiative to benefit the global biomedical community and will greatly accelerate the development of novel therapeutic strategies for patients. |
| Impact | INFLAMMAGE Presentations: Preliminary findings from the elderly RSV challenge pilot study were presented as a poster at the RSVVW meeting in November 2019 by Stephanie Ascough. This is the foremost international RSV vaccines meeting and was well attended by both academic and industry stakeholders. The work was also highlighted at the meeting in Peter Openshaw's plenary talk. Dissemination of these findings enabled fruitful discussions with potential industry collaborators with an interest in accessing the model. Additionally, these findings fed into a successful recent EC IMI grant application on accelerating vaccine development, with the subtopic led by Dr Chiu due to incorporate the model to enable more accurate prediction of vaccine efficacy in the older adult population. |
| Start Year | 2019 |
| Description | EMINENT network |
| Organisation | University of Newcastle |
| Country | Australia |
| Sector | Academic/University |
| PI Contribution | We will adopt a dual approach, studying RSV infection in naturally infected children and experimentally infected adult volunteers. We will identify aspects of the inflammatory and immunological signature that are common to both situations and those that are distinct. From the pathways identified, we will target drug intervention strategies that can be tested experimentally. The proposal is split into two main parts: The first objective will be to identify markers in the childhood disease that can subsequently be used to select endpoints which will be measured in an adult study: 1. A pilot clinical study measuring transcriptomic changes and mediator release will be conducted on samples taken from children admitted with RSV disease by obtaining blood, nasal scrapings, nasal adsorptive strip fluids, rhinoscope, bronchoscope and sputum samples as available. Similar samples will also be captured from adults infected with RSV. 2. Samples will be incubated in vitro with a select panel of inhibitors (PI3Ki, p38, CXCR2, CCR1 or other GSK clinically tested compounds) to deduce which pathway is most susceptible to inhibition, and is therefore optimal to progress into an intervention study in RSV infected adults. The second objective will be a drug intervention study driven by data obtained by the findings from the preclinical and clinical pilot work. 1. Symptomatic/ infected adults will be dosed with drug(s) (or placebo) for up to 7-days. Samples will be taken throughout the study period, with endpoints directed towards understanding the effects of drug intervention. Dosing with drug after onset of symptoms will mimic a clinically realistic clinical intervention scenario and early or delayed intervention will generate abundant translational data. 2. Subsequent clinical studies may test additional compounds, refine sensitive populations, or evaluate different dosing regimens. We envision that this work may also be of benefit to other patient groups with virally driven respiratory diseases, including patients with ARDS, interstitial pneumonitis, common colds, asthma, COPD, and pneumonia. This project could provide training opportunities for a PhD student and a clinical training fellow. |
| Collaborator Contribution | Objective: To establish a unique collaborative network between UK academic and GlaxoSmithKline (GSK) investigators with unprecedented access to GSK's extensive portfolio of advanced clinic-ready compounds and technology platforms to accelerate the understanding of disease mechanisms and the development of new therapeutic strategies for patients in under-served disease areas. Adopting a programmatic, milestone driven approach, the EMINENT network will work flexibly to characterise new innovative pathogenic mechanisms, new drug targets and biomarkers for patient stratification or predictive end points, and new treatment paradigms for prolonged remission or cure. Impacts of collaboration: Patient benefit The overall aim of the Network formed by this initiative is to collectively generate scientific advances and ultimately new therapeutic strategies for both rare and common diseases of high unmet medical need for which industry engagement has traditionally been poor. Projects supported through the EMINENT initiative will be selected to address key scientific questions to further our understanding of disease mechanism by maximally exploiting GSK's portfolio of marketed drugs, deprioritised compounds and compounds in active clinical development (live assets). The scientific focus will be centred on the three areas where there is optimal alignment between UK academia and GSK's UK Research and Development capabilities, and will ultimately lead to experimental medicine studies in humans to decipher new disease pathomechanisms. Each project will begin to develop a road-map for future investigation in these under-served disease areas, and thereby greatly increase the prospect that new therapeutic options are made available to patients within the shortest possible time-frame. Enhanced academic-industry partnerships in the UK This initiative is unique in that the named academic partners already have considerable experience in working successfully between themselves and with the industry partner. As well as enhancing this interaction, the initiative will enable an even greater depth of cross-institutional working and will be rested on the flexible sharing of resource and expertise across the academic centres. New training opportunities will also be provided for both early-career and established researchers within the Network, helping to build a legacy of enhanced expertise in translational and experimental human research. Each academic centre has a Biomedical Research Centre (BRC or Scottish equivalent) and, as part of this initiative, projects will be able to draw on the additional resource and expertise available through them. Importantly, there will also be a flow of knowledge back to the network and back to the BRCs. Information and new knowledge will flow freely throughout the network in the spirit of open-innovation so that new advances will be rapidly transferred from one disease area to the next and thereby maximise the impact of these discoveries for patient benefit. As such, it will pioneer a new model of partnership, which, if successful, could be replicated with other partners and in other areas of biomedicine. Training and capacity building This is a key deliverable for EMINENT. All project proposals will be required to demonstrate how early-career researchers will be engaged and supported as part of the proposed work plan. Building and enhancing UK expertise in experimental medicine will be a key output of the initiative with particular emphasis on the training of clinical fellows, PhD students and post-doctoral fellows in preclinical translational sciences and clinical trials. Cohesion across the network will be enabled in a number of ways: • PhD students and fellows will be assigned an off-campus supervisor/mentor, who will be based at another academic institution within the network. • Students will also be assigned an industry supervisor/mentor to encourage two-way flow of ideas between academia and industry. • We will instigate an inter-institutional post-doctoral mentoring scheme with the opportunity for all early career fellows to spend 3-6 month secondments at GSK in order to expose early-career researchers to the unique drug discovery environment at GSK. • All participants involved in this initiative will meet at least once a year by attending a two-day EMINENT symposium. As well as keynote presentations from industry and academic experts, the symposium will focus on communicating project progress and new scientific discoveries to the network via the submission of abstracts for oral and poster presentation, with prizes awarded for the best student/early career fellow presentation. • GSK scientists will also be strongly encouraged to undertake short-term secondments to an academic centre. Thus the established academic training already available within the participant academic organisations will be complemented by unique exposure to the pharmaceutical industry. The network formed between academic institutions will also provide invaluable opportunities for cross-fertilisation and capacity building across the network. Importantly, the added value of the academic network to training will also be provided by promoting the inter-institutional exchange of researchers in instances where this will benefit both the project aims and the future training and development of high calibre individuals. The training opportunities offered by EMINENT and its linked projects will be enhanced by linking with other established training networks, in particular the NIHR Infrastructure National Training Forum. Prof David Jones, the PI for the Newcastle Centre is Chair of this forum and is the National lead for Training in the NIHR Infrastructure Publication and dissemination of knowledge The EMINENT initiative is predicated on the understanding that new knowledge will be shared throughout the network in a spirit of openness and collaboration. All EMINENT PIs will attend bi-annual meetings to discuss the progress of current projects and emerging scientific data. One of these meetings will also be attended by junior researchers on the projects, providing an opportunity for them to present their work through poster presentations and short talks. These meetings will help foster the generation of new ideas and collaborations to enhance the success of the individual projects and the initiative as a whole. All data generated both pre-clinically and clinically will be submitted for publication in highly regarded peer reviewed journals and made available to the wider scientific community in full compliance with MRC publication and six months open-access policy (although allowing for statutory and regulatory commitments regarding clinical trials). This will maximise the potential for the new knowledge and increased disease understanding generated by the EMINENT initiative to benefit the global biomedical community and will greatly accelerate the development of novel therapeutic strategies for patients. |
| Impact | INFLAMMAGE Presentations: Preliminary findings from the elderly RSV challenge pilot study were presented as a poster at the RSVVW meeting in November 2019 by Stephanie Ascough. This is the foremost international RSV vaccines meeting and was well attended by both academic and industry stakeholders. The work was also highlighted at the meeting in Peter Openshaw's plenary talk. Dissemination of these findings enabled fruitful discussions with potential industry collaborators with an interest in accessing the model. Additionally, these findings fed into a successful recent EC IMI grant application on accelerating vaccine development, with the subtopic led by Dr Chiu due to incorporate the model to enable more accurate prediction of vaccine efficacy in the older adult population. |
| Start Year | 2019 |
| 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 | 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 |