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. There is currently no specific treatment for RSV disease and identification of 'druggable' inflammatory pathways would be of great potential clinical value. Observational studies of natural infection are constrained by sampling, timing and access. The aim of INFLAMMAGE is to investigate the mechanisms of inflammation in adult volunteers using experimental human RSV infections at Imperial College London. This will enable us to investigate the RSV infection in older adult non-smokers and smokers up to 75 years of age; using in vivo and in vitro techniques, we will attempt to define novel clinical end-points and to discover pathways and biomarkers that predict outcome. This will allow us to select from a range of promising drugs in GSK's development pipeline that inhibit specific inflammatory pathways. This next phase of INFLAMMAGE will enable us to predict the possible impact of treatment with validated novel anti-inflammatory agents from GSK in human RSV disease and to discover new treatments for viral exacerbations of chronic respiratory disease, including COPD. The testing of potential drugs in disease will form the future final phase of INFLAMAGE.

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

10 25 50

publication icon
Goya S (2020) Toward unified molecular surveillance of RSV: A proposal for genotype definition. in Influenza and other respiratory viruses

publication icon
McGrath BA (2020) Tracheostomy in the COVID-19 era: global and multidisciplinary guidance. in The Lancet. Respiratory medicine

 
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 08/2021
 
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 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 Senior Investigator Award
Amount £60,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2020 
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