REACT-GE: Multi-omics to identify biological pathways underlying severity of SARS-CoV-2 infection.

Lead Research Organisation: Imperial College London
Department Name: School of Public Health

Abstract

We know that some people are more at risk from COVID-19 than others, for instance if they are older, from a minority ethnic group or have other health conditions. But one of the biggest COVID-19 puzzles is why some people who are younger or previously fit develop very severe symptoms whilst people like them who are seemingly much more at risk, only get mild illness. One of the answers may lie in the genome, the body's instruction manual, and how it interacts with the environment. These interactions may protect or amplify the response to infection with the virus that causes COVID-19. This project brings together a leading international team of researchers with the expertise across different disciplines essential to be able to understand how the virus interacts with the body and to identify new treatment opportunities. It includes the research group which is responsible for patients that have been severely affected by COVID-19 and admitted to intensive care (GenOMICC) and the organisation that sequences and interprets genomes for the NHS (Genomics England) with the REal-time Assessment of Community Transmission (REACT) programme that is responsible for understanding how the virus spreads in the community. GenOMICC and Genomics England are already comparing the genomes and health data from two groups of people who tested positive for COVID-19; people recruited through hospitals who had severe COVID-19 against people who tested positive for COVID-19 but who either had no, or only mild, symptoms. The two groups are being matched for age and ethnicity. By partnering the REACT programme with this ongoing genome comparison we will be able to explore the interaction of the genome with the environment in up to 8,000 individuals who had mild or no symptoms and increase our knowledge about why these people responded more mildly than others. We will be using a so-called "multi-omics" approach, which means that we will not only be looking at the genome's instructions but how they are interpreted by the body at many different levels. This information is critical to understanding who is most at risk in the future and in being able to predict, prevent or treat COVID-19 more effectively. This partnership gives the best possible chance of recruiting the right number of people who have been infected with the virus but experienced no or only mild symptoms, undertaking the necessary research and of getting vital answers quickly in order to provide an effective response to the ongoing COVID-19 pandemic.

Technical Summary

COVID-19 is a new infectious disease responsible for a global pandemic and presenting major knowledge gaps with respect to disease susceptibility, severity of infection and disease mechanisms. While most individuals infected with SARS-CoV-2 virus are asymptomatic or mildly affected, a minority require hospitalisation, need assisted ventilation and some progress to respiratory or other organ failure/death. The mechanisms for these differences in susceptibility and severity of disease are unknown, but are likely to encompass a combination of genetic susceptibility and gene-environment interactions that lead to downstream biochemical disturbances. We have assembled a multi-disciplinary international team of leading researchers to address these knowledge gaps by applying a multi-omics approach encompassing whole genome sequencing (WGS), proteomic, transcriptomic and metabolomic analyses to mild/asymptomatic cases. We will delineate biological pathways that are protective of or deleterious to the response to SARS-CoV-2 infection that may identify novel targets for treatment and ultimately prevention of the disease (e.g. vaccine response). The partnership between REal-time Assessment of Community Transmission (REACT) and Genomics England (REACT-GE) brings together the DHSC-funded GenOMICC programme and the community-wide viral antigen and seroprevalence surveillance (REACT) platform identifying mild/asymptomatic SARS-CoV-2 positive people in the population. We propose that c.8000 mild/asymptomatic participants are recruited through the REACT study for which we will obtain a multi-omic resource to sit alongside WGS already funded, and thus enhance the biological richness and utility of the resource for drug target discovery. Specifically we propose to undertake a series of proteomics, transcriptomics and metabolomics analyses alongside WGS to provide an unparalleled resource for multiomic phenotyping and discovery.

Publications

10 25 50
 
Description In light of the current pandemic, the REACT study has been influential in providing the public (and policy makers) with up to date and authoritative accounts of the spread of the epidemic nationally, regionally and in at risk groups.
First Year Of Impact 2020
Sector Healthcare
Impact Types Societal,Policy & public services

 
Description REACT-GE (COVID controls)
Amount £1,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2020 
End 03/2021
 
Description Collaboration - DecodeME study 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to cleaned data from REACT-GE: use of mild and asymptomatic cohort data in the DecodeME study as controls incl. for people diagnosed with ME/CFS following COVID-19 infection.
Collaborator Contribution Coordination of the DecodeME study which is studying genetic factors underlying ME/CFS in patients following COVID-19 infection and liaison with REACT-GE on subjects for use as controls.
Impact Continuing collaboration
Start Year 2021
 
Description Collaboration - UK Coronavirus Immunology Consortium (UK-CIC) 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Recruitment of REACT-GE study participants and data/sample collection and data quality control. Study coordination and operational management. Collaborating on access to REACT-GE participants to take additional blood sample take part in another study to understand how the immune system works to eradicate/control the SARS-CoV-2 virus.
Collaborator Contribution Consortium effort and expertise in work to improve understanding of the immune response to coronavirus infection and to determine mechanisms of virus-specific immunity and how these relate to clinical outcome in different patient groups. Liaison with REACT-GE to contact participants to invite to take part in another study to understand how the immune system works to eradicate and control the SARS-CoV-2 virus.
Impact Collaboration in initial stages.
Start Year 2021
 
Description Genomics England collaborative partnership 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution Participant recruitment at field assessment centres, working with GE participant recruitment agency (MSS) on recruitment, training and study information. Provision of sample controls for sub-study of vaccine induced thrombosis and thrombocytopenia (VITT)
Collaborator Contribution Advice on participant recruitment procedures, operation of clinic assessment centres, data and sample collection tools and quality control, and database hosting/management.
Impact ongoing collaboration
Start Year 2020
 
Description REACT Long-Covid 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-PI for this study funded by NIHR.
Collaborator Contribution Imperial College lead the study.
Impact No impact yet.
Start Year 2021
 
Description REACT-GE Covid Study 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Member of the Research Delivery Steering Committee
Collaborator Contribution Member of the Research Delivery Steering Committee
Impact As per study website: https://www.imperial.ac.uk/medicine/research-and-impact/groups/react-study/
Start Year 2020
 
Description REACT-GE blood sample processing 
Organisation Affinity Biomarkers Laboratories
Country United Kingdom 
Sector Private 
PI Contribution Study concept, design, methodology, protocols and project coordination
Collaborator Contribution Blood sample processing facilities
Impact continuing collaboration
Start Year 2020
 
Description REACT-GE field centre nurse training and certification 
Organisation Medical Screening Solutions (MSS)
Country United Kingdom 
Sector Private 
PI Contribution Study concept, design, methodology and SOPs
Collaborator Contribution Provision of nurse personnel and responsibility for training and certification, operational participant recruitment procedures, health & safety at field centres
Impact continuing collaboration
Start Year 2020
 
Description REACT-GE sample genomic sequencing 
Organisation Illumina Inc.
Department Illumina Cambridge Limited
Country United Kingdom 
Sector Private 
PI Contribution Study concept, design and methodology, SOPs, project coordination
Collaborator Contribution Genomic sequencing of blood samples from participants
Impact continuing collaboration
Start Year 2020
 
Description REACT-GE spirometry measurements 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Study concept, design, methodology, SOPs, study coordination
Collaborator Contribution Expert advice on gold standard respiratory measurement protocols and specifically on spirometry
Impact ongoing collaboration
Start Year 2021