NIHRDataInsights/HRCSData huggingface dataset:
Title: Colliding crises: antimicrobial resistance and ageing
Funder: Medical Research Council

Abstract: Antimicrobial resistance (AMR) is on the rise, making infections harder to treat and prevent. This public health crisis collides with an increasing population of individuals at substantially higher risk of bacterial infection (the elderly). However, the prevalence of AMR in infection by host age varies by bacteria and antibiotic in a currently unexplained dynamic. In this project, I will fill this knowledge gap by providing the first systematic analysis and mapping, across countries, of trends in AMR prevalence in infection by host age. I will then determine what drives these patterns: "recent" or "distant" AMR acquisition events such as antibiotic exposure or transmission. To do this I will statistically analyse large, detailed individual-patient level data. This approach will be complemented by cohort simulation modelling to determine the relative contribution of different AMR drivers. I will use the conclusions from these two strands of work to inform improved empiric prescribing design and tailored interventions against AMR. Key goals will be the mapping and dissection of the complexity of AMR, by exploiting the host age dimension. With this detail, I can further quantify the dynamics of AMR drivers, leading to an increased understanding of risks of infection with, and the origins of, AMR.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Unlock PsA: Stratifying the Impact of Psoriatic Arthritis in Children and Adults
Funder: Medical Research Council

Abstract: Background: Remission rates in both childhood-onset and adult-onset PsA remain low, with patient-reported outcomes reported for years after diagnosis. There are likely strata of PsA with different impacts of disease and response to treatment. New methods in artificial intelligence can identify and characterise these strata to understand which people have an unmet need for different early treatment options. Key Goals: Identification of previously undetected disease strata within PsA in which to embed a stratified treatment programme, through: 1) Uncovering clusters of people with different of PsA feature combinations 2) Characterising the impact of disease across clusters 3) Uncovering patterns of disease impact following initial disease-modifying drug 'methotrexate' 4) Pooling and mapping commonalities between childhood and adult-onset PsA Methods: Children, young people and adults will be selected from six multicentre inception cohorts of PsA from across the UK, Europe and Canada. Novel methods in artificial intelligence will identify and characterise clusters at diagnosis, find causal pathways between combinations of disease feature and patient-reported outcomes, and uncover novel multivariate disease patterns following methotrexate therapy. Childhood and adult-onset PsA will then be pooled to understand whether disease clusters are common across all ages or whether these are distinct diseases requiring different treatment approaches. Impacts: This work will form the basis for a stratified treatment programme across childhood and adult-onset PsA. Identifying which combinations of disease features are impacted across PsA clusters will facilitate earlier therapy from across multiple disciplines of allied healthcare. A tool will identify likely methotrexate response across multiple impacts of disease, so that targeted anti-rheumatic therapies can be given to the right people, lessening time to remission and the burden of disease


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Mass evaluation of lateral flow immunoassays for the detection of SARS-CoV-2 antibody responses in immunosuppressed people (MELODY Study)
Funder: Medical Research Council

Abstract: The MELODY Study aims to assess: 1. The proportion of immunosuppressed patients who have detectable SARS-CoV-2 antibodies following a primary vaccine course (3 doses), and the demographic, disease, and treatment characteristics that influence antibody status. 2. If the detection of antibodies inversely correlates with subsequent risk of SARS-CoV2 infection and/or severity of disease. Building on the successful methodology used in the REACT2 Study (community assessment of SARS-CoV-2 antibody tests), the study will assess self-administered LFIAs in 36,000 patients, who have completed their primary COVID-19 vaccination course. The study will recruit; a) solid organ transplant recipients, b) patients with autoimmune diseases receiving immunosuppression, c) patients with haematological malignancies. The study will utilise the digital web platform and research expertise of Ipsos MORI linked with the patient registries, UK Transplant Registry and National Disease Registration Service (NDRS) at Public Health England, which comprises the National Cancer Registration and Analysis Service (NCRAS) and the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). Patients will be recruited following a letter of invitation or via an 'opt-in' option on the study web portal. Once consent is registered via the portal, a LFIA kit will be sent to the participant together with instructions to use. Participants will be required to fill in a brief questionnaire and to upload the results of their tests, together with a photograph of the test using a mobile phone, if possible. Once all the data is returned, Ipsos MORI will collate and send the data back to the registries for analysis. The registries will subsequently capture all RT-qPCR proven infection episodes and outcomes over the course of the 6 month study period, and compare outcomes by antibody status.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Reprogramming human T cells for disease tolerance in falciparum malaria
Funder: Medical Research Council

Abstract: Immunity to malaria is a two-step process. First, individuals acquire protection against severe life-threatening disease (often before 12-months of age) and then after many years of exposure protection against febrile malaria is established, which promotes the transition to asymptomatic infection. Immunity to febrile malaria coincides with control of parasite burden (and is therefore supported by mechanisms of host resistance) whereas immunity to severe malaria is acquired independently of pathogen load and is a form of disease tolerance. All current malaria control programmes are designed to minimise exposure or promote host resistance; breakthrough infections can therefore lead to severe disease. If we can elucidate the mechanisms that underpin disease tolerance it may be possible to implement additional control measures that are specifically designed to reduce malaria mortality. In 2018 we developed a human rechallenge model of falciparum malaria to track the development of disease tolerance in real-time in a clinical setting. Our data indicate that reprogramming of adaptive T cells to minimise collateral tissue damage and the harm caused by parasite sequestration underpins immunity to severe malaria. In this programme of work we will perform detailed mechanistic in vivo human studies to reveal the cellular and molecular basis of disease tolerance. Specifically, we will interrogate T cell activation and pathogenicity during a first-in-life infection; ask whether T cell reprogramming is protective upon rechallenge; and determine whether disease tolerance requires cell-intrinsic modifications or tissue remodelling. Importantly, we will also ask whether tolerance has any long-term fitness costs, such as delaying host resistance mechanisms or suppressing immune responses to heterologous antigens or vaccines. Collectively, these experiments can provide a clear path to control programmes that promote tolerance to reduce mortality.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The Language of Zoonosis: Rationalising Receptor-Mediated Spillover of Viral Pathogens at a Molecular Level
Funder: Medical Research Council

Abstract: Genome sequencing initiatives across the globe have expanded our appreciation of the viral universe, clarifying viral diversity, evolution, and distribution. However, despite the conceptual advances achieved from these studies, highly virulent RNA viruses, which exhibit rapid disease progression and high mortality rates, continue to emerge and pose a threat to human health. The research programme proposed here is founded on the hypothesis that detailed knowledge of the mechanics of pathogen transmission will inform on strategies to predict and prevent the emergence of infectious diseases. Maintaining a particular focus on paramyxoviruses, which exhibit some of the highest rates of cross-species transmission, I will utilise a multidisciplinary structural and functional approach to: (i) address the molecular mechanism underlying receptor-mediated entry of a virus into a host-cell, (ii) define virus-host receptor interaction specificity and use this information to rationalise viral spillover into new host species, and (iii) clarify the interplay between a virus and the host humoral immune response during infection. This work will decipher the molecular-level language of zoonosis, both allowing the development of structure-based strategies for predicting viral spillover and strengthening our preparedness for future epidemics, if and when they occur.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Can malaria transmission be prevented through catastrophic failure of gametocyte quiescence?
Funder: Medical Research Council

Abstract: Malaria propagates when Plasmodium male and female gametocytes transmit from humans to mosquitoes. Interrupting this reduces new cases of malaria and the spread of drug resistance, therefore is a recognised therapeutic priority. Gametocytes have no control over when a mosquito bites, and so become quiescent for up to 22 days to maximise their chance of transmission. Mitochondrial (MT) respiration is essential for parasites in the mosquito, however blood stage parasites favour anaerobic respiration. Gametocytes develop a large cristate mitochondrion in readiness for transmission however they divert glucose metabolism away from the mitochondrion and excrete it as acetate. I hypothesise that strong MT activity in quiescent gametocytes will interfere with their dormant lifestyle in humans, and so gametocytes have been forced to develop novel (and potentially drug-targetable) mechanisms to tightly regulate glucose metabolism and thus prevent unwanted MT oxidative damage that would limit their lifespan. Through proteomic analysis I have identified 4 genes specifically expressed by gametocytes that replace or supplement key steps in glycolysis and parasite energy metabolism, including the enzyme putatively responsible for diverting glucose metabolism to acetate and an alternative isoform of phosphofructokinase lacking catalytic residues. I will study their function and essentiality through conditional gene deletion, phenotypic analysis during mosquito transmission, and activity of recombinant protein. I will also study their effects on glucose utilisation through 13C-glucose incorporation and metabolomic analysis. Finally, to discover further regulators of the gametocyte quiescence phenotype, I will track protein synthesis in male and female gametocytes using metabolic labelling to compare and contrast their quiescent proteomes by mass spectroscopy. In this way, I will identify new transmission-blocking drug targets for exploitation to ultimately aid malaria eradication.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: COVID-19 Genomics UK Consortium (COG-UK)
Funder: Medical Research Council

Abstract: MRC are investing £6m through the COVID-19 Genomics UK (COG-UK) consortium (COG-UK), which has received a total of £20.79m in partnership with DHSC and Wellcome, to a large scale and rapid SARS-CoV-2 sequencing capacity and share this knowledge with hospitals and the NHS. Other contributions are from DHSC and Wellcome via Wellcome Sanger. The current COVID-19 pandemic represents a major threat to health in the UK and globally. SARS-CoV-2 whole genome sequencing capacity in UK NHS clinical microbiology network and within Public Health England (PHE) is of limited daily capacity. However, the UK has world leading expertise in genomics within PHE, at multiple regional University hubs, and within large centres such as the Wellcome Sanger Institute. The proposed COVID-19 Genomics UK (COG-UK) – Consortium, will deliver a large scale and rapid SARS-CoV-2 sequencing capacity to local NHS centres and the UK government at pace. The primary achievement of this consortium will be the generation of actionable data which when combined with epidemiological and clinical information has the potential to inform interventions and policy decisions during the current UK COVID-19 epidemic. This sequencing capacity will enable real time evaluation of novel treatments and non-pharmacological interventions on SARS-CoV-2 populations and spread, and provide information on introductions versus community transmission and outbreaks. It will also evaluate signals of changing transmissibility and virulence. In the longer term, the full integration of UK population level SARS-CoV-2 genomics data, with matching NHS electronic health records, patient outcomes, human genomics and metagenomics data has the potential to generate insights into susceptibility to COVID-19 disease. Finally, the substantial new nationwide capacity in sequencing infrastructure, informatics and personnel that will be built by COG-UK will remain at the end of the COVID-19 pandemic as significant asset for the NHS, UKRI and UK Government.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFECTION
Title: ISARIC - Coronavirus Clinical Characterisation Consortium (ISARIC-4C)
Funder: Medical Research Council

Abstract: This COVID-19 Rapid Response award is jointly funded (50:50) between the Medical Research Council and the National Institute for Health Research. The figure displayed is the total award amount of the two funders combined, with each partner contributing equally towards the project. It seems highly likely that SARS-CoV-2 will cause disease and mortality unprecedented in modern times. Despite rapid publication of data from China, many unanswered questions remain that have immediate bearing on control and treatment of COVID-19: • Pathogen: how does transmission occur and over what period? What features of the virus drive transmission and severity? • Host: How can diagnosis be improved? How can severity be predicted? Does prior immunity to other viruses worsen disease severity? How does (non)pulmonary organ injury occur? Can therapy be tailored according to disease mechanisms? Which bacterial or fungal co-infections contribute to critical illness? This is a new disease. There is a high chance that clinical trials will fail to detect therapeutic effects, by enrolling at the wrong time, or missing key subgroups or endpoints. Deep biological phenotyping can mitigate these risks, providing rapid, efficient clinical evidence. Our response has been planned and tested over the past 8 years within the International Severe Acute Respiratory Infection Consortium (ISARIC). We will recruit at least the first 1300 consenting UK patients, and 1000 suspected cases, as the base of a coordinated national response, using our established, internationally-harmonized protocol (ISARIC Clinical Characterisation Protocol) to: • Provide a unified foundation for clinical trials, enriching design and interpretation • Provide an open-access platform for evaluation of diagnostics and therapeutics • Establish a sample repository with independently-managed availability to researchers and to industry. • Use real-time data to inform the response by funders, public health and hospitals ISARIC-4C is a consortium of experts with a proven track record of high-quality outbreak research. We have already recruited 87% of cases reported in the UK.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: COVID-19 National DiagnOstic Research and Evaluation Platform (CONDOR)
Funder: Medical Research Council

Abstract: This project is jointly funded (50%/50%) Between UKRI and DHSC(NIHR). The figures shown on this record represents the UKRI total only. In response to the COVID-19 pandemic, multiple in vitro diagnostics tests (IVDs) have been rapidly developed to detect SARS-CoV-2 infection or immunity. To meet the urgent demand for increased testing capacity, many IVDs have received emergency use authorization. However, clinical evaluations to date have mainly been single-centre, employing differing reference standards with variable protocols. There remains an urgent need for a multi-site, rapid,and methodologically robust approach to in-context clinical validation. CONDOR will contribute to the coordinated national effort to improve COVID-19 diagnostics by providing a collaborative national platform for clinical evaluation. Incorporating community, care home and in-hospital prospective multi-centre studies, CONDOR will provide in-context clinical validation for multiple IVDs, specifically applied to high-priority use cases. This collaborative platform will also place the UK in a unique position to rapidly evaluate and adopt novel diagnostics into clinical practice when faced with future pandemics. The platform has 4 main elements: 1) A central steering committee to create bespoke evaluation plans for Serology Task Force and VDTAG Priority novel IVDs and their associated use cases. 2) In context laboratory verification via a laboratory network. 3) Evaluation of in-context clinical performance (diagnostic accuracy) of IVDs (self-tests, POCTs and laboratory platforms) through efficient, prospective, multi-centre studies using established clinical networks. 4) Cross-cutting methodological workstreams. a. Care pathway analysis informing use case and TPP development (led by DHSC, RCPath and MHRA) and evidence framework development (in collaboration with NICE). b. Evaluating utility and usability in laboratory and clinical settings.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: HICC: Humoral Immune Correlates for COVID19: Defining protective responses and critical readouts for Clinical Trials of Vaccines and Therapeutics
Funder: Medical Research Council

Abstract: A critical gap in knowledge is our understanding of immune correlates of protection from COVID-19, and the fine specificity of protective immune responses to SARS-CoV-2. This gap is a huge impediment to an entire spectrum of major health care issues, ranging from return to work policies for NHS staff and recovered patients to guiding therapeutic interventions, vaccine development and clinical trials. The WHO cautions that simple antibody tests do not correlate with immunity. In fact robust responses correlate with disease severity, while lower titre responses are associated with accelerated viral clearance (Tan et al, medRxiv https://doi.org/10.1101/2020.03.24.20042382). It is essential to have more specific, qualitative humoral assays and Immunoglobulin (Ig) tests that clearly identify protective immunity, and distinguish from deleterious responses to be avoided by vaccination. We will characterise the; fine-specificity of anti-SARS-CoV-2 antigen (i.e. S, RBD, N) specific Ig, cross-reactivity (i.e. of anti-S2) to other circulating human Coronaviruses (HCoV), correlation of Ig Fc-binding glycosylation patterns with Fc-gamma receptors used, with Immunoglobulin effector functions such as Neutralisation, Antibody dependent enhancement (ADE) and Antibody dependent cellular cytotoxicity (ADCC). The powerful combination of diagnostic, high throughput MS and comprehensive functional analysis will be applied to 3 clinical cohorts; 1) severe COVID-19 (progressors), 2) survivors(moderate) and 3) mild or asymptomatic cases. This study has already been initiated with the aim of; quickly providing essential data for critical clinical decisions for management of NHS staff, while providing standardised tests for intervention therapies, vaccine development and immune benchmarks for clinical trials.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: CVR Reagent Repository
Funder: Medical Research Council

Abstract: We wish to create a CVR Reagent Repository that would centralise and consolidate the storage and tracking of currently informal collections of CVR reagents spread across multiple research groups with diverse interests and a range of viruses. Whilst the need to preserve and share research datasets for re-use is now well established, ensuring that materials such as virus isolates, cell lines, antibodies and unique plasmids are preserved and made available to the research community is also important to support reproducibility and further research.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: REACT Long COVID (REACT-LC)
Funder: Medical Research Council

Abstract: This COVID-19 Long COVID award is jointly funded (50:50) between UKRI/Medical Research Council and the National Institute for Health Research. The figure displayed is the UKRI/MRC amount only, each partner is contributing equally towards the project so the Total Fund Amount is £5,436,399. The REACT-Long COVID (REACT-LC) programme aims to characterise the genetic, biological, social and environmental signatures and pathways, and their inter-relationships, that underpin progression to Long COVID, and to understand the natural history and long-term sequelae post-SARS-CoV-2 infection. To identify people with persistent symptoms who have not been hospitalised, we will use a sampling frame generated through repeated random population surveys of SARS-CoV-2 prevalence in the community, the REACT programme, which includes >1.5 million individuals with documented SARS-CoV-2 status (RTPCRor lateral flow test), including >30,000 with positive tests, 90% of whom have consented to be re-contacted and 85% to data linkage. The research is to be delivered through five integrated work packages (WPs). WP1 will describe variations in experience of Long COVID and develop patient reported outcomes (PROMS) in consultation with expert collaborators and through our patient and public partners. We will use online focus groups, discussion forums, individual interviews, and surveys on the VOICEGlobal platform, and recruit a panel of people with Long COVID to provide input on their symptoms and experience. In WP2 we will carry out detailed clinical phenotyping on 8,000 people (4,000 with Long COVID); 2,000 will have repeat measures at 4-6 months including 400 for T-cell function. The WP2 samples will be used in WP3 which includes multi-omic analysis, brain and inflammatory biomarkers. WP4 will use data from surveys sent to 30,000 test-positive and 90,000 test-negative on RTPCR/lateral flow in REACT, plus linked health data, to explore the social and environmental determinants of Long COVID and its long-term sequelae. WP5 is the data analysis and integration to identify genetic, biological, social and environmental determinants of Long COVID. We aim to identify key biomarkers and biological pathways underlying Long COVID and possible drug targets, as well as inequalities and social determinants of variations in outcome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFECTION