NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating local determinants of outcome in human tuberculosis
Funder: Medical Research Council

Abstract: Tuberculosis (TB) remains a global pandemic, killing 1.4 million people a year. An enduring challenge limiting development of transformative interventions is that the host immune response is necessary to control Mycobacterium tuberculosis (Mtb) infection, but also causes immunopathology that leads to tissue destruction and spread. Understanding the relationship between protective and pathological host immune responses is a critical open question in the field. Mtb is exclusively a pathogen of man, and therefore analysis of a human system is necessary to fully dissect the underlying mechanisms. We have developed an advanced cell culture model of human granulomas, validated expression against clinical samples and demonstrated its ability to investigate the host-pathogen interaction in TB. We have shown that antibiotic sensitivity mirrors that in patients, excessive inflammation is harmful and have performed detailed mechanistic translational studies. Here, we will utilise this highly tractable system to systematically analyse factors that regulate control or progression of infection. First, we will modulate cytokine concentrations, T cell numbers and specificity, and extracellular matrix composition, to determine which factors skew the host-pathogen relationship towards control or progression. In parallel, we will design a microsphere imaging system, and quantitate Mtb growth in individual spheres longitudinally. We will characterise controlling versus progressing microspheres by single cell RNAseq to define determinants of outcome by an unbiased methodology. Finally, we will validate key regulatory points by RNA analysis and immunohistochemistry using human TB granulomas biopsied from patients before the initiation of antibiotics. Taken together, these findings will determine the protective versus pathological components of the host immune response to TB, which is essential to inform new vaccination or host-directed therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Uncovering cellular substrates of 3C-like proteases to identify conserved virus-host interactions as antiviral targets
Funder: Medical Research Council

Abstract: Positive-sense RNA viruses include the causative agents behind some of the major pathogens impacting society today: SARS-CoV-2, norovirus, and polio. All these viruses express a 3C or 3C-like protease, which is the focus of this proposal. We understand these proteases are crucial for virus replication and cleavage of viral proteins. Still, we do not know which cellular substrates are cleaved as part of a viral strategy to manipulate infected cells. In brief, our aims are: - Complete a systematic identification of cellular substrates of viral 3C-like proteases encoded by the three major RNA virus families that cause human disease. - Evaluate how essential these cellular substrates and substrate cleavage are for productive norovirus and SARS-CoV-2 replication. - For this subset, develop a mechanistic understanding of how proteolytic cleavage of these cellular substrates subverts their functions in both health and disease. Our prior data on SARS-CoV-2 already identified 14 wholly novel cellular substrates in SARS-CoV-2 infection alone. Our data underlined the vital importance of these interactions for productive viral infection and how little we know about the canonical function of many of these proteins. The controlled, comparative studies I propose will identify further novel fundamental biology in these crucially important virus-host interactions, and may lay a path to developing host-targeting antivirals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The therapeutic potential of targeting bioactive lipids in filariasis
Funder: Medical Research Council

Abstract: Loiasis, lymphatic filariasis (LF) & onchocerciasis (river blindness) are filarial nematode diseases. LF causes the major global disability, lymphoedema (LE). Onchocerciasis (river blindness) is a leading cause of visual impairment. These neglected tropical diseases (NTDs) are prioritised for global or regional elimination. Annual drug treatment for 6-15 years using anthelmintics such as ivermectin (IVM), target microfilariae to break transmission but do not improve pre-existing morbidity. No scalable pharmacological treatment is available for filarial LE. Loiasis causes adverse reactions (AR) following IVM treatment and presents a barrier to elimination of onchocerciasis. The WHO NTD 2030 Roadmap calls for innovations in therapies for LF & onchocerciasis as a critical requirement to reduce morbidity attributed to these NTDs. We have previously shown that type-2 immune-mediated inflammation is associated with loiasis IVM AR and is causal in LF lymphatic pathology. Now we have extensive pilot data indicating bioactive lipid metabolites produced in both scenarios are implicated in pathology. This is exciting because a range of registered, affordable & safe therapies are available which can target biolipid enzymes or receptors. These could be deployed at scale in resource poor settings to treat LF morbidity and protect IVM-based elimination strategies. In this multidisciplinary programme we will develop a multiplex LC/MS-MS bioanalytical platform to quantify a range of lipid metabolites representing the bioactive lipidome. We will utilise our innovations in loiasis and LF infection models and clinical samples to characterise the major metabolites associated with disease. We will undertake genetic and immunological loss of function studies to investigate mechanisms of bioactive lipids in type-2 inflammation and disease formation. Finally, we will identify pharmacological therapies effective in blocking experimental pathology that can be promoted into clinical testing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: AI assisted genomic profiling for the personalisation of treatment and control of infections
Funder: Medical Research Council

Abstract: Infections and infectious diseases, including malaria and tuberculosis (TB), have high public health burden. Whole genome sequencing (WGS) can identify mutations in pathogen genomes that lead to drug resistance (AMR), pinpoint their geographical source, and define strain-types linked to virulence. We have developed informatics solutions that analyse large genomic variation databases and produce lists of mutations linked to AMR, strain-types, and location, enabling the profiling of Mycobacterium tuberculosis (TB-Profiler) and Plasmodium spp. (Malaria-Profiler) from WGS data. However, this approach uses a static database of mutations, requiring laborious manual curation to stay updated with the latest emerging mutations. To address this issue, we have developed several AI models to predict and reveal new mutations underlying AMR (e.g., Treesist-TB, DeepSweep), as well as assign geographical origin (neural network-based). However, implementing these models requires significant technical knowledge and presents a barrier to their use and evaluation in a clinical setting. Here, we propose to integrate the AI models and informatics profiling system, including through the automatic re-training and evaluation of models using our growing large WGS databases (>10k malaria, >50k TB) and newly generated data from collaborating sites across four countries (e.g., UK Health Security Agency malaria reference laboratory). All AI-enabled profiling tools will be made available through both command-line and web-based platforms, reports customised for local use, and WGS data and software put in the public domain. The tools can be extended for use in other types of infections (e.g., nosocomial). Ultimately, the resulting AI-enabled informatics systems will assist with personalisation of treatments within clinical management and aid surveillance activities through identifying outbreaks and transmission hotspots; thereby, leading to both health and economic benefits across populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Developing artificial intelligence (AI) for clinical antimicrobial stewardship in an era of increasing antimicrobial resistance (AMR).
Funder: Medical Research Council

Abstract: The University of Birmingham works closely with University Hospitals Birmingham NHS Foundation Trust (UHB), the single-largest Acute NHS Trust in the UK that serves the healthcare needs of over 1.2m people in the second-largest city in the UK. PIONEER, the Health Data Research Hub for Acute Care, includes >1.2m patient episodes per year with >10yrs longitudinal data, 27.7m measurements/samples related to hospitalised infection and 573k prescriptions for sepsis. We will use data collected from 2010-17 to train the algorithm, and data from 2018-22 to validate the algorithm's performance (data from 2020-21 will be analysed separately). Inclusion criteria will be acute admissions with confirmed bacterial infections. Training data will consist of the patient's electronic health record (EHR) at the time of patient admission, local resistance pressure (% resistance in samples collected in the last 90 days), and prescribing pressure (hospital-wide antibiotic consumption in the last 90 days). Outcome to be predicted will be the resistance profile (across 6 drugs for gram-negative pathogens and 3 for gram-positive) and the narrowest spectrum antibiotic that the infection is predicted to be sensitive to. We will compare the performance of several popular AI algorithms and a simple decision tree. Measures of success will be the % correct predictions of resistance across antibiotics being considered, % correct recommendation of antibiotic, and rates of over/under-prescribing. We will contrast the performance of AI and clinician recommendations across these measures, and where decisions differ we will review a subset with clinicians. We will examine the performance of the AI across species, Gram status, infection type, age, ethnicity and socioeconomic strata of the patient. We will also examine the importance of variables from the EHR, and the relative importance of hospital-level variables (resistance and prescribing rates) versus individual patient-level information.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Combatting Antibiotic Resistance in Philippine lakes: One-health upstream interventions to ease the burden
Funder: Medical Research Council

Abstract: Lakes provide essential natural resources for populations in low-middle income countries. A growing concern has been their contamination with antimicrobial-resistant determinants from animal and human sources. Chief among these are Beta-lactam and carbapenem antimicrobials that are the cornerstone of human antimicrobial therapy. A growing literature supports that Beta-lactam resistance in Asian lakes and rivers is increasing. However, few interventions have been rigorously evaluated to see if environmental contamination from hospitals and agriculture can be reduced. We will develop and deliver interventions to determine their impact on Beta-lactam resistance. Interventions include antimicrobial stewardship programs in hospitals and veterinary settings, campaigns to reduce the use of antimicrobials in backyard farms, and cleaning of effluents feeding the lake. Beta-lactam resistance in lake water will be quantified using methods such as chemical, genetic, and microbiome studies before and after key interventions. The One Health approach is essential to tackle antimicrobial resistance or antibiotic resistance in the human-animal-environment interface. The conditions in and around Laguna Lake in the Philippines ressemble those of many Latin American and African countries, allowing project results to be generalizable. Lower pollution loads will improve water quality and lake resources, and reduce disease outbreaks, benefiting the lakeshore communities and the surrounding area of over 16 million people. The technologies developed are generalizable to other LMICs.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Pre-symptomatic asymptomatic MonkEypox (PRIME) study
Funder: Medical Research Council

Abstract: The aim is to improve understanding of monkeypox (MPX) transmission by identifying the proportion of sexual contacts of MPX cases in whom MPX virus can be detected and the timing of detection in relation to any associated symptoms, to inform intervention strategies and modelling of disease spread. In this prospective cohort study, identified sexual contacts of confirmed MPX cases as well as individuals who self-report sexual contact with a confirmed MPX case will be asked to undertake self-sampling of nose and throat swabs, ano-genital swabs, and or urine samples depending on participant characteristics and the nature of sexual contact with the index case. Optional serologic testing will be performed by self-sampling at baseline and one month after the last exposure to a MPX case. Informed consent will be obtained and all results will be fed back to individual participants. The primary objective is to estimate the proportion of secondary MPX cases who develop pre-symptomatic or asymptomatic MPX infection, defined as detectable viral DNA at any body site before the onset of symptoms or in the absence of symptoms, respectively. This will be achieved by PCR testing of swabs from nose and throat swabs, ano-genital swabs and/or urine tests at two intervals until 21 days following last sexual exposure with a confirmed MPX case, and optional serology testing at baseline and one month after the end of the first participants' exposure to a MPX case. Secondary objectives are to: a) Estimate the secondary attack rate (SAR) of MPX infection in a defined cohort of known sexual contacts of confirmed cases. SAR is defined as the proportion of sexual contacts of MPX cases who have detectable viral DNA at any body site and/or seropositivity b) Estimate the vaccine effectiveness (VE) of smallpox vaccination for asymptomatic infection c) Estimate the incubation period before development of, and the duration of, asymptomatic and pre-symptomatic viral shedding


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: A single-blind, randomised, phase II UK multi-centre study to determine reactogenicity and immunogenicity of booster vaccination against ancestral and novel variants of SARS-CoV-2 (COV-BOOST)
Funder: Department of Health and Social Care

Abstract: The 2 vaccines which have been delivered at scale in the UK so far have been the mRNA vaccine BNT162b2 (Pfizer) and the chimpanzee adenovirus vector vaccine ChAdOx1-nCov19 (Oxford/AstraZeneca). Studies are underway currently to examine the effect of heterologous prime-boost regimens using these differing vaccine technologies (the COM-COV trial, IRAS Project ID: 291055 EudraCT Number: 2020-005085-33). The COV-BOOST trial aims to establish the safety and efficacy of annual boosting vaccination with different authorised vaccine candidates for participants who have received homologous prim-boosting with either BNT162b2 or ChAdOx1-nCov19 early in the UK NHS deployment campaign. In addition, this study will examine the safety and efficacy of boosting using vaccines designed specifically to target novel variants of the SARS-CoV-2 virus when these vaccines become available.

Lay abstract: As of April 8th 2021 the MHRA in the UK has granted Regulation 174 approval for emergency use of 3 vaccines for protection against COVID-19 in the UK, including the mRNA vaccines BNT162b2 (Pfizer) the mRNA-1273 (Moderna) vaccine, and the chimpanzee adenovirus vector vaccine ChAdOx1-nCov19 (AstraZeneca/Oxford). So far over 30 million people in the UK have received at least one dose of either BNT162b2 or ChAdOx1-nCov19, with supplies of the mRNA-1273 expected imminently. Annual or seasonal booster vaccination for high risk groups is thought likely to be required, especially in light of the emergence of new variants of the SARS-CoV-2 virus. There is concern from studies in South Africa and elsewhere that existing vaccines may be less effective against these variant strains. It is currently unclear which booster vaccine schedule will provide the best safety profile and immune responses, according to which vaccine was originally given. The Joint Committee for Vaccination and Immunisation and UK Chief Medical Officers need timely information regarding the effects of different booster vaccinations on the safety profile and immunity to previous and new variants of SARS-CoV-2 in order to inform national policy for autumn and winter 2021. This study will determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: REMAP-CAP: Randomized, Embedded, Multifactorial Adaptive Platform trial for Community- Acquired Pneumonia (COVID-19)
Funder: Department of Health and Social Care

Abstract: REMAP-CAP is a randomised clinical trial, which has been specifically designed to be able to adapt in the event of a pandemic. Prior to COVID-19 REMAP-CAP was running in 12 countries worldwide and was recruiting patients admitted to an intensive care unit (ICU) with pneumonia which had developed in the community. Since the COVID-19 pandemic, REMAP-CAP has used its novel design, which enables it to adapt, to change to evaluate the most relevant treatment options in patients admitted to an ICU with severe COVID-19. This change includes, evaluating both new and existing interventions targeted at patients with COVID-19, and using different clinical outcomes to obtain an answer quicker. The design of REMAP-CAP allows it to assess different types of treatment at the same time to understand which are the best treatment strategies. The original treatment types being tested in REMAP-CAP are: 1) use of COVID-19 antiviral medication; 2) use of COVID-19 immune modulation; 3) choice of antibiotic; 4) duration of macrolide treatment; and 5) steroid treatment. REMAP-CAP also uses the results within the trial to allocate more patients to interventions that are more likely to be effective and can provide an efficient way of generating time-critical evidence to improve patient outcomes during a global pandemic.

Lay abstract: REMAP-CAP is a randomised clinical trial, which has been specifically designed to be able to adapt in the event of a pandemic. Prior to COVID-19 REMAP-CAP was running in 12 countries worldwide and was recruiting patients admitted to an intensive care unit (ICU) with pneumonia which had developed in the community. Since the COVID-19 pandemic, REMAP-CAP has used its novel design, which enables it to adapt, to change to evaluate the most relevant treatment options in patients admitted to an ICU with severe COVID-19. This change includes, evaluating both new and existing interventions targeted at patients with COVID-19, and using different clinical outcomes to obtain an answer quicker. The design of REMAP-CAP allows it to assess different types of treatment at the same time to understand which are the best treatment strategies. The original treatment types being tested in REMAP-CAP are: 1) use of COVID-19 antiviral medication; 2) use of COVID-19 immune modulation; 3) choice of antibiotic; 4) duration of macrolide treatment; and 5) steroid treatment. REMAP-CAP also uses the results within the trial to allocate more patients to interventions that are more likely to be effective and can provide an efficient way of generating time-critical evidence to improve patient outcomes during a global pandemic.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Eligibility, uptake, safety and effectiveness of COVID-19 therapeutics in real world settings
Funder: Department of Health and Social Care

Abstract: The UK is experiencing a new wave of COVID-19 infections with the Omicron variant at the same time as high circulating levels of DELTA. There is evidence that the Omicron variant is more transmissible and concerns that existing therapeutics (e.g. COVID-19 Vaccines) may be less effective and some monoclonal antibodies (MABs) may become ineffective due to mutations. _x000D_ _x000D_ Novel MABs are limited resources and need to be targeted to those at highest risk of poor COVID-19 outcomes who are most likely to benefit. Interim guidance has been produced for new COVID therapeutics and there is an urgent need to determine the numbers/proportion of the population likely to be eligible for these treatments based on existing guidance to help the NHS and government plan ho best to respond. We also need to find out who is getting these new treatments and make sure determine the new treatments are being used in line with guidance. We also need rapid real-world evidence of the likely effectiveness of treatments alone and in combination and to identify those patients who remain at risk despite treatments_x000D_ _x000D_ This proposal will address a number of key questions, using existing research ready datasets. The overall aim is to determine the uptake, safety and effectiveness of monoclonal antibodies in the community. These questions can be addressed very quickly using the QResearch TRE linked datasets with additional questions answered according to DHSC priorities.

Lay abstract: The UK is experiencing a new wave of COVID-19 infections with the Omicron variant at the same time as high circulating levels of DELTA. There is evidence that the Omicron variant is more transmissible and concerns that existing therapeutics (e.g. COVID-19 Vaccines) may be less effective and other therapeutics, such as monoclonal antibodies (MABs) may become ineffective due to mutations. _x000D_ _x000D_ Novel MABs are limited resources and need to be targeted to those at highest risk of poor COVID-19 outcomes who are most likely to benefit. Interim guidance has been produced for MABs and there is an urgent need to determine the numbers/proportion of the population likely to be eligible for these treatments based on existing guidance to inform planning/ordering. It is also necessary to determine the uptake of treatments as they start to be used to ensure they are being used in line with guidance. We also need rapid real-world evidence of the likely effectiveness of treatments alone and in combination and to identify those patients who remain at risk despite treatments_x000D_ _x000D_ This proposal will address a number of key questions, using existing research ready datasets. The overall aim is to determine the uptake, safety and effectiveness of monoclonal antibodies and antivirals in the community. These questions can be addressed very quickly using the QResearch TRE linked datasets with additional questions answered according to DHSC priorities.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION