NIHRDataInsights/HRCSData huggingface dataset:
Title: Blood borne viruses
Funder: Medical Research Council

Abstract: Infectious diseases remain major causes of mortality and morbidity worldwide. In the Blood Borne viruses (BBV) programme we have focussed on hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV), the blood borne viruses with the greatest global burden of mortality and morbidity. Chronic BBV infections also have indirect effects, by increasing the risks or adverse consequences of non-communicable diseases. It therefore remains essential that prevention efforts across the spectrum of key BBVs continues, especially if the WHO targets for global elimination are to be achieved. Our studies are aligned with the major strategic priorities of the World Health Organization, and results are expected to, and have change guidelines, policy and practice across the age spectrum. In particular, the advent of new highly effective direct acting antivirals against hepatitis C provides a unique opportunity for large strategic trials to identify how these drugs might be used best to support the elimination agenda and increase access, in low-and-middle-income countries and in the challenging “hard-to-reach-and-treat” populations. Our research objectives are to exploit new, short effective oral regimens to test strategies which might successfully cure patients whilst minimising drug exposure and/or course duration, including stratified medicine approaches, in large randomised trials. We also aim to develop a trial to cure hepatitis C virus in pregnant women living with HCV and prevent vertical HCV transmission. In HIV infection, the prevention trials that we have led have played a major role in reducing new HIV infections, and we have implemented novel designs to improve efficiency in both the vaccine (MAMS designs) and self-testing (electronic randomisation and follow-up) areas. We have also completed a large randomised trial in late HIV presenters, identifying an adjunctive package of prophylaxis which reduced mortality after starting treatment by 25%. We continue to address relevant questions to the management of HIV-infected children, particularly focussing on questions relating to the efficacy, toxicity and pharmacokinetics of antiretroviral drugs in new fixed dose combination solid dispersible formulations, using new ratios and following WHO-recommended weight-bands. However, the continued and improving success of treatment of vertically infected HIV-infected children surviving into adolescence as a consequence of antiretroviral therapy, has to be balanced with the poorer treatment outcomes in adolescents, and emphasises the need to investigate more acceptable, less toxic, treatment and prevention strategies to improve long-term health outcomes in this population, including the utility of long-acting injectable antiretrovirals. This objective will be achieved through the design, conduct and analysis of large randomised trials in low and middle-income settings.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Syndromic infections
Funder: Medical Research Council

Abstract: Infectious diseases remain major causes of mortality and morbidity worldwide, but their effects are particularly prominent in low and middle-income countries. Some infectious diseases often present acutely as a collection of symptoms without any specific infectious agent ever being identified (termed “syndromic infections” here); such presentations are particularly common in low-income settings and in children, place large burdens on healthcare resources and lead to unacceptably high rates of death, often occurring rapidly after admission. A major challenge is the weak evidence base underpinning relevant guidelines, which consequently may be in conflict (eg between guidelines for managing malaria and anaemia, even though these conditions commonly co-exist). This programme aims firstly to develop and test generic strategic approaches to manage acutely sick children presenting to hospital services in Africa, in order to improve outcomes and ensure that harms do not outweigh benefits, and ensure guidelines are evidence-based. This will be achieved through designing, conducting and analysing large mortality-endpoint randomised trials to inform definitive management guidelines in this challenging and relatively under-researched area. We will also develop and conduct underpinning early phase trials to ensure that the design of these Phase III trials is optimised. We will address questions in severe malaria, diarrhoeal disease and bacterial infections, and their common presentations (e.g. anaemia) as these are major global contributors to childhood morbidity and mortality. Second, antimicrobial resistance is a key priority for the MRC and many organisations worldwide. It represents an enormous global threat; again infecting organisms are commonly not identified meaning antibiotics are widely used empirically, potentially accelerating spread of resistance. Other major challenges include the generally lack of a single standard-of-care, and difficulties in defining, and ascertaining objectively, non-mortality endpoints. The overall goal of this part of the programme is to improve the treatment and management of serious bacterial infections, particularly bacterial sepsis, in neonates, children and adults across the world; and to address the threats posed by increasing levels of antimicrobial resistance. This will be achieved through conducting large randomised trials and developing novel trial designs to optimise the assessment of different approaches to reducing the morbidity and mortality burden associated with serious bacterial infections, particularly considering drugs and course durations. We will particularly focus on conducting trials in neonates and children that can lead to licensing of appropriate antibiotic doses, since most use is based on historical precedent rather than evidence.


Research activity codes: 6.1 PHARMACEUTICALS;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFECTION
Title: MICA: Development of a novel host blood test using TRanscripts to Identify bacterial Meningitis - TRIM test study
Funder: Medical Research Council

Abstract: Bacterial meningitis remains a significant cause of morbidity and mortality in the UK and worldwide, with considerable costs. The key step in early patient management is to distinguish bacterial meningitis, which needs immediate antibiotic treatment, from the many mimics, such as viral meningitis, which do not. The essential test for distinguishing the two is the lumbar puncture, but this is often delayed, or not performed at all. Many patients are therefore treated with unnecessary antibiotics until a diagnosis of bacterial meningitis is excluded, contributing greatly to the burden of antimicrobial resistance. A novel, rapid blood test measuring TRanscripts to Identify bacterial Meningitis (TRIM test) will improve management and reduce unnecessary antimicrobials. Using samples from our multicentre observational UK Meningitis Study, funded by the National Institute for Health Research and the Meningitis Research Foundation, we have identified 5 highly discriminatory host transcripts in the blood of adults with bacterial meningitis. The markers exhibit high sensitivity (100%), specificity (90%) and negative predictive value (100%) in distinguishing patients with bacterial meningitis from the mimics Working with Fast-Track Diagnostics Ltd, we have developed the TRIM test, a real-time PCR multiplex assay. We will validate it in an independent set of samples recruited through our UK and European clinical networks (France, Denmark and Holland). We will also begin to assess test accuracy in lower-middle income populations in Brazil and Malawi. This work builds on the Liverpool Brain Infection Group's experience for delivering diagnostic tests for brain infections, for example, tests for Japanese encephalitis, now used across Asia. The results will be used to produce the TRIM test system as a commercial diagnostic, and apply for subsequent funding, through the National Institute for Health Research, to assess its impact and health economic benefits.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: ;Structural studies into novel membrane associated virulence factors of Legionella pneumophila
Funder: Medical Research Council

Abstract: Legionella pneumophila, is a facultative Gram-negative bacterium, which is ubiquitous in aquatic systems and highly prevalent in large buildings such as hospitals and hotels. In the environment L. pneumophila lives within biofilms or as an intracellular parasite of biofilm-associated protozoa. However, upon entering human lungs via aerosolized droplets, it can also invade and replicate inside resident macrophages and epithelial cells. L. pneumophila causes Legionnaires' disease, an often-fatal pneumonia, and Pontiac fever, a milder flu-like disease; and rates of infection are increasing each year, across the UK and globally. After invasion of eukaryotes, L. pneumophila resides within a membrane bound replication vacuole (the Legionella containing vacuole; LCV) and exports many proteins into the host cytoplasm, which allows it to replicate to large numbers. L. pneumophila uses a type II secretion system (T2SS) to translocate substrates across its outer membrane. These support biofilm formation, replication in the host, dampening of cytokine output and survival in mammalian lungs. In L. pneumophila, these substrates can be targeted to the bacterial surface during extracellular growth but they are also exported into the host cytoplasm during intracellular infection and can localize to the LCV surface, which represents a new role for the T2SS. These substrates carry out novel functions and are important for both intracellular and extracellular growth of L. pneumophila. We plan to (i) investigate the molecular details of how these substrates function to enable L. pneumophila infection/persistence and (ii) ascertain the atomic mechanisms by which they are targeted to their respective membranes. These studies will provide insight into new mechanisms related to Legionella fitness and disease and may have implications for the development of novel strategies to disperse biofilms and reduce bacterial virulence.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Temporal changes to cellular bioenergetics, cholesterol metabolism, innate immune responses and microbiota during infection
Funder: Medical Research Council

Abstract: With only few exceptions, most studies of pathogen-host interactions report static observations of a single point in time. Here, we will use the Citrobacter rodentium model to investigate the temporal consequences of bacterial infection on metabolism and immune responses in intestinal epithelial cells (IECs), as well as dysbiosis. IECs will be isolated from infected mice at various days post infection; uninfected mice will be used as a control. Proteins will be extracted from IEC pellets, digested with trypsin, the resultant peptides labelled using the isobaric mass tag (TMT), pooled, fractionated offline and analysed by nanoscale online LC-MS. Multiple bioinformatics platforms and robust statistics will be used for data analysis. We will employ Q-RT-PCR, ELISA and WB, as well as metabolomics and lipidomics and functional assays, to cement the proteomics data and bioinformatics predications. We have recently found that EspO impacts the expression of IL-22-regulated proteins 8 days post infection (e.g. iNOS, Lcn2, Reg3, S100). We will investigate how EspO, and its partner protein Hax-1, modulate signalling downstream of the IL-22 receptor (as well as dysbiosis). We will infect WT mice with an espO mutant and use commercially produced IEC-specific hax-1 KO mice to investigate the role Hax-1 plays in C. rodentium infection and host inflammation. We will investigate the role cholesterol biogenesis and efflux plays in pathogen-host interactions and inflammation using small molecules that impact on the activity of the transcription factors Srebp2 (regulating expression of genes involved in cholesterol biogenesis) and LXRs (regulating expression of gene involved in cholesterol efflux). We will use transgenic mice that either constitutively express LXR_alpha, or LXR_alpha/beta KO, specifically in IECs (using in-house bred control mice). Using the above approaches we will determine changes in protein abundance and link this to infection, inflammation and dysbiosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Informing shigellosis treatment and management in resource-poor settings through pathogen genomics
Funder: Medical Research Council

Abstract: Shigellosis is the leading bacterial cause of moderate-to-severe diarrhoea in children under five years old in low-to-middle income nations. Our understanding of the agents of shigellosis, bacteria of the genus Shigella, is currently being transformed through Whole Genome Sequence Analysis (WGSA) studies which informs shigellosis treatment and management through an enhanced understanding of pathogen epidemiology, evolution and biology. However, WGSA studies on Shigella to date focused on defining population structures or characterising emerging national or risk-group-associated sublineages. To inform on treatment and management of shigellosis in its most important demographic, WGSA must be applied to a relevant, representative, contemporary collection of shigellae from endemic areas. The Global Enteric Multicentre Study systematically-collected 1349 Shigella isolates from children under five years old from across Asia and Africa and represents just the collection needed to develop of most advanced overview of shigellosis to date relevant for informing treatment and management of the disease. This project will achieve the following objectives: 1. Identify those Shigella subtypes and antimicrobial resistance profiles responsible for causing the most disease in the key demographic for shigellosis. This is crucial for epidemiological tracing and evaluating treatment recommendations. 2. Inform on the likelihood and potential timeframe of vaccine escape for both serotype-based and protein-based vaccine candidates currently in development for Shigella. We will work with industry to ensure our predictions are integrated into future development and implementation strategies. 3. Test the hypothesis that genomic factors are involved in the manifestation of clinical shigellosis by comparing Shigella isolates from case and control patients. This may identify novel pathogenesis factors for future functional research and perhaps therapeutic targeting.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Helicobacter pylori in Vietnam: Prevalence, AMR and Vaccination
Funder: Medical Research Council

Abstract: Control of H. pylori (HP) infection is problematic because the pathogen carries multiple AMR and there is no vaccine. This consortium will address two aspects of the disease. First, we will characterise a large collection of HP strains previously collected from biopsies of dyspeptic patients in Vietnam. These strains are present in a number of national hospitals and will be collated and characterised for their genotype and AMR profile. For genotype we will examine the ureA, ureB, vacA and csgA genes since there exist considerable variation between strains of different virulence as well as geographic/regional variations. This data will provide important information regarding virulent HP strains within Vietnam and may help influence decisions regarding use of antibiotics. Second, we will construct and evaluate an oral vaccine candidate to HP infection using bacterial spores for antigen display. Bacillus spores have been shown able to stably display HP antigens and in this project we will construct recombinant spores that are unable to proliferate should spores germinate. This is an innovative system for gene expression in B. subtilis developed by the UK partner and addresses long-term issues over biological containment of recombinant spores. The multivalent spore vaccines will carry combinations of the UreA, UreB, VacA and CsgA HP antigens all of which are considered protective. The best performing vaccines will be evaluated in two animal models, the mouse colonisation model and gerbils. For the mouse model the aim is to determine if oral or sublingual administration of the spore vaccine can prevent colonisation of HP while for the gerbil model the best performing spore vaccine candidate will be evaluated to determine whether it can prevent 'human' symptoms of HP infection, i.e., gastritis (histopathology).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Using whole genome sequencing to reveal malaria parasite genetic diversity and drug resistance in Vietnam
Funder: Medical Research Council

Abstract: Malaria, caused by Plasmodium parasites, remains a barrier to social and economic development in resource poor areas of Viet Nam. Between 2012 and 2016, Viet Nam achieved a 52% reduction in malaria cases to ~4,200 (P. falciparum 56%, P. vivax 42%). The campaign against malaria by the Vietnamese Government is now being refocused from control to elimination by year 2030. However, this campaign is challenged by the threat of parasites, which are resistant to existing frontline artemisinin combination treatments and spreading in the Greater Mekong Sub-region (GMS); five Vietnamese provinces have been identified to harbour these drug-resistant parasites. Compared to P. falciparum, very little is known about drug resistance in Pv, but is driven by genetic mutations in the parasite genomes. New molecular tools to characterise circulating parasites are warranted. Here we propose to characterise the genetic diversity and the molecular basis of drug resistance of malaria parasites in Viet Nam using whole genome sequencing (WGS). By examining the genomic variation from both Pf and Pv sourced from 5 malaria endemic provinces, we will be able to detect crucial mutations in drug resistance genes (e.g. PfKelch, PfPlasmepsin2, Pfmdr1 and related genes in Pv), and potentially identify new loci by using population genetic approaches to uncover "selective sweeps". The genomic variation will allow an assessment of differences in population structure across time, between the geographical areas, and within the GMS context and beyond. We will also perform comparative Pf and Pv species analysis to highlight any differential effects of control practice. As part of this application, it is also proposed to build capacity in Viet Nam in the area of malaria genomics and its applications through on-site training and workshops, as well as exchange of researchers between the UK and Viet Nam. These activities will assist Vietnamese scientists to undertake genomics research studies in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Establishing and evaluating minimally invasive autopsy to determine cause of death from infectious disease in Vietnam
Funder: Medical Research Council

Abstract: Knowledge of cause of death is an important public health metric to guide interventions and research. Infectious disease are estimated to contribute 10-15 % of all cause mortality in Vietnam but the exact aetiology of the cause of death in these cases remains unknown in the majority of patients. Diagnostic autopsy to establish cause of death is not part of standard of care and is rarely performed in Vietnam. Reasons for this are that most deaths occur outside the health system, there are no facilities for full autopsy, and there may be negative attitudes toward post-mortem examination due to religious and cultural traditions. Minimally invasive autopsy (MIA)), in which hollow needles are used to sample a selection of body fluids and organs, has been proposed as an alternative to full autopsy and a simplified standardized protocol was recently described and validated. The project consists of three arms. Social scientists will explore the cultural sensitivities surrounding autopsy among community and religious leaders, healthcare professionals, and patients' relatives. Simultaneously, diagnostic pathology capacity building and implementation will be cerried out at the two hospital sites, overseen by a UK based pathologist. The results from the social sciences work will be used to construct a tailor-made consent procedure and MIA protocol for use in a Vietnamese context, after which we will evaluate the efficacy of MIA in establishing cause of death in a total of 100 patients with three infectious syndromes (central nervous system infection, respiratory infection and sepsis/septic shock) as compared to standard of care. We will use routine microbiology and pathology techniques including immunostaining, followed by specific molecular diagnostic assays and next generation sequencing (MiSeq) to establish an aetiological diagnosis.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INFECTION
Title: Whole genome sequencing for the rapid prediction of drug susceptibility in patients with suspected multi-drug resistant tuberculosis in Vietnam
Funder: Medical Research Council

Abstract: Multi-drug resistance (MDR) is a growing threat to global tuberculosis (TB) control. Central to the problem is the difficulty determining drug susceptibility sufficiently quickly to guide effective therapy. Current standard laboratory methods include phenotypic (culture-based) drug susceptibility testing (DST), which requires specialist laboratories and takes 8-12 weeks. Only two laboratories in Vietnam perform full DST. Inadequate diagnosis leads to missed cases, onward transmission, morbidity and mortality, and increased costs. There is a clear need for fast, accurate DST that guides appropriate treatment. Our proposal addresses one overarching question: can Whole Genome Sequencing (WGS) replace current methods for the DST of MDR-TB in Vietnam's tuberculosis National Reference Laboratory (NRL)? We will address four hypotheses: 1. WGS of M. tuberculosis cultured from patients with suspected MDR-TB can predict susceptibility to second-line drugs faster and with equivalent accuracy to current phenotypic methods 2. Direct WGS of sputum from patients with suspected MDR-TB can predict susceptibility of MTB to second-line drugs with equivalent accuracy to WGS of cultures 3. WGS of sputum taken from patients with suspected drug-susceptible TB who are failing treatment (bacteria still seen in sputum by microscopy) can detect mutations associated with MDR-TB development 4. WGS generates economic benefits resulting from the earlier diagnosis and treatment of MDR-TB. We will test these hypotheses by developing a sequencing and bioinformatics platform within the NRL. We will sequence sputum and the bacteria subsequently cultured from patients with suspected MDR-TB to address hypotheses one and two, and sputum from patients failing therapy for suspected drug susceptible disease to address hypothesis three. To address hypothesis four we will perform detailed microcostings of the different diagnostic methods for detecting MDR-TB and the associated treatment strategies.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION