NIHRDataInsights/HRCSData huggingface dataset:
Title: MICA: Performance evaluation of a point-of-care whole blood viral load test (SAMBA) to optimize HIV treatment in resource-limited settings
Funder: Medical Research Council

Abstract: Access to antiretroviral therapy (ART) for HIV-1 infected individuals in developing countries is expanding rapidly, improving survival and preventing transmission. Routine viral load (VL) monitoring of HIV-infected individuals on ART is necessary to assess treatment efficacy and adherence. Currently the monitoring of HIV-1 VL is performed largely in centralised laboratories using plasma. Therefore, patients living outside of the capital city in developing countries often cannot access VL testing and if they can there are regularly unacceptable delays in obtaining test results, with consequent loss to follow-up (LTFU). These issues could be overcome by point of care (POC) VL testing. The Diagnostics Development Unit (DDU) and its spin out company, Diagnostics for the Real World (DRW), have developed the SAMBA HIV-1 Semi-Q Test for the diagnosis of ART failure (VL >1,000 copies/ml). The SAMBA HIV-1 Semi-Q Test uses plasma as has been used for VL testing of >37,500 patients at Médecins sans Frontières sites in Malawi and Uganda since August 2013 using the semi-automated CE-marked SAMBA I instrument. DDU have recently improved the SAMBA chemistry for use with small volume whole blood (WB) samples by incorporating a leucodepletion step to remove CD4+ cells containing integrated HIV RNA and DNA. This integrated DNA and RNA interferes with the VL quantification. A preliminary study assessed the feasibility of using venous WB on the SAMBA I Semi-Q Test. The leucodepleted WB had a 3-log reduction in CD4+ cells without significantly affecting plasma VL. The clinical performance of the assay was evaluated in Kenya compared to the Roche Cobas TaqMan HIV-1 test. A concordance of 96.5% was obtained between the Roche (plasma) and SAMBA (whole blood). The key aims of this proposal are to integrate whole blood SAMBA chemistry onto the fully-automated CE-marked SAMBA II POC instrument, perform a prospective, cross-sectional evaluation in Africa and Europe and submit for CE-marking


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Assessing the situation of AMR of bacteria in Vietnam, determining genomic characteristics and associated factors of common AMR-bacteria in Vietnam
Funder: Medical Research Council

Abstract: The National Institute of Hygiene and Epidemiology (NIHE) in Viet Nam, in partnership with Cardiff University (UK), propose a programme focused on the burden of antimicrobial resistance (AMR) in pathogenic bacteria in Viet Nam and will use data and outcomes as an exemplar for South East Asia. The steep rise of MDR/XDR in Viet Nam endangers the overall effectiveness of antibiotic treatment which will increase the burden of infectious diseases even more particularly in HRPGs emphasising the need for antibiotic stewardship and better patient management. We will address four broad over-lapping research challenges: 1. Clinical Epidemiology: provide detailed and focused clinical demographics on high- risk patient groups (HRPGs) most vulnerable to AMR infections e.g. neonates, ICU and post-surgical infections [6,11]. 2. Pathogen Biology: development of molecular tools for analysing and visualizing functional genomics data on bacteria for identification and characterization of novel resistance determinants and virulence factors. 3. Genomic Epidemiology, Evolution and Population Genetics: development of bioinformatics tools for analysing, manipulating, visualizing and archiving data from large-scale genomics studies. 4. Integrating bacterial genomics: combining clinical information and relevant molecular epidemiological data. The key deliverables are the following: 1. Deliver a full picture of antimicrobial resistant in four leading hospitals in Viet Nam from 2015-2017. 2. Detail the evolution of MDR/XDR, including the direction (horizontal gene transfer) of inheritance. 3. Provide scientific evidences (burden of AMR, epidemiology of AMR, risk factor for infection and outcome with AMR) in Viet Nam in order to develop intervention strategies. 4. International support for emerging Vietnamese researchers.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION
Title: Understanding pharmacokinetic - pharmacodynamic determinants of outcome to inform dose optimisation for non-MDR TB re-treatment patients in Vietnam
Funder: Medical Research Council

Abstract: In many countries, patients presenting with a second episode of non-multidrug resistant (MDR) pulmonary tuberculosis (TB) are treated a WHO approved Category 2 re-treatment regimen. Despite widespread use, this regimen has never been assessed in clinical trials and outcomes are variable (60-75% treatment success in Vietnam). This study will assess whether careful study of pharmacokinetic/pharmacodynamic (PK/PD) parameters can explain treatment failure and relapse amongst Vietnamese non-MDR pulmonary TB patients. PK/PD modelling will be used to develop target parameters for treatment success. Design: Non-MDR pulmonary TB patients due to initiate the Category 2 re-treatment regimen will be longitudinally followed. PK exposure to first-line TB drugs will be determined from plasma sampling on day 14 of therapy. PD parameters will be recorded at baseline (MIC of the infecting Mycobacterium tuberculosis isolate to first-line drugs, and time-kill phenotyping assays using a high-content imaging platform to study antibiotic effects on intracellular organisms). Time to positivity measurements from liquid culture of serial sputum samples will be used to generate a Bacillary Elimination Rate (BER) during the first 8 weeks. PK/PD models will be developed to establish the exposure-effect relationship between TB drugs and clinical outcomes. A parallel cohort of new TB patients will be studied to determine differences in the PK/PD characteristics of new and re-treatment patients. The new clinical PK/PD datasets, including the under-studied Category 2 regimen and using new intra-cellular PD assays, from a high-burden TB setting in Vietnam will inform meta-analyses and simulations of dose-optimisation strategies to predict and improve treatment. Establishment of clinical, microbiological and pharmacological capacity for novel and advanced PK/PD studies in Vietnam will lay essential and sustainable foundations for future pharmacology studies and clinical trials.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Epidemiological features, national burden of several HPV-related diseases and estimation of cost-effectiveness of HPV vaccines in Vietnam
Funder: Medical Research Council

Abstract: This project will study the rate of HPV infection among young university students in north, south and central Vietnam to get a national perspective. We will also study two important high risk groups, sex workers and men who have sex with men in both the north and south. We will use the records of the cancer hospitals in Vietnam to estimate the proportion of the population who were affected by HPV associated cancer, and to understand better the ages affected and the outcome and treatment costs of cases. This will enable us to predict the effect of HPV vaccine introduction on the community and calculate the money that will be saved by the health system if those cancers are prevented. Finally we will develop, within Vietnam, the laboratory skills that are needed to study HPV disease, and especially to undertake a trial of HPV vaccines in Vietnam. The trial is not covered by this proposal, but we hope in future to do a trial that will help us to decide the simplest, and therefore least expensive, way to introduce HPV vaccine into a developing country like Vietnam. The project will be undertaken jointly by five institutions. The three Vietnamese institutions (two in the north and one in the south) will be able to share their expertise in this area and also develop new skills with help from expert groups in London (London School of Hygiene and Tropical Medicine) and Australia (Murdoch Childrens Research Institute).


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Whole-genome sequencing to investigate the prevalence and transmission multidrug-resistant organisms in intensive care units in Hanoi, Vietnam
Funder: Medical Research Council

Abstract: Clinical studies will be based in the ICUs the National Hospital of Tropical Diseases (NHTD) and Bach Mai Hospital (BMH),Hanoi, Vietnam. Study 1: A prospective observational cohort study of all patents admitted to ICU. All patients admitted to the ICU during the study period will be screened for MDRO. Samples will be collected on admission to ICU, on discharge from ICU, and weekly from patients whose duration of admission is 7 days or more. We will also collect environmental samples during the study period. Samples will be processed to identify target organisms e.g. methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and carbapenem-resistant GNB. Samples will also undergo DNA extraction and quantification at NHTD and DNA extracts will be shipped to the Wellcome Trust Sanger Institute (WTSI) for high-throughput sequencing. Clinical and laboratory data will be collected and analysed using a standard statistical methods. Bacterial sequence data will be analysed using WTSI bioinformatic pipelines. This study will provide information about the prevalence and transmission rates of MDRO in this setting, and will provide genomic context for Study 2. It will also train Vietnamese scientists in sequencing and bioinformatics, and build clinical and laboratory capacity to tackle HCAIs using WGS. Study 2: Investigation of a putative outbreak of MDRO on the ICUs All patients admitted to the ICUs during the study period will be screened for MDRO using methods determined in Study 1. If a suspected outbreak of infection occurs (e.g. an increase in the number of patients colonised with a particular organism) intensified surveillance will be performed (e.g. twice weekly screening). Samples will also undergo DNA extraction, library preparation and WGS on a rapid sequencing platform in the microbiology laboratory at NHTD. Bacterial sequence data will be analysed using bioinformatics pipelines developed during study 1. This study


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Exploring Natures Silent Pharmacy
Funder: Medical Research Council

Abstract: Genome sequencing of fungi has revealed an unexpectedly large number of uncharacterised secondary metabolite pathways, particularly amongst ascomycete fungi. These pathways are usually not active during routine culture so are unlikely to have been assessed as part of conventional drug discovery programs. From genome data as a starting point, we aim to develop an expression system to engineer the deliberate over-expression of each cluster either in situ or in heterologous hosts to more readily access their resulting metabolites. This will be achieved by exploiting yeast-based recombination systems to directly clone large segments of DNA from genomic material, coupled with the use of synthetic DNA or PCR-derived fragments to allow refactoring of promoters where necessary to achieve the required expression. The resulting metabolite will then be purified by preparative HPLC and characterised using the full range of NMR methods to give structural data, whilst also profiling against a panel of medically relevant bacterial species including those with known modes of resistance, to assess both antibiotic activity and potentially novel modes of action. This will demonstrate whether there are indeed novel antibiotics yet to be discovered in fungi. Fungal species selected as candidates for analysis span a range of environmental niches, to maximise the range of likely selection pressures and hence metabolite profiles. Where compounds display the desired antibiotic properties, we will characterise their biosynthetic pathways giving the possibility of genetic intervention at various stages to purify intermediates for subsequent chemical modification or for assisting with structure-activity relationships. The expression systems developed will be both scalable and readily transferable to other labs to allow higher throughput in the future should this prove to be a successful approach.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Optimising Innate Host Defence to Combat Antimicrobial Resistance
Funder: Medical Research Council

Abstract: The SHIELD consortium will combat antimicrobial resistance by enhancing phagocyte microbicidal responses. We will investigate microbicidal mechanisms and host responses in macrophages and neutrophils in response to Streptococcus pneumoniae and Staphylococcus aureus and validate key findings with antimicrobial resistant bacteria. Automated genetic screens (e.g. CRISPR) will be performed in macrophages to identify microbicidal mechanisms. A reverse phase proteomic array (RPPA) of core neutrophil transduction responses to bacteria will be followed by screening the effects of pathway inhibition on bacterial killing and regulation of inflammation. Screen 'hits' will be supplemented with candidate regulators we have already identified. Mechanisms will be validated in phagocytes and in genetically modified mice and zebrafish models of infection. Compound libraries will be screened in phagocytes and zebrafish to enhance microbicidal responses that maximize bacterial clearance and minimise inflammation. After lead optimization we will confirm efficacy using super-resolution microscopy and mouse models of bacterial infection. Animal adapted strains of bacteria will be serially passaged in human phagocytes to identify bacterial mutations arising from selective pressure. Analysis of how mutations influence microbicidal function will further clarify mechanisms and we will explore if mutational 'hot-spots' can be neutralized with monoclonal antibodies to limit immune escape. The physiological relevance of selected mechanisms and pharmacological 'hits' will be confirmed in primary tissue macrophages and neutrophils isolated from inflamed tissue in healthy adults and patients at risk of bacterial infection. We will use molecular optical imaging with SmartProbes to document key phagocyte microbicidal responses to bacteria in the alveolar space. We will also use this platform to perform initial micro-dosing of lead compounds and expedite delivery of future phase I trials.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: MICA: Accelerating Development of Infection Diagnostics for Patient Management and Reduction of Antibiotic Misuse
Funder: Medical Research Council

Abstract: The lack of instant and accurate diagnostic tools for infectious diseases leads to inappropriate or unnecessary antibiotic prescribing. In primary care and hospital settings, this contributes directly and significantly to antimicrobial resistance (AMR). The aim of this programme is to address this challenge by developing innovative approaches for the next generation biosensors. This programme aims to develop three biosensors that (a) distinguish between viral and bacterial infections and (b) specifically diagnose Clostridium difficile infection (CDI) and (c) detect common subtypes carbapenemases which cause the most problematic forms of Carbapenem Resistant Enterobacteriaceae (CRE) infections. Diagnostic biomarkers have been previously established to for these infection diagnosis applications and in this programme synthetic antibody mimetics (Adhirons) will be raised/selected against these biomarkers. Using the Adhirons as 'recognition elements', multiplexed, impedimetric and fluormetric biosensors will be constructed based on established and novel technologies, respectively. Furthermore, this programme aims to develop novel biosensor platforms with improved accuracy and sensitivity. The majority of biosensors use passive capture molecules, such as antibodies or antibody mimetics, as 'recognition elements'. However, while antibody-biomarker binding is generally highly specific, changes in dielectric upon binding of biomarkers can be small, limiting the sensitivity and reproducibility of the sensor. Furthermore, non-specific binding of other molecules onto the sensor can lead to false-positive signals. Here, these bottlenecks will be targeted by designing new classes of antibody mimetics that generate an active electrochemical signal upon binding of the biomarkers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: EVOBIOTIC: Capturing the natural antibiotic'ome: Developing Nature's EVOlved AntiBIOTIC
Funder: Medical Research Council

Abstract: Naturally evolved antibiotics are our primary mode of treating drug-resistant pathogens. Although individual antibiotics do succumb to resistance via pressures they place on organisms, the producers of these agents innovate through modular antibiotic drug (bio)synthesis programs to naturally thwart drug resistance mechanisms. Moreover these same antibiotic drug biosynthesis programs, are now revealed to construct other agents that perturb microbial physiology apart from killing (i.e. blocking resistance). The evolutionary constraints that have produced these evolved genetically encoded natural drugs are difficult to envision but their specificities, dynamic actions, multi-pronged functions have clearly rendered them as privileged molecules. Much research has defined the codes embedded within these natural small molecule biosynthesis programs and surprisingly these codes and rules are largely followed across all known organisms that generate polyketide and nonribosomal peptide molecules. In addition to the cracking of the nonribosomal and polyketide codes, further facilitating their genomic-based identification is the clustering of genes associated with the synthesis of a particular molecule-type (natural product/antibiotic) and a collinear pattern used in their synthesis. Collectively, these natural principles and rules have now created an exceptional opportunity to drive the detection and discovery of these molecules using a genomic start point. New transformative approaches to antibiotic discovery are needed, and the research in this proposal will lead to disruptive innovation, and a major departure in how historically antibiotics have been found and investigated. With our unique approaches we will enrich in agents with new modes of action, and those with a high likelihood of synergizing with clinically used antibacterials. The following aims are designed to provide this forward-looking view of how to treat antibiotic resistant bacteria: AIM 1) Uncover the secondary metabolomes of antibiotic producers and define antibiotic chemical-chemical interactions and synergy. AIM 2) Interrogate the bioproduction of antibiotics from genomically identified unexplored microbes using metabolomics AIM 3) Test naturally evolved drugs against secretion systems and serum resistance systems of gram negative/drug-resistant organisms


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: NAPCLI: Non-conventional approaches for peptidoglycan cross-linking inhibition
Funder: Medical Research Council

Abstract: Peptidoglycan (PG) is an attractive and validated target for antibacterial drug development for two main reasons. First, it is an essential and unique bacterial cell wall polymer with no counterpart in human cells, minimizing the risk of drug toxicity. Second, the essential PG synthases are exposed at the outer surface of the cytoplasmic membrane, making them highly accessible for antibiotic inhibition. Formation of the PG network requires glycosyltransferases for glycan chain elongation and transpeptidases for peptide cross-linking. Transpeptidation involves two stem peptides that act as acyl donor and acceptor substrates, respectively. The acyl donor site is targeted by the β-lactams, which form covalent adducts, and this interaction is well characterized. In contrast, nothing is known on the interaction of the transpeptidases with the acceptor substrate. To combat the erosion of the activity of β-lactams, we propose to identify additional drugable sites in the transpeptidases, including the acceptor binding site, and develop lead antibacterial agents acting on these sites. Our first objective is to characterize the mode of recognition of the acyl acceptor by transpeptidases and identify compounds blocking the binding of this substrate. We will use NMR spectroscopy to map the acceptor site and develop specific inhibitors based on modeling and virtual screening. Our second objective is to identify the partners of transpeptidases that regulate the coordinated elongation of glycan chains and cross-linking of stem peptides. This will allow us to select additional drugable sites in transpeptidases and associated proteins within the PG polymerization complexes. We will map key interactions by FRET analyses in live bacteria producing fluorescent proteins and by in vitro transpeptidase/glycosyltransferase assays in complexes obtained by tandem-affinity purification. Microfluidic cultures and time-lapse microscopy will assess the impact of inhibitors on cell division and viability. The interaction of lead compounds with their targets will be characterized by X-ray crystallography. These complementary approaches will enable the consortium to develop novel strategies for transpeptidase inhibition and obtain leads active against β-lactam-resistant bacteria.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION