NIHRDataInsights/HRCSData huggingface dataset:
Title: NTD Highlight Notice - Defining PK/PD relationships of anti-leishmanial drugs - a novel approach for anti-leishmanial drug development
Funder: Medical Research Council

Abstract: Leishmaniasis is caused by obligate intracellular parasites of the genus Leishmania. Visceral leishmaniasis (VL) is a systemic manifestation of disease with more than 50 000 deaths per year and fatal if not treated. There are no vaccines and few drugs available with severe limitations. The full pharmacological profile of an anti-infective agent entails characterisation of its i) pharmacodynamics (PDs) and ii) pharmacokinetics (PKs). In antibiotic therapy PK/PD analysis has emerged as a new discipline which aims to understand the relationship between drug concentration and effect. This knowledge base can i) guide selection and optimisation of potential drug candidates, ii) provide the scientific rationale for selecting dosing regimens that increase efficacy and reduce probability of emerging drug resistance and iii) decrease the risk and cost of drug development. However current knowledge of the PK/PD basis of anti-leishmanial drug activity is severly limited. We aim to fill this gap by defining PK/PD relationships of anti-leishmanial drugs as a novel approach for anti-leishmanial drug development. Our specific objectives are to characterise PK/PD relationships of established anti-leishmanial drugs in models of infection, construct PK/PD parameters that are predictive of clinical efficacy, perform dose simulation studies and provide a basis for refined lead optimisation and adjusted methodologies in the drug development process. We will then move to demonstrate that methodologies established can be translated into future anti-leishmanial lead optimisation, design of drug combinations and use for clinical trials. We will use a reverse translational approach with inclusion of clinical data for approved anti-leishmanial drugs, novel technologies for assessment of PKs and an iterative process in our investigations. The outcome of our studies will contribute to the understanding and refinement of the anti-leishmanial drug development process.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Understanding herd immunity for influenza using archived sera from the UK and mathematical models
Funder: Medical Research Council

Abstract: Serological studies of the 2009 pandemic illustrated how patterns of infection were different to patterns of clinical cases. Therefore, standard approaches for the estimation of incidence (e.g. based on surveillance for influenza-like-illness) did not give a clear understanding of how the pool of susceptible individuals is being depleted at any point in time (herd immunity). In order to fully characterize the transition from Sydney 1997-like to Fujian 2002-like viruses, we will measure the concentration of antibodies in the UK population for both H3 strains for all 6 seasons from 1998/1999 to 2003/2004. Our background knowledge for influenza A H1N1 and B is less complete than for H3N2. Therefore, we focus on a period when both H1N1 and B vaccine strains were changed, 1999-2000 to 2001/2002. To our knowledge, there are no population-wide serological surveys of influenza B. We will use 3 analytical approaches: 1) we will classify each assay result as either positive or negative based on a titre threshold and then use logistic regression to test interesting hypothesis for the risk of infection; 2), we will incorporate serology as one of a number of data sources to infer parameters for strain-specific healthcare oriented dynamics model; 3) to better understand the relationship between our assay results and; infection, infectivity, susceptibility, and decay; we will propose the most parsimonious transmission model that can represent the full range of assay results and these fundamental processes. The combination of data and models we propose will allow us to address hypotheses such as: absolute rates of infection with influenza B are lower than those with H3N2 and have a different pattern across age groups; infectivity at intermediate titres is age specific; and the use of pre and post seasonal titres would enable the detection of some strains being more severe than others by allowing the measurements of clinical outcomes against a 'true' measure of infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The identification of the disulfide bonds in HIV gp120 whose reduction is required for cell entry and their manipulation for immunogen design
Funder: Medical Research Council

Abstract: There is ample evidence in support of the fact that HIV gp120 undergoes reduction at the cell surface concomitant with its action, together with gp41, in viral entry. Reduction affects at least 2 disulfide bonds, occurs after CD4 binding and is required before fusion can occur. As such it is a key intermediate stage in the entry process. However, the exact identity of the reduced intermediates, that is, which cysteines are reduced and exactly where and when they arise, is not known. We have developed an assay system that is able to identify reduced Cys residues in a complex of gp120/CD4 /reductant and we plan to identify the gp120 disulfide bonds that are reduced during cell entry and confirm the cell surface isomerase responsible for cleavage. We suggest that, as key intermediates, partially reduced gp120s may represent novel immunogens able to generate antibodies that access and block the fusion reaction. We will test this hypothesis by immunisation of small mammals and assessing the sera generated for breadth of antibody response and for the presence of neutralising antibodies. Our work will contribute new information to models of the mode of action of HIV Env and test rationally chosen gp120 variants as novel vaccine candidates.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: A high throughput model of Cryptococcus Infection and Cell Biology In Vivo for identifying host and pathogen disease determinants and new therapeutics
Funder: Medical Research Council

Abstract: Cryptococcus is a fatal fungal pathogens of humans causing death through meningitis. As a major pathogen of the immunocompromised, especially AIDS patients Cryptococcus causes an estimated six hundred thousand deaths per year. By evading or manipulating phagocytes, particularly macrophages, Cryptococcus is able to cross the immune barriers that normally prevent fatal disseminated disease. Current studies focus on in vitro analysis in isolated cells, such as macrophages or in vivo studies in rodent hosts. However, such approaches are unable to capture the complex cellular events that define how this fatal disease progresses or is stopped. Therefore I have developed a new integrated model of cryptococcosis in zebrafish to simultaneously study host and pathogen factors that determine disease progression and outcome in vivo. The objectives of this model are to identify the underlying causes of cryptococcosis, molecular targets for therapeutic intervention and new therapeutics through my chemical screen. Phase 1a) I will produce quantitative data on disease progression including spatial and temporal growth kinetics. b) I will analyse the innate response to Cryptococcus infection through both imaging of macrophages and neutrophils and measuring expression and activity of molecular markers of innate immunity c) I will study the cell biology of the Cryptococcus:phagocyte interaction in vivo, including the function of the vomocytosis of Cryptococcus from macrophages. Phase 2. I will identify genetic basis of pathogen virulence by examining 4 different groups (directed mutants, 2 hyper-virulent outbreaks and clinical isolates from HIV patients) in my model. Phase 3. I will determine host immune requirements by a) depleting neutrophils and macrophages b) and inhibiting effectors of the innate immune system through knock-down and mutagenesis. Phase 4. I will perform an automated chemical screen to identify new drugs for the reduction of Cryptococcus burden during infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: NOx Technology: A "solution" for prevention of ventilator associated pneumonia in critically ill patients.
Funder: Medical Research Council

Abstract: We have developed, a novel, non-enzymatic, system for exogenous generation and local delivery of nitric oxide (NO) and higher oxides of nitrogen (NOx). Prepared via an admixture of sodium nitrite and ascorbic, or citric, acid, the system generates large amounts of exogenous NOx via the chemical reactions of acidified nitrite. We propose to deliver the solution in liquid form to the stomach and oral cavity of mechanically ventilated patients. There is now persuasive evidence that the oxides of nitrogen (NOx) play a key role in the maintenance of host defence against various microbial pathogens. In health, NOx is present in high concentrations in the stomach where it plays an important role in maintaining intragastric sterility and preventing gastrointestinal infections. Ventilator associated pneumonia (VAP) is a nosocomial infection occurring in patients who have been mechanically ventilated for more than 48 hours [1]. These patients are usually sedated, they produce little or no saliva and their swallowing reflex is inhibited or abolished. VAP is caused by aspiration of infected secretions from the aerodigestive tract. Our own pilot studies have confirmed that during critical illness, production of oxides of nitrogen, which play key roles in host defense, is markedly reduced. This predisposes to colonization of the stomach and oral cavity by pathogenic bacteria and hence the subsequent development of VAP. Our NO-generating solution is designed to restore normal physiological activity of NOx by nasogastric and oral administration. Our aim is to reduce significantly the incidence of VAP and the associated prolonged length of stay, morbidity, mortality and treatment costs. Phase I and II developmental clinical studies with a prototype product will pave the way for future Phase III studies, dependent on confirmation of efficacy and development of an easy-to-use delivery system.


Research activity codes: 6.7 PHYSICAL
Health categories: INFECTION
Title: Identifying Mycobacterium tuberculosis transmissions using whole-genome sequences
Funder: Medical Research Council

Abstract: Aims: I plan to use Whole Genome Sequencing (WGS) to undertake a genealogical investigation of M tuberculosis (MTB) isolates in a high incidence region of the UK in order to further refine clusters of disease as defined by the current gold standard 24-locus MIRU-VNTR typing. I have 3 aims: (i) I will investigate the distribution of M tuberculosis genome-wide sequence diversity within active cases across space (isolates from different anatomical loci), time (sequential isolates from individuals with a persistent infection) and household outbreaks. This data will be used to estimate the range of times to the most recent common ancestor (MRCA) of these samples which are known to be related (akin to "transmission"). (ii) Using results from (i) to provide thresholds for determining whether recent transmission is plausible, I will estimate most likely times to the MRCA within groups defined by 24-locus MIRU-VNTR, and use the 95% credible intervals from Bayesian phylogenetic methods to subdivide groups into clusters credibly representing recent transmission of tuberculosis. (iii) I will then compare these genealogically identified clusters with those identified by the public health team using standardised epidemiological and demographic questionnaires. Methods: (i) I will sequence further samples and use Bayesian statistics to estimate the range of time to the MRCA (ii) I will analyse 4-5 years' worth of whole-genome sequenced samples (~ 2000 samples) from central Birmingham, and a further 250 samples from the MIRU-VNTR groups across the Midlands, using classical statistics. Opportunities: (a) Translational: This study will provide a pathway for the implementation of these techniques into routine service. (b) Scientific: Robust genealogical analyses will provide a technique to better investigate the incubation period and transmission dynamics (including the possibility of super-spreaders), and provide a foundation for model base transmission analyses.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The investigation of human polymorphisms impacting on HIV/AIDS pathogenesis
Funder: Medical Research Council

Abstract: I aim to investigate the molecular mechanisms of polymorphisms identified by GWAS and exome sequencing which are associated with rapid progression of HIV to AIDS. I will begin with a polymorphism in the XRCC-5 promoter that drives expression of the Ku80 protein a member of the non homologous end joining pathway (NHEJ). I will (1) use reporter gene assays to assess polymorphic promoter activity, I will clone the polymorphic XRCC5 promoter sequences into a plasmid such that they drive luciferase expression. I will then transfect a variety of cells and assess promoter activity by measuring luciferase activity. (2) I will seek differential transcription factor binding sites using electrophoretic mobility shift assay (EMSA). I will prepare radioactively labeled oligonucleotides encoding the polymorphic promoter sequences and incubate with nuclear extracts from human T cell lines and seek evidence for differential transcription factor binding to the different sequences. Factors will be identified by supershifting with specific antibodies. Candidates will be identified by inspection of publicly available ChIP Seq data which will inform us as to which transcription factors have been found to be bound to the XRCC5 promoter. (3) I will investigate the role of Ku 80 it's heterodimeric partner Ku70 and other members of the Non Homologous End Joining Pathway for a role in pathogen associated pattern recognition and HIV replication. I will reduce protein expression by expressing specific shRNA sequences and over-express proteins using lentiviral vectors. I will also make mutant proteins, particularly focusing on residues described to be under positive selection and express these proteins in T cell lines. I will then examine whether the ability of the cells to replicate HIV-1 and detect virus is altered by measuring interferon induced gene expression by quantitative PCR and expression array and HIV-1 replication by measurement of viral protein (p24) production.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Optimal trial design for a confined release of malaria-refractory transgenic mosquitoes
Funder: Medical Research Council

Abstract: Research into genetically modified (GM) mosquitoes is quickly progressing. The first release of sterile male GM mosquitoes to control dengue fever took place in the Cayman Islands in 2009, and enthusiasm is growing for future releases to control malaria in Africa. Malaria is proving particularly difficult to control in highly-endemic areas where it is predicted that elimination may not be possible with currently-available tools. The use of selfish genetic elements capable of spreading malaria-refractory transgenes from one mosquito population to another is appealing for wide-scale control, but also draws into question the ability to conduct a confined field trial. The aim of this project is to compare proposed strategies for a field trial of malaria-refractory mosquitoes in terms of their potential for confinement and their ability to significantly reduce malaria prevalence. The first objective is to develop models of mosquito population dynamics based on ecological data from potential field sites such as the Comoros Islands and Bioko Island. Mosquito populations are structured spatially and temporally, and important features include seasonal fluctuations in population size, relative abundances of different vector species, and rates of gene flow between populations. The second objective is to link these models to a model of malaria transmission. Parameters for this model will be fitted using parasite prevalence data. Proposed strategies for introducing malaria-refractory genes will then be contrasted. Possibilities include releasing large numbers of malaria-refractory males, and releasing males engineered with selfish genetic elements that only spread if they exceed a critical frequency in the population. These models will be of great use in designing field trials that are both spatially limited and effective as a means of malaria control and, if successful, could lead the way to more ambitious projects with the potential to control malaria on a much wider scale.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: An integrated geospatial analysis framework for neglected zoonotic diseases
Funder: Medical Research Council

Abstract: This project aims to develop a "One Health analytical framework" to provide advances in our understanding of the spatially heterogeneous risk of neglected zoonotic disease (NZD) in humans and animals and the relationships between animal and human NZD prevalence within different landscapes (e.g. varying land cover). Geo-referenced human and animal prevalence of several NZDs will be provided by collaborators. Remote sensor images and field visits will provide environmental covariate data (e.g. land cover, precipitation). Exploratory analysis will include: spatial mapping; descriptive analysis; cluster detection and spatial correlation analysis, to allow the selection of up to three datasets for further analysis. Preliminary, non-spatial regression will examine the influence of covariates on human and livestock NZD prevalence. This will be extended with a spatially explicit model-based geostatistics approach (to account for spatial autocorrelation) and the integrated analysis of both human and animal prevalence using joint-distribution modelling, to (a) quantify the influence of external variables on the spatial distributions of human and animal infections, (b) quantify the relationship between livestock and human prevalence of disease and (c) identify variations in relationship b in different environmental conditions. Model extrapolation will provide spatial predictions of disease prevalence in humans and livestock across the study areas. Further spatial analysis will provide estimates of the population at risk, identify priority control areas and assess the utility of sentinel screening in livestock to detect risk to humans. The results will provide significant evidence to support the control of NZDs, and the One Health analytical framework represents a new paradigm for the analysis of zoonotic disease data, allowing integrated analysis of human and animal data in a single model and generating a substantially greater depth of understanding than individual analyses.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Maximising the impact of chemoprevention on the malaria burden in children in areas of seasonal transmission
Funder: Medical Research Council

Abstract: Aims and Objectives Understand where replacing standard antimalarials with LACTs would be useful by quantifying the burden of repeated malaria and the heterogeneity in malaria risk in different epidemiological settings. Evaluate the potential for extended SMC and LACT in different epidemiological situations using a mathematical model and data from a clinical trial of SMC and LACT. Use a spatial modelling framework to determine the geographical areas where SMC and/or LACTs are likely to be advantageous, estimate the population at risk and the public health impact. Methodology Statistical models will be fitted to data from clinical trials to quantify dispersion in malaria incidence, and frailty models used to explore event dependence. The burden of repeat malaria will be determined and factors associated with high risk will be identified. A compartmental mathematical model of SMC and treatment of malaria will be fitted to trial data and extended to include multiple exposure/susceptibility strata, variable treatment access, and correlation of access with exposure. Sensitivity analyses will indicate the range in impact. Receiver-operating characteristic analysis will identify climatic predictors of suitable epidemiology for SMC and LACT. Areas will be mapped using high resolution climatic data, the populations at risk estimated using spatial population data, and the malaria burden estimated using published methods. The fitted compartmental model will be incorporated into an individual-based simulation to allow impact, effect on transmission, and effect of other control tools to be explored. Scientific opportunities Understanding heterogeneity in malaria risk is important for predicting the impact of all interventions accurately. The research may establish LACTs as a novel form of chemoprevention. Medical opportunities The research has direct implications for policy changes that could reduce morbidity and death from malaria among African children.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFECTION
Title: Combining epidemiological and phylogenetic models of infectious disease dynamics
Funder: Medical Research Council

Abstract: Coalescent models are commonly used to model the population dynamics of viruses using viral sequence data. This approach is attractive epidemiologically, as information on the past transmission dynamics of a virus can be obtained even using a single, cross-sectional sample of viruses. Coalescent models are also appealing computationally, as only the evolutionary past of the sample of sequences needs to be considered, rather than that of the population from which the sample has been obtained. However, these coalescent models originate from considering the dynamics of single populations or species, and while these models can be fitted to viral sequence data, the resulting parameter estimates are extremely hard to interpret, as they are so far abstracted from meaningful epidemiological quantities. For example, we have previously shown that the `effective population size' of a viral epidemic is not, as is commonly assumed, proportional to the number of infected individuals, rather it is related to both the incidence and the prevalence. We propose the development of evolutionary models that incorporate explicit models of viral transmission, considering factors such as geographic spread of viruses, differences in sampling effort, demographic stochasticity and selection. While progress has recently been made in some of these areas, we argue that the failure to consider the details of the transmission process may lead to incorrect conclusions being drawn. This additional flexibility in allowing biological realism comes at the cost of considering the evolutionary dynamics of the entire population via simulation-based techniques, and part of the research associated with addressing the main aims involves alleviating at least some of this computational cost, partly through the adoption of approaches which parallelize easily, and partly through algorithmic development.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION