NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving The Longevity Of New Infectious Disease Therapeutics Using Machine Learning / Artificial Intelligence In Early Stage Drug Discovery
Funder: Medical Research Council

Abstract: Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections globally. The increasing power of sequencing is offering new ways to rapidly detect and respond to the development of antimicrobial resistance. To fully leverage this information, sophisticated approaches are required to identify potential resistance mutations. This project exploits the wealth of in-house and publicly available genome wide association studies linking single nucleotide polymorphisms to drug resistance. It utilises the latest tools for measuring the biophysical effects of these mutations along with measures of the effects on protein function, experimental phenotype and genomic measures of resistance. This will be used to construct new tools exploiting the latest developments in machine learning to anticipate mutations leading to resistance before they become fixed in a population. It will build and extend the successful preliminary implementation of data collection, curation and modelling and subsequent analysis made by us in the study of resistance to first and second line treatments against Tuberculosis. This new computational method will be applied to significant human pathogens. Firstly, through validation based on new data from studies of M. tuberculosis, with the additional outcome of potentially discovering new potential mutations that could lead to resistance. Secondly, the application to existing drug discovery pathways led by us in the development of novel therapeutics to treat schistosomiasis and within programs managed by collaborators targeting a wider range of infectious diseases. The results of the application to real situations along with validation will be used to iteratively feedback and improve the machine learning tool. The new approaches can be used to inform the development of novel therapeutics and has the potential to be applied in identifying early emergence of resistance and in clinical diagnostics.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Structural studies of Plasmodium PIR proteins and their interactions with human inhibitory immune receptors
Funder: Medical Research Council

Abstract: This project will use the expertise of the Higgins group at structural and functional characterisation of host-parasite interactions. This will be complemented by collaborators who bring expertise in genomic analysis, analysis of immune cell function and animal models of malaria infection. PIR proteins, human receptors and antibody Fab fragments will expressed in a secreted form from mammalian cell culture systems. Monoclonal antibodies may be generated by immunizing mice, fusing splenocytes, selecting clonal hybridomas in semi-solid media and screening reactivity by ELISA. Fab fragments will be produced by papain cleavage. Proteins, antibodies and protein complexes will be purified by standard chromatography methods. Protein-protein interactions will be assessed by surface plasmon resonance, microscale thermophoresis and isothermal titration calorimetry. Structures will be determined by x-ray crystallography using molecular replacement, sulphur SAD and heavy metal-based approaches for phasing. Binding surfaces will be determined using hydrogen-deuterium exchange mass spectrometry and confirmed using mutagenesis. Sequence analysis will be conducted using MEME analysis with sequence determinants identified from structural features, or from sequences identified as containing ligand binding determinants.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: MICA: Novel mode of RNA polymerase inhibition by a new natural rifamycin, which is active against rifampicin-resistant RNA polymerases and bacteria
Funder: Medical Research Council

Abstract: WWe will investigate the mechanism of action of a newly discovered natural rifamycin, B1, that has a novel mechanism of inhibition of bacterial RNA polymerase (RNAP), and through that bring new insights into mechanisms of transcription initiation. B1, unlike known rifamycins, inhibits synthesis of the first phosphodiester bond. In addition, B1 is up to ~1000 times more potent against rifampicin-resistant RNAPs than known rifamycins, and is active against rifampicin-resistant M. tuberculosis. We will use a combination of organic chemistry, molecular biology and crystallography to understand the mode of action of B1 and how it manages to overcome rifampicin-resistance. We will apply semisynthesis and bioengineering to target the unique chemical groups of B1 in order to understand their functions. We will analyse B1 and derivatives by a large arsenal of in vitro transcription techniques to investigate unusual for rifamycins features of B1 action, proposed by preliminary data. Using crystallography and biochemistry we will solve the structures of B1 derivatives with promoter open complex and mutant RNAPs carrying the most frequent rifampicin-resistant mutations (which has already been achieved for B1 in preliminary work), and will use structure-based mutagenesis and in vitro assays to understand the structural principles of B1 ability to overcome rifampicin-resistant mutations. We will also investigate biochemically ADP-ribosylation (another rifampicin-resistance mechanism, which does not appear to affect B1) of rifampicin, B1 and its derivatives and the consequences for inhibition of transcription in in vitro assays. The study will not only shed light on fundamental understanding of early stages of initiation of transcription and the plasticity of RNA polymerase active centre, but may highlight new targets for drug development and will be essential for the future development of B1 as an antimicrobial for the treatment of drug resistant TB.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Investigation of the impact of the mosquito immune system on shaping the transmitted malaria parasite populations
Funder: Medical Research Council

Abstract: The Anopheles gambiae immune system forms a barrier to infection of the malaria parasite Plasmodium. Soon after entering the mosquito via a blood meal, parasites are attacked by an array of immune responses that greatly impact on their population size. In nature, only a handful of parasites survive these responses to establish infection. Prior to ookinete traversal of the mosquito midgut epithelium, the antibacterial Imd pathway significantly reduces the number of parasites. However, most losses are recorded after ookinetes traverse the midgut epithelium and encounter the complement-like response. We recently identified several genes that appear to be important for parasite protection from this response. Disruption of any of these genes leads to a variable number of ookinetes that traverse the mosquito midgut epithelium but are eliminated by complement reactions upon reaching the basal sub-epithelial space. Silencing key components of the complement-like system restores parasite development and transmission to a new host. These results led us hypothesise that either all of these genes have essential functions in parasite immune evasion or that loss-of-function of any of them bears a fitness cost exceeding a certain threshold required for parasites to endure the mosquito immune response. With the latter hypothesis, the mosquito immune system acts as a purifying selection filter for parasite populations permitting only the fittest parasites to survive and be transmitted to a new host. This project will further investigate this hypothesis by: (1) examining how the mosquito immune system shapes the parasite populations transmitted between hosts, (2) investigating the impact these responses may have on parasite populations transmitted by different vectors, and (3) characterising the function of prioritised parasite genes and proteins found to play important roles in mosquito infection and examining their potential as targets of transmission blocking interventions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: New advances in insecticide resistance genomics: using Machine Learning to predict resistance phenotype from large-scale genomic data.
Funder: Medical Research Council

Abstract: Malaria prevalence in Sub-Saharan Africa (SSA) has been reduced by 50% since 2000, primarily due to insecticide-based mosquito control measures. However, progress has stagnated in recent years, and has even reversed in some areas, due in part to the rise of insecticide resistance in mosquitoes. High-throughput genetics offers the prospect of accurate and reliable methods for large-scale characterisation of resistance in mosquito populations using routine collections, avoiding the laborious work of phenotypically testing mosquito resistance. The scientific community is currently at the advent of an exciting era in genomics where whole-genome sequencing can be performed at a rapidly increasing scale. These very large genomic datasets require novel analytical methods to deal with challenges of auto-correlation and over-fitting. Machine learning is a promising approach that has been used extensively to produce powerful classifiers in big data analyses, but is has yet to be applied to the field of vector-borne disease control because the necessary genomic data have been lacking. Through our involvement and leadership of the Vector Observatory and Genomics for African Anopheles Resistance Diagnostics projects, we will be whole-genome sequencing thousands of mosquitoes with known insecticide-resistance phenotypes from across SSA. The proposed project will leverage these unprecedented amounts of data to develop genomic predictions of insecticide resistance, and to design low-cost assays that can be used to determine resistance profiles using routine mosquito collections. We will experiment with different machine learning approaches and explore the possibility of combining a range of different information, for example combining gene expression and genomic data in a single analysis. We will also work with collaborators in SSA to design use-case scenarios for the implementation of our genetic screens in malaria-endemic areas.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Establishing the acceptability and feasibility of using social network-driven recruitment to test for hepatitis C in men who have sex with men.
Funder: Medical Research Council

Abstract: Aim: to develop and pilot a social network-driven recruitment (SNDR) intervention and establish its acceptability and feasibility in identifying men who have sex with men (MSM) at risk of hepatitis C (HCV). Objectives: 1. Explore barriers and facilitators to HCV testing and partner notification. 2. Develop SNDR questionnaire and methodology to explore HCV risk, social networks and test for HCV. 3. Evaluate the acceptability of SNDR. 4. Understand MSM networks to identify potential targets for intervention. 5. Design a randomised controlled trial to investigate efficacy and cost effectiveness. Method: A feasibility study with qualitative, developmental, pilot and evaluation phases. Qualitative: explore HCV risk, testing and the acceptability of recruiting peers and home HCV testing to inform the development stage. Development stage: develop questionnaire and SNDR methodology. Pilot stage: 20 MSM newly diagnosed with HCV ('seeds') to complete a questionnaire and recruit their contacts ('alters'), then explore which potential alters accepted/declined recruitment and why. Alters will complete a questionnaire and collect and return a dried blood spot sample for HCV testing (and HIV if status is negative/ unknown). Alters will then recruit successive rounds of alters, continuing for up to 12 months. Any HCV or HIV positive cases will be linked into clinical care. Qualitative interviews of participants will explore acceptability of SNDR. Analysis: Interview data will be coded, grouped into categories to create an analytical framework and then analysed thematically. The social and sexual networks will be analysed descriptively. Key outcomes will include dropout and kit return rates. Scientific and medical opportunities: This study is an opportunity to improve targeted testing of at risk MSM, understand their networks and inform development of a larger study mapping social networks with phylogenetic analysis to explore transmission pathways.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: Investigating the rising incidence of Gram-negative bloodstream infections in England using large linked epidemiology, clinical and genomic datasets
Funder: Medical Research Council

Abstract: Gram-negative bloodstream infections (GNBSI) are associated with significant morbidity and mortality and represent a significant factor in the global problem of antimicrobial resistance (AMR). GNBSI have been increasing in incidence in England and worldwide over the past decade although the precise reasons for this are unknown. Recent research in Oxford has suggested that for E. coli, the increase is primarily driven by community rather than nosocomial onset infections and that antibiotic resistant infections are increasing faster than susceptible ones. Identifying causal risk factors for acquisition and transmission is a significant research priority. In this study I will leverage large national databases to systematically identify healthcare exposures which are driving the increasing numbers of GNBSI cases and associated AMR across England. I will investigate in detail the role of the mobilome in the dissemination of AMR within and also between species. My initial analysis suggests that a subset of E. coli bloodstream infections are genetically highly similar to isolates from different patients which may suggest transmission or point source acquisition plays a role in some of these infections; I will explore the evidence for this. I will conduct genome wide association studies to search for pathogen genomic factors which may be contributing to the increasing incidence of community associated infections or are predictive of clinical severity. Interrogating such vast and rich datasets provides an opportunity to identify epidemiological exposures driving the increase of GNBSIs and the underlying pathogen biology which these may be selecting for, aiding the identification of potential future interventions. In addition, a more robust evidence base regarding the potential for iatrogenic factors such as excess antibiotic prescribing and urinary tract instrumentation to cause severe invasive infections would be a powerful incentive for better stewardship.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Indoor behaviour maps to guide arbovirus vector control
Funder: Medical Research Council

Abstract: Aedes aegypti is the most important vector of dengue, Zika, yellow fever and chikungunya viruses to humans worldwide. It is abundant in urban environments but as it is notoriously difficult to control, outbreaks continue to place a major burden on communities that are powerless to protect themselves. Development of effective new tools to target Ae. aegypti and reduce the frequency and magnitude of arbovirus outbreaks is urgently needed. It is well known that Aedes aegypti spend almost their entire adult life inside the human home but precisely where they rest when they are not biting is unknown. We propose to identify Ae. aegypti behaviours or events that can be targeted with simple low-cost tools or practices. Working in a semi-field system based in Recife, Brazil, our preliminary research indicates that resting Ae. aegypti have a strong preference for the lowest positions on interior walls within limited surface areas suitable for rapid insecticide treatment. If confirmed, this would dramatically reduce speed, cost and effectiveness of indoor insecticide treatments for this vector. We also investigated flight behaviour in African malaria mosquitoes, and using a similar approach, we identified novel behavioural activity that rapidly led to successful exploitation using a novel control tool. We propose that with better knowledge of a vector's flying or resting behaviour, targeting with insecticides residues could be simpler, faster and more cost-effective. This proposal aims to use video tracking technology, developed by the applicants, to map the resting and flight patterns of Ae. aegypti within an experimental 'simulated home' environment, to identify key locations within the human home where this difficult vector can be targeted rapidly, effectively and safely.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Roll out the radical cure with primaquine for vivax elimination: development grant
Funder: Medical Research Council

Abstract: We propose to accellerate the roll-out the radical cure for vivax malaria by demonstrating to the decision makers that radical cure with 7-day primaquine regimen not only benefits the individual patients but also makes an impact on vivax malaria transmission. We intend to demonstrate such an impact in a large cluster randomised trial in Cambodia, Laos, Vietnam, and Bangladesh. Intervention villages will be randomised to receive radical cure with the acute management of vivax malaria while the control villages receive only acute management, consistent with current national treatment guidelines. The development grant used to prepare for this demonstration project has three components: policymaker interviews, evaluation of the available G6PD tests, an assessment of acceptability and adherence of patients to radical cure using primaquine at the village level. We will ask policymakers regarding their views on the radical cure. To reach maximum effectiveness these regimens have to be rolled-out at village level. What evidence would policymakers need to support the roll-out of the radical cure at village level? Second, diagnostic test options to assess G6PD activity have rapidly expanded over the last years. We expect that at least one accurate biosensor will be available for field testing by the middle of 2019. We will compare the use of a biosensor in a field setting with a fluorescent spot test and the gold standard, spectrophotometry. Third, we will assess the acceptability by the village health workers and patient adherence to the primaquine regimen in the management of vivax patients. We will assess the feasibility and adherence to the primaquine regimen in 80 patients with uncomplicated vivax malaria with normal G6PD activity. Village health workers will administer the schizontocidal therapy and the primaquine regimens. Adherence will be assessed by self-reporting/interviews, drug counts and day 7 drug concentrations (primaquine and carboxyprimaquine).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Insecticide treated eave nets and window screens for malaria control
Funder: Medical Research Council

Abstract: We will conduct an efficacy study of 2 ITENs and ITWS against local mosquitoes. We will use the Ifakara semi-field site, comprising 4 experimental huts, each in its own enclosure. Volunteers sleep in the huts and mosquitoes are introduced into the enclosures. The following morning, the mosquitoes are assessed in terms of mortality, blood feeding and hut entry. The two ITENs to be tested are 1) the insecticide deltamethrin together with the synergist piperonyl butoxide PBO 2) the insecticide clothianidin; both of which are effective against resistant mosquitoes. The other 2 huts will be controls: one will be a negative control with no insecticidal intervention to ensure experimental validity; in the other, the sleeper will use a LLIN treated with deltamethrin and (PBO) for comparison with the standard of care. An experiment will last 4 weeks. In the first week, each of the huts will be randomly assigned to one of the 4 arms. For 4 nights, 60 (30 anopheles and 30 aedes) mosquitoes will be released into each enclosure each night and the outcomes will be recorded the following morning. Then the 4 interventions will be rotated between the 4 huts in a Latin square design and after 3 nights' washout the procedure will be repeated until each intervention has been in each hut. During the 4 nights each week, the sleepers will be rotated between huts. The experiment will be done 6 times, with new ITENs and ITWS then with artificially aged ones to approximate 1, 2, 3, 4 and 5 years of field use. We will conduct a second study on feasibility and acceptability. We will put up ITENs and ITWS in 200 houses in local villages to demonstrate that they can easily fitted and learn lessons of how to do this in the local environment. At baseline, we will conduct a survey on acceptability and attitudes to the products. We will follow up 1 year later and ask acceptability. In the one year survey we will assess the proportion of products still in place, and the condition of the products.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Azithromycin and cefixime combination versus azithromycin alone for the out-patient treatment of typhoid in South Asia; a randomised controlled trial
Funder: Medical Research Council

Abstract: More than 14 million children and adults develop typhoid fever each year with 10-15% at risk of the severe forms of disease and 140,000 deaths. Fluoroquinolones, such as ciprofloxacin, have been successfully used in this role for the last 20 years but in South Asia resistance to ciprofloxacin in typhoid is now widespread. In the face of fluoroquinolone resistance, a seven-day course of oral azithromycin is commonly recommended. In areas of Pakistan affected by the current outbreak of XDR typhoid with strains resistant to all commonly used antimicrobials including the ciprofloxacin, cefixime and ceftriaxone, azithromycin is the only oral option. It has been suggested that antimicrobial combinations may improve the efficacy of treatment and mitigate the problems of resistance in typhoid fever, but no good quality evidence exists. Small studies suggest a combination of azithromycin and cefixime gives a better outcome than azithromycin alone. The ACT-South Asia trial is designed to test this suggestion in a 3-year phase IV, double-blinded, randomized, controlled trial. The randomization (1:1) will be a superiority blinded design to evaluate whether a 7-day combined regimen of azithromycin and cefixime is superior to a 7-day regimen of azithromycin alone in the out-patient treatment of uncomplicated typhoid fever in 1500 children and adults in Bangladesh, India, Nepal and Pakistan. The primary endpoint is treatment success at the end of one week of treatment and an absence of relapse at one month. The trial will also address the duration of faecal shedding of S.Typhi and S.Paratyphi A, the safety of the drugs, the cost-effectiveness and acceptability of each regimen, the effect of the intervention on the patients clinically suspected of typhoid who are blood culture negative and the effect of the regimens on resistance in the patient's normal flora.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION