NIHRDataInsights/HRCSData huggingface dataset:
Title: Novel interventions for eliminating one- health mobile antimicrobial resistance genes from human and animal microbiomes
Funder: Medical Research Council

Abstract: The most important cases of one-health antimicrobial resistance are caused by the rapid spread of plasmids carrying AMR genes between bacterial strains and species. In this project, we will test the of plasmid-dependent lytic bacteriophages (PDB) to selectively decontaminate bacterial communities by killing AMR plasmid-containing bacteria and by preventing the transfer of AMR plasmids to commensal and pathogen strains. First we will test the impact of key variables on the efficacy of PDB therapy (antibiotic treatment, bacterial diversity, phage mono culture or cocktail) using an established PDB-host system. We will then (i) screen an established collection of phages from agricultural sources to discover new PDBs that have activity against a broader range of one-health AMR plasmids and (ii) test the impact of the aforementioned key variables on the efficacy of these phage in vitro.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Chemigenetic analysis and efficacy of novel antifungal drugs that target fungal pH signalling
Funder: Medical Research Council

Abstract: The repertoire of antifungal agents available to treat fungal diseases is sparse, the rate at which we discover new antifungal modes of action (MOAs) is unacceptably slow, and antifungal resistance is on the rise. The focus of this project is a highly conserved and fungus-specific signalling pathway used by fungi to adapt to the pH of the extracellular environment. Extracellular pH profoundly influences the production and functionality of fungal secreted proteases, toxins, and substrate degrading enzymes, as well as ion and nutrient transporters. As such, fungal viability is heavily dependent upon versatile adaptations to pH flux. pH adaptation is driven by the fungus-specific PacC/Rim signalling pathway which we discovered, and extensively characterised, in the model ascomycete Aspergillus nidulans. PacC/Rim signalling is highly conserved, and indispensable for full infectivity, in the overwhelming majority of fungal pathogens. With recent BBSRC iCASE funding we devised a powerful genetic screen with which to seek chemical inhibitors of PacC/Rim signalling. We achieved this by repurposing of a genetic selection technique which was initially devised to seek novel regulators of PacC processing in A. nidulans. The aim of this programme is to identify novel antifungal MOAs which inhibit fungal pH signalling. To this end we have assembled an integrated workflow comprising phenotypic, genetic and chemical profiling intended to maximise efficiency of lead discovery and mitigate attrition due to off target or toxic activities. The programme is comprised of four research objectives. 1. Screen reference libraries for hit-like chemistries and extant drugs which inhibit PacC/Rim signalling 2. Establish proof of on-target and pan-fungal activity and low toxicity 3. Pursuit and definition of Structure-Activity Relationships (SARs) 4. Identify targets and modes of action, and study antifungal efficacy


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: 21-EEID Cross-scale dynamics of LASV spillover within human-driven ecosystems
Funder: Medical Research Council

Abstract: Understanding how anthropogenic and environmental drivers contribute to disease emergence is one of the most intractable problems in modern disease ecology. The animal-borne Lassa virus (LASV), when spread to humans, causes Lassa fever (LF), a hemorrhagic fever of public health significance in West Africa, which has recently been designated a global health priority. This has been partly driven by an apparent increase in cases in recent years, though little is known about the disease's true endemic burden. LF epidemics are dominated by regular spillover of LASV from animal reservoirs to humans within a rural context, which means LASV provides an ideal system in which to study cross-scale disease dynamics, from an ecological and anthropological perspective. Here, we will first conduct local-scale anthropological studies of human, rodent, and LASV ecology, set within a quantitative modelling framework. These analyses, will then inform spatially-explicit individual-based transmission models, constructed to simulate LASV within anthropogenic landscapes. These infectious disease agent-based models will unpick the processes that determine the spatial and temporal distribution of LASV and risky human exposures, and build scenarios for participatory examination of LF interventions in the context of, for example, poverty and food insecurity. Finally, we will integrate emergent patterns from our individual-based model back into an existing broad-scale model using regression-based approximations. Thus, our local-scale study, broad-scale predictions, and the tools we create from these analyses, will not only fill key gaps in our understanding of how risk is propagated across scales, but will also inform the ongoing disease management efforts of our collaborators, the Nigeria Centre for Disease Control (NCDC), thereby reducing disease burden and improving lives in Nigeria.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: VIRTACs - Protein Degradation as an Anti-Viral Strategy
Funder: Medical Research Council

Abstract: As highlighted by the current Covid-19 pandemic, viruses are a constant threat to human health and prosperity. Viral infections kill millions of people every year and population growth, international travel and climate change mean that human populations are increasingly vulnerable to emerging viral threats. Further to the severe morbidity and mortality caused by viruses, lost productivity and livestock deaths mean viruses place a considerable burden on the global economy (estimated in the tens of billions of pounds worldwide each year). Developing new strategies to combat viral threats is of tremendous importance, as recognized by many organizations including the United Nations, World Health Organization, and UK Government. Most antiviral drugs work through a classical mechanism that involves a 1:1 interaction of the drug with its target. An emerging strategy in Medicinal Chemistry seeks to overcome this "occupancy based" limitation using a new mechanism called protein degradation. There are lots of potential advantages to the protein degradation approach, but its new enough that it hasn't really been explored much in an antiviral context. This project will explore the protein degradation mechanism in targeting 3 viruses of importance to human health: HIV, influenza, and the SARS-CoV-2 virus that is causing the current Covid-19 pandemic. Although we're not aiming to generate a new drug during this project period (that takes longer and costs more), we believe that this project will lay the groundwork for important new therapies in the future. There's no doubt that these therapies will be needed, as viruses are constantly developing resistance.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: ISARIC CCP activation for acute hepatitis of unknown cause
Funder: Medical Research Council

Abstract: A series of cases of severe hepatitis in young children of unknow cause were recognised in Central Scotland in March 2022. By 18 May 2022, there had been 198 such cases across the UK, predominantly in children under 5 years old. The aetiology is unknown but an infection or co-infection is a strong possibility and preliminary data from our work suggests that co-infection with adenovirus 41F and an adeno-associated virus 2 (AAV2) may be responsible. The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Clinical Characterisation Protocol (CCP) is a global sleeping protocol to facilitate immediate academic research to characterise new infections and other syndromes. We seek urgent support to enable ongoing recruitment to the ISARIC CCP-UK study of cases of unexplained hepatitis in young children. We will obtain consent and biological samples, in partnership with public health agencies, in order to characterise the clinical features of this new outbreak, focusing initially on three core questions: 1. What are the clinical features of acute disease? 2. What is the causative agent? 3. What is the role of prior immunity, immune compromise or systemic inflammation in acute disease? Building on our extensive body of work during the Covid-19 outbreak, we will investigate clinical features of disease using structure case report forms for all consenting cases in the UK. We will perform metagenomic sequencing on samples from cases in order to determine the underlying cause of disease, and characterise the histopathological, immunological and host genetic features mediating the pathophysiology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Advancing influenza antigenic analysis to improve vaccine effectiveness
Funder: Medical Research Council

Abstract: Seasonal influenza is a major cause of disease nationally and globally. Vaccination is the primary countermeasure against influenza virus infection. The influenza virus evolves by changing the major antigenic surface protein necessitating frequent vaccine updates. Antigenic cartography is a method of synthesising and visualising binding or neutralisation assay results, and has proved very effective in characterising influenza evolution. I will improve antigenic cartography tools to address emerging questions in influenza surveillance and research 1. How to optimize antigenic cartography to handle higher measurement error 2. How to optimize the construction of antigenic maps with large numbers of viruses and relatively few antisera 3. What are the evolutionary patterns in, and mechanisms that drive, the evolution of the current H3 viruses 4. How to incorporate age-specific human serological differences into antigenic analyses 5. How to integrate experimental work on viral evolution with surveillance data I will test the limits of the current antigenic cartography method and develop statistical tools to quantify map quality. I will explore different aspects of the data that affect map quality such as the number of antigens/sera, the magnitude of random measurement error and the amount of missing data, using simulated data. I will apply these tools to surveillance data from Public Health England and the World Health Organization, and laboratory engineered mutants from research studies from the Centre for Pathogen Evolution. Due to changes in viruses, different methods are used in surveillance characterisation; mainly neutralisation assays and human serology. I will integrate antigenic data from traditional and novel high throughput assays on laboratory engineered viruses with surveillance data. These results will be used to support the selection of vaccine viruses, understand virus evolution and the human serological response, and develop better vaccines.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Diagnostic Algorithms for Tuberculosis
Funder: Medical Research Council

Abstract: Ten 10 million people fall ill and 1.4 million died of TB each year, the second cause of death due to infection after COVID-19. A major barrier for TB control is inaccessibility of diagnostics. WHO recommends the use of WHO-recommended molecular diagnostics (WRDs), but these tests require a laboratory infrastructure usually located in reference laboratories. Most people with TB seek medical advice at health centres with basic laboratory facilities and thus we need point of care (POC) diagnostics. Tests for the POC should identify most patients with TB (a rule-in test), exclude most patients unlikely to have TB (a rule out test) and identify individuals requiring WRDs. Although these diagnostics are unavailable, diagnostics that partially meet these criteria could 'patch up' each other limitations. In Nigeria, FujiLAM, a urine-based test, identified 66%/70% of people with TB with/without HIV; while patients with normal C-Reactive Protein (CRP) had <1% probability of having TB, excluding 50% of patients. WRDs are also tested using single cartridges, and pooling methods, where samples are pooled together, can significantly reduce workloads and costs. We propose to develop diagnostic algorithms that that are rapid, patient-centred, cost-effective and articulated with the WHO WRDs that combine tests suitable for the POC. We will develop mathematical models of diagnostic combinations. The models will be informed by data generated by our studies and will estimate sensitivity, specificity, predictive values of test combinations, the location of the diagnosis. We will simulate tables of performance by TB and HIV prevalence. We will then conduct a pilot implementation study to estimate cost-effectiveness and qualitative studies with patients, health service staff and stakeholders. Once the diagnostic algorithms are optimised, we will seek funding for clinical trials in low income settings.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The epidemiology of Chagas disease in the UK: a mixed methods study to inform equitable and evidence-based approaches to migrant health screening
Funder: Medical Research Council

Abstract: Chagas disease is a chronic disease endemic in the Americas, caused by the parasite Trypanosoma cruzi. Due to globalisation and migration, Chagas disease is increasingly recognised as a public health problem among migrants in Europe such as the 250,000 Latin American migrants in the UK. In endemic settings it is principally transmitted via triatomine vectors. In all settings, T. cruzi can be transmitted through vertical transmission and, in the absence of screening, through blood transfusion and organ transplantation. Left undiagnosed and untreated, Chagas disease leads to cardiac and gastrointestinal complications in 30-40% of infected individuals, typically 20-40 years after initial infection. Disease phenotype may be related to parasite genetics, as gastrointestinal complications are only rarely reported outside of regions where the TcII genetic lineage T. cruzi predominates. The complex pathophysiology and gaps in diagnostic coverage of Chagas disease have led to a lack of any granular data on where people are (or could have previously been) exposed to T. cruzi infection. This "epidemiological silence" presents a major challenge in developing evidence-based screening policies in non-endemic settings. This Fellowship aims to generate the knowledge required to design an equitable and impactful screening intervention for Chagas disease in the UK, through: - Three sero-epidemiological cross-sectional studies to determine the burden of Chagas disease in core groups of migrants living in London (in primary care, antenatal care and community-based), and identify factors associated with increased risk of infection. - A nested serological study of parasite-lineage on cases identified through these cross-sectional studies. - A nested qualitative study with migrants from endemic countries and key stakeholders in the screening pathway to understand their perspectives on the barriers and facilitators of a successful screening programme


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Investigating the distribution & impact of HIV-specific broadly neutralising antibodies on mucosal immunity and the HIV reservoir in rectal tissue
Funder: Medical Research Council

Abstract: Broadly neutralising antibodies (bNAbs) are a promising novel HIV therapeutic, potentially capable of inducing long-term immune responses even after treatment interruption. The RIO trial is a placebo-controlled randomised trial of single dose long-acting dual bNAbs and treatment interruption. I will establish a sub-study collecting 7 rectal biopsies per person, in 20 RIO participants to investigate the effect of bNAbs on gut tissue, the largest HIV reservoir site in the body. The project aims to determine 1) if bNAbs in rectal tissue achieve concentrations comparable to blood; 2) immunohistochemistry analysis of bNAbs interaction with rectal lymphoid tissue; and 3) the effect of bNAbs on the rectal latent HIV proviral reservoir. Methodology: Homogenised rectal tissue bNAb concentrations will be measured using a single-molecule ELISA and compared with paired serum bNAb concentrations for pharmacokinetic analyses (n=10, 5-7 timepoints per participant). Formalin fixed, paraffin embedded biopsy sections exposed to bNAbs will be used to optimise conjugated bNAb-specific fluorescent-labelled anti-idiotype and immune cellular markers antibodies. Once optimized, the sections will be screened with the high-throughput Vectra Polaris multiplex automated imaging system and the HALO multiples imaging analysis platform. Regions of interest comprising isolated lymphoid follicle structures and bNAbs (n=20, 3 timepoints per participant) will be identified using cellular markers (see CfS) and bNAb antibody stains. The development of a novel IPDA using double emulsion droplet technology will improve on the existing IPDA, to allow sorting and sequencing of rare intact HIV DNA sequences in tissue and PBMCs in addition to intact reservoir size quantification. Phylogenetic analyses will compare the intact HIV reservoir sequences to determine the presence of changes in the HIV reservoir compared at baseline and post viral rebound and ART restart (n=20,2 timepoints per participant).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A longitudinal study of SARS-CoV-2 evolution and molecular characterisation of variants in immunocompromised individuals with persistent infection
Funder: Medical Research Council

Abstract: Immunocompromised individuals can develop persistent infection with SARS-CoV-2. Mutations accrue due to ongoing replication, creating new 'variants' of the virus. These mutations have the potential to alter host-pathogen interaction, potentially affecting pathogenesis, transmissibility, severity of disease and susceptibility to vaccines or treatment. This longitudinal study will characterise viral evolution and the variants that arise during persistent infection with SARS-CoV-2, followed by molecular characterisation of these variants in vitro. By studying longitudinal viral isolates and sera from the same individual, sequential mutations can be studied to judge their effect on host-pathogen interaction. The aims of this proposal include to 1) describe the patterns of SARS-CoV-2 intrahost evolution longitudinally during persistent infection, 2) correlate the emergence of SARS-CoV-2 variants with clinical course, immunosuppression and antiviral treatment, 3) characterise emergent variants in vitro, including experiments to judge neutralisation by antibodies and resistance to interferon. Genomic sequencing of viral isolates using a deep sequencing protocol on Illumina technology will allow determination of the consensus genome and intrahost single nucleotide variants (iSNVs). The presence and frequency of iSNVs over time will be monitored, and in response to treatments for SARS-CoV-2 and other immunomodulating therapies for pre-existing conditions. Viral isolates will be cultured for in vitro molecular characterisation experiments. Successive genomic mutations will be judged for their effect on neutralisation by antibodies and changes in susceptibility of the virus to interferon. Longitudinal serum samples from persistently infected individuals will be used in autologous neutralisation studies on the cultured virus. Initial research utilises existing ethical approval to analyse already stored, residual samples from GSTT in collaboration with KCL and UCL.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Identification of Novel Efficacious Anti-Malarial Transmission Blocking Antigens Targeting the Female Gametocyte
Funder: Medical Research Council

Abstract: We propose to examine a novel dataset of female gametocyte proteins, with putative surface localisation and implication in transmission blockade, and assess their immunogenicity and ability to initiate a transmission blocking response after vaccination, while examining levels of natural exposure by serological studies on cohorts of individuals naturally infected with P. falciparum in Papua New Guinea (PNG). Specifically, we will generate a series of recombinant proteins, encoding 23 previously uncharacterised P.berghei TBV candidates that putatively have sexual-stage localisation on the surface of the female gametocyte. The expression of each protein will be performed a range of systems (E.coli/wheat germ), and assessed by western blot and Ni-NTA purification. For each protein generated, immunisation will be performed in groups of mice. Post-immunisation, mice will be infected with P.berghei, and in vivo challenge to assess transmission-blocking efficacy by direct-feeding will be performed. Efficacy will be quantified by assessing reductions in intensity and prevalence in comparison with non-immunised cohorts. Sera will be harvested from mice post-feed, followed by western, IFA and ELISA to assess immune response to putative vaccines. Titre will be correlated to efficacy. For the 5 individual vaccines that demonstrate highest efficacy the P. falciparum homologue will be cloned and expressed, followed by immunization to generate sera. Resulting antibodies will be examined for their ability to block transmission of P.falciparum to mosquitoes within a malaria-endemic setting PNG) by DMFA. In parallel, for each P.falciparum antigen, seroepidemiological studies will be performed on serum cohort samples (12 month longitudinal studies) from PNG, to assess natural exposure/immunity. Using a proven Luminex platform, we will measure the acquisition, longevity and prevalence of antigens using exposed plasma in high and low transmission settings.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES;5.1 PHARMACEUTICALS
Health categories: INFECTION