NIHRDataInsights/HRCSData huggingface dataset:
Title: Immunological investigation for the implementation of Live Attenuated Influenza Vaccination
Funder: Medical Research Council

Abstract: The UK launched universal annual childhood vaccination with quadrivalent live attenuated influenza vaccine (LAIV4) in 2013, with phased roll-out to progressively older children each year. Although LAIV has higher vaccine effectiveness (VE) in children than inactivated influenza vaccine (IIV), it was recently found to have lost VE against pH1N1 in the USA resulting in its discontinuation. In the UK, VE against pH1N1 has been lower than expected and lower than IIV but the programme continues. This marked reduction of VE to pH1N1 (but not the other subtypes in LAIV4) suggests a mechanism specific to pH1N1 while the complete loss of VE in the USA suggests a mechanism that is accentuated specifically in US children (the only population to have been vaccinated annually for several years). We hypothesise that: (a) there is reduced local in vivo nasal replication of pH1N1 resulting in impaired vaccine take (and consequently impaired immunogenicity and VE) (b) pre-existing LAIV-induced pH1N1-specific immunity exacerbates the reduced take and immunogenicity. Our aim is to identify the reasons for loss of VE by testing these hypotheses and thereby to inform optimal implementation of LAIV. Given that evidence for annual vaccination is scarce and that correlates of protection are unknown, we will also generate data on longevity of LAIV-induced immunity to inform vaccination schedule and shed light on protective correlates by studying vaccine failures. With Public Health England (PHE), we have recruited 3 unique child cohorts undergoing LAIV vaccination but with differing vaccination histories. We will conduct the most comprehensive study of LAIV immunogenicity to date, quantifying vaccine take and correlating it with LAIV-induced cell-mediated immunity, mucosal IgA, humoral immunity and blood transcriptome. The causes of impaired vaccine take and immunogenicity will be investigated by correlating these with prior LAIV vaccination status and pre-existing LAIV-induced immu


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Control of pathogen gene expression during symbiotic maintenance.
Funder: Medical Research Council

Abstract: Understanding the role of translational control in host response to pathogen infection is critical for developing intervention strategies as protein synthesis is a central process in all cells. However, currently most global studies are at the level of transcription (e.g. RNASeq and ChIP-Seq). Analysing genome-wide responses at the level of protein synthesis has only recently become possible due to the development of ribosome profiling (RiboSeq). Using a combination of RiboSeq, RNASeq and ChIP-Seq, I will investigate the translational responses to intracellular bacterial and protist infections and address the hypothesis that rapid translational responses following pathogen perturbation shape later transcriptional landscapes. I will test a key prediction of this hypothesis, namely that mRNAs with immediately enhanced translation include some that encode nuclear-localized proteins such as transcription factors. My research program will focus initially on the prokaryote Salmonella enterica serovar Typhimurium (a mouse model for the typhoid fever pathogen) and the eukaryote Toxoplasma gondii. As intracellular pathogens, we can observe host responses unimpeded by cell lysis/autophagy. Both enter the host through ingestion, initially entering gut-epithelial cells, followed by macrophage infection. This will allow an interesting cross-Kingdom comparison of common host responses besides the elucidation of pathogen-specific responses, at both the translational and transcriptional levels. I will characterize the regulatory elements responsible for temporal switches in translational efficiencies - e.g. riboswitches within the mRNAs or trans-effectors that interact with the mRNAs. I will also investigate the anti-host mechanisms employed by each pathogen, and the molecular basis for pathogen adaptation to the highly acidic intra-macrophage environment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Understanding host factors that regulate the hepatitis B viral epigenome
Funder: Medical Research Council

Abstract: Hepatitis B virus infection is a significant and global health burden. Over 300 million chronically infected individuals are at risk of developing life-limiting liver disease. Current therapies are effective at reducing viral load but do not clear the persistent HBV DNA, leaving these patients at significant risk of viral reactivation. Following host cell entry, HBV DNA is established as a persistent episome of covalently closed circular DNA (cccDNA). This episome serves as a template for virus transcription. It is known that HBV cccDNA recruits cellular histones but the dynamic epigenetic regulation of HBV and viral promoter usage is not understood. This project aims to dissect the temporal control of HBV transcription during de novo infection of primary human hepatocytes. The HBV epigenome at early and late stages of infection will be characterised by ChIP- and DNaseI-Seq of cccDNA to map epigenetic boundaries and the formation of regulatory elements. These data will be aligned with rigorous and time-resolved analysis of viral transcripts. Our preliminary data provide compelling evidence that the host cell transcription regulator CTCF binds the HBV genome to positively regulate enhancer activity. Using a combination of mutagenesis and shRNA methodologies to abrogate CTCF binding we will dissect the function of CTCF in the establishment and maintenance of the HBV epigenome. We also provide evidence that CTCF co-operates with the transcription regulator YY1 to stimulate enhancer activity. We aim to determine the interplay between CTCF and YY1 in the epigenetic regulation of HBV enhancer activity and virus transcription. This in-depth analysis of HBV transcription in a physiologically relevant HBV infection model, and molecular dissection of key host factors will provide a step-change in our understanding of the HBV life cycle. The outcomes of this project will impact on future anti-viral strategies that will be effective in the clearance of chronic HBV infections.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Using a comparative One Health approach to investigate the structural basis of antigenic variation among human and avian influenza viruses
Funder: Medical Research Council

Abstract: Biophysical model: A Bayesian model of the genotype-antigenic phenotype relationship will extend previous models by (a) incorporating additional parameters to better describe virus-antibody and receptor binding; (b) accounting for 3-D haemagglutinin (HA) structure allowing spatial inference of the extent of epitopes; and (c) developing a matrix describing the general antigenic distance of amino acid pairs allowing inference across the HA structure. Human influenza model refinement: The biophysical model will be applied to human influenza A H1N1 and H3N2 data consisting largely of titres haemagglutinin inhibition (HI) and virus neutralisation assays and genetic sequence data for HA1. This process will be used to test and refine the model, analysing existing HA structures to determine spatial relationships between residues within epitopes and binding sites, incorporating existing avidity analyses to parameterize the biophysical model, and tuning the substitution model using antigenic and sequence data. Avian influenza data and modelling: Antigenic and genetic data from avian influenza subtypes will be collated and modelled. The human influenza virus model will now be refined on the avian data. The phenotypic impact of amino acid substitutions in the AIV HA will be characterised and contribution to vaccine escape will be assessed. The phenotypic impact of previously unobserved amino acid substitutions will also be predicted. Model validation: Mutant recombinant viruses will be generated using site-directed mutagenesis and reverse genetics using available HA backbones. Recombinant viruses will be assessed using the HI assay performed with polyclonal antiserum and monoclonal antibodies. Changes in HI titre, relative to the backbone, will be attributed to changes in antigenicity and avidity. Changes in receptor binding avidity will be directly assessed using the receptor-binding destroying enzyme assay and surface biolayer interferometry.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Integrating data from multiple African countries to identify and validate novel insecticide resistance candidates in the malaria vector An. gambiae sl
Funder: Medical Research Council

Abstract: I will use big data integration techniques in R to combine noisy field -omics and populations genetics data with the aim of identifying and characterising novel insecticide resistant candidate transcripts or pathways in Anopheles gambiae sl. Knockdown (KD) of identified transcripts through dsRNA injection and the phenotypes after exposure to a panel of insecticides will determine whether the candidate is involved in insecticide resistance and hence carried forward to characterisation. If the candidate transcript is hypothesised to be part of a pathway, KD of pathway partners and qPCR on these for each of the KDs will be used to verify the pathway. Once the upstream candidate is identified microarray experiments comparing the KD mosquitoes with GFP-injected controls will identify larger-scale changes. Characterisation of the transcript will depend upon its hypothesised function. To identify these putative functions, a variety of resources are available, including literature trawling, enrichment analysis and homology-based methods. An array of techniques can be employed to determine the function of the candidate including insecticide binding assays, behavioural assays, localisation studies, proteomics, structural resolving, up-regulation through transgenic lines and complete knock out via CRISPR. Population genetics tools and heritability analysis can then be employed to determine whether there is scope and value to use the transcript as an in-field diagnostic. By identifying SNPs or other variable genetic regions in-field resistance diagnostics via PCR, or restriction digest PCR can be developed. A further output from this fellowship will be to inform industry partners such as IVCC of potential candidate targets for new insecticides. To this end, Plasmodium falciparum competence of the mosquito will be assessed to ensure that disruption of the transcript will not affect this in a significant way.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The global burden of Chikungunya virus
Funder: Medical Research Council

Abstract: The aim of this project is to estimate the global burden of CHIK in terms of infections, acute and chronic cases, deaths, disability-adjusted-life-years and the associated economic costs. The study will follow a multistage approach where first key parameters of the spread of the infection will be estimated, with particular interest in patterns of age specific attack rates, from both primary or secondary data sources. Second, a progression model that accounts for chronic outcomes will be built based on clinical data from a cohort study already available. Third, global projections will be produced based on environmental suitability and population data. Fourth, direct and indirect global costs (direct and indirect) will be projected based on the disease burden and the gross domestic product country. This will be a unique scientific opportunity to explore and combine multiple sources of information to inform future research on one of the less studied arboviral infections. Also, this research with require multidisciplinary and multilateral collaboration, which will strengthen relations with other research groups and health officials in endemic countries and at WHO. The results will be an important basis for informing policy makers and funders of vaccine and other control interventions.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Big Data approaches to identifying potential sources of emerging pathogens in humans, domesticated animals and crops
Funder: Medical Research Council

Abstract: Despite the importance of cross-species disease transmission, there has been relatively little attention paid to which species are the most important sources cross communities, and by what means the diseases entered new species or populations. A reason for this is the lack of comprehensive data on pathogens in animals and plants and, often, poorly documented information on how they are transmitted. The objective of this fellowship is to transform host-pathogen interactions extracted from EID2 into multi-host ecological networks. Using network analysis: typology; bridge species; and metrics of networks will be studied. By implementing a centrality index based on a cohort of centrality measures, potential super-spreaders will be identified. Transmission routes play a role in determining the parts of the population that are infected, the range of species that can be infected, and the measures required to bring an outbreak under control. A transmission route identification system, utilising an ensemble of classifiers, will be developed to categorise scientific publications to identify transmission routes. Consequences of different routes will be assessed, and their effect on centrality will be quantified. The range of hosts that a pathogen infects influences the dynamics of pathogen transmission and emergence in novel hosts. Statistical models will be developed to rank different traits of hosts in relation to host-specificity. The effects of the traits on centrality will be quantified. Predicting unobserved or future host-pathogen interactions is imperative for one-health, enabling identification of potential emergence and spill-over events. A link prediction model on host-pathogen networks, with links either positive or negative, will be constructed. A system will be developed to capture host-pathogen negative interactions from scientific literature. The results will be incorporated into the multi-host networks; the effect on centrality will be quantified.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Understanding zoonotic disease risk using dynamic ecological models
Funder: Medical Research Council

Abstract: The natural world is expected to undergo a significant transformation over the next century, driven by climate change, habitat destruction, human population increases and greater globalisation. Many animal-borne or zoonotic human diseases (e.g. Ebola, Plague, Anthrax) are caught from non-domesticated, wild species and these host species will likely alter their spatial distribution and behaviour in response to environmental change. To examine how this process will impact human zoonotic diseases, I will first create a dynamic, species distribution model that incorporates the latest, fine-scale remote-sensed data, to predict the real-time environmental suitability for disease-carrying host species. On these suitability surfaces, I will run mechanistic models of host species population dynamics, which I can use to assess the role of seasonal and annual changes to the environment and to better predict host abundance and, subsequently, host-human contact rates. I will then create two environmentally-responsive movement networks, the first consisting of major animal migrations and the second of human transportation methods, which I can then apply to historical and future environments to model zoonotic disease spread and animal invasions. I will then integrate these major work threads into a global, dynamic, 'whole systems' modelling framework of zoonotic diseases, containing both a dynamic ecological model component and a previously developed, empirically-based model of human population density, poverty and behaviour. This framework, when validated against empirical animal occurrence and disease case data, will be allowed to run on a set of high priority zoonoses in Africa to test policy interventions in present day conditions and then test how different drivers of expected future global change will impact the efficacy of these interventions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Predicting evolutionary dynamics of multi-drug resistance
Funder: Medical Research Council

Abstract: The aim of this project will be to combine mathematical modelling and experimental approaches to understand the origin and evolution of multi-drug resistance evolution under biologically-realistic conditions. The programme of work will follow three lines of investigation. I will first develop a stochastic model of multi-drug resistance evolution incorporating in-host pharmacokinetics and bacterial growth models. I will investigate factors leading to environments with sub-inhibitory antibiotic concentrations, such as differences in pharmacokinetic profiles, or as during the use of antibiotics as growth promoters in animals. This will be modelled by varying bacterial growth rates as a function of time. This will create predictions for the probability that multi-drug resistance can evolve during the course of combination therapy. I will parametrise the model by developing a predictive framework for epistatic interactions between arbitrary combinations of resistance mutations, using high-throughput transcriptomics together with growth rate and competitive fitness assays. This will allow us to model the effects of multi-drug resistance on bacterial fitness, without needing to exhaustively screen all possible combinations. Finally, predictions from the model will be tested by experimentally evolving E. coli populations in environments with multiple antibiotics. Combinations will be evaluated for their ability to reduce the likelihood of multi-drug resistance evolving.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Development of a Live Attenuated Vaccine Against Salmonella Paratyphi (VASP)
Funder: Medical Research Council

Abstract: Salmonella Paratyphi A is the major cause of paratyphoid and causes more than 5 million cases of enteric fever annually, and accounts for 50% of enteric fever cases in returning travellers in the UK. Cases may increase as a result of replacement disease after deployment of typhoid vaccines. There are no licensed paratyphoid A vaccines, and two approaches are being considered - namely development of live-attenuated vaccines or LPS conjugates. There are currently no efficacy data for either approach but phase I data, available only for the live attenuated vaccine, indicates that it is highly immunogenic. Furthermore, our recent data from an MRC funded experimental medicine challenge grant shows that individuals experimentally infected with paratyphoid A are resistant to reinfection, providing support for the development of an oral live attenuated vaccine which mimics natural infection, without causing disease. In this application we propose to manufacture a live attenuated guaBA/clpX deletion strain oral vaccine, CVD 1902, to GMP. This vaccine, engineered at the University of Maryland's Center for Vaccine Development, was well tolerated and highly immunogenic in phase I providing immune responses against S. Paratyphi A and B. We will orally immunise volunteers with the strain, or a placebo of bicarbonate solution, and then challenge them with 1-5000 CFU of wild-type Salmonella Paratyphi A one month later in our controlled human paratyphoid infection model. Volunteers will then be followed for 2 weeks to identify paratyphoid infection. All those developing disease, defined as fever for 12 hours or a positive blood culture, will be treated with ciprofloxacin and all volunteers who remain uninfected will be treated on day 14. We will measure the protective efficacy of the vaccine in the model and study the cellular and humoral immune response to Salmonella serovars to identify correlates of protection and drive development of the first efficacious paratyphoid vaccine.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: MICA: Pre-Clinical Development of a Small Molecule anti-Wolbachia Candidate Macrofilaricide Drug
Funder: Medical Research Council

Abstract: Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Both diseases are caused by parasitic filarial nematode infections and control efforts are hindered by the lack of a safe macrofilaricidal drug. Current drug regimens principally target the microfilarial stage of the parasites, thus requiring long treatment periods with high coverage to counter the long lifespan (10-14 years) of adult worms. A validated approach for delivering macrofilaricidal activity is to target the Wolbachia bacterial endosymbiont of these nematodes. These bacteria are essential for multiple components of the nematode life-cycle including larval growth, development, embryogenesis and, ultimately, survival of the adult worm, making Wolbachia a valuable chemotherapeutic target. Targeting Wolbachia in these parasites with tetracycline antibiotics such as doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. As part of an ongoing macrofilaricide drug discovery project we have successfully completed a lead optimisation programme to deliver a pre-clinical candidate anti-Wolbachia based macrofilaricide. The candidate AWZ1066S shows superior efficacy compared to doxycycline in a range of validated animal models of infection, meets all current Target Candidate Profile characteristics, including extensive non-GLP safety pharmacology and DMPK evaluation, and is positioned for onward development. We now request funding to support the critical formal pre-clinical development programme in order to progress AWZ1066S to the first into human transition.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION