NIHRDataInsights/HRCSData huggingface dataset:
Title: One for All, All for One?
Funder: Wellcome Trust

Abstract: How people think about vaccines is a global concern1. ‘One for All?’ asks: “How does engagement with herd immunity influence attitudes to immunisation?”. By working in close partnership with communities, researchers, artists, healthcare professionals, experts by experience, policy-makers and creative engagement practitioners in Africa and the UK, we will co-create a range of graphic-based, online and print resources focused on herd immunity. Developing, testing, evaluating and sharing ‘One for All?’ resources will • Empower people who make decisions about immunisation (e.g. parents, guardians, community leaders, influencers, older children) to: ◦ Make informed choices about vaccination, informed by a set of resources based on robust research, common concerns and in context; ◦ Contribute actively and meaningfully to future research. • Enable researchers, fieldworkers, practitioners, policy-makers and healthcare professionals to ‘do’ engagement with vaccines, based around concepts of herd immunity through the use of our creative, accessible and transferable resources; • Inform research and engagement practice by testing and evaluating our central question and sharing our learning; • Potentially reach further global audiences through strategic branding, campaigning and stakeholder engagement. ‘One for All?’ ultimately contributes to the goal of decreasing vaccine hesitancy and increasing vaccine uptake by contributing to the learning and practice of engagement with immunisation.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Impact of a Typhoid Conjugate Vaccine Campaign on Antimicrobial Use in Harare, Zimbabwe
Funder: Wellcome Trust

Abstract: Typhoid fever is a common cause of non-specific febrile illness in low-resource settings. Empirical treatment for typhoid may be a major driver of AMR in typhoid-endemic communities, where estimates suggest that up to 25 additional cases receive antimicrobial treatment for each one confirmed. Harare in Zimbabwe has experienced a major increase in typhoid since 2016, with recent emergence of ciprofloxacin-resistance. In February 2019 a mass typhoid vaccine campaign was performed, targeting infants and children living in 9 affected suburbs with the new typhoid conjugate vaccine (TCV). In work being performed at primary health clinics in these densely-populated suburbs as part of the FIEBRE study, which aims to assess the causes of febrile illness in low-resource settings, we have already identified a significant reduction in typhoid in vaccinated children. In this project our key goals are to investigate the impact of the 2019 mass TCV campaign on antimicrobial resistance in S. Typhi and on antimicrobial prescribing and related practices in community clinics. Defining these effects will have major policy implications for TCV use, both locally, in determining the benefits of further routine/repeat vaccination, and internationally to inform estimates of the direct and indirect impacts on AMR infection and antimicrobial use.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Could vaccinating at risk populations with Meningococcal B vaccine reduce incidence and antimicrobial resistance in gonococcal infections in the UK?
Funder: Wellcome Trust

Abstract: Antimicrobial resistance (AMR) threatens public health and individual patient care. Gonococcal (GC) infection incidence has been increasing year on year for the last decade in the UK. AMR in GC infection is relatively low in the UK, but it has been increasing too. We propose to develop, simulate and parameterise a model for Neisseria gonorrhoeae and Neisseria meningitidis circulation. Control of gonorrhoea is likely to become increasingly difficult due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recent studies where meningococcal B (MenB) vaccine is given to adolescents reported a reduction in incidence rates of GC in those vaccinated, as the vaccine potentially offers some cross protection. Counterfactual scenarios can be investigated with a model (with potential uncertainty in outputs) to consider appropriate health economic evaluation. Goals: • Develop a transmission model of GC and MenB infection for the UK • Investigate the cost-effectiveness of MenB vaccine in infants, adolescents and targeted at-risk populations in reducing MenB and GC infection incidence and AMR. • Investigate the potential impact in areas of low, medium and high incidence of GC infection and low and high level AMR in GC.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Dissecting the genetic basis of melioidosis infection
Funder: Wellcome Trust

Abstract: Melioidosis is a rapidly progressing and frequently fatal disease caused by a soil bacterium Burkholderia pseudomallei (Bp). Healthy individuals living in disease hotspots such as northeast Thailand develop serological evidence of exposure from early childhood. However, not all exposure leads to disease and infections can have variable outcomes, suggesting that there may be bacterial, host or environmental components that influence disease acquisition and severity. Our goals are: i) identify Bp genetic factors that determine disease severity; ii) identify host biomarkers associated with susceptibility to melioidosis and disease severity; and iii) construct models scoring Bp and host factors to predict disease outcome. As diabetes mellitus is a major predisposing risk factor for melioidosis, we will also test whether the factors in i) - ii) are modulated by host diabetic status. Building upon our previous collections, I propose to additionally collect and sequence or genotype 2,000 bacterial and 1,500 host samples. Studies of genome-wide association (GWAS), differential expression, and expression quantitative trait loci (eQTL), each of which will be conditioned on host diabetic status, will be performed to address aims i)-iii). A dual understanding of Bp and host factors leading to poor melioidosis outcomes could improve our ability to manage this disease.

Lay abstract: Burkholderia pseudomallei (Bp) is an environmental bacterium and potential bioterrorism agent. It causes melioidosis, an infection that can be rapidly fatal within 48 hours. Humans can acquire Bp through contact with contaminated soil or water, yet not all exposure results in disease. We hypothesise that genetic variations in both the bacteria and host may contribute to whether individuals would develop the disease and how severe the infection is. Building upon a previous dataset from Northeast Thailand, we propose to collect and sequence Bp genomes and patient blood genetics to identify markers that lead to poorer outcomes. Moreover, people with diabetes are more susceptible to developing melioidosis. For each human and bacteria genetic variant we will investigate how patient diabetic status would modulate disease severity. We will construct a model predicting the likely disease outcomes. This will inform vaccine design by targeting the most harmful bacteria and individuals at greatest risk.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Construction and characterisation of Chlamydia transposon knock-out libraries
Funder: Wellcome Trust

Abstract: We will generate saturation transposon mutagenesis libraries of human pathogenic Chlamydiae (C. trachomatis (trachoma and LGV) and C. pneumoniae) and the 'model' species C. muridarum using TraDIS methodology. This approach has been successfully developed during my current Technology Development Grant with urogenital C. trachomatis. We have now refined the method so it will be straightforward to apply to other species, the application of the technology to generate a new series of key resources will greatly accelerate research. Our ultimate aim is to develop an ordered library of mutated/knock-out chlamydia isolates akin to the E. coli Keio collection. These mutants (knock-outs of non-essential genes) will be genome-sequenced in Southampton to mitigate off-target mutations. The collections will provide a unique and important biomedical resource, along with the saturation mutagenesis libraries and transposon delivery vectors. The transposon delivery vectors will form the basis for the development of further vectors for other chlamydial species. All resources generated during this project will be made available to the research community via the Chlamydia Biobank (www.chlamydiabiobank.co.uk) (BMR 101502/Z/13/Z). This will enable other researchers to test their hypotheses in the pursuit of gene function ascertainment - a critical step in identifying novel targets for drug or vaccine development.

Lay abstract: The aim of this proposal is to provide as a biological resource an ordered collection of Chlamydia knockout mutants and the genetic tools needed for other researchers to generate their own mutants. This will be of enormous benefit to the research community, as pre-existing methodologies for mutant generation are difficult and time-consuming and also can suffer from off-target affects. The main tools have already been developed during my current TDG, so there will be immediate availability of these to the research community. The availability of randomly generated mutants/collections of mutants will enable testing of gene function, which is a critically important step in the development of novel drugs and vaccines. Collections of mutants of various Chlamydial species will be generated during the course of the grant, and will be characterised and deposited in the Chlamydia Biobank for easy unrestricted access by members of the researcch community.

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Understanding the contribution of influenza vaccines to antibiotic prescribing in the UK population.
Funder: Wellcome Trust

Abstract: Vaccination should reduce antibioticl prescribing (AP), the driver of antimicrobial resistance. Looking for reductions in Randomised Controlled Trials of vaccine is problematic as they are usually powered for large effect sizes of specific end-points. An alternative approach is to undertake observational studies using large routine data sources. The problem with this approach is ensuring major confounding is identified and accounted for when linking vaccine status and outcome and, demonstrating a causal relationship. We will conduct an observational study using the Clinical Practice Research Datalink (2007-2019) and The Health Improvement Network (THIN) (2007-2019) from the United Kingdom. Our primary aim is to measure AM prescribing in adults over 65 and children under 5 by frequency of influenza vaccination. We will use three complimentary approaches and different methods to adjust for confounding: 1 A Self-controlled case series – comparing annual AM prescribing within individuals by annual receipt of influenza vaccine and vaccine/pathogen match. 2 A Cohort study - balancing comparator populations using propensity scoring to control for major determinants of health care utilisation and underlying health status. 3 An Interrupted time series analyses – investigating paediatric influenza vaccine uptake (September 2013) and AM prescribing


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Evaluating the impact of a Lao language mobile phone antimicrobial use guideline application on antimicrobial prescribing in Laos
Funder: Wellcome Trust

Abstract: Antimicrobial resistance (AMR) is a Lao major public health concern. We will evaluate whether Lao-language antimicrobial prescribing guidelines mobile phone application (app), will improve antimicrobial prescribing in in- and outpatients across Laos. Stepped wedge randomized controlled trial in six central/provincial hospitals will be performed. The intervention will be the guidelines mobile app. Hospital pairs will be randomly allocated to start the intervention (every eight months) until all have received the intervention. This will give 24 months for both control and intervention groups. Control period will start eight months before intervention. Outcome will be the changes in proportion of prescribing consistent with guidelines and the cost-effectiveness of the intervention. Point prevalence survey (PPS) on in- and outpatients antimicrobial usage will be performed every 4 months throughout the trial to collect prescribing data and hospital cost data. Hospitals will receive a training of guidelines handbooks usage at the control starts, training on the app usage at the intervention starts, PPS feedback and focus group discussion. AMR in Laos remains less severe than elsewhere in Asia, this simple technology may help reduce further worsening. This trial would have a significant impact in Laos, and inform policy globally, by improving prescribing and reducing AMR.

Lay abstract: Antimicrobial resistance is a public health concerns in Laos. We would like to know whether a mobile phone application (app) with antimicrobial use guidelines in Lao-language, will improve doctors’ prescriptions in six hospitals across Laos. We will divide our time into two phases (24 months equally). First, all hospitals will have a guidelines handbook with a training of its usage. Eight months later hospital pairs will be randomly selected to have a mobile phone app with guidelines, then every eight months for another hospital pairs until all hospitals have received a mobile app. Throughout 24 months, we will visit all six hospitals every 4 months to record the progress of the prescriptions and the hospital cost. We will then discuss with the hospitals about what we have found during our visits. By 24 months, we would be able to tell whether the mobile app improve doctor’s prescriptions.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION
Title: Responsive Dialogues to Improve Public Engagement on AMR
Funder: Wellcome Trust

Abstract: The diminishing effectiveness of antimicrobials is a public health challenge of major global importance. In the Global South, where health systems are weaker and the burden of severe bacterial infection greater, the impact is already being acutely felt. In Malawi, a Ministerial AMR Unit has been established to coordinate Malawi’s response, culminating in a National Action Plan. However, the implementation of the Action Plan needs key stakeholders – including affected community members – to develop and implement interventions. This project will undertake facilitated dialogues with stakeholders in two different contexts: rural Chikwawa and urban Blantyre. Through four Responsive Dialogues events per area, participants from national, district and community levels will share their understandings, experiences and perspectives on AMR, leading to the co-creation of concrete policy asks and actions. Conversations will be carefully designed and facilitated to enable evidence about AMR to be shared, understood and used to generate ideas, as well as to inform policies governing how AMR is addressed. Through this approach the project will work closely with the AMR unit to cocreate local actions, that communities themselves can carry out to reduce the burden of AMR as well as policies and interventions that reflect people’s lived realities.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION
Title: Development of metagenomics-based diagnostics of infectious diseases
Funder: Wellcome Trust

Abstract: During this fellowship I will use high throughput sequencing (HTS) and novel analytical methods to develop a framework for the investigation and diagnosis of infectious diseases. The focus will be on complex and difficult to diagnose diseases, such as encephalitis and meningitis, where pathogen detection rates remain poor. I will first optimise my existing Bayesian mixture model approach1–7 to ensure its wider application to a range of infections and suspected pathogens. I will then analyse metagenomic RNA-seq data from brain biopsy, cerebrospinal fluid (CSF) and whole blood samples towards pathogen detection. For selected samples where the cause of the disease is known, I will investigate whether host transcript signatures can distinguish infectious or autoimmune encephalitis, motivated by successes in other infectious diseases8–12. I hypothesize that diagnosis will benefit from the joint analysis of pathogen and host genomic data. A distinct but related problem is to characterize single pathogen mixed infections and to better understand their effect on disease phenotype and severity. This proposal goes beyond diagnostics to provide a platform for discovery research including novel virulence determinants, tropism, association of genotype and phenotype, description of novel pathogens, host gene expression patterns and characterization of co-infections and mixed infections.

Lay abstract: For several infectious diseases, establishing the cause is difficult. Standard techniques are rapid and sensitive but require prior knowledge of potential infectious agents. The lack of a timely diagnosis has a negative impact on patient prognosis and results in increased health care costs. Sequencing of both host and microorganisms nucleic acids from clinical samples (i.e clinical metagenomics) can fill this diagnostic gap. Metagenomics data analysis for pathogen detection is a complicated task, not unlike searching for a needle in a haystack. My solution was to develop a novel probabilistic method which has already allowed diagnosing eight encephalitis patients. With this fellowship, I aim to broaden our understanding of devastating infectious diseases, such as encephalitis and meningitis. My background in statistics and genomics will allow me to determine whether joint analysis of pathogen and host data can result in a definitive diagnostic test. Definitive diagnosis would mimimise the risk of medical mismanagement, such as incorrect prescription of antibiotics. To achieve these aims, I will collaborate with prominent clinician scientists who lead UK-wide patient cohort studies. I will therefore be in the unique position to analyse large collections of metagenomic datasets generated from patients with a variety of infectious diseases.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Impact of malaria elimination on immunity and risk of malaria rebound in Myanmar
Funder: Wellcome Trust

Abstract: The emergence and spread of ACT resistant falciparum malaria ,and the discovery that there were substantial reservoirs of subpatent parasites in populations residing at low transmission area has led to calls for radical interventions to eliminate the disease from the Greater Mekong SubRegion. Several pilot studies of mass drug administration (MDA) have now taken place, including two in Myanmar. With adequate population coverage MDA leads to rapid reductions in malaria incidence. It is hoped that these reductions will be sustained by networks of village health workers who provide early malaria diagnosis and treatment to symptomatic cases. However submicroscopic malaria (undetectable by conventional diagnostic tools) could be a substantial source of resurgent malaria and undermine the success of MDA. Defining the probability of malaria resurgence relies on knowledge of the immune status of a population overtime. I plan to study longitudinal changes in malaria antibody responses in individuals residing in villages where MDA was implemented along the Thai-Myanmar border, and see if they can predict reintroduction of submicroscopic malaria infection. Using high-throughput ELISA, I will measure antibodies to P. falciparum and vivax antigens to evaluate whether there is any change in antibody level which could predict submicroscopic (or symptomatic) malaria infection.

Lay abstract: The increase in drug-resistant malaria in Southeast Asia has led to calls to eliminate malaria from the Region before it becomes untreatable and to prevent spread to high burden countries in Africa. One approach which has been tried is Mass Drug Administration (MDA) where the whole community is treated with antimalarial drugs. The reason for doing this is that a proportion of the population carry malaria parasites at low levels which cannot be detected by usual diagnostic tests but can still spread from person-to-person. Results from studies in Cambodia and Myanmar suggest this approach can bring about a rapid decrease in malaria. I would like to study the long-term effects of MDA in Myanmar in relation to immunity against malaria. I plan to study the immune response and its relationship to reintroduction of malaria in areas where elimination has taken place.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Investigating antimicrobial susceptibility of Rickettsia typhi
Funder: Wellcome Trust

Abstract: Rickettsia typhi is an obligate intracellular Gram-negative bacterium causing murine typhus. The disease is globally distributed but neglected. It is an important cause of acute febrile illness in Laos. Although murine typhus is treatable, a clinical trial by Newton P et al. (2019) suggested that azithromycin is inferior to doxycycline. However conventional antibiotic susceptibility testing was not performed to corroborate this finding since no methods exist. Therefore, there is a need to develop a highly sensitive qPCR method comparable with the gold standard method of the plaque assay to assess antimicrobial susceptibility of R. typhi isolates as well as investigation of the genetics and/or metabolism of this bacteria, and to correlate the findings with clinical response to treatment. To estimate the rickettsia clearance, we will characterise the R. typhi DNA load using qPCR in patients from a pilot study of murine typhus patients receiving doxycycline or azithromycin. Moreover, optimised conditions for R. typhi growth including nutrient requirement for development of a host cell-free culture medium using R. montana as a model to simplify antibiotic susceptibility testing of this bacteria will be investigated. The proposed work will improve our understanding of appropriate murine typhus treatment in Laos.

Lay abstract: Background to the research project- Murine typhus is a global neglected disease and cause of fever, transmitted by fleas, that can cause severe disease. It is an important cause of febrile illness in Laos. However, there has been little research to inform treatment guidelines for this disease and there are very few data on antibiotic resistance of murine typhus. There have been reports from Laos of murine typhus antibiotic treatment failures. My approach- I plan to develop a test to assess which antibiotics are most effective against typhus bacteria grown from Lao patients' blood. I will investigate whether there is any evidence for drug resistance. I plan to study the bacterial genome by sequencing murine typhus genes to try to identify markers allowing us to predict antibiotic resistance. Expected impact- This study would improve our understanding of rickettsia antibiotic susceptibilities, and guide treatment recommendations.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION