NIHRDataInsights/HRCSData huggingface dataset:
Title: Enteric Pathogens and Post-discharge Outcomes among Children in sub-Saharan Africa and South Asia (The EPPO-SASA Study)
Funder: Wellcome Trust

Abstract: Enteric pathogens are a major cause of hospitalisation among children and are associated with diarrhoea, enteric dysfunction, dysbiosis, and increased risk of mortality and readmission especially in low- and middle-income countries. When admitted to hospital, treatment failure may occur despite following guidelines. Furthermore, carriage of pathogens or disturbance in the intestinal microbiome may be hospital-acquired and/or resistant to first-line antimicrobials potentially increasing the risk of readmission. I aim to determine whether molecular evidence of enteric pathogens and gut dysbiosis at hospital discharge, when children were judged as clinically well, is associated with readmission post-discharge among children across the nutritional stratum. This case-control study is nested within the completed CHAIN cohort study (six countries) that aims to characterise demographic, clinical, and social risk factors for mortality among children <2 years old, with an extensive nested case-cohort systems biology sub-study targeting mortality. Cases will be children readmitted to hospital within 6 months of index discharge and controls will be age, nutritional stratum and site matched children who were not readmitted. I will utilise targeted faecal TaqMan multiplex PCR (Kilifi, Kenya), culturomics and metagenomics (Sanger Institute, UK). Findings may support policies for post-discharge screening, prophylaxis, targeted diagnostics, and revision of treatment protocols.

Lay abstract: Intestinal pathogens are a major cause of serious illness among children. Hospitalised children may acquire carriage of new pathogens from the hospital environment. We have observed a high rate of post-discharge death and hospital readmission in low-and middle-income countries. Pathogens present during discharge from hospital may increase risk of readmission and may be more difficult to treat than purely community-acquired organisms. I aim to determine whether specific intestinal pathogens and the overall population of microorganisms (microbiome) in the gut during hospital discharge, when children are judged to be clinically well, are associated with readmission. I will utilise samples stored from a major international study and technologies that can identify nucleic acids of pathogens in faecal samples. My study findings may help establish the need for treatment intervention post-discharge among children, improvement of diagnostic methods in hospitals, creation of awareness on antimicrobial resistance and changes to the treatment of readmitted children.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Vaccines and the evolution of antibiotic resistance: elucidating transmission mechanisms and public health impact using deep sequencing of Streptococcus pneumoniae and mathematical models
Funder: Wellcome Trust

Abstract: Vaccines can, in principle, alleviate antibiotic resistance by preventing infections and reducing the need for antibiotic use. However, the impact of pneumococcal conjugate vaccines (PCVs) on antibiotic resistant disease is unclear because resistance in non-targeted serotypes is increasing and we do not understand the mechanisms driving this phenomenon. To overcome this issue , we have assembled a multidisciplinary team to leverage an ongoing three-year Phase IV cluster-randomised PCV trial in Vietnam which will provide unparalleled predictive power to calculate the long-term consequences of PCV on resistant infection. First, we will develop a suite of novel bioinformatics tools to determine antibiotic susceptibility using deep sequence data that will allow us to evaluate both the dynamic changes in antibiotic resistance in the three years following PCV introduction and, for the first time, the frequency of resistant–sensitive strain co-colonisation. Second, we will analyse surveys to evaluate the longitudinal impact of PCV on antibiotic use. Third, we will integrate these results into a mathematical modelling approach to disentangle the mechanisms driving pneumococcal resistance. We will use this calibrated model to predict the long-term effect of PCV on pneumococcal resistance. Our results will, for the first time, accurately predict the wider health impact of PCVs.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Preclinical Development of QM owned SARS-CoV-2 specific human neutralising antibodies
Funder: Barts Charity

Abstract: The SARs-Co-V2 omicron variant has prompted high concern regarding infectivity and susceptibility to existing vaccines and treatments. While vaccines remain the best strategy to prevent COVID-19, neutralising monoclonal antibodies (nmAbs) were developed to treat vulnerable immune compromised individuals who may not mount an adequate immune response to COVID-19 vaccination, or those who may have severe adverse reactions to a COVID-19 vaccine. FDA has approved several nmAbs, e.g., REGEN-COV, bamlanivimab, etesevimab and sotrovimab. Unfortunately, developed nmAbs retained no neutralisation activity to omicron variant. Only sotrovimab (GSK) and DXP-604 (BeiGene) retain some efficacy. On January 24 FDA revised the authorization for bamlanivimab and etesevimab and REGEN-COV because they are highly unlikely to neutralise omicron. Although we are competing with giant pharmaceuticals, we believe we are in a strong position. We have already generated a very potent cross neutralisation SARS-CoV-2 neutralising antibody from human SARS-CoV-2 immune phage display antibody library. Under Queen Mary Antibody Engineering Platform (funded by Barts Charity) we have built a library from recovered asymptomatic Bart?s Healthcare Workers (HCW). We selected the library against spike protein from UK variant (alpha, B.1.1.7), Brazil (gamma, P.1, B.1.1.28.1) and South African, (beta, wB.1.351 RBD mutations) and identified a panel of nmAb candidates that can neutralise variants of concern (VOCs) including alpha, beta, delta and gamma. One promising clone is very potent cross-neutralising antibody against all tested VOCs and has clear potential for further development. We are in the process of testing its efficacy against the omicron variant. Our aim is to further develop the leads neutralising mAbs. We plan to develop in house cocktail nmAbs and/or antibody fragments with multi-paratope specificity (non-overlapping epitopes on the same protein) for further clinical validation. Indeed, as new SARS-CoV-2 variants frequently emerge we will prepare our platform for future VOC.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Use of hospital cases of uncomplicated malaria to identify malaria hot spots, risk factors and map malaria heterogeneity to guide targeting of malaria control interventions in under-five children in Malawi.
Funder: Wellcome Trust

Abstract: Malaria control programmes are increasingly encouraged to define the variation in malaria risk within their countries and districts to help them take evidence informed decisions how to make the best use the available malaria control tools and resources. While variations in vector ecology, environment, and malaria control efforts may all contribute to variations in malaria risk and disease burden in place and time, control programs need tools that can be part of their existing routine malaria surveillance system. As an extension of previous work which focused on the use of malaria infection prevalence data to model and map malaria risk and develop adaptive sampling methods for household prevalence survey, we propose to use under five uncomplicated malaria hospital cases to identify hotspots, risk factors, and map heterogeneity in malaria burden, to inform targeting of malaria control interventions in an area with declining clinical malaria burden due to intense malaria control interventions in Malawi. Utilizing the DHIS2 linked tracker tool, we will explore geostatistical method to model sub-district level malaria incidence e, accessible, and cost-effective option available to national control programmes to model and map malaria heterogeneity and understand risk factors in areas with declining malaria burden to guide malaria control.

Lay abstract: Knowing the variation in malaria disease burden and risk within their countries help malaria control programmes to take evidence informed decisions how to make the best use of the available malaria control tools and resources. While academic teams have mainly been modeling and mapping the variation of malaria infection risk based on community level surveys, malaria control programs are interested to get similar maps based on malaria cases that are diagnosed in health facilities, which are reported to the existing national malaria surveillance system. Building on previous work modelling work I propose to assess the use of a DHIS2 linked DHS-tracker to track and map individual cases of uncomplicated malaria at the point of care in health facilities as a simple, routine surveillance option available to national control programmes to determine malaria heterogeneity in areas with declining clinical malaria burden.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: The cost effectiveness and impact of an optimised TB diagnosis intervention on incidence, prevalence and mortality due to TB in Malawi.
Funder: Wellcome Trust

Abstract: Early diagnosis of tuberculosis (TB) reduces transmission thus impacting TB incidence and prevalence. Research undertaken in developing countries shows that current TB diagnosis algorithms act as a barrier to poorer people seeking TB diagnosis and treatment. Patients accessing these services may incur catastrophic costs therefore hindering the achievement of WHO’s target of 0% incidence of catastrophic costs due to TB. This has led to concerted efforts to develop interventions that simplify TB diagnosis and treatment pathways. In Blantyre, Malawi, one such intervention based on computer-aided x-ray diagnosis (TB-CAD) is currently being investigated in the PROSPECT study, a randomised controlled trial. My research will investigate the public health benefits and cost-effectiveness, – from the health provider and societal perspective – of TB-CAD. By fitting statistical models using the PROSPECT study’s trial data, I will estimate the long-term impact on TB prevalence, incidence and mortality in Malawi, assuming that TB-CAD were to be scaled-up at country-level. I will additionally estimate whether the health benefits and reduction in costs are equally distributed between the poorest and the least poor in society. These data will provide policymakers with evidence for whether TB-CAD offers a cost-effective and equitable approach to reversing TB epidemics in Malawi.

Lay abstract: Current sub-optimal tuberculosis (TB) diagnosis and treatment pathways in developing countries limits progress towards ending TB epidemics. Despite free healthcare services, these pathways cause the poor people to face high costs when seeking diagnosis and treatment for TB. New TB diagnosis strategies are being tested in Malawi, including computer-aided chest x-ray diagnosis (TB-CAD), which provides accurate and rapid TB screening. However, it is not known if TB-CAD would be cost-effective in improving population TB control if rolled-out nationwide, or whether this would offer equal benefits between the poorest and least poor in society. My research will use data from the PROSPECT Study to model the costs and impacts of scaling-up TB-CAD in Malawi. The results will provide evidence to policymakers on whether TB-CAD can reduce the amount of people who become unwell and die with TB, and whether implementation strategies that favor the poor are needed in the health system.

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: Measuring the impact of past, present and future environmental changes on schistosomiasis transmission in southern Malawi
Funder: Wellcome Trust

Abstract: Schistosomiasis, a trematode infectious disease, is highly endemic in Malawi. Approximately 40-50% of the population are at risk of being infected with urinary and intestinal schistosomiasis, with transmission being dependent on humans encountering an intermediate freshwater snail host. As such, the spatial pattern in disease risk is strongly influenced by the natural environment. The overarching goal of this project is to combine remotely sensed and georeferenced snail survey data to quantify the relationship between the snail host and the environment, and to understand the impact of environmental changes such as land-use and climate change on transmission risk. Focusing on the highly endemic region of Southern Malawi, I will use geospatial statistical methods and publicly available satellite imagery to generate habitat suitability maps over a 30-year period (1990-2020) to visualize the changing patterns in transmission risk over time. Data on various climate change scenarios will be used to predict future changes in snail habitat for the region. I will undertake snail surveys and drone image capture to generate snail habitat suitability maps which complement the ongoing epidemiological surveys. Outputs generated will provide valuable insight into the spatial patterns in schistosomiasis risk, and mitigating future risk caused by environmental and climatic changes.

Lay abstract: Schistosomiasis, a neglected tropical disease, is highly endemic in Malawi, with nearly half of Malawians at risk of being infected. Spatial patterns in schistosomiasis transmission risk are driven by environment. As the environment changes due to human activities and climate change, there is need to better understand how this affects health of local population. To address this, I will apply geospatial methods to map snail habitat suitability, using covariates obtained from satellites to produce maps for Southern Malawi, and drone imagery to produce detailed maps of smaller area where transmission risk is known to be high. I will use snail survey data over a 30-year period to generate larger scale maps, and to quantify changes in risk over time. Climate change predictions will allow potential changes in future transmission to be estimated. These outputs will provide the schistosomiasis control community with valuable insights into future challenges facing their elimination efforts.

Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFECTION
Title: Hospital antibiotic resistance in Vietnam and the cost-effectiveness of antibiotic stewardship programs
Funder: Wellcome Trust

Abstract: Antibiotic resistance is a major public health threat, mainly driven by (over)use of antibiotics, particularly in low- and middle-income countries (LMICs). In this fellowship I will evaluate the impact and cost-effectiveness of antibiotic stewardship programs (ASPs) in reducing the amount of inappropriate antibiotic use, improving patient outcomes and decreasing resistance levels in hospitals in Vietnam. Firstly, I will assess the impact of ASPs using an interrupted times-series design in three hospitals that have implemented the programme, using data on antibiotic use, mortality and resistance levels in 12 months before and after intervention. Secondly, I will collect the costs of implementing ASPs using the “time-driven activity-based costing” method. Both data on the actual impact and costs of the programme will be used to inform the economic evaluation model to identify under what circumstances ASPs are cost-effective in Vietnam. Finally, I will analyse existing datasets from the national resistance surveillance network to characterise trends, patterns and associations of antibiotic use and resistance in hospitals. This will provide a background understanding of antibiotic use and resistance and identify the possibilities for using surveillance data to inform the design and implementation of ASPs in Vietnam and other LMICs.

Lay abstract: Uncontrolled use of antibiotic drugs to treat or prevent human infections with bacteria causes these bacteria to become resistant against antibiotics, particularly in countries with limited resources. Actions are required to reduce and restrict (unnecessary) antibiotic use. This study will assess the impact of interventions that aim to improve antibiotic use in hospitals to determine if these are good value for money. I will collect data on the amount of antibiotic use, the number of patients who died, bacteria resistant to important antibiotics, and costs of these interventions in three hospitals in Vietnam. In addition, I will use the existing data from the national resistance surveillance programme to understand the patterns of antibiotic use and resistance and how these data can help to plan interventions in hospitals. The findings are useful to support governments to make decisions on how best to address the antibiotic resistance problem in resource-limited countries.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: Intra-host dengue virus genetic diversity among primary and secondary infections in Laos
Funder: Wellcome Trust

Abstract: There are an estimated 100-400 million cases of dengue worldwide per year with the highest burden of disease in Asia. The virus (DENV) is a positive-sense single stranded RNA virus belonging to the genus Flavivirus. There are four serotypes: DENV1 to DENV4. Dengue virus RNA dependent RNA polymerase has no proof-reading activity, resulting in accumulation of mutations at each replication cycle.Therefore, within an infected individual, there is diversification of the DENV genome sequence leading to the presence of intra-host genetic variants (quasispecies), which may then lead, under selective pressure, to the emergence of a new strain of higher virulence. Previous findings suggested that immune pressure drives intra-host diversity.My research will explore whether serotype-specific past immunity influences intra-host DENV genetic diversity during acute infection.Objectives: • To describe intra host DENV genetic diversity in patients with primary and secondary infections • To compare quasispecies profiles between primary and secondary infections • To compare quasispecies profiles in secondary infections between two patient groups previously exposed to a different serotype. Impact :We expect the findings of this project would permit a better understanding of processes leading to viral genetic variation, and could eventually be useful for improving viral surveillance systems and epidemic forecasting.

Lay abstract: Background - There are an estimated 100-400 million cases of dengue annually with most occurring in Asia. There are four different types of dengue virus: DENV1 to DENV4. Therefore one person can be infected by dengue four times in his or her life. Severe disease is more common in patients who have been infected before. The genetic make-up of DENV also contributes to disease severity.My approach- I will collect blood samples from patients hospitalised with dengue fever and use sequencing techniques to investigate the genetic diversity of the dengue virus causing their infection. I will assess whether there are differences in patients having their first infection compared to patients who have had two or more infections.Expected impact-The results of our project will help us to understand how new more virulent strains of DENV emerge and could lead to development of better tools for viral surveillance and epidemic forecasting.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: COVIDENCE
Funder: Barts Charity

Abstract: The COVIDENCE Research Study has been developed in response to the outbreak of coronavirus disease (COVID-19). 12,000 people aged 16 years or over, from all parts of the UK and from all walks of life, will be asked to provide some baseline information about their lifestyle and health. This will be done using an on-line questionnaire. They will subsequently be contacted every week to check if they have developed any symptoms of coronavirus disease, and/or tested positive. Once a month, a slightly more detailed questionnaire will be sent, asking questions about their more general health and social circumstances. All information will be stored on secure university servers under the terms of the Data Protection Act 2018, with patient-identifiable data held in a separate database to clinical data, linked by a unique identifier. Data will be analysed to achieve four goals: 1. To learn more about risk factors for coronavirus disease in UK adults 2. To find out how quickly people recover from coronavirus disease, and whether there are any long-term complications of this illness 3. To evaluate the impact of coronavirus disease on the physical, mental and economic well-being of the UK population 4. To establish a database of people who may be interested in taking part in further research on coronavirus disease in the UK.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: MAXIMIZING THE KNOWLEDGE GAINED FROM CALIFORNIA SENATE BILL 27
Funder: Wellcome Trust

Abstract: On January 1, 2018, California enacted Senate Bill 27 (SB27), first-of-its-kind and potentially precedent-setting legislation, which will require a veterinarian’s prescription for use of antimicrobial drugs and ban non-therapeutic antimicrobial uses for routine disease prevention and growth promotion in livestock. To assess the effectiveness of this important legislation at reducing antimicrobial resistant bacterial infections in humans, we propose the following specific aims: Aim 1. Quantify the effect of SB27 on E. coli, Campylobacter and Salmonella resistance rates from retail meat. Aim 2. Estimate the proportion of human Campylobacter, Salmonella, and extraintestinal pathogenic E. coli infections caused by strains of food-animal origin in California. Aim 3. Characterize the effect of SB27 on the antimicrobial susceptibility of Campylobacter, Salmonella, and extraintestinal E. coli infections caused by strains of food-animal origin in California. Implementation of SB27 provides a unique natural experiment to assess the effectiveness of restrictive agricultural antimicrobial-use policies at reducing antimicrobial-resistant human infections. The proposed research will have a positive impact by prospectively measuring the effect of this policy on the antimicrobial susceptibility of E. coli (an important colonizing opportunistic pathogen) and Campylobacter and Salmonella (two frank foodborne pathogens) and thereby maximizing the information gained from this singular opportunity


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION