NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding TB treatment response: a cross-disciplinary approach
Funder: Wellcome Trust

Abstract: Tuberculosis is the leading cause of death from infectious diseases and requires a long treatment. Various initiatives aim to develop shorter and more effective treatment. However, this is complicated by the (1) absence of a biomarker that can predict treatment response during early phases of treatment and; (2) interactions between drugs when given together which makes dose selection/optimisation difficult. My aim is to address these shortcomings by, for the first time, studying relationships between pharmacology, microbiology and immunology markers, using data from patients with drug sensitive and multidrug resistant tuberculosis and statistical modelling. This will help developing a test that predicts cure during the first 2 months of treatment which can contribute to improved efficiency of clinical trials evaluating tuberculosis treatment. Secondly, I aim to characterise overall antimicrobial activity and emergence of persistence and resistance, whilst accounting for drug-drug interactions using an innovative combination of in-vitro kill-curve and hollow-fibre experiments, in-vivo pharmacokinetic data and statistical modelling. This will inform optimisation of tuberculosis treatment. I will undertake this work at University College London in collaboration with the University of Cape Town, South Africa, giving me access to a large and diverse tuberculosis patient population and state of the art laboratory facilities.

Lay abstract: Treatment of tuberculosis is long (&ge;6 months) and requires a combination of drugs. Scientists have been trying to develop more effective drug combinations although this is not straightforward. Firstly, there is no test that can predict if the patient will be cured early in their treatment course. One part of my research will focus on generating information that can be used to develop such a test. I will study (1) the response of the patients’ own defence system, (2) the amount of drug in the patients’ blood and (3) the amount of tuberculosis in the patients’ sputum. Secondly, deciding on the best combination and amount of drugs for tuberculosis treatment when they are given in combination is challenging. I will generate information that can be used to optimise the combination of drugs. I will study which drug combination, and which amounts of drugs, are needed to maximise the effect.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Schistosome and Snail Resource (SSR); supporting global schistosomiasis research
Funder: Wellcome Trust

Abstract: Schistosomes, transmitted by freshwater snails, infect >200 million people in low/middle-income countries, particularly sub-Saharan Africa. While substantial advances have been made in the control of human schistosomiasis, the diversity and complexity of schistosomes and their specific fresh-water snail hosts warrants fundamental research requiring lifecycles and live material. Without the availability of Schistosoma lifecycles, future research faces substantial obstacles; currently very few labs are able to maintain the parasites and/or the snail hosts and current long-term cultures lack the genetic heterogeneity observed in natural populations. Our proposal is for the creation of a Schistosome and Snail Resource (SSR), maintaining live material and lifecycles that are currently limited or that do not exist elsewhere. The SSR will provide access to 1) the “standard/model” Schistosoma and snail species; 2) key African Schistosoma species/strains; 3) cultures of diverse snail vectors, enhancing current research and capacity while enabling new research avenues. Our historical expertise in establishing and maintaining unique schistosome and snail isolates from different endemic settings, together with our state-of-the-art snail facility (NHM) and LSHTM rodent facility will facilitate the development of the resource. The SSR will add considerable value by facilitating priority research needed to support schistosomiasis control and elimination.

Lay abstract: Schistosomiasis (bilharzia) is a parasitic disease affecting over 200 million people globally, most in sub-Saharan Africa. It is caused by schistosomes – flatworms – transmitted by freshwater snails. The disease, causing ill-health and death, is especially prevalent among children in rural communities. The lack of parasites and snail hosts maintained in labs causes two problems for research: • Many researchers do not have access to the parasites and snails • Very few species/strains are available to those that do Most biological research on schistosomiasis uses strains that have been maintained in the lab for decades, that do not originate from sub-Saharan Africa, and that do not represent the endemic natural diversity. Our proposal brings together two institutions with a long history of schistosomiasis research (Natural History Museum and London School of Hygiene and Tropical Medicine) providing access both to the “standard” strains and new strains/species to enable and enhance priority schistosomiasis research.

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Analyses of paired host-virus genomic data to understand disease heterogeneity of chronic viral infections.
Funder: Wellcome Trust

Abstract: Host and pathogen genetic variations are major causes of clinical outcomes of infectious diseases. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. However, there is strong theoretical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology. The major limiting factor to date has been the lack of cohorts with paired host-virus data. Recent technological developments and reductions in the cost of high-throughput viral sequencing from clinical samples have provided new opportunities to analyse host-virus genomic data generated from the same patients. In this project I propose to analyse paired host-virus genomic data from patient cohorts infected with HBV, HCV and HIV (clinically the most important chronic viruses worldwide) to answer the following questions: 1) What are the host genetic pressures driving virus evolution across different host populations and virus lineages? 2) What host and virus genetic interactions drive disease phenotypes? 3) What are the host genetic variants and pathways linked to disease phenotype across the three chronic viral infections of HBV, HCV and HIV?

Lay abstract: Globally, 1.34 million deaths per year are attributable to hepatitis B and C viruses (HBV and HCV) and one million deaths to HIV infections. There are no curative treatments for HBV, no vaccine for HCV and neither for HIV. In this study I will use the genetic information of the infected individual and the virus they are infected with to understand why patients respond so differently to these viruses. By investigating both host and virus genetic data, we can track how the virus is changing in response to immune system and how different clinical outcomes relate to the differences in host cell and virus machinery. This will allow us to design better vaccines and drugs as well as stratifying patients so that clinicians can give appropriate drugs to each patient based on the genetic information of the patients and the virus they are infected with, improving treatment and lowering costs.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Socio-ecological dynamics of zoonotic and vector-borne diseases in changing landscapes: implications for surveillance and control
Funder: Wellcome Trust

Abstract: Landscape changes disrupt infectious disease dynamics, requiring new approaches to characterise risks and prevent outbreaks. Focusing on emerging (Chikungunya, Zika) and epidemic (malaria, dengue) zoonotic and vector-borne diseases in Malaysia and the Philippines, I aim to design and evaluate enhanced surveillance systems linking health and environmental data to detect and prevent pathogen spillover and transmission. By developing novel models relating social and ecological processes across spatial and temporal scales, I will bridge critical gaps linking environmental change with human behaviour and health systems. Fine-scale studies of human mobility, behaviour and infection risks will be integrated within a large-scale experiment on tropical forest modification to understand how landscape change both interacts with and alters environmental factors (e.g. seasonality, biodiversity) and socioeconomic and biological factors (e.g. demography, mobility, immunity) to determine disease dynamics. Statistical and mathematical models will be used to explore factors across ecological settings, integrating routine surveillance data, population-based serological surveys and multitemporal Earth Observation data to reconstruct historical disease transmission over major environmental shifts. Predictive models will be designed to identify how future land use can reduce disease risks and how control programmes can use environmental data from new sources of real-time Earth Observation data to improve disease surveillance.

Lay abstract: Landscape changes such as deforestation can increase infectious disease spread between people, wildlife and insects. Recent pandemics highlight the urgent need to improve surveillance systems to monitor risks and prevent outbreaks; however, there are substantial knowledge gaps on how disease dynamics respond to ecological changes and how to mitigate risks. Focusing on Southeast Asia, I will study diseases transmitted by mosquitoes to monkeys and people, including dengue, malaria, Zika and Chikungunya. I will use combinations of field studies and mathematical modelling to understand how landscape changes disrupt social, biological and environmental systems to create new pathways for pathogen spread. This will be used to design enhanced surveillance systems using new sources of environmental data to more effectively detect and predict disease spillover and transmission. Generating new insights into linkages between environment, disease and health systems, I will identify how land use decisions and sustainable development can reduce emerging disease risks.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Using social networks to understand and intervene on HIV epidemic spread
Funder: Wellcome Trust

Abstract: Young people in sub-Saharan Africa are central to ending the HIV epidemic. However, uptake of proven protective interventions is low and evidence on who does/does not engage is limited. Theory predicts that behaviours and intervention uptake cluster within social networks. Interventions in other settings have successfully leveraged social ties to improve intervention impact. I aim to: (1) use novel methods to identify how social networks pattern risk for HIV acquisition; and (2) test the feasibility of using such knowledge to improve intervention uptake. I will undertake this work at the Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Following qualitative interviews with young people exploring their social networks and social norms, we will then quantitatively follow 600 15-24 year-olds, together with their close friends and family, for three years. Using these longitudinal data, we will statistically model how social contacts influence behaviour and HSV/HIV acquisition. We will then quantitatively and qualitatively evaluate the feasibility of using network-selected peer-educators to promote uptake of HIV self-tests and subsequent treatment. We will compare how influential peer-educators differ from randomly selected ones in terms of willingness to be involved, training dynamics and health impact.

Lay abstract: Despite many advances, HIV remains a major problem worldwide, especially in South Africa. One reason for the ongoing epidemic is low uptake of proven interventions, like regular HIV testing and taking medicines to protect at-risk people and their partners. We know that people are often more willing to change their behaviour when someone they respect suggests it. My goal is to identify who influences the behaviours of at-risk people, and how these influencers can help prevent HIV transmission. We will follow a large group of young South Africans for three years. We will see how the important people in their lives change, and how that affects their behaviour and risk of getting HIV. Then we will pick people to become peer-educators based on how influential they are. We will see if these influential people are better at getting their friends to take up interventions than people chosen at random.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: RNA-communication between arboviruses and their hosts
Funder: Wellcome Trust

Abstract: Flaviviruses such as Zika virus, dengue virus and yellow fever virus transmit their RNA genomes between arthropods and humans, causing widespread pathology and death. During infection, the viral RNA genome resides inside the host cells’ cytoplasm. However, whether the viral genome folds differently inside human and arthropod cells, and whether it interacts with the hosts’ own RNA remain largely unexplored. The aim of this proposal is to dissect the dynamics and function of the flaviviral RNA interactome. I will employ my recent developed COMRADES method to investigate the base pairing capacity and function of two related flaviviruses: Zika virus and yellow fever virus, and to address the following little-explored aspects in their biology: (i) Do viral genomes base-pair with host RNAs? What are the roles of host-virus RNA base-pairing? (ii) Do viral genomes base-pair differently inside different hosts? What are the functional implications?The results will cast light on how RNA viruses utilise RNA base-pairing to enhance their replication and pathogenicity; offer new opportunities to develop antiviral therapeutics targeting the host-virus RNA-RNA interactome; and establish a new role for RNA base-paring in zoonosis.

Lay abstract: RNA is the infectious ingredient of most human viruses, and the direct product of the genes of all living organisms. RNA has an inherent capacity to form structures and interactions. However, how viral RNA folds inside our cells and whether it interacts with our own RNA remain largely unexplored. Using my newly developed methodology, I will monitor RNA structures and interactions as they occur during the infectious cycle of two flaviviruses: Zika virus and yellow fever virus. I will investigate structural differences between viruses replicating inside human and mosquito cells and study the functional consequences. I will identify how viral RNA interacts with host RNA, what are the roles of such interactions, and can blocking them offer therapeutic opportunities. The outcome will illustrate how viruses are evolving sophisticated ways to manipulate their host and to cycle between different hosts, with a potential to enable future development of new antiviral medicines.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: What makes phleboviruses tick? Examining the molecular interactions of tick-borne phleboviruses with their arthropod vector.
Funder: Wellcome Trust

Abstract: There is a fundamental lack of understanding regarding how tick-borne viruses replicate in ticks and how the tick innate immune system controls infection. My proposal will focus on tick-borne SFTS phlebovirus, its overarching goals are to understand how tick-borne viruses interact with ticks and tick cells and how this facilitates transmission to mammalian hosts. To achieve my goals, I will carry out in vitro and in vivo studies that can be divided into three specific aims: (i) to elucidate the basic molecular biology of tick-borne virus replication, (ii) to define the innate immune factors that control virus replication in the tick cell environment and (iii) to examine whether virions derived from tick or mammalian cells have similar biological properties and virulence? I will conduct in vitro experiments in tick cell lines to examine virus-vector interactions. Importantly, I will also establish unique tick colonies and infection capabilities for the UK. Through combined cell culture approaches and in vivo animal experiments I will investigate the replication of phleboviruses in the live tick for the first time. I will also explore the infectivity of virions derived from different sources and assess if tick-derived viruses are more virulent to mammals in animal inoculation studies.

Lay abstract: The blood feeding behaviour of ticks on multiple host species (including humans) has led to them be implicated in the transmission of many diseases and cases of tick-borne diseases have been rising at an alarming rate. Despite this increase, we still do not fully understand how ticks transmit disease nor how arboviruses interact with ticks. One such arbovirus is a new emerging bunyavirus called SFTS phlebovirus (SFTSV). During this fellowship, I will use molecular tools to explore how tick-borne phleboviruses interact and modulate the immune system of ticks to spread to mammalian hosts. I will also investigate whether virus particles that originate from tick cells can induce more severe disease symptoms in mammalian hosts than those originating from mammalian cells. By carrying out this work, I will increase our understanding of how arboviruses interact with ticks and how this interaction influences disease transmission and ultimately human health.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Treating hepatitis C in Pakistan. Strategies to avoid resistance to antiviral drugs
Funder: Wellcome Trust

Abstract: Hepatitis C infection can be cured by affordable drugs, leading to calls to expand treatment among the 70 million infected people worldwide. Many countries have initiated ‘test and treat’ programmes. e.g. India have reported treatment for ~40,000 patients in Punjab. However, 5-10% of infected people don’t respond and may develop viral resistance and go on to develop liver cancer. Salvage regimens are often unaffordable/unavailable. We will address the remaining questions in hepatitis C therapy. We will work in Pakistan where hepatitis C is highly endemic (4.8% sero-prevalence) with regions reaching sero-prevalences of 10-20% (hot-spots). We will link with the government HCV programme to determine the most effective treatment for people who don’t respond to initial therapy. We will examine viral resistance in treatment failures to determine whether resistance dissemination is problematic and develop strategies to address it. We will determine whether some viruses are more oncogenic, allowing targeted surveillance. We will measure incident infection in the uninfected population (in hot-spot areas) and treated people, using modelling to determine what proportion of people must be cured to prevent disease recurrence. These data will inform the global elimination agenda and provide crucial data to develop optimised elimination programmes.

Lay abstract: Chronic infection with hepatitis C virus causes liver damage and, in many, liver cancer. We have effective drugs allowing us to cure most infected people and this stops the liver becoming damaged. Hepatitis C is common in Pakistan and government is planning a massive national program to find and treat everyone who is infected. We don't know how effective the drugs that will be used in Pakistan will be and we will study this. We will look at why people don't respond to treatment by studying viral resistance and we will look at ways to avoid and overcome this. This work will help make treatments more effective in Pakistan and we will work out, by modelling, how many people need to be cured to stop the spread of infection. We will look at which viruses cause cancer to help find better ways to screen and treat hepatitis C induced cancers.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Thailand Major Overseas Programme core grant renewal 2015-2020.
Funder: Wellcome Trust

Abstract: The mission of the Wellcome Trust Thailand Major Overseas Programme is to carry out targetedclinical and public health investigations, using the best science, to provide appropriate andaffordable interventions which produce measurable improvements in the health of resource-poorpopulations in the tropics. Over the past 35 years the Programme has built substantial clinicaland laboratory research capabilities, deployed across a well-integrated network of strategicallyplaced permanent study sites and research units in seven countries across Asia and Africa. Wewill use this expertise and research capacity to tackle the epidemiology, diagnosis,pathophysiology, treatment, prevention, and, in the case of malaria, elimination of thoseunderstudied infectious and nutritional diseases that cause significant morbidity and mortality inthe populous rural tropics. In doing so we will strengthen local research capacity, a majorobjective of the programme, and build lasting south-south research collaborations with ourpartners across the developing world. We will inform health policy, change clinical practice, andmake a global impact on mortality from tropical infectious disease.

Lay abstract: No Data Entered

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION