NIHRDataInsights/HRCSData huggingface dataset:
Title: Childhood tuberculosis: Integrating tools for improved diagnosis and vaccines
Funder: Medical Research Council

Abstract: Tuberculosis causes significant morbidity and mortality in children worldwide. Bacteriological confirmation of TB in children is rare and lack of suitable alternative diagnostics is a major bottleneck to progress in identifying patients in need of treatment and in clinical trials of new vaccines and therapies. The MRC Unit, The Gambia can make a significant contribution in this field, since it has a track record in TB research, established data collection tools and state-of-the art laboratory facilities. Suitable cohorts of children with TB disease, infected and controls can be predicted. Our team of local and international investigators is developing and evaluating existing and new tools based on both host immune response and microbiology. We also work with new external collaborators, who are highly experienced in statistical analysis. We are testing samples from TB-affected children (exposed, infected or diseased) identified in household cohorts by using a combined approach of host and pathogen signatures and cellular and molecular methods, such as GeneXpert and biosignatures (ERJ 2015, IUATLD 2016). We characterise host responses associated with protection against infection in TB-exposed children who remain uninfected and who can serve as a model for protective immunity (MRC PhD studentship). We have expaned our existing epidemiological database to include the epidemiological and microbiological context of household transmission and its impact on host responses. We are developing a novel statistical approach to design prediction algorithms for the diagnosis of childhood TB. Translation to Policy: Our research activities have doubled the notification figures for childhood TB in The Gambia. We have developed and patented a novel diagnostic biosignature. Integration of measurable host responses into diagnostic algorithms is informing not only the diagnosis of the individual patient but also facilitate clinical trials of new vaccines and drugs. Understanding of protective immune mechanisms will guide vaccine design. Epidemiological datasets that link TB exposure, infection and disease can serve as a model for public health and TB control. We are working with the NLPT to transfer the household contact tracing into the national program.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: MRC-LSHTM West African Global Health Research Fellowship Programme
Funder: Medical Research Council

Abstract: PURPOSE AND INTENDED IMPACT OF THE PROGRAMME: Goal: The Programme goal is to strengthen the ‘pipeline’ of researchers from the West Africa region and the UK/EU with the talent and experience to become leaders of global health research in the future by bridging a critical career gap - at immediate/early postdoctoral level not covered by existing schemes. The output will be a growing cadre of talented researchers able to compete for intermediate and senior fellowships and academic lectureships. Through their fellowships and subsequent careers, they will enhance the excellence of Gambia Unit and the LSHTM, contribute to MRC’s global health strategy, and enhance the UK/EU capacity for and reputation in this field of research. Aims: We aim to: • leverage the complementary research and training strengths of The Gambia Unit and the LSHTM • attract and appoint three outstanding early-career scientists from the West Africa region and the UK over three years with the ambition and capability to work in West Africa on important global health problems • enable the Fellows to develop into highly competitive, mobile, career scientists with leadership potential • help Fellows obtain a further academic or research position on completion of their fellowship, while sustaining productive relationships with the Gambia Unit, LSHTM, regional and international collaborators and mentors • develop a cadre of potential global health researcher leaders, able to work across disciplinary, sectoral, translational and geographic boundaries. • create the basis for a sustainable regional postdoctoral ‘training and development platform,’ at a manageable scale, focused on complementary interests and capabilities, aligned with funders’ strategies including those yet to emerge for EDCTP-2 Impact: Our ambition is to enhance the global health research capacity of the UK/EU and the West Africa region, by nurturing a cohort of emerging research leaders, who will: • bring new insights into disease and health challenges, based on world-class science and deep local knowledge • enable translation of knowledge into appropriate and effective interventions, working with policy makers, industry and services • develop and sustain research partnerships aligned with long-term, strategic global health programmes • attract new funding to global health research that is well aligned with UK and West Africa’s regional needs The Programme is open to clinical and non-clinical scientists from West Africa and the EU who have up to 3 years’ postdoctoral experience. We will appoint three Fellows. Selection will be through a competitive process. The primary criterion for selection will be quality of both candidate and project proposed.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INFECTION
Title: Reactive household-based self-administered treatment against residual malaria transmission: a cluster randomised trial
Funder: Medical Research Council

Abstract: Malaria elimination presents operational and technical challenges that would require adapting existing interventions and health systems. The majority of parasite carriers are asymptomatic and these contribute significantly to maintaining transmission. Incidentally they are difficult to identify and target by existing health systems. The study evaluates a novel approach to decrease and possibly stop residual malaria transmission by combining targeted treatment of potential malaria carriers with a strong community involvement. The main research questions are i) whether malaria patients (or their parents for children) can administer a full course of antimalarial treatment provided at health facilities to all individuals living in their households and, ii) if treating all household members of clinical malaria cases reduce and possibly eliminate residual malaria transmission where this is already low? A cluster (village)-randomized trial is planned. In the first year, formative research consisting of a mixed-methods approach, combining qualitative (participant observation, in-depth interviews, case studies and focus group discussions) and quantitative research will be applied to gain an in-depth comprehension of the study setting as well as community- based participatory techniques to improve participation in the intervention and adherence to the treatment. The data generated will be used to adapt the intervention to the local context in order to obtain the best possible adherence and compliance to treatment. The final RHOST will be implemented during the second year of intervention. The primary outcome will be the prevalence of malaria infection (determined by molecular methods) in all age groups at the end of the second intervention year. Other outcomes include the incidence of clinical malaria; prevalence of antimalarial drug resistance molecular markers; impact on the local health system; treatment coverage; and comprehension and acceptability of the intervention, cost and cost-effectiveness analysis. The proposed intervention would be implemented through the health system at the village level, with village health workers supervised by nurses based in health facilities. The results and strategy of the trial may be taken up by other African countries with similar malaria endemicity to drive down transmission. Information on possible approaches to engage communities, the impact(s) upon the local health system and the cost-effectiveness of the intervention will also be provided.


Research activity codes: 6.1 PHARMACEUTICALS;8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: Evaluating novel diagnostics and enabling preventive measures for childhood tuberculosis between the UK and partners in Sub-Saharan Africa
Funder: Medical Research Council

Abstract: Tuberculosis causes significant morbidity and mortality in children worldwide. Bacteriological confirmation of TB in children is rare and lack of suitable alternative diagnostics is a major bottleneck to progress in identifying patients in need of treatment and for enrolment into clinical trials of new vaccines and therapies. As shown by our ongoing work, suitable cohorts of children with TB disease, infected and controls can be reliably recruited and their specimens analysed, and our expertise can now be extended to the new sites in Africa. Supported by the state-of-the art technologies, bioinformatics and public health expertise available to the PI in the UK, our team of local and international investigators will further develop and evaluate existing and new tools based on both host immune response and microbiology to build similar expertise in other LMIC where childhood TB remains a major problem. Building on our previous MRC-supported work, we will test samples from children suspected to have TB by using a combined approach of cellular and molecular methods to validate protein and transcriptome -based diagnostic biosignatures. In this period of available funding, we will also set up pilot sites to administer preventive treatment to childhood contacts and translate our knowledge from the UK and the MRCG to the new partners in Africa. Translation into Policy: Integration of measurable host responses into diagnostic algorithms for patient care will not only secure the diagnosis of the individual patient but also facilitate clinical trials of new vaccines and drugs at participating sites. This project will build capacity for such future studies by creating a network of excellence for childhood TB. Epidemiological datasets that link TB exposure, infection and disease can serve as a model for public health and TB control and enable the wider roll out of IPT in the countries via the national TB programs with whom this proposal is engaging, as recommended by the WHO.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION
Title: Mass drug administration of ivermectin and dihydroartemisinin-piperaquine as an additional intervention for malaria elimination
Funder: Medical Research Council

Abstract: We propose to evaluate a novel approach to decrease and possibly stop residual malaria transmission; it consists of mass drug administration (MDA) with an artemisinin-based combination treatment, dihydroartemisinin-piperaquine (DP), and a systemic endectocidal drug, ivermectin (IVM), toxic to Anopheles mosquitoes when biting treated individuals. This intervention will be tested through a community-based, cluster-randomized trial to be implemented in the Upper River Region of The Gambia where there is still residual malaria transmission despite high coverage of standard malaria control activities. Thirty two villages (clusters) at least 3-4 km apart and with 200-600 inhabitants will be randomized to either the intervention or the control arm. MDA with IVM and DP will be implemented in 16 intervention villages and a buffer zone of 2 km around each of them, and will consist of 3-monthly rounds per year during the malaria transmission season for two years. At the peak of each transmission season, a cross-sectional survey to determine malaria prevalence (200 individuals per cluster) will be carried out in both study arms. The vector population will be monitored throughout the transmission season. In addition, qualitative social science data on coverage, potential bottlenecks for the intervention, adherence and acceptability will be collected; a health economics study on the cost-effectiveness of the intervention will be carried out. The primary outcomes will be malaria prevalence (by molecular methods) in all age groups and vector's parous rates after 2 MDA seasonal cycles (3 rounds each). Secondary outcomes will include incidence of clinical malaria, serological markers of recent infection or recent exposure to the vector, other entomological variables, intervention coverage, and costeffectiveness of the intervention.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A non-inferiority trial to assess the safety and immunogenicity of yellow fever vaccine dose sparing strategies for campaign and programmatic use
Funder: Medical Research Council

Abstract: A phase 3, randomized, observer-blind non-inferiority trial will be undertaken to assess the safety and immunogenicity of fractional doses of the yellow fever vaccine when administered to 9-12 month olds in The Gambia. In 2016, the worst epidemic of yellow fever in 30 years occurred in Central Africa on a background of year on year increases in disease despite the availability of a safe and highly effective vaccine. A revised global strategy for epidemic elimination published by the WHO highlighted the critical role played by vaccine supply shortages in the current disease resurgence. These shortages became acute during the recent epidemic when, faced with the impending exhaustion of vaccine stockpiles, fractional (one fifth, 0.1mL) doses of the vaccine were recommended for ongoing emergency campaigns. This trial aims to generate a comprehensive data set on which to base future policy decisions regarding the use of fractional dose of the yellow fever vaccine in infants and children in sub-Saharan Africa. The following research questions will be addressed: 1. Does the administration of a fractional subcutaneous or intradermal dose of a yellow fever vaccine result in seroconversion rates which are non-inferior to those induced by a full subcutaneous dose of the same vaccine? 2. Is there a difference in the geometric mean antibody titres induced by fractional yellow fever vaccine doses according to whether administered by the subcutaneous or intradermal route? 3. Is there a difference in the safety profile of fractional yellow fever vaccine doses according to whether administered by the subcutaneous or intradermal route? Immunogenicity will be compared based on neutralizing antibodies. Local and systemic reactogenicity will be collected according to standard criteria. Other adverse events following immunization will also be recorded. The data are expected to influence future global vaccine policy decisions regarding fractional dose yellow fever vaccine use.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Reduction of Early mortaLITY in HIV-infected African adults and children starting antiretroviral therapy: REALITY trial
Funder: Medical Research Council

Abstract: REALITY is an open-label randomised trial of 1800 adults, adolescents and children (600 aged 5-12 years) with low CD4 counts (!U100 cells/mm3) initiating antiretroviral therapy(ART), to be enrolled over 18 months and followed for 48 weeks in centres in 4 African countries (Uganda, Kenya, Zimbabwe, Malawi). The trial will simultaneously evaluate three potential interventions to reduce early mortality following ART initiation using a 2X2X2 factorial design: (i) increasing ART potency with 12-weeks induction using 4 antiretroviral drugs from 3 classes; (ii) augmented early prophylaxis against opportunistic and bacterial infections and helminths (5 days azithromycin, plus fluconazole, antihelminthic and isoniazid prophylaxis at ART initiation in addition to cotrimoxazole (for all); (iii) macronutrient intervention using ready-to-use food for 12 weeks to all (rather than only to those with malnutrition). Randomisation will be open for logistical reasons and because a key objective is to identify the acceptability of enhanced interventions around ART initiation which would not be possible using placebo pills. Use of an objective endpoint (mortality) will minimise potential bias. A major reason for including all three approaches in the same trial is efficiency: each targets a different mechanism and therefore running one large trial addressing all three questions rather than three large trials separately is more efficient. Furthermore, by using a factorial design in a large trial, interactions between interventions can be identified and the relative contribution of each explored; this has been allowed for in the sample size calculations. The design is pragmatic, aiming to recruit those as typical as possible of future late presenting patients, and treat them with practical interventions which could be implemented in ART rollout programs in Africa. Inclusion criteria are therefore broad, and prophylaxis and nutritional control groups are based on standard of care in national guidelines. We justify inclusion of children !Y5 years because the criteria for starting ART and risk factors for progression are the same as for young adults (in contrast to younger children) and early mortality following ART initiation and spectrum of causes of death overlap considerably (data from joint analysis of DART and ARROW trials); toxicity and tolerability can be addressed with inclusion of 600 children. The inclusion of children also adds to the efficiency and value for money of the trial as well as promoting family-based approaches to care and treatment. Key further areas will include economics and social science, as well as separately funded pharmacokinetic and diagnostic substudies.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC)
Funder: Medical Research Council

Abstract: Our aim is to achieve sufficiently accurate genetic prediction of resistance to all anti-tuberculosis drugs for whole genome sequencing (WGS) to replace slow, cumbersome, culture-based drug susceptibility testing (DST) for Mycobacterium tuberculosis complex (MTBC). This would enable rapid-turnaround near-to-patient assays to revolutionize drug-resistant TB identification and management. This multidisciplinary collaboration including TB experts from five continents, WHO, statisticians/mathematicians and software engineers will integrate machine-learning, statistical genetics and molecular genetics methods to uncover all genomic variation causing at least 1% resistance to first- and second-line anti-TB drugs with >1% resistance prevalence. We will use largescale global and clade-representative WGS (>90,000), with initially >37,000 isolates with extended DST. Approaches include better WGS assembly to identify more variants with more precision, improved statistical methods to detect associations between variants and DST, and selected molecular validation of predicted resistant variants. The project will create an automatically-updating, free, publically accessible, comprehensive data repository of resistance-conferring variants. This will provide accurate genetic resistance prediction for all drugs for any new MTBC WGS; superior design of near-to-patient amplification-based molecular drug-resistance tests as alternatives to ‘WGS-only’ solutions; and better, faster and more targeted drug-resistant TB treatment, facilitating improved control and WHO’s initiative to eliminate TB by 2050.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION
Title: Genetic approaches to reducing vector competence of Aedes aegypti for chikungunya virus
Funder: Medical Research Council

Abstract: Dengue, chikungunya and other arboviral diseases impose significant morbidity and mortality. In few cases are licensed drugs or vaccines available. However, the dependence of these viruses on specific mosquito species, combined with advances in mosquito synthetic biology, potentially provides new approaches. We will engineer reduced-vector-competence traits in the major vector mosquito Aedes aegypti, focusing on chikungunya virus, though successful development would be significant for a much wider range of viruses. We will pursue three approaches in parallel (i) to mitigate the risk that one of these ambitious approaches may not fully achieve its design goals; (ii) to provide multiple independent means to interfere with virus transmission, which in combination would greatly reduce the possibility of virus escape mutants. Two of these approaches aim to make mosquito cells more resistant to incoming viruses, (exploiting RNAi and super-infection exclusion mechanisms, respectively), the other aims to kill cells on infection so that they are unable to support virus transmission, using synthetic substrates for virus replicase that will be replicated and expressed following infection. Each of these approaches is inspired by natural anti-virus defence mechanisms and uses components and designs based on our strong collective track record in molecular virology and mosquito synthetic biology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: ENhancing Appropriate Antimicrobialc use via mHealth and other techniques in the Republic of South Africa
Funder: Medical Research Council

Abstract: The overall aim of this proposal is to develop sustainable innovations to improve the rational use of antimicrobials (AM) in South Africa (SA) in order to reduce the antimicrobial resistance (AMR) rate and its devastating health consequences where AMR is a major threat to the sustainability of the health care system. This would be achieved through conducing a situation analysis to understand the current utilisation/use of AM and the uptake of vaccines, as well as any present strategies/guidelines around the appropriate use of AM in both public sector hospitals and the primary health care (PHC) system alongside the extent of their uptake/compliance by clinicians. This includes point prevalence studies (PPS), questionnaire surveys and retrospective reviews of medical records and prescriptions among representative samples of public sectors hospitals and PHC centres in SA to provide a baseline understanding of the current situation around AM use and infectious disease (ID) treatment guidelines and their uptake. mHealth technologies, including Apps, would be developed and used to collect surveillance data around AM consumption and vaccination uptake, in both primary and secondary care settings. Workable mHealth technologies would also be developed to improve AM use in both sectors through their use as clinical decision support tools to assist and guide healthcare professionals to adhere and implement suggested guidelines and antimicrobial stewardship programmes (AMSPs) alongside their use as data collection tools for AM consumption and surveillance. The key deliverables of this proposal would be developing strategies to improve the appropriate use of AM across public sectors using mHealth approaches. This includes interventions to improve surveillance of AM consumption, AMSPs as well as adherence to treatment guidelines. This proposal would enhance capacity building in SA through the inclusion of postgraduate and undergraduate students, leading to PhD and master qualifications. Additionally, the proposal would result in several publications in international conferences and peer-review journals that would ultimately enhance and enrich the research records, quality and experience of both partner institutions. Lastly, the findings and implications will be of interest to other Africa countries.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION