NIHRDataInsights/HRCSData huggingface dataset:
Title: Tracking Haulage in East Africa to support COVID-19 surveillance- THEA-C19
Funder: Medical Research Council

Abstract: The goal of contact tracing is to identify COVID-19 cases and their recent contacts then have them isolated to break the virus transmission chain. In Uganda, 68% of 1265 cases are haulage truck drivers and the control of transmission from this group has been through mandatory COVID-19 testing at the borders. However, this requires drivers to wait for a result, causing a 7-15 day delay in the regional supply chain for the landlocked countries. To mitigate this, the ministry of health proposes to allow drivers to continue with the journeys pending results, however, this requires a rapid approach for tracing positive cases. From the ministry's reports, it is evident that such an approach must pay critical attention to a distinct transmission profile i.e. from regional to local haulage drivers who are introducing the virus into communities. To fill this gap, we propose to develop and test a digital contact tracing tool. The novelty here is in its enhanced privacy using a unique universal identifier (UUID), digital tracking boundary defined by the road infrastructure and simplicity based on conventional time-stamped GPS. The mobile application will be open source, which means it can simultaneously be tested by other parts of the world thereby contributing to its robustness. In Uganda, all stakeholders support it's development and deployment, which ensures uptake. Ultimately, this technology will dramatically increase the speed and efficiency of tracing of cases (drivers) and contacts, which reduces spread into communities in the region as well as improve flow of the regional supply chain.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: A targeted combination intervention approach for acute HIV infections to curb the explosive epidemic among high-risk populations in Indonesia
Funder: Medical Research Council

Abstract: There is an uncontrolled HIV epidemic among key populations at highest risk of HIV exposure in Indonesia, including men who have sex with men (MSM), transgender people and sex workers. Innovative, context-specific approaches are urgently needed to break HIV transmission. In high-income countries, multifaceted intervention models based on detection of individuals with acute HIV infection (AHI), using symptom and behaviour risk scores and point-of-care HIV viral load testing, have been successful in curbing local HIV epidemics, by enabling direct linkage to care and immediate initiation of antiretroviral therapy (ART). There is a thus a strong impetus to tailor those successful models to explosive epidemics in low- and middle-income countries (LMIC). Our research proposal will address one overarching question: can we curb the rapidly growing HIV epidemic among key populations in Indonesia by implementing a person-centered AHI diagnosis and treatment pathway? The proposed research will adopt these successful evidence-based intervention models to the Indonesia context. We will implement an AHI care pathway in three community sexual health clinics serving key populations in Jakarta and Bali, combined with innovative community outreach to promote AHI screening and partner notification services. The uptake, yield, feasibility and acceptability will be evaluated using qualitative and quantitative analytical methods. Ultimately, mathematical modelling and cost-effectiveness analysis will be used to estimate the population impact of this intervention strategy if rolled out at scale. The proposed research will strengthen local capacities to adopt implementation science approaches to improve HIV service delivery, reduce new HIV infections, death and health costs, and provide critical evidence to health policy makers in Indonesia and in other LMIC.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: INFECTION
Title: MICA: Community Based Point-of-Need Integrated Diagnostics for SARS-CoV-2
Funder: Medical Research Council

Abstract: Currently, validated diagnostic tests for SARS-CoV-2 infections include laboratory-based tests involving Reverse Transcriptase (RT) Polymerase Chain Reaction (PCR) or RT-isothermal Loop-Mediated Amplification (RT-LAMP), using swabs from the upper respiratory tract, as well as blood-based IgM/IgG/IgA enzyme-linked immunosorbent assays (ELISAs). Rapid diagnostic tests (RDTs) lateral flow immunodiagnostic devices (LFD) are also available for community testing. Most recently DNA testing ex-laboratories has been achieved, albeit with complex and expensive units (e.g. DNAnudge). In general, although these commercial products provide solutions for testing in many scenarios, there remains a need for low-cost, point-of-need nucleic acid sensors, able to detect SARS-CoV-2 infections in a timely manner, providing multiplexed tests (e.g. with RSV, influenza), without the need for expensive equipment. We have developed a novel SARS-CoV-2 LAMP assay, targeting sequences in the ORF1 ab region and N gene simultaneously (as recommended by China CDC and FDA). The assay has been optimised, now giving a limit of detection <64 copies/ml and validated clinically against 7 other respiratory viruses, showing no cross reactivity. We propose to incorporate this into a multiplexed community-use, hand-held nucleic acid-based sensor as a self-contained single-use disposable device. A nasopharyngeal swab or saliva sample will be placed into an injection-molded cartridge, containing all reagents to perform sample enrichment and RT-LAMP. The multiplexed result is read visually on an integrated paper-LFD. The device enables (i) sample enrichment, reducing the elution volume from a swab and (ii) simple methods for thermal management, and will be validated in a statistically-powered study, to accelerate translation.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Implementing genomic surveillance to support SARS-CoV-2 control and mitigation strategies in the Philippines
Funder: Medical Research Council

Abstract: The rapid emergence and spread of SARS-CoV-2 has caused an unprecedented global emergency. The first case in the Philippines was detected January 30th and the country recorded the first COVID-19 death outside China. From mid-March the Philippines implemented one of the world's strictest and longest lockdowns. However, over 300,000 cases and 5,000 deaths have since been reported and the Philippines has the most cases per capita in Southeast Asia(1). Genomic surveillance is a powerful component of the pandemic response, characterising circulating virus diversity to pinpoint sources of introductions, to identify and quantify community transmission, geographic spread, and the extent of importations and health-care associated infections. Yet, there has been limited application of these technologies in low- and middle-income countries (LMICs); only ~7% of 60,000+ genomes contributed globally are from LMICs. This project will operationalize genomic surveillance and inform responses across the Philippines, in collaboration with the national laboratory network, the Epidemiology Bureau and its surveillance units within the DOH and the provincial health offices. Our approach embeds large-scale real-time sequencing capacity at the national reference laboratory and builds local sequencing capacity at Sub-National Laboratories (SNLs). Resources, training and accessible workflows will fast-track interpretation of real-time sequencing and results will directly inform stakeholders and national, regional, and local-scale responses. The research will further enable evaluation of control measures across settings, from infection controls to prevent hospital-acquired infections, lockdowns to interrupt community transmission, and quarantining and movement restrictions to contain introductions, whilst increasing our understanding of SARS-CoV-2 transmission and control. (1)WHO Coronavirus Disease Dashboard, https://COVID-1919.who.int/, accessed 07/10/2020


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Ensuring access to health care and medicines during COVID-19: critical challenges and feasible policy options for the medicines retail sector
Funder: Medical Research Council

Abstract: Governments around the world are facing extraordinary challenges in tackling coronavirus disease 2019 (COVID-19). In Africa, community transmission is rising (Ntoumi et al 2020; Senghore et al 2020). Ways of minimising transmission while ensuring access to medicines must be found. In Uganda, drug shops, small private clinics and retail pharmacies deliver approximately 50% of the country's essential medicines including antibiotics and antimalarials (Ministry of Health, pers comm). Known collectively as the medicines retail sector (MRS), 40-70% of children with febrile illness (Mayora et al 2018) and 80% percent of malaria cases are treated in these settings (Mbonye et al 2013). As government facilities are reserved for COVID-19 case management, the need for access to health care through the MRS is likely only to rise. In tackling COVID-19, however, global health actors and governments have failed to engage effectively with the MRS (O'Hanlon et al, 2020). In Uganda, the MRS has been excluded from all COVID-19 related training schemes, distribution of personal protective equipment, and exemptions from the 6-week lockdown and ongoing curfew. No advice has been issued on protecting staff or clients against infection; engaging MRS in surveillance or future testing. Lack of a whole system approach in the pandemic response could unintentionally restrict access to life-saving medicines. This project, building on a decade of research in the Ugandan MRS, aims to understand and mitigate the vulnerability of supply and access to medicines within the Uganda health system (WHO Roadmap priorities 9.9, 9.11). We will document how COVID-19 and the national response to the pandemic has shaped the ability of the MRS to deliver antibiotics, malaria medicines and contraceptives; identify feasible, costed policy actions to mitigate any negative impact of COVID-19 on access to medicines; and identify ways that the MRS can play an active role in response to ongoing and future pandemics.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: The COVID-19 Clinical Neuroscience Study (COVID-CNS)
Funder: Medical Research Council

Abstract: Acute neurological complications of COVID-19 affect 20-30% of hospitalised patients, including encephalopathy/delirium, encephalitis, stroke, and Parkinsonism. These are often otherwise unexplained (i.e. excluding risk factors/hypoxia/iatrogenic causes) and often occur in younger patients. Survivors frequently report cognitive impairment, fatigue, and depression. The limited regenerative capacity of the brain means these complications may cause lifelong disability. There is an urgent, unmet need to understand the biological causes of acute neurological complications of COVID-19 and their sequelae. In collaboration with CoroNerve and ISARIC-4C's, we have already identified 800 patients who have been hospitalised with these complications. We will: (1) invite these patients to join the COVID-CNS NIHR BioResource, using existing HRA approvals and protocols; (2) conduct a case control study to determine the phenotypes and genotypes of these patients relative to 500 previously hospitalised controls including those from ISARIC-4C's and PHOSP-COVID (400 with COVID-19; 100 non-COVID); (3) collect data from clinical case notes and electronic records, then assess neurological/cognitive/psychiatric sequelae at 3-6 months post-discharge; (4) analyse brain injury, virologic, and immunological mechanisms in serum and cerebrospinal fluid, and analyse acute MRI's and, at follow up, functional MRI to study the pathophysiology of these complications. By understanding these mechanisms, we will be able to stratify patients into clinical care pathways and into trials using existing and novel therapies. We will apply this knowledge through our WHO-commissioned Task Force (co-Chair Michael) to have immediate impact on patient care and through our PPI programme. The NIHR BioResource will provide sustainability and, through linkage to the community cohort (n=35,000), will allow us to determine if similar, but milder, symptoms are being experienced more widely.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: CARE: COVID-19 and Antimicrobial Resistance in East Africa - impact and response
Funder: Medical Research Council

Abstract: There is mounting evidence that COVID-19 prevention measures are changing patient treatment-seeking behaviours for other illnesses. This includes changes in antibiotic (AB) usage which risks driving up antimicrobial resistance (AMR). This is a priority concern within LMIC countries, including those of East Africa, where the circulating pathogen population is responsible for a high burden of infectious disease. This project will address the knowledge gap of the impact that COVID-19 is having on AB usage and provision, and gather evidence to inform policy and interventions to reduce inappropriate AB usage. Employing an interdisciplinary approach, we will conduct a program of research in Uganda and Tanzania to investigate the extent to which COVID-19 has changed health-seeking behaviour for common bacterial illnesses and the availability and usage of ABs. We will target three interconnected AMR domains: Landscape - we will investigate the impact of COVID-19 on formal health care providers' and community drug sellers' experiences and attitudes to antibiotic provision and response to official COVID-19 advice; Patients - in health clinics we will enrol patients and examine how COVID-19 restrictions are affecting patient treatment seeking, AB use, and understanding of illness, and for a subset we will assess shifts in the AMR profile of urinary pathogens; and Communities - we will investigate how community members have received and responded to health messages on COVID-19 and how perceptions about illness and medications may have altered. Data will be compared to baseline data from our ongoing study that was collected in the study areas pre-COVID-19 to investigate changes in AB usage and provision and linkage to COVID-19 disease and/or interventions. A synthesis of the findings will be provided to a range of stakeholders from communities to governmental, to help improve AB stewardship activities and messaging as part of the pandemic response in East Africa and beyond.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION
Title: Serological tools for COVID-19 control and vaccine roll-out in Southeast Asia
Funder: Medical Research Council

Abstract: The unprecedented spread of SARS-CoV-2 has led to the rapid development of diagnostics of active disease, serological assays for infection exposure, and the evaluation of potential vaccines in clinical trials. Governments have begun to consider and evaluate possible exit strategies underpinned by surveillance and vaccination. Surveillance, utilising mass testing and contact tracing, will limit the damage of future sporadic outbreaks in the short term, while vaccination will ideally lead to elimination. To date, many rapid serological tests and vaccines under evaluation are based on the same SARS-CoV-2 targets (e.g. spike protein), but surveillance activities will need to distinguish vaccine from natural infection. Research supporting the deployment of these measures will prove vital to their timely implementation and long-term efficacy. Our project builds on an existing collaboration of LSHTM with its genomic-immunology tools for the active surveillance of SARS-CoV-2, and the Thailand Ministry of Public Health (MOPH) and Philippines Department of Health (DOH), who are at the forefront of clinical management of COVID-19 and involved in their countries infection control taskforces. We will evaluate new serological targets and establish assays that can be implemented to assist a surveillance system to monitor the progress of vaccination and SARS-CoV-2 elimination in the community. To achieve this, we will apply tools that can differentiate immune responses to vaccines and those elicited by SARS-CoV-2 infection; something that cannot yet be achieved with current front-line rapid testing kits. This will provide vital data for the direction of vaccine rollout and containment strategy, develop deployable tools, and make a lasting contribution to Thailand and Philippines COVID-19 surveillance infrastructure.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Exploiting the SARS-CoV-2 nsp14 3'-5'-exoribonuclease as a target for antiviral chemotherapy
Funder: Medical Research Council

Abstract: RNA viruses exhibit high mutation rates due to the lack of proof-reading by their RNA-dependent RNA polymerases, imposing a restriction on genome size. In contrast to other positive-strand RNA viruses, coronaviruses have large genomes (~30kb). To ensure high fidelity replication the coronavirus non-structural protein 14 (nsp14) possesses 3'-5'-exoribonuclease (ExoN) activity, which also renders coronaviruses resistant to mutagenic nucleoside analogues (eg ribavirin). Nsp14 ExoN activity is stimulated by nsp10 binding, and structures of the SARS-CoV nsp14:nsp10 complex have been determined to 3.2Å resolution. Importantly, SARS-CoV and SARS-CoV-2 nsp14:nsp10 exhibit 95% amino-acid conservation, allowing us to build a homology model of SARS-CoV-2 nsp14:nsp10. In conjunction with protein dynamic simulations, this model will be subjected to virtual screening to identify small molecules able to bind to either the ExoN active site, or the nsp14:nsp10 interface. Compounds will be tested in combination with mutagenic nucleoside analogues for effects on the replication of SARS-CoV-2, exploiting in-house BSL-3 containment facilities. Specificity and mode of action of compounds will be confirmed by virological and biochemical assays. Our priority is to seek existing clinically approved compounds that inhibit the SARS-CoV-2 ExoN, and could be rapidly repurposed to treat SARS-CoV-2 infection. To this end, we will interrogate the DrugBank database of approved or investigational drugs. This will be followed by an expansion of virtual screening to an in-house library, and a ZINC library subset, comprising available drug-like compounds. In the longer term these could lead to early-stage drug discovery to provide further therapeutic options for SARS-CoV-2, or other future emerging coronaviruses.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: 'REBRACOVID' - multicentre cohort study of the natural history and immunology of COVID-19 in Brazil
Funder: Medical Research Council

Abstract: While a number of COVID-19 cohort disease demographic and mechanism studies are in progress, many unknowns remain, and each setting has offered distinctive insights. The clinical imperative to better understand the specific challenges in Brazil is strong: WHO data places Brazil 2nd in the world for COVID-19 cases and deaths. Furthermore, this huge country poses challenges of urban crowding and socioeconomic disparities and a healthcare system stretched by disease burden. On a COVID-19 disease trajectory lagging about 1-month behind Europe, there is potential to establish a large cohort during acute disease, taking into account mechanistic insights already gained. In doing so, we benefit also from building a consortium that bolts-on to our established consortium, international,collaborative studies, REPLICK (Brazil) and SPIICA (Anglo-Brazil, MRCNewton ref MR/S019553/1), designed to conduct analogous cohort studies in relation to the immunopathology and chronic disease phenotype in Chikungunya virus infection. We aim to recruit a cohort of 20,000 total infected, PCR+ COVID-19 cases from 9 centres across Brazil, as well as household contacts and healthcare workers. We will characterise basic demographics of those affected, including impacts of age, gender, occupation, ethnicity, co-morbidities, socio-economic factors, blood biochemistry, antibody and T cell immunity (and durability), CT findings, as well as defining chronic sequelae. We will also investigate treatment modalities and co-infections in relation to disease outcome. Communication of findings from this cohort study will be valuable to inform management of the pandemic in Brazil and elsewhere


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFECTION
Title: COVID-19 Modelling Consortium: quantitative epidemiological predictions in response to an evolving pandemic
Funder: Medical Research Council

Abstract: Mathematical and statistical modelling has been hugely influential providing rigorous estimates of the COVID-19 epidemic in the UK and making short-term and long-term predictions for decisions on interventions. We are leaving the first phase of this epidemic, cases are slowly declining but there are local outbreaks and variation between regions is of increasing importance. Although standard epidemiological modelling tools have worked well so far, a suite of new tools are now needed that can deal with spatially- and socially-structured stochastic dynamics and population heterogeneities. The teams of epidemiological modellers and statisticians in this consortium represent a core of committed and experienced research groups that have dedicated the last six months to generating predictions, forecasts and insights feeding into SPI-M and SAGE. To tackle the challenges of the next 18 months, these teams require investment in staff time and personnel. The proposed consortium will support these established and collaborating research teams, build national capacity and help train the next generation of applied epidemiological modellers. We have developed a core set of eight overarching questions that we feel underpin the future challenges that will need to be addressed by SPI-M, SAGE & JBC: 1. Data collation, processing and analysis 2. Statistical and computational fundamentals for outbreaks 3. Detection of hotspots or regions in need of greater control 4. Surveillance, Test and Trace 5. Structured environments (workplaces, care homes, hospitals, schools, universities) 6. Realistic individual-scale modelling of contemporary social interactions 7. Implications of finer-scale individual-level characteristics 8. Detailed retrospective analysis of the first wave


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION