London School of Hygiene and Tropical Medicine

UKRI Gateway to Research · FY 2024 · 2024-12

Context Public health policymakers, academics, and government bodies are increasingly aware of, and committed to, mitigating the commercial determinants of health (CDOH) globally. CDOH are the “private sector activities that affect people’s health, directly or indirectly, positively or negatively”.  In addition to influencing health, it is understood that corporate activities may negatively impact the underpinning health evidence base, using strategies that distort the evidence and prevent its robust synthesis, which include: funding and promoting industry-friendly science, undermining the evidence and developing parallel evidence bases, active intimidation of scientists, specific types of corporate social responsibility (CSR) activity, and the funding and influencing of journals, editorial boards and conferences. The challenge the project addresses  Systematic reviews are a key method for synthesising evidence on the impacts of commercial determinants and on the strategies and processes by which they exert their effects, but as yet no CDOH-specific review methods exist. Aims and objectives This project aims to develop novel methods for the conduct of evidence syntheses within the field of the CDOH, with an explicit health equity lens. The objectives are to: (1) Synthesise the evidence base to assess what is known about industry influence on systematic review processes, to identify the key stages at which systematic reviews and other forms of evidence synthesis are susceptible to industry influence, and how other researchers have mitigated these biases; (2) Investigate individual industry practices, and mitigation methods, using three case study critical reviews; (3) Conduct qualitative interviews with experts to triangulate review findings; (4) Conduct and validate consensus exercise; and (5) Publish and disseminate findings   Potential applications and benefits This methodological research will help advance CDOH research to minimise industry bias and influence in evidence and its synthesis, where this would be appropriate. This research will also validate these novel methods, develop a framework and typology of considerations, and package the methods in tailored guidance for researchers and journal editors.  The outcome of this research will be methodological advances in evidence synthesis for CDOH research, which should improve the quality of evidence and its synthesis; leading to better population and planetary health in the medium-to-long term.

UKRI Gateway to Research · FY 2024 · 2024-09

IMPACT AMR is a transdisciplinary network of national and international researchers and stakeholders seeking to address key policy questions around antimicrobial resistance (AMR) mitigation investment priorities through the development of an evaluation framework to compare the impact and attributes of mitigation interventions. There is rising attention to the problem of AMR and political impetus to mitigate it, however currently there is little to guide decision-makers about which of the many interventions to address AMR, across multiple sectors and domains, will be best to invest in to reduce the AMR burden most effectively, feasibly, acceptably and economically. We address the need to establish consensus on key AMR impact metrics as a basis for developing intervention priorities across all One Health (i.e. human, animal, and environmental) settings. In methodological terms we draw on experience and learning in other complex policy spheres, and climate change mitigation in particular. The network will work with the AMR community and wider stakeholders to collate evidence to evaluate the technical, economic, behavioural, social and policy effectiveness, feasibility and acceptability of existing AMR interventions. A systematic approach to evaluate interventions with these criteria would not normally be possible, and requires the opportunity for transdisciplinary working, which extends beyond the boundaries of academia to bring science into conversation with policy, publics, civil society, industry, farmers, food manufacturers, water industry and health practitioners. The evaluations put forward by the multi-stakeholder groups and desk reviews will be set in an evolving appraisal framework that will cumulate data across different domains, including (a) optimising antimicrobial use, (b) managing infection without antimicrobial use, (c) preventing infection and (d) minimizing antimicrobial pollution. The network activities will take place across four workstreams which will serve as a basis for identifying impacts of AMR interventions, prioritising interventions, identifying data gaps and directing onward research in intervention development. The two tasks of defining impact and identifying priority AMR interventions form the central ambition of the IMPACT AMR network and will be tackled as Workstreams (WS) 1 and WS2, involving a range of consultative, review, mapping and framework development activities. WS3 will work across four domains of AMR intervention, each involving human, animal and environmental health, to map existing intervention evidence, evaluate impact, and to stimulate the development of new research to apply the IMPACT AMR framework and address emergent gaps. WS4 will provide a coordination and communication function within the network and with external stakeholders. This network presents a unique opportunity to drive forward answers to this critical challenge, filling a conspicuous gap in the AMR policy landscape and providing a framework to link in data and parameters from other networks, initiatives and organisations with a focus on reducing the AMR burden. The IMPACT AMR network presents value-for-money in both its approach to galvanising wide-ranging stakeholders around a tangible goal as well as for those tasked with making AMR expenditure decisions. Initially UK focused, the network is poised to support global efforts for AMR prioritisation in a second phase of funding.

UKRI Gateway to Research · FY 2024 · 2024-08

Epidemics threaten human and animal health. However, they can also have devastating consequences on the economy of nations. This occurs through a variety of mechanisms, including mandated or voluntary behaviour change that reduce the risk of transmission and protect health systems but which also result in changes in consumption patterns; interruption of trade and restriction of labour or capital allocation. Standard health economic evaluations fail to capture most of these effects, as they concentrate on the direct costs and benefits of epidemics or control interventions only. This can lead to inefficient decision-making; leading to under-investment in epidemic prevention measures, and distorted and disjointed analyses during epidemics, from an inability to appropriately weigh the full benefits and costs of a given course of action. This inability to perform integrated analyses can be very problematic as decision-makers are forced to weigh separate pieces of evidence (on the health and economic side) that were typically produced by separate groups working with different assumptions and aiming to optimise different objective functions. The health of the country and its economy are intimately entwined, but these separated analyses lead to potentially false trade-offs being assumed. The problems faced by governments during crises are compounded by the need to make rapid decisions whilst managing the enormous uncertainty around epidemiological and economic consequences of those choices. There is therefore a need to have tools available to policy-makers that they can integrate macro-economic and epidemiological analyses in a shared framework. The lack of these integrated analyses became very apparent during the COVID-19 pandemic resulting in debates about the cost-benefit trade-offs of many interventions, such as travel restrictions, closure of schools, lockdowns, etc, that are still unresolved. We propose to address these problems to aid epidemic preparedness and response, through a number of activities. The ultimate aim is to develop an ecosystem of integrated epidemiological and macro-economic models and to develop a network of individuals and institutions capable of conducting these analyses at pace, as well as policy-makers capable of interacting with and utilising these tools. The work in this preparatory phase will follow three strands: Construction of an interdisciplinary network of researchers across academia, policy-makers, government agencies and other sectors; Engagement with policy-makers to ensure that models are being developed to answer the right questions, are able to provide answers in a time-frame and format that makes them useful, and have the confidence of policy-makers; Building on an initial scoping review of models used during the COVID-19 pandemic, categorisation of the models used for joint epidemiological and macro-economic analyses; assessment of their capabilities for addressing different policy options; as well as their data and computational needs. It is envisaged that these activities will create an interdisciplinary network that is responsive to demands from policy-makers and capable of driving this field forward. This should help ensure that future responses to epidemics are more effective by providing more rounded guidance on how to respond to epidemics in real-time and helping to ensure better preparedness by guiding investments now.

UKRI Gateway to Research · FY 2024 · 2024-08

Our goal is to enable small island Caribbean nations to address the threat of emerging mosquito-borne diseases. In recent years, these islands have suffered unprecedented epidemics of mosquito-borne diseases (MBDs), including dengue, Chikungunya, Zika, and malaria [1], [2], [3]. Since tourism is a major source of national income, these epidemics have substantial economic as well as health impact [4]. Anthropogenic changes, such as population growth, urban expansion, and climate change can damage ecosystems, decrease biodiversity, create artificial habitats, and introduce invasive species; these changes make environments more vulnerable to disease outbreaks, such as MBD epidemics [5], [6], [7], [8], and small islands in the Caribbean are especially vulnerable [1]. At present, the response to these threats in most islands is to deploy insecticide spraying and fogging against adult mosquitoes, or larviciding to control breeding. The impacts of such interventions are transitory: insecticide-fogging may mitigate an ongoing epidemic, but does not reduce the risk of future mosquito-borne epidemics. In addition, it can cause further damage to ecosystems by affecting non-target species, including predators of mosquito larvae and adults [9], [10], [11]. Mitigating the effects of anthropogenic change that damage environments and opting for sustainable nature-based alternatives could manage epidemic threats, whilst benefiting ecosystems as a whole [8], [12], [13]. Aside from the peri-domestic risks posed by Aedes aegypti, many other known and potential vector species breed in natural and created wetlands [14]. In particular, we are concerned with native wetland-breeding Culex and Aedes spp., potential vectors of emerging pathogens of epidemic potential (such as West Nile Virus and encephalitides ), and with the malaria vector Anopheles albimanus [3], [15], [16], which has recently been detected for the first time in the Turks and Caicos Islands and the British Virgin Islands [14]. Local officials are especially concerned about the latter. There is plenty of evidence from other parts of the world that increased plant and predator biodiversity keeps wetland mosquito populations in check [17], [18], [19]. Economic development is of course essential, but negative effects on the environment are not inevitable. Experience elsewhere suggests that by understanding the ecological mechanisms through which anthropogenic activities reduce environmental resilience and increase epidemic risk, it is possible to identify "win-win" solutions - whereby local economies develop, without growing mosquito populations and without sacrificing ecosystems [13]. So far, there has been very little research on environmental drivers of MBD risk in the Caribbean. To understand these interactions requires a One Health perspective [20], [21]. The UK government currently supports public health programmes in the UK Overseas Territories (UKOTs) in the Caribbean, and the Medical Entomology and Zoonoses Ecology (MEZE) team at the UK Health Security Agency (UKHSA) have provided support to local vector control teams over the past decade, particularly in relation to the prevention of Aedes aegypti-transmitted arboviruses. These small islands are home to a diversity of mosquito vectors and have experienced recurring arboviral outbreaks that strain under-resourced health systems, but face barriers to sustainable, nature-based approaches [14]. Our broad aim is to assess these MBD threats, the anthropogenic changes that drive them, and identify possible mitigation strategies that will enable development to proceed without increasing epidemic risk. Our project team combines experience in medical and wetland entomology, practical vector control, plant sciences, epidemiology, policy, ecology, data modelling and One Health principles.

UKRI Gateway to Research · FY 2024 · 2024-08

Context There are over 317 million children globally with developmental disabilities (DD), 95% of whom live in low- and middle-income countries (LMICs). Children with DD experience worse health and are at substantially greater risk of mortality than their peers. Families of children with DD have an important role as caretakers. Yet, they experience social isolation, stigma, and poverty and most receive no formal support. We developed “Ubuntu” - a peer group intervention that is used in 40 countries; It improves caregiver knowledge and confidence to care for their child, and addresses caregiver mental health. However, the problem remains that most children with DD experience social isolation and do not attend school, and the burden of care mostly remains with the mother. Solutions to address this issue are currently lacking. We aim to fill this gap. Challenge and potential impact Play is essential for the cognitive, social, and emotional development of all children, yet children with DD experience widespread exclusion, including from play, which can impair their development and well-being. Mothers already experience a high care burden that results in severe caregiver stress. Placing additional demands on mothers to increase the child’s opportunities for play will exacerbate their strain. Solutions to promote social inclusion of children with DD are currently lacking. The ‘Friendship Bench’ program, first implemented by “grandmothers” in Zimbabwe, is an effective task-shifting approach in fostering well-being within communities. It offers a culturally sensitive and accessible platform for people to seek emotional support, guidance, and companionship. We hypothesise lay community members (henceforth termed grandmothers) would provide play support, and improve wellbeing of children with DD and the mental health of caregivers in South Africa. It is not clear what barriers and facilitators would affect the engagement of grandmothers, or if social interventions delivered by grandmothers would be acceptable and feasible to address the needs of these children and their caregivers.  This project in South Africa will be the first to develop a social intervention delivered by grandmothers for children with DD and their caregivers, by leveraging insights from community-based models (Friendship bench) and our experience with the Ubuntu model. Aim and objectives We aim to develop and refine a complex social intervention delivered by a lay community member to improve the wellbeing of children with DD and the mental health of their caregivers. The objectives are to: 1.    Use interviews with caregivers of children with DD, community leaders, and community grandmothers to identify barriers and facilitators to delivering play based interventions  2.    Establish a theory of change, i.e., identify expected factors that will need to be evaluated for change along the intervention to explain how the intervention works 3.    Co-develop an intervention to be delivered by grandmothers based on caregivers’ and community and grandmothers’ perspectives 4.    Pilot test and refine the intervention by collecting and analysing perspectives of caregivers and grandmothers on the intervention’s potential, design, and ideal delivery method. Potential applications and benefits We will emphasise co-production throughout the project, using different participatory approaches. Participating in the project will further enrich grandmothers' roles and foster deeper connections within their communities. This work will help design a future randomised trial that will evaluate how effective the intervention is in improving child wellbeing and caregiver mental health, as well as reducing social isolation among children with DD and their caregivers.

UKRI Gateway to Research · FY 2024 · 2024-06

This multi-country project aims to establish the health benefits of large-scale land restoration in Africa's Sahel region. We will leverage the Great Green Wall (GGW) of Africa initiative, the largest land restoration effort in the world, as a natural experimental system. Drylands host nearly 40% of the global population. The GGW and other similar land-restoration efforts currently underway around the world are set to reshape landscapes and the lived experiences of billions of people globally. Such restoration efforts are increasingly being regarded as potential 'Nature-based solutions' as the world seeks to confront and adapt to the triple challenges of climate change, biodiversity loss and food security. At present however, human health considerations play a very minor role in the design and implementation of restoration projects, including the GGW. This project aims to fill this critical gap, to ensure restoration projects can maximally serve human health alongside other objectives. We will use a novel combination of activities spanning 4 integrated work packages to do this. Briefly, WP1 will comprise a literature review and community consultations to develop an iteratively refined, gender-sensitive logic model describing the causal linkages between dryland restoration and human health. This will guide the project by helping to refine key hypotheses and identify a suitable subset of secondary health outcomes to be evaluated in subsequent WPs. In WP2 we will collate as much existing data as possible for GGW countries to conduct a Sahel-wide village-matched health impact evaluation. The primary outcome to be investigated will be weight-for-age z score (WAZ) of children (0-59 months) as a measure of acute nutritional status. A subset of secondary outcomes in children and women emerging from WP1 as of particular relevance will also be considered. We will compare health outcomes between communities with and without GGW activities to evaluate the health impacts of restoration. WP3 will be a follow-up of WPs1-2 in which we will conduct a more targeted, community-prioritised, village-matched health impact evaluation with primary data collection in three focal countries (The Gambia, Senegal, Burkina Faso). Based on our current understanding of the linkages between health and environmental restoration, these are likely to include other anthropometric measures (e.g., height-for-age z score, HAZ), and outcomes reflecting risk factors on the nutrition, infection and mental health / well-being pathways. We will again focus on children and non-pregnant women. Some secondary outcomes require collection of biological samples from children for laboratory analysis. Follow-up sampling will give information on seasonal effects and an opportunity to compare child growth over a 12-14 month period between groups with and without GGW interventions. WP4 comprises a set of integrating tasks aimed at marrying the results of the health impact evaluations with current activities guiding the design and implementation of the GGW and understanding the role of and benefits to health of completing the GGW. With an anticipated cost of around $50 billion to reach its 100 million hectare target of restored drylands by 2030, it is essential for health impacts (benefits and costs) to be brought into existing decision-support tools for applied purposes. We will do this via a combination of steps from health economic evaluation, cost-benefit and trade-off analysis, and systems and scenario modelling in the context of a changing climate. In all WPs, our Project Partners and Scientific Steering Committee will further ensure local relevance and streamline the research-to-practice pipeline, enhancing impact.

UKRI Gateway to Research · FY 2024 · 2024-06

This proposal aims to change how we predict and manage infectious diseases through the application of advanced mathematical methods to the development and analysis of models of infectious disease transmission. Recognizing limitations in current models exposed by the COVID-19 pandemic, such as delayed response times and challenges in adapting models to a new disease, this project proposes a novel approach. It centres on creating a flexible, transparent toolkit for building transmission models that can rapidly adapt to new information, enabling real-time decision-making during health crises. The methodology combines applied category theory (ACT) with operational modeling to simplify the construction and adaptation of complex disease models. ACT is a mathematical framework to describe complex systems in a structured and relational way, like a language for understanding how different parts of a system can fit together and interact, making it particularly useful for building and analyzing models in various fields, including epidemiology. By decomposing models into reusable components, the project intends to make the process of modeling more accessible and adaptable, fostering an environment where models can be quickly tailored to specific diseases or scenarios. Moreover, the research addresses the integration of these models with decision-making processes, acknowledging the uncertainty inherent in predicting disease spread and the effectiveness of interventions. It explores optimizing decisions under this uncertainty, aiming to provide robust support for public health strategies. Applications of this research will be demonstrated through models of measles and SARS-CoV-2, the virus that causes COVID-19, showcasing the toolkit's ability to replicate existing models and create new ones that can inform policy decisions. These demonstrations will benefit from a large and detailed dataset on the transmission dynamics of these infections, and will be run in a trusted research environment, where detailed epidemiological information can be used in the models in a safe, secure manner. Through workshops and open-source distribution of the underlying software, the project seeks to empower modelers, policymakers, and researchers, enhancing preparedness for future pandemics. This initiative not only advances the field of epidemiological modeling but also contributes to a more informed and flexible response to public health threats, potentially saving lives and resources by enabling swift, evidence-based action.

UKRI Gateway to Research · FY 2024 · 2024-06

Of all the bacteria that cause food poisoning, the most common - and most costly - is Campylobacter. In the UK, out of around a million cases of foodborne disease each year, Campylobacter is responsible for 450,000-750,000 cases. Just one species, Campylobacter jejuni, causes more than 80% of these cases. C. jejuni is increasingly resistant to antibiotics, particularly the quinoline-based drugs routinely used to treat these infections. C. jejuni infection (campylobacteriosis) is considered the major bacterial cause of diarrhoeal disease in humans worldwide and is highly prevalent in Low- and Middle-Income Counties (LMICs). C. jejuni naturally colonises birds, in which trillions of cells can exist in the gut without causing overt disease, whereas just 100 cells cause severe illness in humans. Eating and handling poultry is therefore the main route of transmission to humans. Beyond the direct human cost, the economic consequences of such frequent disease, through absence from work and lost productivity, are substantial. The Food Standards Agency estimates that Campylobacter infections cost the UK economy alone £900 million every year, out of £1.5 billion for all foodborne infections. A viable solution to combat C. jejuni is to vaccinate poultry, to reduce transmission to humans. However, no effective C. jejuni poultry vaccines are yet available. A promising approach for developing new cost-effective vaccines is to engineer tiny, fluid-filled compartments called Outer Membrane Vesicles (OMVs). These are released from the outer membrane of bacterial cells, and are thought to play a critical role in C. jejuni virulence and survival, including in cell-to-cell communication and delivering toxins to host cells. Crucial to the formation of OMVs is a multi-protein assembly called the Maintenance of Lipid Asymmetry (MLA) system, which transports glycophospholipids to and from the outer membrane. This pathway plays a major role in virulence and antibiotic resistance in many human pathogens and represents a potential target for new inhibitors and vaccines. It is conserved in all Gram-negative bacteria, but C. jejuni possesses an unusual MLA system (called the type II MLA system) with a distinct architecture that is not yet well understood. We propose to investigate the role of different components of this system in producing and regulating OMVs in C. jejuni. We believe that understanding this better will help us to engineer C. jejuni OMVs to use for cost-effective vaccine development in commercial broilers, and to test the efficacy of different OMV vaccine candidates. Between us, we have expertise in characterising host-pathogen interactions (Gundogdu) and biotherapeutics (Mallick) in C. jejuni. We will combine these strengths to i) elucidate the mechanistic role of the C. jejuni type II MLA system in OMV biogenesis and virulence; ii) characterise the biophysical and functional attributes of C. jejuni OMVs in avian models; and iii) assess the vaccine potential of OMVs against C. jejuni colonisation in commercial broilers. Our research programme will use methods including mutant construction, lipidomics, and in vitro and in vivo infection models to assess biogenesis and virulence. We will assess the composition and function of mutant OMVs as well as investigating the vaccine potential with industrial partners in both the UK and India. The continued rise in Campylobacter infections, along with increasing antimicrobial resistance, is taking an unacceptably high toll on public health. Our innovative, multidisciplinary project will improve our understanding of how to develop C. jejuni poultry vaccines that are efficacious and affordable. This knowledge will reduce Campylobacter in poultry, and subsequent transfer to humans, with far-reaching potential to benefit animal and human health.