Infectious diseases continue to have major detrimental impacts on health and development in in low-income countries (LICs). They are also pose a global threat, as shown by recent Ebola and Zika epidemics. Vaccines are potent weapons against them, and a potential solution to emerging antibiotic resistance. However, some important vaccines have lower efficacy, or induce weaker immune responses, in tropical LICs and in rural, compared to urban, settings. An important example is BCG (used to protect against tuberculosis [TB]) which provides 80% protection in some temperate countries, but 0% in some tropical settings. New vaccines (including for TB, malaria and Ebola) seem also to be affected. Our goal is to understand why this is so. Greater exposure to parasites, such as worms and malaria, is one possible explanation, and addressed in this proposal. Parasites have evolved over millennia to control host immune responses so that they can survive and reproduce, sometimes for decades, if left untreated. It has long been suggested that these mechanisms might spill-over to impair responses to vaccines and to unrelated infections, but it is not yet clear to what extent this is so. We plan to address this among adolescents in Uganda. Parasites are very common in this age group, which is also the target for school-based immunisation programmes. First, we will compare vaccine responses between three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort [we have followed up these children from birth and know that they have low parasite exposure]; (2) island communities where over 80% have schistosomiasis [a worm infection transmitted through snails in the lake]; (3) rural communities with high malaria exposure, where over 50% of school-children have malaria infection, without knowing it. Of course, differences between urban and rural people, other than parasite infections, probably influence vaccine response. So, to obtain stronger evidence that parasites have an effect, we will randomly select half the participants in each rural group to receive intensive treatment for the main parasite in their setting. If this alters the vaccine responses (we predict it will improve them), we can be sure that parasites are involved. Some parasite effects may be indirect. As well as parasites (from the biological kingdom "Animalia"), humans host many bacteria and viruses. Interactions between these major life-forms, within the host, have been termed "transkingdom" effects. For example, immune suppression by parasites can activate dormant viruses which, in turn, may add immunological effects. Also, worms damage the intestinal lining. This causes leakage of bacterial products into the blood, stimulating the immune system. So, we will test whether parasite infections and their treatment change levels of viral replication and of bacterial products in the blood, and relate this, also, to vaccine responses. Vaccines are given to deliver lasting protective immune responses against specific infections. Thus, parasite effects on vaccine responses must act via the host immune system. We will use immunological tools, including the cutting-edge method "mass cytometry" which can examine immune cell types in unprecedented detail, to investigate which cells and mediators are altered by parasites. To bring all our work together, we will undertake a statistical approach called "causal mediation analysis" to explore how urban-rural environment, parasites, "transkingdom" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in low-income, tropical settings, where they are greatly needed; and help public health experts to know whether controlling parasites will also improve effectiveness of vaccine programmes: ultimately leading to better health (and greater wealth) for all.

Injuries are a leading cause of death among children around the world. Globally, nearly 650,000 children under the age of 15 lose their lives every year to injuries and violence. This burden is unequally distributed between low- and middle-income countries (LMIC) and high-income countries (HIC) with the mortality rate from unintentional injuries in LMICs being nearly double that of HICs. In particular, Sub-Saharan Africa has the highest proportion of under 5 deaths in the world. More than 70% of these injuries are non-transport unintentional or "accidental" injuries. Evidence shows that a large proportion of childhood unintentional injuries take place in and around the home, where children are generally believed to be well supervised. Children, especially those under 5 years, spend a significant amount of their time in and around the home which exposes them to various injury hazards e.g. stairs and windows without safety grills, access to poisonous substances and chemicals, areas of open water, access to ground level stoves. Despite an overall global reduction in child injury mortality rates over the past two decades, available data indicates that the rate of decline has been much slower in LMICs and the gap between LMICs and HICs is widening. This is due in part to higher risks, inadequate preventive measures and a lack of access to timely medical care in LMICs. The nature of household injuries among children has been well documented in HICs but much less is known in LMICs. Much of what is known about preventing child injuries in the home stems from research conducted in HICs where preventive measures have been shown to be effective e.g. safety caps, smoke alarms, stair gates coupled with education of parents/carers. What is not known is how effective these measures would be in LMICs. This study aims to test the effectiveness of a child safety kit (developed through co-design to reflect differing risk profiles, cultural appropriateness and availability/affordability) against traditional education. The study will be carried out in Jinja, Uganda and will involve two phases: Phase 1 (the focus of this development grant, conducted over 1 year) will focus on contextualizing the child injury problem and developing the child safety kit through mixed methods (a review of hospital data, focus groups with parents/carers, in-depth interviews with key informants, an affordability/availability survey and a market survey to ascertain willingness to pay for safety equipment); and Phase 2 which will measure behaviour change and reductions in injuries through a cluster Randomised Control Trial (cRCT). We will assess the reduction in child injuries in two villages (clusters) - one which will have the full child safety kit of equipment plus educational material, workshops and awareness campaign for parents versus the other cluster with only education - over 3 years. A key component of Phase 1 will be to support collaborative research between scientific researchers, policy makers and parents such that all stakeholders involved in the health of under 5's have the opportunity to be full participants from conceptualisation to communication of results. The co-design approach will result in the development of a holistic intervention to include the child safety kit, educational material, training workshops for parents and a community-based awareness campaign. Engaging the community from the beginning will result in improved knowledge and awareness through the sharing of opinions and experience and will optimise equipment usage during Phase 2. The results of Phase 1 will identify any challenges to implementing the intervention, provide accurate data on which to calculate sample sizes for the cRCT and determine the key outcomes. To our knowledge, this will be the first cRCT on child safety equipment and education conducted in Africa.

Injuries are a leading cause of death among children around the world. Globally, nearly 650,000 children under the age of 15 lose their lives every year to injuries and violence. This burden is unequally distributed between low- and middle-income countries (LMIC) and high-income countries (HIC) with the mortality rate from unintentional injuries in LMICs being nearly double that of HICs. In particular, Sub-Saharan Africa has the highest proportion of under 5 deaths in the world. More than 70% of these injuries are non-transport unintentional or "accidental" injuries. Evidence shows that a large proportion of childhood unintentional injuries take place in and around the home, where children are generally believed to be well supervised. Children, especially those under 5 years, spend a significant amount of their time in and around the home which exposes them to various injury hazards e.g. stairs and windows without safety grills, access to poisonous substances and chemicals, areas of open water, access to ground level stoves. Despite an overall global reduction in child injury mortality rates over the past two decades, available data indicates that the rate of decline has been much slower in LMICs and the gap between LMICs and HICs is widening. This is due in part to higher risks, inadequate preventive measures and a lack of access to timely medical care in LMICs. The nature of household injuries among children has been well documented in HICs but much less is known in LMICs. Much of what is known about preventing child injuries in the home stems from research conducted in HICs where preventive measures have been shown to be effective e.g. safety caps, smoke alarms, stair gates coupled with education of parents/carers. What is not known is how effective these measures would be in LMICs. This study aims to test the effectiveness of a child safety kit (developed through co-design to reflect differing risk profiles, cultural appropriateness and availability/affordability) against traditional education. The study will be carried out in Jinja, Uganda and will involve two phases: Phase 1 (the focus of this development grant, conducted over 1 year) will focus on contextualizing the child injury problem and developing the child safety kit through mixed methods (a review of hospital data, focus groups with parents/carers, in-depth interviews with key informants, an affordability/availability survey and a market survey to ascertain willingness to pay for safety equipment); and Phase 2 which will measure behaviour change and reductions in injuries through a cluster Randomised Control Trial (cRCT). We will assess the reduction in child injuries in two villages (clusters) - one which will have the full child safety kit of equipment plus educational material, workshops and awareness campaign for parents versus the other cluster with only education - over 3 years. A key component of Phase 1 will be to support collaborative research between scientific researchers, policy makers and parents such that all stakeholders involved in the health of under 5's have the opportunity to be full participants from conceptualisation to communication of results. The co-design approach will result in the development of a holistic intervention to include the child safety kit, educational material, training workshops for parents and a community-based awareness campaign. Engaging the community from the beginning will result in improved knowledge and awareness through the sharing of opinions and experience and will optimise equipment usage during Phase 2. The results of Phase 1 will identify any challenges to implementing the intervention, provide accurate data on which to calculate sample sizes for the cRCT and determine the key outcomes. To our knowledge, this will be the first cRCT on child safety equipment and education conducted in Africa.

Evidence-led policymaking for COVID-19 control relies on accurate understanding the epidemiology of SARS-CoV-2 infections by correlating diagnostics, molecular fingerprinting and patient metadata (intrinsic (e.g. age), and extrinsic (e.g. travel history)). Efforts to correlate these data in Uganda are stalling, despite available local expertise, because laboratories designated for diagnosing and tracking COVID-19 are under-resourced, and widespread mistrust of diagnostic workflows. Current policy is therefore shaped by data from industrialised countries, which may be misleading due to significant differences in the population demographics and underlying health status. Laboratory facilities in northern Uganda are lacking: i) reagents and experience of reliable workflows for processing of COVID-19 diagnostics; ii) whole genome sequencing equipment and consumables for providing robust epidemiological information. We will address these needs by bringing together UK-based academics and industrial partners with Ugandan biologists and policymakers to rapidly build local capacity for SARS-CoV-2 diagnostics and real-time epidemiology. Specifically: Transfer knowledge of SARS-CoV-2 diagnostic workflows from leading UK testing centres (NHS, Lighthouse Labs) to Uganda. Establish Nanopore sequencing and bioinformatics in northern Uganda, supported by Salford/Liverpool/COG-UK partners, and facilitate their long-term adoption by Ugandan laboratories (UVRI, Makerere University). Combine WGS with new survey-based patient metadata to provide real-time SARS-CoV-2 genomics, including strains circulating around refugee settlements, to support the Ugandan Ministry of Health and Prime Minister's Office to promptly mitigate local and national COVID-19 spread. Bring together industry and logistics partners with Ugandan policymakers, to identify and address bottlenecks in the equipment and consumable supply chain, to support cost-effective, future Ugandan bioscience.

According to United Nations High Commissioner for Refugees (UNHCR), until June 2017, 65.6 million people were forcibly displaced worldwide of whom 22.5 million were refugees. Historically, health services for refugee populations have been provided primarily through dedicated health clinics located within refugee camps run by UNHCR or international non-governmental organizations. However, as patterns of mobility and emergency duration have changed, there is recognition that these parallel health services in camps are unsustainable and insufficiently benefit the surrounding host populations, many of whom are also vulnerable. Instead, UNHCR has called for the integration of refugee populations into national health systems, and the World Bank recently established a US$2 billion fund for refugee-hosting governments to support the integration of refugees and host communities, covering multiple sectors, including health. This move towards a "humanitarian-development nexus" has the potential to support refugees and nationals, while increasing the capacity of national systems. There has been limited research exploring the issue of integrating refugees into health systems and its effects on such systems. Thus, there is limited evidence available to international, regional or national actors in terms of which types of arrangements may work best in a particular context. We will conduct case studies in three different countries currently hosting large numbers of refugees: Lebanon (1.1m), Jordan (655,624), and Uganda (940,800). We plan to focus on Syrian refugees in Lebanon and Jordan, and South Sudanese refugees in Uganda. While policies in Lebanon, Jordan and Uganda have all integrated refugees into health systems to some degree, they differ widely in their approach, and in the structure of the underlying health system. We will analyse each country case separately and then seek to identify patterns across the three cases, so as to be able to draw conclusions that are relevant to other contexts. Specifically, our research will seek to understand the perceptions and experiences of stakeholders as well as host and refugee populations towards refugees' integration into national health systems including how these stakeholders understand the meaning of integration and perceive its desirability. It will identify the structural, institutional and individual/community factors that have shaped policies on integration of refugees, including refugee health workers, into national health systems. The study will also assess how the pattern and extent of refugee integration across these three contexts has affected health services received by refugee and host populations and how financial mechanisms and flows affected financial sustainability of services. We will then convene national, regional and international policy and decision-makers to reflect upon the findings from these analyses, and identify their implications for future policy and practice. Within each of the three country cases we will employ a mixed-method approach that will be tailored to match local circumstances. We plan to identify timelines for the development of refugee policies and will conduct a policy analysis to understand how policies and practices evolved and why. We will then use existing datasets and primary data collection within district level cases, to explore how different aspects of refugee integration into national health systems over time has affected availability, access to health services and quality of health care. A comparative study, across these three different contexts, will enable decision-makers within the three countries to learn from and consider alternative approaches to refugee integration, but will also provide evidence and policy recommendations that will be transferable to other existing and future refugee settings. We also seek to inform global policy and guidance on this issue, working with actors such as the UNHCR, the World Bank and WHO among others.