Crimean-Congo haemorrhagic fever (CCHF) is a World Health Organisation (WHO)-listed priority disease due to its high mortality and lack of vaccines and effective treatment and diagnostics. Patients with CCHF have a high mortality and there is only one antiviral used that may only be effective if given early in disease. However, the current turnaround of test results for CCHF diagnosis is slow with a 2-5-day delay causing reduced treatment efficacy and poor patient recovery. The development of rapid diagnostic tests (RDTs) for rapid diagnosis of CCHF has been identified as a priority by the WHO. This proposal seeks to address this need and the Liverpool School of Tropical Medicine (LSTM) in collaboration with Global Access Diagnostics (GADx) have achieved the development of the first RDT prototype to diagnose CCHF with a sensitivity and specificity that fulfils the recommendations from WHO for RDTs. LSTM in collaboration with GADx will optimise the RDT to refine sensitivity and specificity within an ISO-accredited environment. GADx will perform up-scale of manufacturing techniques including bulk conjugations and use quality control systems within their Quality Management System to ensure that the RDT preserves its original performance between batches and when manufactured at commercial volumes. We will do a market scoping exercise to identify the customers and pull through mechanisms to market for this important RDT. We will design-lock the product with all the kit components for evaluation. Firstly, we will perform analytical evaluations across all CCHF viral lineages with UK Health Security Agency (UKHSA) and following this we will evaluate the RDT in banked samples at the Ministry of Health (MoH) in Turkey and the Centers for Disease Control and Prevention (CDC) in Iraq. Also, in collaboration with the MoH, LSTM will set up clinical trials for diagnostic evaluation of the RDT among 492 patients attending secondary health clinics in CCHF hyperendemic regions in Turkey. Data from these trials will be used for preparation of regulatory submission under UKCA marking.

Community-acquired pneumonia (CAP) is the commonest cause of infection-related death in the UK and accounts for 6% of admissions to Intensive Care. Patients with CAP who require Intensive Care still have a hospital mortality of 49.4%, despite antibiotics and optimal supportive care. Steroids and some immune-modifying treatments have been investigated as additional treatment in severe infection, but evidence for any survival benefit is heavily disputed. New therapies are needed to improve outcome, particularly as the Department of Health has highlighted the urgent threat of antibiotic resistant infections in the UK. This proposal investigates a strategy to stimulate immune responses both in the lung and the blood in patients with severe pneumonia by improving phagocyte (white blood cells that ingest and kill bacteria) function in the presence of antibody binding to the infecting bacteria. Pneumococcal surface adhesin A (PsaA) is a surface molecule of Streptococcus pneumoniae with a vital role in bacterial adherence. P4 is a 28-amino acid peptide fragment of PsaA which activates human phagocytes (both macrophages and neutrophils) resulting in adherence and internalization of pneumococci, staphylococci and gram negative bacteria in laboratory experiments. Furthermore, P4 administered with intravenous immunoglobulin (IVIG) as a source of anti-bacterial antibody increases uptake and killing of pneumococci by human lung macrophages, together with dramatically improving survival in animal models of pneumonia and infection by significantly reducing or clearing bacteria in both lungs and blood. This partnership aims to develop Augmented Passive Immunotherapy (API) trials to improve patient survival in the ITU, particularly from severe pneumonia. In this specific project, we will take the next step by synthesising a small quantity of P4, screening this for toxicity and checking that it works in established laboratory assays. Our immediate follow-on priority will be phase 1 study with both P4 and the P4/IVIG combination.

Antimicrobial drugs, such as antibiotics, antivirals and antifungals, revolutionised medicine. They are essential for fighting diseases, and make surgery and cancer therapies safer. Unfortunately, many of the microbes which these drugs fight are becoming 'resistant' and the antimicrobial drugs no longer work. Worldwide, more than 700,000 people each year die due to antimicrobial drug-resistant disease. Antimicrobial resistance (AMR) is increasing rapidly; the United Nations predicts that number of deaths due to antimicrobial drug-resistant disease may climb to as many as 10 million deaths per year by 2050 if no action is taken. Our work focuses on AMR in Shigella bacteria. Shigella are the main cause of severe diarrhoea among children in low-and middle-income countries and also cause sexually transmissible illness in men who have sex with men. Over 200 million people become ill from Shigella each year and over 200,000 people die. There is no widely available vaccine against Shigella and, like many other bacteria, they are becoming resistant to antimicrobials. The World Health Organisation list Shigella as one of twelve priority organisms for antimicrobial resistance (AMR). When bacteria reproduce, they typically divide into two daughter cells. The process by which AMR genes are passed from parent to daughter cells is well understood and monitored. However, many bacterial species are also able to transfer genes for AMR between different cells using mobile genetic elements (MGEs). This is called 'transmissible AMR' and - as the name suggests - involves direct transfer of genes between two bacteria. Our pilot work shows that about half of the AMR in Shigella is transmissible. We don't fully understand how MGEs move about in bacterial populations, but it is clear that some AMR-MGEs stay in bacteria which go on to cause lots of infections, while others don't. Understanding how AMR MGEs spread amongst bacterial populations, and which MGEs will be successful is challenging; we need to consider the AMR gene, the MGE, the bacteria, and the human hosts. Shigella is an excellent model to study transmissible AMR because Shigella infections are already tracked by national public health surveillance teams, and because it only causes infections in humans (so we don't need to consider the effects of different hosts). This means that we can use routine surveillance data to understand how the bacteria and the human hosts interact. This project will, for the first time, create a global overview of the most important Shigella bacteria in their human hosts. It will characterise all the MGEs carrying medically important AMR to understand which ones are causing the most infections and how the MGEs are moving through the bacterial populations. We will then study which types, and what features, of MGEs are the most important factors for driving this transmissible AMR in the real-world. This will enable us to understand the biology of AMR-MGEs and identify features that might act as 'early warning signs' for the emergence of new AMR bacteria. We want our research to make health systems better by identifying newly emerging AMR and understanding which groups of people are at most risk from Shigella AMR. In the future this will enable these people to be given specialised healthcare, such as screening and tailored antimicrobial recommendations. We have built a team that includes academic researchers specialising in AMR and public health specialists who are responsible for disease surveillance across four countries. This will ensure that our new findings and new approaches are useful for public health practitioners and that they will be adopted for use in real-world settings in the near term. Although this project focuses on Shigella, our new methods will be designed to make them easy to use for other bacterial species in the future.

Context of the research Each year over 30 million pregnancies occur in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. The control of malaria in pregnancy in parts of East and southern Africa is under threat. Pregnant women are often infected with malaria without showing any outward signs or symptoms which, if left undetected and untreated, can cause anaemia and interfere with the development of the foetus leading to loss of the pregnancy, or premature birth and low birth weight, which in turn increases the risk of early infant death. The World Health Organisation (WHO) therefore recommends a preventive strategy called 'intermittent preventive treatment in pregnancy' (IPTp) in which mothers receive a single dose of 3 tablets of medication called sulphadoxine-pyrimethamine (SP) at each scheduled antenatal visit starting in the 2nd and 3rd trimester. However, the effectiveness of this strategy is being compromised due to high levels of resistance to SP in the malaria parasite population. The recent search for safe, effective and well-tolerated alternatives drugs has proven elusive because most of the new candidates tested were not tolerated well enough to be used for preventive purposes. Other trials evaluating test and treat strategies have also proven disappointing. All hopes are now pinned on an antimalarial called dihydroartemisinin-piperaquine (DP), which is known to be safe in the 2nd and 3rd trimester of pregnancy and highly effective for treatment of clinical malaria. The high profile journals Lancet and the New England Journal of Medicine recently published the results of two exploratory trials, completed in 2015 (including one by this research team in Kenya). These showed that DP, when taken as IPT by pregnant women, was well tolerated and much more effective than SP in preventing malaria. However these two trials were not big enough to be able to evaluate the impact on the pregnancy outcome and the health of the newborn. WHO reviewed the evidence in July 2015 and concluded that DP is indeed a promising alternative to SP and recommended that a larger, confirmatory, trial is needed, before it can consider whether to recommend this drug as an alternative to SP in areas of high resistance. Study aims and objectives This multi-centre trial will enrol about 3,000 pregnant women in six hospitals in Kenya and Malawi and compare the safety, tolerance and beneficial effects of IPTp with DP to the current strategy with sulphadoxine-pyrimethamine in reducing pregnancy loss, low birthweight, preterm birth and small-for-gestational-age babies, and early infant deaths. The trial will include sub-studies on health economics to determine the cost of the strategy in relation to its benefits, the acceptability of the intervention among pregnant women and health providers, paying particular attention to adherence to the 3-day regimen, and the operational feasibility of implementing the intervention in the routine health system. Potential applications and benefits After a decade of intensive multi-centre trials to find new prevention strategies for malaria in pregnancy, DP has been shortlisted as the only potential alternative to SP for IPTp, but evidence of its benefits on infant outcomes is needed. As an experienced network, specialised in malaria prevention trials in pregnancy, we are in a unique position to address these gaps in an expedited manner. The findings of this new trial will provide the definitive evidence for whether or not this drug should be recommended to replace SP in areas with high levels of resistance by the parasite to SP. A positive result may lead to a direct policy change by the WHO in countries experiencing these levels of parasite resistance, including most countries in East and southern Africa, benefiting women at risk of malaria in these regions resulting in healthier pregnancies and healthier newborns.

The COVID-19 Parenting project will reach 57 million families in DAC countries during the COVID epidemic, with evidence-based resources to prevent violence against children and reduce parenting stress. DAC countries are facing far-reaching COVID epidemics, with cyclical periods of lockdowns and school closures (Mahler, 2020). Parents and caregivers globally are caring for children under exceptionally stressful conditions. Even the most secure families are struggling to manage children within extended lockdowns. Shouting and physical violence are worsened by stress, poverty, alcohol use, confined and crowded conditions (Meinck, 2017), all heightened under COVID-19. UNICEF reports global escalation in child abuse, with severe health, social and economic impacts. We will work with the World Health Organisation, UNICEF, the Global Partnership to End Violence, UNODC, USAID, the US Centers for Disease Control and other NGOs including the Special Olympics, World Without Orphans and local DAC country community organisations to: 1. Adapt parenting programs with demonstrated effectiveness into scalable resources for DAC countries, using the best evidence. This will include text message-based systems and low-data ir or offline app support for families. 2. Deliver parenting support programs and resources to 57 million families in an initial 14 DAC countries, through partnerships with UN agencies, NGOs and faith-based organisations. Translate resources into relevant DAC country languages to facilitate uptake. 3. Evaluate mechanisms of delivery, costs and their impact on reduction in violence, parenting and stress through online pre-post repeated surveys and in-depth qualitative research with families in DAC settings. We will achieve a rare outcome for research translation: direct delivery of support to 57 million families in DAC countries. It is exceptional value for money, with a cost to UKRI of less than one penny (£0.008) per DAC family receiving evidence-based violence prevention support during COVID-19.