NIHRDataInsights/HRCSData huggingface dataset:
Title: Optimising dosing of dihydroartemisinin-piperaquine for malaria preventive treatment in Malawian infants
Funder: Wellcome Trust

Abstract: The World Health Organisation recommends use of sulphadoxine-pyrimethamine (SP), administered with routine immunisation, for intermittent preventive treatment of malaria in infancy (IPTi) in areas of moderate to high transmission in sub-Saharan Africa. However, there is limited uptake of this recommendation and increasing resistance of malaria parasites to SP. Fortunately, another antimalarial drug, dihydroartemisinin-piperaquine (DP), has shown higher protective efficacy than SP. However, there is paucity of evidence to guide its optimal dosing in infants. Additionally, IPTi is usually given to infants born to women who received SP or DP for intermittent preventive treatment of malaria in pregnancy (IPTp). The impact of using DP for IPTp on subsequent metabolism and efficacy of DP in infancy is not well understood. In this Fellowship, I will develop optimised dosing regimens of DP for IPTi by applying population pharmacokinetic-pharmacodynamic modelling techniques on data obtained from: 1. Evaluating the pharmacokinetics, efficacy and safety of DP for IPTi, in a randomised-controlled trial, in infants born to Malawian women who received DP compared to SP for malaria prevention in pregnancy. 2. Understanding age-related changes in piperaquine pharmacokinetics during infancy. This work will provide the much-needed evidence to inform DP dosing for IPTi, when administered with routine immunisation.

Lay abstract: The World Health Organisation recommends that a commonly used malaria treatment called sulphadoxine-pyrimethamine should be given to infants (babies, aged less than 1-year old) together with their routine vaccinations to prevent malaria. However, malaria parasites are increasingly becoming resistant to sulphadoxine-pyrimethamine. A newer malaria treatment called dihydroartemisinin-piperaquine has been identified as a more effective alternative. However, we do not yet understand how to best- and safely dose dihydroartemisinin-piperaquine to prevent malaria in these infants. In this Fellowship, I will use mathematical model methodologies to develop optimised dosing strategies of dihydroartemisinin-piperaquine in order to prevent malaria in infants. To do this, I will assess the efficacy and safety of dihydroartemisinin-piperaquine, and measure piperaquine drug levels in the blood of Malawian infants who receive dihydroartemisinin-piperaquine together with routine vaccinations. This work will provide the much needed evidence on how to best dose this promising treatment, dihydroartemisinin-piperaquine, for malaria prevention in infants.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Maternal and Infant Lactation pharmacoKinetics (MILK)
Funder: Wellcome Trust

Abstract: Worldwide many women require drug treatment during breastfeeding, but data surrounding transfer of drug from mother to breastfed infant are scarce and of very low quality. This fellowship will provide robust pharmacological data to inform evidence-based decision-making, through collaboration between University of Liverpool, UK; Infectious Diseases Institute, Makerere University, Uganda (IDI); and University of Cape Town, South Africa (UCT). The drug exposure of infants of breastfeeding mothers requiring treatment for TB (drug-sensitive or drug-resistant), malaria and peri-partum infection, identified as local priorities, will be described. Intensive pharmacokinetic sampling of maternal plasma, breastmilk and infant blood will be undertaken. Bioanalysis will be done in the country of study, with capacity building at IDI supported by Liverpool and UCT. Consolidation of an integrated clinical and modelling approach for clinical pharmacology at IDI will ensure the generation of high-quality, robust data, and a sustainable group generating fresh ideas and proposals alongside the fellowship. South-north knowledge transfer will help define research priorities for the UK and build expertise in lactation pharmacology in Liverpool. Public engagement activities in both the UK and Uganda will communicate about study activities and harness the views and concerns of community members and healthcare workers about medication use in breastfeeding.

Lay abstract: Many women require medication while they are breastfeeding. There is usually very little information to describe how much drug enters the breastmilk, how much gets into the system of the breastfed infant and whether the treatment is safe or carries risks. Consequently, healthcare workers may lack confidence in prescribing to breastfeeding mothers, and the mothers themselves may be very concerned about how their treatment affects their baby. This project strengthens existing collaborations by studying treatments for several major infections (TB, malaria and infection in labour). Mothers requiring treatment will be invited to have samples taken of their blood, breastmilk and their infant’s blood. Detailed mathematical analysis will be used to fully understand the amount of drug in mothers and their babies. Work with communities and stakeholders will surround this Fellowship and shape future work. Our research programme aims to address priority questions around drugs in breastfeeding, informing policy and practice.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: The development of a live biotherapeutic product for clinical use, preventing NEC in preterm babies.
Funder: Innovate UK

Abstract: **BoobyBiome is developing breakthrough breast milk-derived live biotherapeutic products (LBPs) for infants with compromised microbiomes**. The microbiome describes the collection of microorganisms, including bacteria, which reside on and in us. A healthy microbiome is crucial in regulating digestive, immune and metabolic functions. Human breast milk (HBM) contributes 40% of the beneficial bacteria in an infant's gut. Without access to HBM, babies are vulnerable to microbiome-related diseases (necrotising enterocolitis (NEC), sepsis, diabetes, IBS etc.). Most at-risk are preterms, the largest population of neonatal mortality in the UK (8% of births). Despite this, preterm disease remains an underfunded sector in healthcare research, and there is a strong demand for new treatments. BoobyBiome is developing a world-first, **multi-strain** LBP to improve the health outcome of preterms at a reduced cost to standard interventions. Our LBP will mimic the microbiota of HBM, restoring the gut to a healthy state by replenishing the bacteria that these babies are lacking. Our product will contain a community of strains informed by rigorous scientific testing and precise characterisation of the HBM. **Our clinically validated multi-strain LBP** **will fill an unmet need in the expanding microbiome market**, with current products poorly regulated and containing minimal bacterial strains sourced from infant stool. With this project, BoobyBiome aims to develop a clinical LBP product for NEC prevention in preterms. During the project, multiple clinically relevant strains will be formulated to a proof-of-concept LBP. Subsequently, the LBP will be safety tested and manufacturing processes scaled up with expert regulatory, CMC and commercial support. The key to the completion of these milestones is our team. BoobyBiome is a female-led team of highly qualified scientists with entrepreneurial expertise whose success lies in their diverse skill sets. The team is based at the Institute of Child Health, UCL, collaborating with esteemed infant microbiologist Dr Bajaj-Elliott. Assisting the team are non-executive directors David Ford and Andrew Martin (New Atlantis Ventures Ltd), who have substantial experience in early-stage science and technology ventures. Further, ??Elizabeth Klein, with a proven track record in the UK's Life Sciences investment community, provides strategic and commercial guidance and will help the team raise funds alongside existing investors for future clinical work. Ultimately, BoobyBiome aims to deliver clinically tested, commercial products accessible to all babies with compromised microbiomes, including C-section and formula-fed babies. We are committed to producing clinically validated LBPs to exert real change in the healthcare sector.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Will the ongoing use of a two-dose, rather than three-dose schedule of pneumococcal conjugate vaccine, have similar impact in rural Gambia?
Funder: Medical Research Council

Abstract: Global control of pneumococcal disease is hampered by the cost of pneumococcal conjugate vaccine (PCV). GAVI will spend 2.8 billion USD on PCV in the next 5 years and country co-payments to GAVI are substantial. Cost prevents middle income countries from introducing PCV. We propose to test a schedule that includes a booster dose at 9 months of age. We hypothesise that the first dose in the new schedule, at age 6 weeks, will provide protection against a low risk of disease from 2-9 months of age in our setting and that the booster dose will provide superior direct and herd protection effects from 1-3 years of age. The trial will compare two- versus three-dose schedules in a cluster-randomised fashion according to immunisation clinics which serve subpopulations in discrete geographic areas. We will deliver two-dose ('1+1') or three-dose ('3+0') schedules to infants resident in the trial area over a period of 4 years. The national immunisation programme will administer vaccines at 68 immunisation clinics serving separate catchment populations (clusters). The clusters will be randomised to either group in a 1:1 ratio. Safety monitoring for IPD, radiologic pneumonia and mortality in the 1-59 month age group will be conducted throughout. The trial endpoints will be measured during the 4th year of the trial. The primary endpoint will be the prevalence of nasopharyngeal (NP) vaccine-type (VT) pneumococcal carriage in children aged 1-59 months with clinical pneumonia. The secondary endpoint will be VT pneumococcal carriage in unimmunised infants aged 6-12 weeks. Analysis will test whether the difference in VT carriage between the two groups is less than a pre-set threshold. Mathematical modelling will explore the role of the booster dose and the coverage needed to induce herd protection. We will conduct a cost-effectiveness analysis comparing 1+1 and 3+0 schedules, and a multi-country investigation of factors influencing the implementation of 1+1 schedules.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION;RESPIRATORY
Title: MICA: Effect of CRTH2 Antagonist OC459 on Response to Rhinovirus Challenge in Asthma
Funder: Medical Research Council

Abstract: Exacerbations of asthma are the main cause for morbidity, mortality and healthcare costs associated with the disease. Rhinovirus infection (the common cold) is the dominant cause for these exacerbations. The rhinovirus challenge model in asthma offers the ability to investigate treatment effects on exacerbations with a small number of volunteers. In contrast, trials of therapies powered to evaluate an effect on naturally occurring exacerbations require several hundred volunteers, a long study period to capture enough events and are significantly more expensive to carry out. Using this model we have shown that type 2 cytokines and PGD2 (a key mediator of type 2 inflammation) are significantly increased during a rhinovirus-induced exacerbation in asthma with levels of PGD2 strongly correlating with the severity of the exacerbation (P<0.001). In addition, previous trials with the CRTH2 antagonist OC459 have reported fewer respiratory tract infections than in patients treated with placebo. It is hypothesised that this effect is due to dampening of type 2 immunity which is opposing the beneficial effects of Th1 and innate immune responses. Blocking the PGD2 receptor CRTH2 therefore appears an extremely promising target with potential to limit the virus-induced Th2 inflammation underlying many asthma exacerbations. However to date trials of CRTH2 antagonists have been short in length and therefore not addressed the effect on exacerbations. This application requests funding for a phase 2a proof-of-concept study to determine the effect of CRTH2 blockade on the airway responses of asthmatics challenged with rhinovirus. We will utilise the virus challenge model and inoculate 28 asthmatics in conjunction with a double-blind, placebo-controlled trial of OC459 (noted for its excellent safety profile and a once-a-day tablet formulation). A treatment that is effective in reducing virus-induced exacerbations is a major unmet need in asthma and would be a huge benefit to patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION;RESPIRATORY
Title: The role of Cathepsin S in PAR-1 mediated lung inflammation - a new paradigm for neutrophilic inflammation
Funder: Medical Research Council

Abstract: Neutrophil recruitment to sites of infection is a common and necessary process to remove bacteria in the lung. In some cases of disease, neutrophils arrive in significant numbers to the lung, and other organ sites, not as result of infection but as a result of a poorly-defined inflammatory process. In the case of acute lung inflammation, excessive neutrophil recruitment can lead to damage which is mediated, in part, by the neutrophil. We have uncovered a new pathway by which neutrophils migrate to the lung involving the role of the protease, cathepsin S (CTSS). The identification of CTSS in this role has been uncovered by the use of specific inhibitors of CTSS. We now wish to confirm further the role of CTSS in neutrophil recruitment using novel new genetically generated models in which a new target for CTSS activity - protease activated receptor 1 (PAR-1) is genetically ablated thus allowing us to confirm the role of CTSS in neutrophil recruitment via PAR-1. We will also expand this project beyond simple mouse models to confirm a role for CTSS in neutrophil recruitment in unique porcine and human ex vivo lung perfusion (EVLP) acute inflammation models and using specific PAR antagonists. The very clear application of this study is in the targeting of CTSS to regulate neutrophil recruitment in disease, particularly lung disease, although there is a potential role for this CTSS-mediated pathway in other disease processes including gastrointestinal and dermatological disorders. To this end, we have a very active collaboration with companies that are involved in the design and clinical testing of CTSS inhibitors including Virobay. Future studies looking at the evaluation of CTSS inhibitors in lung disease in collaboration with Virobay and other pharma is a very real possibility as we are set-up to carry out such studies in Queen's Belfast as part of the UK Respiratory Translational Research Partnership.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;RESPIRATORY
Title: Supportive care and antibiotics for severe pneumonia among hospitalized children: A pragmatic randomised controlled trial
Funder: Medical Research Council

Abstract: Pneumonia is the leading cause of deaths among young children, with inpatient mortality exceeding 10% for the most severe form of the syndrome (severe pneumonia). WHO pneumonia case management guidelines recommend empirical treatment with injectable benzylpenicillin or ampicillin and gentamicin for children at the highest risk of mortality (severe pneumonia). Following the introduction of vaccines against the dominant causes of pneumonia to national immunization programmes in many low-income countries, there has been growing debate over the appropriateness of the current recommendations for empirical treatments. The first key question is whether either intravenous amoxicillin-clavulanic acid or ceftriaxone is superior to benzylpenicillin plus gentamicin (standard care) for the treatment of children hospitalized with severe pneumonia. Some authorities, including the British Thoracic Society, advise against nasogastric hydration in severely ill children, citing concerns of compromised respiratory status and increased risk of aspiration with nasogastric feeding. However, administration of intravenous fluids demands careful monitoring - a common challenge in many low resource settings. Intravenous fluids are also deficient in nutritive value to match the raised metabolic demands associated with acute illness. The second key question is therefore whether nasogastric feeding is superior to intravenous fluid therapy for supportive management of children with severe pneumonia. This 3x2 factorial pragmatic trial will enrol 4392 children at 12 hospitals in Kenya. The primary endpoint will be mortality at Day 5 post-enrolment. Secondary outcomes will be length of hospitalisation, and mortality at Day 30. Chest radiographs and blood cultures will be performed on a representative sample of patients to provide data on aetiology. We will assess cost effectiveness of the interventions as well as social perceptions of caregivers and health workers towards the study treatments.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;RESPIRATORY
Title: Investigating the antimicrobial efficacy of mesenchymal stromal cells as a novel potential therapy for Mycobacterium avium pulmonary infection
Funder: Medical Research Council

Abstract: The prevalence of non-tuberculous mycobacterial (NTM) pulmonary disease has increased rapidly over the past decade in Europe and the United States. NTM pulmonary infection occurs primarily in patients with pre-existing structural lung disease (such as cystic fibrosis, bronchiectasis and COPD) and causes further progressive inflammatory lung damage. There is also an association with T-cell immunodeficiency, with growing patient populations with primary immunodeficiency or using anti-TNF agents partly attributable to the rise in case numbers. Isolates from the Mycobacterium avium complex (MAC) are the commonest cause of NTM pulmonary infections outside of the cystic fibrosis population. MAC are resistant to many antibiotics and typically require a 15-18 month course of combination antibiotics which are poorly tolerated and only successful in 60% of cases. There is an urgent need to develop more efficacious and better tolerated therapies for this infection. The developing field of cell therapies has identified the therapeutic potential for mesenchymal stromal cells (MSCs) in a number of inflammatory and infective conditions. Our preclinical data has demonstrated their antimicrobial properties through potentiation of phagocytes and secretion of antimicrobial peptides, including those that have activity against NTM. We intend to study whether MSCs can target intracellular and extracellular MAC and determine their anti-mycobacterial mechanism. Once this is understood, we plan to investigate their effectiveness in an in vivo model of NTM lung infection, as a step towards their translation into a clinical therapy. This work is important because of its potential in developing a new approach to treating chronic and resistant NTM infections. By characterising the immune-enhancing and antimicrobial properties of MSCs, this project will also facilitate researchers in the fields of regenerative medicine and antimicrobial resistance.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION;RESPIRATORY
Title: A lung-oriented controlled human infection model using live BCG to evaluate tuberculosis immunopathogenicity and vaccine efficacy (TB-CHIM).
Funder: Medical Research Council

Abstract: Elimination of tuberculosis (TB), a global crisis, is hampered by the lack of an effective vaccine. BCG, a live attenuated TB strain, is generally ineffective in adults. Several promising vaccine candidates have failed phase 2 studies and no subunit vaccines have yet entered phase 3 trials. This is due to our incomplete understanding of TB immuno-pathogenesis, which comes primarily from animal models and studies involving the use of human blood. Another unmet need is uncertainty about the optimal route for TB vaccine administration. A pragmatic method to prioritize the most promising vaccine candidates is urgently needed as existing approaches are time-consuming and extremely expensive. In our recently completed TB-HART study, we established the safety and feasibility of a first-in-man lung-oriented controlled human infection model (CHIM). Live BCG and sterile PPD were bronchoscopically instilled into the lungs of 3 groups of healthy participants representing a gradient of TB susceptibility (sterilizing immunity; latent TB infection; recurrent TB). Repeat bronchoscopy was performed after 3 days. The gradient-based design allowed us to hierarchically rank different components of the immune response. The next step is to leverage these achievements to gain a more granular understanding of lung-specific host immunity, and to refine a model for rapid and affordable evaluation of vaccine candidates. TB-CHIM will leverage a similar model to evaluate aspects of longer term (90-day) immunity in the different susceptibility sub-groups (Aim 1), refine a generic challenge model for the evaluation of TB vaccines (Aim 2), and to compare BCG performance when administered via different routes (skin vs. lung; Aim 3). This will likely provide us with (i) vaccination-induced immune mechanisms associated with TB risk (hitherto, poorly understood); (ii) a platform to test the efficacy of future vaccine candidates, and (iii) determine the optimal route of vaccine administration.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION;RESPIRATORY
Title: Understanding acquisition and evolution of antifungal resistance in chronic respiratory disease
Funder: Medical Research Council

Abstract: Aspergillus species are ubiquitous, saprophytic fungi with airborne conidia that grow on organic matter. Aspergillus fumigatus is the principal causative agent of human aspergillosis, which can range from allergy to invasive aspergillosis, a life-threatening infection in immunocompromised hosts. In chronic respiratory disease, there is a significant global burden of Aspergillus related disease with high mortality and morbidity with oral triazole antifungal drugs the front-line therapy. We have shown a rapid global emergence of multiple triazole resistance (MTR) in A. fumigatus over the past decade with ~15% prevalence in chronic respiratory disease patient isolates. The major target for MTR mutations is the Cyp51A-gene which is the target for triazole antifungals. The acquisition of MTR in this increasing population of patients is however as yet unclear with MTR selection environments including patient azole therapy and organic matter containing agricultural triazole fungicide residues. Detection is further hampered by poor sensitivity of Aspergillus culture methodology and PCR commercial testing of sputum in culture-negative patients. This project aims to validate and use a novel TR34-loop-mediated isothermal amplification assay to map prevalence of MTR in chronic respiratory disease and through population genomic methods link spatial, environmental and biological covariates into a description of patterns of genome wide diversity in A. fumigatus in which resistance evolves. The TR34-LAMP assay will be validated in clinical A. fumigatus MTR and wild-type isolates, prospective sputum from 2 clinical sites and a sample biobank of sputum DNA from a European cohort of non-cystic fibrosis bronchiectasis patients. A landscape whole genome sequencing approach of prospective chronic respiratory patients on azole therapy alongside comprehensive environmental and nosocomial sampling will be used to enable a phylogenomic analysis of A. fumigatus MTR acquisition and evolution.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;RESPIRATORY