TB causes the most deaths than any other infectious disease worldwide. People who live in poor countries are most affected; this is at a large personal and financial cost to the individuals, their families and communities. Disease can be prevented by giving TB drugs to people who are infected with the bacteria that causes TB, this is called TB preventive treatment. The World Health Organization (WHO) currently recommends TB preventive treatment for people who are most at risk of developing TB such as people who live in the same house as a person with TB, and also for people living with HIV. For these individuals, it is acknowledged that TB preventive treatment will achieve more benefit than harm. People with diabetes also have an increased chance of developing TB disease and dying from TB. However, WHO does not currently recommend TB preventive treatment since it is not clear if the benefit would outweigh the risks of treatment. There is not enough evidence to inform this decision especially since the only option on offer is the standard TB prevention treatment with 6 or 9 months of isoniazid which is taken daily and can cause harm especially to the liver. Moreover, benefit may be limited since providing good WHO standard care for diabetes could already reduce the risk of TB in the future. The aim of WHO standard care for diabetes is to control blood sugar levels and by so doing, research suggests the risk of developing TB would also be reduced. In addition, standard care for diabetes includes a medicine called metformin which has been recently shown to reduce the risk of developing TB in people prescribed this medicine compared to those not prescribed the medicine. The new short-duration treatment with one month of the TB drugs rifapentine and isoniazid (1HP) was shown to prevent TB disease in people infected with HIV. Moreover, 1HP has other benefits since more people complete the short treatment, and it causes fewer side effects. We think this new treatment may alter the balance of benefit against the harms. This would result in a change in WHO policy in favour of providing TB preventive treatment to people living with diabetes. The treatment has not not been studied in people with diabetes or people without HIV. We plan to find the best strategy for TB prevention for people with diabetes who are HIV-uninfected and likely infected with TB (as shown by a test of exposure to TB). A positive test would indicate an increased risk to develop TB in the future. We will carry out a study that will place people in a random manner, like tossing a coin, to a group that receives the standard care for diabetes with 1HP or a group that receives diabetes care alone. That type of study is called a randomised controlled study. In this study, we will assess who gets TB disease and who develops side effects from the treatments in each group. If 1HP reduces the chance of developing TB and does so without substantial side-effects, we think WHO policy will change quickly to recommend prevention of TB in people with diabetes. However, if giving 1HP in addition to standard care for diabetes is not better than standard care alone, the current recommendation would not change thus avoid unnecessary harm from TB drugs. Our trial will recruit 4,130 male and female individuals aged 15 years and older with diabetes, and who reside in Philippines and South Africa. The project will run for 5 years.

The COVID-19 pandemic saw the rapid development and deployment of a range of vaccine platforms. While essential to protect against severe disease, these vaccine platforms need further optimisation to provide long-term and local protection against infection including future variants. This vaccine optimisation requires an improved understanding of how a protective immune response is induced, how it is maintained, and the role of immunity in the nose and the lungs. Building on the experience our consortium amassed during the COVID-19 pandemic, we will answer some of the key outstanding questions in the field: 1.MEMORY We will delineate the mechanisms which influence the duration of protective immune responses. Improving understanding of immune memory is critical for the development and deployment of future vaccines with long-lasting protection against both pandemic and endemic pathogens. 2. LOCATION We will determine the role of the immune response in the airways, as the entry route for virus, in protection against infection. The aim is to understand if nasally administered vaccines can stop infection and onward transmission, as well as protect against severe disease. 3. PROTECTION We will define which aspects of the immune response protect against disease and how to maximise these responses. This will enable vaccine developers to focus on new vaccines that deliver improved protection. 4. DATA There exist large datasets from clinical trials and real-world studies that, if combined with the data from this programme, would generate a unique resource for understanding how vaccines work. To achieve this, we will develop an integrated data structure and open-source computational tools to integrate disparate data and maximise data usefulness. 5.IMPACT We will bolster pandemic preparedness by the training and empowerment of future leaders in vaccine development and engaging public understanding of the need for vaccines. Targeting these questions will lead to increased capability for rational, immunologically-driven vaccine development and uptake.

Drug-target binding kinetics has recently emerged as a critical parameter in determining the in vivo efficacy and toxicity of lead compounds. Unfortunately, the rational optimisation of this parameter to design more effective and less toxic drugs is extremely difficult as the features of small ligands and their protein targets that affect binding kinetics remain poorly understood. The aim of this project is to systematically fill this knowledge gap by combining state of the art computational approaches. We propose to combine our state-of-the-art enhanced sampling and QM/MM methods to compute reliable association free energy profiles and rationalise the binding kinetics of receptor-ligand complexes in terms of the structures and energies of the transition state ensemble. We will test and validate these methods, which have not been previously combined for this purpose. Together, they tackle the two central challenges of biomolecular simulation, i.e. conformational sampling and accuracy of potentials. We will apply the techniques we develop to well-characterised biomolecular systems of real biomedical importance, such as the influenza target neuraminidase, the anti-cancer targets p38a, Abl, Src and FGFr tyrosine-kinases, the chaperone HSP90, and other drug targets in collaboration with our pharmaceutical industrial partners (UCB, GSK and Sanofi). The results will shed new light on the kinetics of drug binding and their molecular origins. The methods we develop should find wide application, and we will make them available and accessible.

The holy grail of a cure for Parkinson's disease has been held back for decades by the extreme difficulty of measuring whether proposed new drugs actually improve the patient's symptoms and daily life. The TORUS research programme aims to solve that problem through a novel platform of sensing technologies for use in patients' own homes along with an advanced data fusion and machine learning pipeline that measures changes in specific mobility-related behaviours over weeks and months. Neurological disorders are the single largest cause of disability - in the UK alone there are 150,000 people with Parkinson's disease, the fastest-growing neurological condition. Parkinson's disease is incurable, and symptoms worsen over time, severely reducing quality of life and creating heavy burdens on the patient's family. The cost to the NHS each year is £375M, with families and social services contributing a further £877M (Centre for Health & Social Care Research, 2017). The number of people with Parkinson's disease in the UK is expected to nearly double by 2040. To get a new drug to market, pharmaceutical (pharma) companies need to evidence by a clinical trial whether the drug improves symptoms such as freezing when walking, tremor and the ability to undertake daily tasks such as standing up from sitting or moving between rooms. Currently, to gather this evidence, each patient in the trial must travel to hospital to be observed performing standardised tests by a clinician. However, these (at most) monthly "snapshot" samples of symptoms are a poor representation of the hour-by-hour variation of the patient's true symptoms. The vision of TORUS is therefore to create the capability to autonomously, continuously and objectively measure symptoms of illness (mobility-related activities of daily living) many times every day during the clinical trial of a new drug, in the patient's own home and for months at a time TORUS will achieve this goal by using a wrist-worn wearable integrated synergistically with AI-enabled cameras. The data from the wearable and cameras is fused to give metrics of the quality of mobility-related activities. The programme concluses with a clinical proof of concept.

Pharmaceutical R&D is a powerhouse in the UK, valued at £4.7 billion in 2019, equivalent to nearly a fifth of all R&D spending by industry across the UK economy. Projections indicate that it will generate an impressive £45 billion for the broader economy in the next 30 years from the 2019 R&D investment alone. However, it faces a significant skills gap, with traditional doctoral training programs failing to adequately prepare graduates for the dynamic and diverse demands of the industry. Research has tended to focus on empirical product development or specific process operations, leaving graduates unprepared to innovate in dynamic, multifunctional teams and explore diverse challenges, roles and career paths. This limitation not only hinders their potential but also stalls industry progress. Having a multi-skilled workforce is of paramount importance to accelerate sustainable medicine development and the introduction of ground-breaking patient-centric medicines. These elements are not only vital for enhancing the competitive edge of pharmaceutical manufacturing in the UK but also for guaranteeing that the future pharmaceutical industry is sustainable, resilient and human-centric - key pillars of the Industry 5.0 transformation. CEDAR will address this critical need by training 90 future leaders with multidisciplinary skills that combine pharmaceutical science and engineering with AI, data analytics, and robotics. CEDAR employs a cohort-based approach to equip graduates not only with technical proficiency but also with skills in leadership, collaboration, entrepreneurship, sustainability, and industrial and regulatory expertise. This well-rounded skill set will position them to thrive in modern, project-driven, cross-functional teams and therefore create excellent career opportunities. CEDAR's research projects aim to provide a digital, and advanced processing toolbox that covers the entire system from drug particle creation to precise prediction of their performance in the body. This will be achieved through the development and exploitation of digitally-enabled platform technologies - cyber-physical systems (CPS). These emerging technologies are crucial for accelerating drug development, particularly for emerging medicines like nanomedicines, peptides, and oligonucleotides where material sparing approaches are key and where patient-centricity is paramount. Recognising the transformative potential of CPS in the pharmaceutical industry, CEDAR's graduates will contribute innovative CPS solutions and pioneering methods that promise to revolutionise how future medicines are developed and manufactured. CEDAR draws upon the expertise of an internationally-leading, multidisciplinary team spanning four universities, working in conjunction with industry partners and non-profit organisations. With access to state-of-the-art facilities and dedicated operational support, CEDAR is exceptionally well-placed to address the skills gap and deliver the transformative research needed to drive the pharmaceutical industry towards sustainability, resilience, and human-centricity and deliver wider societal, economic and environmental benefit for all.