Infection of the skin and surrounding tissue (SSTI) by the bacteria Staphylococcus aureus is very common and often results in the need for antibiotic treatment or a hospital visit. Over 1.1million patients attended NHS A&E departments with cellulitis (a type of SSTI) in 2020/2021. While most SSTI can be easily treated, in severe cases infection can invade the blood stream and become life-threatening. S. aureus infection is the leading bacterial cause of death in most countries, and so managing SSTI effectively is vital but also highly costly and time-consuming. Worldwide, the number of cases of SSTI caused by S. aureus is increasing each year. While the reasons for this increase are not totally clear, contributing factors include antibiotic resistance, an increasing number of vulnerable people, and changes in climate. We therefore urgently need new tools to prevent infection and to better manage patients with S. aureus SSTI. Effective vaccines to prevent S. aureus infection would be highly desirable, both for use in high-risk patient groups and in vulnerable communities in which infection is common or endemic. Risks for patients include requiring invasive surgical procedures or frequent healthcare contact, while diabetes, obesity and ectoparasite infections are common pre-disposing factors often associated with poorer social determinants of health. Several recent efforts to develop S. aureus vaccines have failed in late-stage testing despite promising results from pre-clinical and animal models. To succeed in developing effective vaccines we need to better understand how the immune response reacts to S. aureus skin infections, specifically in humans. This will enable us to optimise the selection of future vaccine components, with the aim of generating a protective response at the stage of skin infection, preventing further bacterial invasion and blood stream infection. The main purpose of my research is to actively investigate the immune responses which occur early after skin infection. I aim to identify the early interactions occurring in the human skin which ultimately determine the development of a protective immune response. To study this in the most realistic way, I will create a S. aureus skin infection model in healthy humans using a fully-characterised, clinically relevant, strain of bacteria (CHAL3) made to GMP-standard. To set this model up safely, I will use a gradual, staged approach: initially using dead bacterial cells (UV light-killed) before using live bacteria. This model will be dose-adjusted so that approximately three-quarters of participants develop evidence of some superficial skin infection. Using this innovative model, I will measure local changes occurring in the surface bacterial populations and skin structure and function, and the immune responses occurring in the skin and blood after S. aureus infection to determine which aspects are important in the response to infection and protection. In addition to discovering and optimising potential new S. aureus vaccine approaches, the potential long-term benefit of this research include a new model for evaluating candidate vaccines in order accelerate development and public health impact. To realise this potential, a detailed understanding of the risks and benefits of using a human infection model in addition to the traditional development pathway needs to be weighed against the potential societal benefit of an effective S. aureus vaccine. I will therefore perform parallel work to identify the key ethical criteria under which the use of a human infection model might be considered as an additional step in the development pathway, and, with clinical, academic, industrial and policy-making sector consensus produce an ethical framework to guide future S. aureus vaccine development.

The aim of this place based impact acceleration account (PBIAA) is to support the translation of University research in medical technologies into new clinical products and services. There is a vibrant Medical Technology (MedTech) business cluster in the Yorkshire region, with over 200 companies employing more than 16,000 people, mostly in high value technical roles. The Universities of Leeds and Sheffield have strong track records in engineering and physical sciences research related to MedTech, particularly in areas that mirror the local business strengths (e.g. orthopaedics, dental, implantable devices and surgical technologies). While there is clear synergy between University research strengths and the business prominence in the region, there is currently a gap in the innovation funding pathway that is preventing technology innovations developed at the region's universities from being adopted by local companies. The aim of this PBIAA is to provide support to bridge this gap and build the connections between the academic, industrial and clinical assets in the region that will help grow the regional economy. It is particularly timely because the MedTech sector is transforming and there is increasing integration of new technologies into products and services. There are growing numbers of high-growth, high-innovation MedTech companies in the region with an absorptive capacity to benefit from this PBIAA, but we will also proactively engage with established companies that need to adopt new innovations to address the changing markets. We have worked with civic partners including the West Yorkshire Combined Authority and South Yorkshire Mayoral Combined Authority, NHS Trusts through the Leeds and Sheffield Biomedical Research Centres, local industry, investors and innovation support organisations to develop this proposal and shape the activities to most effectively enable impact to be realised from the region's engineering and physical sciences research base. Commercialisation of innovations in the MedTech sector is challenging due to the regulatory barriers for products intended for use in humans, with evidence from extensive pre-clinical testing required to demonstrate the safety and efficacy. The PBIAA will fund Impact Projects that aim to generate evidence to derisk a technology, both to prove the technical concept is effective and to demonstrate that it is a commercially attractive proposition. A stage-gated approach will be used to encourage higher risk in the early stages and fast failure. These projects will act as exemplars to encourage further business engagement and outcomes will form a portfolio of evidence to inform future activities. The PBIAA will also support activities to build the regional innovation environment. These include a suite of training activities and events that raise understanding of technical advances and translational processes in the MedTech sector, and act to bring together academic, clinical and industrial partners to help build a lasting innovation community. The PBIAA will support events to identify clinical needs, two-way secondments, as well as public and patient engagement activities that aim to improve understanding of needs across the diverse regional population. A dedicated collaboration fund will be used to support impact activities at universities across the region, nurturing the wider regional strengths in this sector, and draw on wider collaborations that utilise the full strengths of the UK research base. The PBIAA will provide regional industry with a vital connection to state-of-the-art research, enabling a sustainable regional research-derived product development pipeline. It will help drive regional economic growth, with new innovations being adopted by regional industry, creating high value jobs and unlocking private sector investment in R&D, supporting a £3bn/year industry beyond 2035.