Investigating human immune responses to Staphylococcus aureus skin infection to accelerate vaccine development

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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.