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

由金黄色葡萄球菌引起的皮肤和周围组织（SSTI）感染非常常见，通常导致需要抗生素治疗或住院治疗。于2020/2021年度，超过110万名患有蜂窝组织炎（SSTI的一种）的病人前往NHS急症室就诊。虽然大多数SSTI可以很容易地治疗，但在严重的情况下，感染会侵入血流并危及生命。S.在大多数国家，金黄色葡萄球菌感染是导致死亡的主要细菌原因，因此有效管理SSTI至关重要，但也非常昂贵和耗时。在世界范围内，由S.金黄色葡萄球菌每年都在增加。虽然这一增长的原因尚不完全清楚，但促成因素包括抗生素耐药性，越来越多的弱势群体以及气候变化。因此，我们迫切需要新的工具来预防感染和更好地管理S。金黄色葡萄球菌SSTI。有效的疫苗，以防止S。金黄色葡萄球菌感染是非常需要的，用于高风险患者群体和感染常见或流行的脆弱社区。患者的风险包括需要侵入性外科手术或频繁的医疗接触，而糖尿病、肥胖和体外寄生虫感染是常见的诱发因素，通常与健康的社会决定因素较差相关。最近的几个努力，发展S。金黄色葡萄球菌疫苗在后期测试中失败了，尽管从临床前和动物模型得到了有希望的结果。为了成功开发有效的疫苗，我们需要更好地了解免疫反应如何对S。金黄色葡萄球菌皮肤感染，特别是在人类。这将使我们能够优化未来疫苗组分的选择，目的是在皮肤感染阶段产生保护性反应，防止进一步的细菌入侵和血流感染。我研究的主要目的是积极研究皮肤感染后早期发生的免疫反应。我的目标是确定在人类皮肤中发生的早期相互作用，这些相互作用最终决定了保护性免疫反应的发展。为了以最现实的方式研究这一点，我将创建一个S。金黄色葡萄球菌皮肤感染模型在健康人中使用完全表征的、临床相关的细菌菌株（CHAL 3），其按照GMP标准制备。为了安全地建立这个模型，我将使用一种渐进的、分阶段的方法：首先使用死细菌细胞（紫外线杀死），然后使用活细菌。该模型将进行剂量调整，以便大约四分之三的参与者出现一些浅表皮肤感染的证据。使用这个创新的模型，我将测量局部变化发生在表面细菌种群和皮肤结构和功能，以及免疫反应发生在皮肤和血液后，S。金黄色葡萄球菌感染，以确定哪些方面是重要的，在应对感染和保护。金黄色葡萄球菌疫苗的方法，这项研究的潜在长期效益包括一个新的模型，用于评估候选疫苗，以加快开发和公共卫生的影响。为了实现这一潜力，除了传统的发展途径之外，还需要详细了解使用人类感染模型的风险和益处，并权衡有效S.金黄色葡萄球菌疫苗因此，我将开展平行工作，以确定关键的伦理标准，在该标准下，人类感染模型的使用可能被视为开发途径中的额外步骤，并与临床，学术，工业和决策部门达成共识，以制定一个伦理框架，以指导未来的S。金黄色葡萄球菌疫苗开发。

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.