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

研究人体对金黄色葡萄球菌皮肤感染的免疫反应以加速疫苗开发

• 批准号: MR/X032736/1
• 负责人: Thomas Darton
• 金额: $ 237.31万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX032736%2F1
• 关键词: Investigating; human; immune; responses; Staphylococcus

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.

由金黄色葡萄球菌引起的皮肤和周围组织感染（SSTI）非常常见，通常需要抗生素治疗或去医院就诊。在2020/2021年，超过110万名蜂窝织炎（一种SSTI）患者在NHS急诊科就诊。虽然大多数性传播感染很容易治疗，但在严重的情况下，感染可能侵入血液并危及生命。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，因此有效管理性传播感染至关重要，但也非常昂贵和耗时。在世界范围内，由金黄色葡萄球菌引起的性传播感染病例每年都在增加。虽然这种增长的原因尚不完全清楚，但造成这种增长的因素包括抗生素耐药性、易受感染人群数量的增加以及气候变化。因此，我们迫切需要新的工具来预防感染并更好地管理金黄色葡萄球菌性传播感染患者。预防金黄色葡萄球菌感染的有效疫苗将是非常可取的，既可用于高危患者群体，也可用于感染常见或流行的脆弱社区。患者面临的风险包括需要进行侵入性外科手术或频繁接触医疗保健，而糖尿病、肥胖和体外寄生虫感染是常见的诱发因素，往往与较差的健康社会决定因素相关。尽管临床前和动物模型取得了令人鼓舞的结果，但最近开发金黄色葡萄球菌疫苗的几项努力在后期测试中失败。为了成功开发有效的疫苗，我们需要更好地了解免疫反应对金黄色葡萄球菌皮肤感染的反应，特别是对人类的反应。这将使我们能够优化未来疫苗成分的选择，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。我的目标是确定人类皮肤中发生的早期相互作用，最终决定保护性免疫反应的发展。为了以最现实的方式研究这一点，我将在健康人身上创建一个金黄色葡萄球菌皮肤感染模型，使用一种完全特征的、临床相关的、符合gmp标准的细菌菌株（CHAL3）。为了安全地建立这个模型，我将采用渐进的、分阶段的方法：在使用活细菌之前，首先使用死细菌细胞（紫外线杀死）。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，我将测量表面细菌种群和皮肤结构和功能发生的局部变化，以及金黄色葡萄球菌感染后皮肤和血液中发生的免疫反应，以确定哪些方面在感染反应和保护中是重要的。除了发现和优化潜在的新的金黄色葡萄球菌疫苗方法外，这项研究的潜在长期效益包括评估候选疫苗的新模型，以加速开发和公共卫生影响。为了实现这一潜力，除了传统的开发途径外，还需要详细了解使用人类感染模型的风险和益处，以权衡有效的金黄色葡萄球菌疫苗的潜在社会效益。因此，我将开展平行工作，以确定关键的伦理标准，在这些标准下，人类感染模型的使用可能被视为开发途径中的一个额外步骤，并在临床、学术、工业和决策部门达成共识的情况下，制定一个伦理框架，以指导未来的金黄色葡萄球菌疫苗开发。