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.

细菌金黄色葡萄球菌感染皮肤和周围组织（SSTI）非常普遍，并且通常导致需要抗生素治疗或医院就诊。 2020/2021年，超过110万患者患有蜂窝炎（一种SSTI）的NHS A＆E部门。尽管大多数SSTI可以轻松治疗，但在严重的情况下，感染会侵入血液并威胁生命。金黄色葡萄球菌感染是大多数国家的主要细菌死亡原因，因此有效地管理SSTI至关重要，但也很昂贵且耗时。在全球范围内，金黄色葡萄球菌引起的SSTI病例数量正在增加。虽然这种增加的原因尚不完全清楚，但促成因素包括抗生素耐药性，越来越多的脆弱人群以及气候变化。因此，我们迫切需要新的工具来防止感染并更好地管理Aureus SSTI的患者。预防金黄色葡萄球菌感染的有效疫苗是非常需要的，无论是用于高风险患者群体和感染是普遍或流行的脆弱社区。患者的风险包括需要进行侵入性外科手术或频繁的医疗接触，而糖尿病，肥胖和异位岩感染是常见的前疾病前因素，通常与健康的社会决定因素较差有关。尽管临床前和动物模型产生了有希望的结果，但在晚期测试中，最近开发金黄色葡萄球菌疫苗的几项努力仍失败了。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金黄色葡萄球菌皮肤感染，特别是在人类中的反应。这将使我们能够优化未来的疫苗成分的选择，以便在皮肤感染阶段产生保护性反应，以防止进一步的细菌侵袭和血流感染。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。我的目的是确定人类皮肤中发生的早期相互作用，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，我将使用针对GMP标准的完全特征的，临床上相关的细菌（CHAL3）创建一个健康人的金黄色葡萄球菌感染模型。为了安全地设置该模型，我将使用一种渐进的，分阶的方法：最初使用死细菌细胞（UV Light-Killed），然后再使用活细菌。该模型将进行剂量调整，以便大约四分之三的参与者会产生一些表面皮肤感染的证据。使用这种创新模型，我将衡量在表面细菌种群以及皮肤结构和功能中发生的局部变化，以及在金黄色葡萄球菌感染后的皮肤和血液中发生的免疫反应，以确定在对感染和保护的反应中哪些方面很重要。在发现和优化潜在的AUREUS疫苗接种方法中，该研究的长期受益于对新的研究的效果以及对新的研究的潜在效果，以验证新的阶级效果。为了实现这一潜力，除传统的开发途径外，还需要权衡对使用人类感染模型的风险和益处的详细理解，以与有效的金黄色葡萄球菌疫苗的潜在社会利益相比。因此，我将进行平行的工作，以确定可以将人类感染模型的使用视为开发途径中的额外步骤，并且通过临床，学术，工业和政策制定部门共识，可以产生一个道德框架，以指导未来的S. Aureus疫苗开发。