Identifying the correlates of protection against Streptococcus pneumoniae respiratory tract infection using a human challenge model

使用人体挑战模型确定预防肺炎链球菌呼吸道感染的相关性

基本信息

批准号：
MR/Z503721/1
负责人：
Jeremy Brown
金额：
$ 240.53万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
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%2FZ503721%2F1
关键词：
Identifying correlates protection against Streptococcus

项目摘要

Challenge:Despite widespread use of the existing capsular polysaccharide vaccines, in the UK there are still 92,000 admissions and 40,000 deaths per year due to Streptococcus pneumoniae pneumonia in adults. New approaches to prevent S. pneumoniae lung infections are needed, and this is the challenge our proposal addresses.Context:Recurrent S. pneumoniae nasopharyngeal colonisation throughout life boosts immunity against severe infections. Hence, nasal administration of genetically modified S. pneumoniae strains unable to cause severe infection could prevent S. pneumoniae pneumonia. We used a human challenge model to investigate two avirulent S. pneumoniaemutant strains ?fhs/pia and ?proABC/piaA. Nasal administration of the ?fhs/pia mutant protected against re-colonisation with wild-type S. pneumoniae, whereas the ?proABC/piaA strain did not. Preliminary data also identified differences in epithelial and serological responses between these strains, but these remain poorly characterised. At present the mechanism(s) that prevent re-colonisation, the additional effects of nasal administration of mutant strains on lung and systemic immunity, and how these relate to differences between mutant and wild type strains in their interactions with the nasopharyngeal epithelium are not known.Potential benefits:This proposal will characterise in depth the effects of nasal administration of wild type and mutant S. pneumoniaeon nasopharyngeal, lung and systemic immunity to S. pneumoniae, define mechanisms of protection against re-colonisation, and link significant differences between strains to nasopharyngeal epithelial responses. The results will be crucial for the further development of attenuated S. pneumoniae as a novel approach to prevent pneumonia. The results will also further our understanding of how S. pneumoniae colonisation affects subsequent infection, data which are relevant for multiple other mucosal pathogens.

挑战：尽管广泛使用现有的囊囊多糖疫苗，但在英国，由于成人肺炎链球菌肺炎链球菌肺炎，每年仍有92,000次入院和40,000人死亡。需要新的预防肺炎链球菌肺部感染的方法，这是我们提出的提出的挑战。Context：复发性肺炎鼻咽鼻咽定植在整个生命中，都可以增强免疫力对严重感染的免疫力。因此，鼻腔施用了无法引起严重感染的基因修饰的肺炎链球菌菌株会预防肺炎链球菌肺炎。我们使用人类挑战模型研究了两种无毒的肺炎链球菌菌株？fhs/pia和proabc/piaa。鼻施用的？FHS/PIA突变体免受野生型肺炎链球化的重新持续化，而？proABC/PIAA菌株没有。初步数据还确定了这些菌株之间上皮和血清学反应的差异，但这些菌株的特征仍然很差。目前，防止重新持续化的机制，突变菌株对肺和全身免疫力的额外影响，以及这些与突变体和野生型菌株之间的差异之间的差异如何与鼻咽上皮相互作用中的差异相关。鼻咽，肺和对肺炎链球菌的全身免疫，定义了防止重新殖民化的保护机制，并将菌株之间的显着差异与鼻咽上皮反应联系起来。结果对于肺炎链球菌的进一步发展至关重要，作为预防肺炎的新方法。结果还将进一步了解肺炎链球菌定植如何影响随后的感染，这些数据与多种其他粘膜病原体相关的数据。