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

• 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

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：尽管现有的荚膜多糖疫苗已广泛使用，但在英国，每年仍有 92,000 例成人因肺炎链球菌肺炎入院，40,000 例死亡。需要新的方法来预防肺炎链球菌肺部感染，这就是我们的提案要解决的挑战。背景：一生中反复出现的肺炎链球菌鼻咽定植可增强对严重感染的免疫力。因此，经鼻给予不能引起严重感染的转基因肺炎链球菌菌株可以预防肺炎链球菌肺炎。我们使用人类攻击模型来研究两种无毒力的肺炎链球菌突变株?fhs/pia和?proABC/piaA。鼻腔施用Δfhs/pia突变体可以防止野生型肺炎链球菌的重新定植，而ΔproABC/piaA菌株却不能。初步数据还确定了这些菌株之间的上皮和血清学反应的差异，但这些特征仍然很少。目前，防止重新定植的机制、鼻腔给予突变株对肺和全身免疫的额外影响，以及这些与突变株和野生型株在与鼻咽上皮相互作用方面的差异有何关系，尚不清楚潜在好处：该提案将深入描述野生型和突变型肺炎链球菌鼻腔给药对肺炎链球菌鼻咽、肺和全身免疫的影响，定义防止再定植的保护机制，并链接菌株之间对鼻咽上皮反应的显着差异。这些结果对于进一步开发减毒肺炎链球菌作为预防肺炎的新方法至关重要。这些结果还将进一步加深我们对肺炎链球菌定植如何影响后续感染的理解，这些数据与多种其他粘膜病原体相关。