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

挑战：尽管现有的胶囊多糖疫苗得到了广泛使用，但在英国，每年仍有92,000人因肺炎链球菌肺炎入院，40,000人死亡。需要新的方法来预防肺炎链球菌肺部感染，这是我们建议解决的挑战。上下文：一生中反复出现的肺炎链球菌鼻咽定植可以增强对严重感染的免疫力。因此，鼻腔给药不能引起严重感染的转基因肺炎链球菌可以预防肺炎链球菌肺炎。我们使用人类挑战模型研究了两个无毒肺炎链球菌突变株？FHS/PIA和？proABC/PIAA。鼻腔给药？fhs/pia突变体可防止肺炎链球菌与野生型肺炎链球菌重新定植，而？proABC/pIAA株则不能。初步数据还确认了这些菌株之间在上皮和血清学反应方面的差异，但这些差异的特征仍然很差。目前，防止重新定植的机制(S)尚不清楚，鼻腔给药变异株对肺和系统免疫的额外影响，以及这些与变异株和野生型菌株在与鼻咽上皮相互作用方面的差异如何相关尚不清楚。潜在的好处：这项建议将深入描述经鼻给药野生型和变异肺炎链球菌对鼻咽、肺和系统免疫的影响，确定防止重新定植的保护机制，并将菌株之间的显著差异与鼻咽上皮反应联系起来。这一结果将对进一步发展减毒肺炎链球菌作为一种预防肺炎的新方法至关重要。这些结果也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，这些数据与其他多种粘膜病原体有关。

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.