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

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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.