Every year in the UK, 40,000 adults die from pneumonia caused by *Streptococcus pneumoniae*, despite existing vaccines. Current vaccines target the bacterium’s outer capsule, but they do not stop the bug from living harmlessly in the nose and throat. This “colonisation” is actually useful: it naturally boosts the immune system against severe lung infections. The problem is that no one knows exactly how that protection works. This project aims to find out. Researchers will give volunteers nasal doses of harmless, genetically modified *S. pneumoniae* strains, then compare immune responses in the nose, lungs, and blood. They will also track which strains prevent re-colonisation and why. The goal is to identify the specific immune mechanisms that shield the lungs. If successful, this work could lead to a new type of pneumonia vaccine—one that is sprayed up the nose and mimics natural, protective colonisation without causing disease. That would bypass the limits of current shots and potentially save thousands of lives each year. The findings will also inform vaccine development for other mucosal infections, such as those caused by *Neisseria* or *Haemophilus* species.
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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.
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