| Summary: | Rationale: Nasopharyngeal administration of live virulence-attenuated <i>Streptococcus pneumoniae</i> strains is a potential novel preventative strategy. One target for creating reduced virulence <i>S. pneumoniae</i> strains is the capsule, but loss of the capsule reduces the duration of <i>S. pneumoniae</i> colonisation in mice which could impair protective efficacy against subsequent infection. Objectives: To assess protective efficacy of nasopharyngeal administration of unencapsulated <i>S. pneumoniae</i> strains in murine infection models. Methods: Strains containing <i>cps</i> locus deletions combined with the <i>S. pneumoniae</i> virulence factors <i>psaA</i> (reduces colonisation) or <i>proABC</i> (no effect on colonisation) were constructed and their virulence phenotypes and ability to prevent recolonisation or invasive infection assessed using mouse infection models. Serological responses to colonisation were compared between strains using ELISAs, immunoblots and 254 <i>S. pneumoniae</i> protein antigen array. Measurements and Main Results: The <i>∆cps/piaA</i> and <i>∆cps/proABC</i> strains were strongly attenuated in virulence in both invasive infection models and had a reduced ability to colonise the nasopharynx. ELISAs, immunoblots and protein arrays showed colonisation with either strain stimulated weaker serological responses than the wild type strain. Mice previously colonised with these strains were protected against septicaemic pneumonia but, unlike mice colonised with the wild type strain, not against <i>S. pneumoniae</i> recolonisation. Conclusions: Colonisation with the <i>∆cps/piaA</i> and <i>∆cps/proABC</i> strains prevented subsequent septicaemia, but in contrast, to published data for encapsulated double mutant strains they did not prevent recolonisation with <i>S. pneumoniae</i>. These data suggest targeting the <i>cps</i> locus is a less effective option for creating live attenuated strains that prevent <i>S. pneumoniae</i> infections.
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