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RATIONALE: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonisation increases local and systemic protective immunity, suggesting nasal administration of live attenuated S. pneumoniae strains could help prevent infections. OBJECTIVES: We used a controlled human infection model to investigate whether nasopharyngeal colonisation with attenuated S. pneumoniae strains protected against re-colonisation with wild-type (WT) S. pneumoniae (Spn). METHODS: Healthy adults aged 18-50 years were randomised (1:1:1:1) for nasal administration twice (two weeks interval) with saline, WT Spn6B (BHN418) or one of two genetically modified Spn6B strains - SpnA1 (∆fhs/piaA) or SpnA3 (∆proABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). MEASUREMENTS AND MAIN RESULTS: 125 participants completed both study stages as per intention to treat. No Serious Adverse Events were reported. In Stage I, colonisation rates were similar amongst groups: SpnWT 58.1% (18/31), SpnA1 60% (18/30) and SpnA3 59.4% (19/32). Anti-Spn nasal IgG levels post-colonisation were similar in all groups whilst serum IgG responses were higher in the SpnWT and SpnA1 groups than the SpnA3 group. In colonised individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in stage 1 were partially protected against homologous challenge with SpnWT (29% and 30% recolonisation rates, respectively) at stage II, whereas those exposed to SpnA3 achieved recolonisation rate similar to control group group (50% vs 47%, respectively). CONCLUSION: Nasal colonisation with genetically modified live attenuated Spn was safe and induced protection against recolonisation, suggesting nasal adminstration of live attenuated Spn could be an effective stategy for preventing pneumococcal infections.

Original publication




Journal article


Am J Respir Crit Care Med

Publication Date



Streptococcus pneumoniae, attenuated strains, human challenge, nasal administration