A Randomised Controlled Trial of Nasal Immunisation with Live Virulence Attenuated Streptococcus pneumoniae Strains using Human Infection Challenge

RationalePneumococcal 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. ObjectivesWe 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). MethodsHealthy 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 ({Delta}fhs/piaA) or SpnA3 ({Delta}proABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against re-colonisation (Stage II). Measurements and Main Results125 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 but not SpnA3 in phase 1 were partially protected against re-colonisation with SpnWT (recolonisation rates of 29% versus 30% respectively). ConclusionNasal 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.