Intranasal vaccination with pneumococcal protein antigens presented on Salmonella outer membrane vesicles confers broad, serotype-independent protection

Despite widespread vaccination, an unmet need remains for a broadly protective pneumococcal vaccine preventing colonisation and transmission, critical precursors of disease and spread. An intranasal, protein-based vaccine with intrinsic adjuvant activity may represent a promising alternative to pneumococcal conjugate vaccines (PCVs). We developed an antigen delivery platform based on Salmonella -derived outer membrane vesicles (OMVs) engineered for SpyCatcher-SpyTag-mediated covalent coupling of heterologous antigens, thereby combining modular antigen display with intrinsic adjuvant activity. OMVs displaying pneumococcal antigens AliA and PnrA (OMV-A-P) were produced under GLP conditions, characterised and evaluated in toxicology and potency studies in mice and rats. Intranasal administration of OMV-A-P was well-tolerated and elicited robust systemic and mucosal antibody responses capable of recognising a broad range of pneumococcal strains. Vaccination also induced local and systemic pneumococcal-specific IL-17 recall responses, supporting its potential as a serotype-independent vaccine candidate. Protection against pneumococcal colonisation was demonstrated for two distinct clinical strains and persisted for at least 15 weeks after the third vaccination. Notably, in animals previously vaccinated with PCV, OMV-A-P remained immunogenic and conferred superior protection against pneumococcal colonisation compared to PCV-only vaccinated mice. Collectively, this indicates that OMV-A-P is a promising next-generation intranasal pneumococcal vaccine candidate warranting development towards a first-in-human study.