Abstract Streptococcus pneumoniae remains a major public health concern, largely due to the limited serotype coverage and other constraints of pneumococcal conjugate vaccines, as well as the increasing antimicrobial resistance among circulating strains. In the pursuit of protein-based pneumococcal vaccines, pneumolysin (PLY), a secreted multifunctional cholesterol-dependent cytolysin, represents a promising target. To date, the relationship between the B-cell epitope landscape and neutralising PLY-specific antibody responses has remained elusive, hindering the rational design of effective PLY-based vaccines. Using a panel of PLY-specific monoclonal antibodies, functional assays, multimodal protein mass spectrometry and data-driven computational modelling, we mapped the structural epitope landscape of native PLY and linked epitope-paratope interactions to neutralising potency. We further refined and structurally characterised a protective cross-species epitope conserved among homologous cholesterol-dependent cytolysins (CDC). This epitope provides a promising foundation for rational, epitope-focused vaccine design, offering a pathway toward species-independent vaccines targeting the CDC protein superfamily.
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