Staphylococcus aureus is a major antimicrobial-resistance-associated pathogen causing skin and soft-tissue infection, pneumonia, bloodstream infection, device-associated disease and sepsis, yet no licensed vaccine exists despite decades of effort. This DPhil project will focus on novel protein antigen discovery and immunogen design, aligned to OVG's developing S. aureus nasal-colonisation CHIM/experimental medicine programme, including the ReSET study.

The student will integrate literature-supported and well-characterised S. aureus vaccine antigens as baselines with AI/ML-guided reverse vaccinology to identify up to 30 novel candidate protein antigens from S. aureus pangenome/proteome data. Candidate selection will consider conservation, predicted surface exposure or secretion, virulence biology, immune-evasion functions, strain diversity, developability and relevance to colonisation.

These candidates will be evaluated for association with human immune protection or colonisation outcomes using ReSET samples and systems serology, including IntelliFlex/Luminex-based multiplex measurement of antigen-specific IgG, IgA and IgM. Recombinant S. aureus proteins will also be used in ELISA to validate antigen-specific antibody responses, antibody avidity assays, Fc-receptor binding assays, complement deposition assays, opsonophagocytic killing assays, and inhibition-of-adhesion or toxin-neutralisation assays where relevant to antigen function. Cellular immunity will be assessed using peptide-pool stimulation, ELISpot, intracellular cytokine staining and flow-cytometry analysis to define CD4/CD8 T-cell responses and cytokine profiles. Additional analyses will explore B-cell and T-cell epitope features for correlates-of-protection discovery. Antigens showing promising human immune signatures and functional immune readouts will be produced as recombinant proteins using OVG protein-production capability and prioritised for structure-informed engineering.

The engineering component will aim to improve antigen stability, epitope presentation, expression and manufacturability, with particular attention to removing non-protective or immune-diverting regions. A multi-epitope immunogen approach may be developed for antigens or epitopes most strongly associated with protective immune signatures. The expected output is a ranked, experimentally supported panel of S. aureus protein antigens and engineered immunogen designs suitable for future preclinical vaccine evaluation.