Proteomics-Driven Reverse Vaccinology for Gonorrhea

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ABSTRACT Neisseria gonorrhoeae (Ng), the gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. In the US, over 50% of Ng isolates are resistant to at least one antimicrobial and the CDC has ranked Ng as one of the top 5 urgent antibiotic resistant threats. Gonorrhea outcomes are especially devastating in sexual, gender, racial, and ethnic minorities and resource-limited countries. Ng’s “superbug” status, its high morbidity, and the serious health and psychological impacts of gonorrhea necessitate vaccine development. To address the urgent need for an effective and safe vaccine against gonorrhea, we propose to use a powerful Virus-like-Particle (VLP) vaccine platform with a highly effective split-protein conjugation system to deliver promising Ng antigens (Ag) as full- length and natively folded proteins. We selected for this proposal six promising lipoproteins based on their: 1) exceptional conservation in >5K sequenced Ng isolates worldwide; 2) surface-exposure; 3) ability to elicit bactericidal antibodies (Abs); 4) expression in geographically and temporally diverse Ng strains, during different in vitro conditions and Ng infection in the gonorrhea mouse model; and 5) important functions in Ng pathogenesis and physiology. We will: 1) Design and produce antigen-VLP formulations; 2) Identify Ag-VLP and adjuvant combinations that generate robust immune responses; and 3) Evaluate efficacy of promising vaccines and elucidate the immune correlates of protection. Our approach presents conceptual and technical innovations in the gonorrhea vaccine field by pioneering VLP-display of conserved, full-length Ng lipoproteins, which will be comparatively assessed for efficacy and potential mechanisms of protection.