Expanding efforts to develop preventive gonorrhea vaccines is critical because of the serious health consequences combined with the prevalence and the dire possibility of untreatable gonorrhea. Reverse vaccinology, which includes genome and proteome mining, has proven successful in the discovery of vaccine candidates against many pathogenic bacteria. Here, we describe proteomic applications including comprehensive, quantitative proteomic platforms and immunoproteomics coupled with broad-ranging bioinformatics that have been applied for antigen mining to develop gonorrhea vaccine(s). We further focus on outlining the vaccine candidate decision tree, describe the structure-function of novel proteome-derived antigens as well as ways to gain insights into their roles in the cell envelope, and underscore new lessons learned about the fascinating biology of Neisseria gonorrhoeae.
23Bacterial surface lipoproteins are emerging as attractive vaccine candidates due to their 24 biological importance and the feasibility of their large-scale production for vaccine 25 manufacturing. The global prevalence of gonorrhea, resistance to antibiotics, and serious 26 consequences to reproductive and neonatal health necessitate development of effective 27 vaccines. Reverse vaccinology identified the surface-displayed L-methionine binding 28 lipoprotein MetQ (NGO2139) and its homolog GNA1946 (NMB1946) as gonococcal and 29 meningococcal vaccine candidates, respectively. Here, we assessed the suitability of 30 MetQ for inclusion in a gonorrhea vaccine by examining MetQ conservation, its function 31 in Neisseria gonorrhoeae (Ng) pathogenesis, and its ability to induce protective immune 32 responses using a female murine model of lower genital tract infection. In-depth 33 bioinformatics, phylogenetics and mapping the most prevalent Ng polymorphic amino 34 acids to the GNA1946 crystal structure revealed remarkable MetQ conservation: ~97% 35 Ng isolates worldwide possess a single MetQ variant. Mice immunized with rMetQ-CpG 36 (n=40), a vaccine containing a tag-free version of MetQ formulated with CpG, exhibited 37 robust, antigen-specific antibody responses in serum and at the vaginal mucosae 38 including secretory IgA. Consistent with the activity of CpG as a Th1-stimulating adjuvant, 39 the serum IgG1/IgG2a ratio of 0.38 indicated a Th1 bias. Combined data from two 40independent challenge experiments demonstrated that rMetQ-CpG immunized mice 41 cleared infection faster than control animals (vehicle, p<0.0001; CpG, p=0.002) and had 42 lower Ng burden (vehicle, p=0.03; CpG, p<0.0001). We conclude rMetQ-CpG induces a 43 protective immune response that accelerates bacterial clearance from the murine lower 44 genital tract and represents an attractive component of a gonorrhea subunit vaccine. 45 3
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