Investigation of Correlates of Protection Against Gonococcal Infection by Comparative Immunoprofiling of Responses in Experimental and Clinical Studies

Background: Neisseria gonorrhoeae is a major sexually transmitted pathogen with rising antimicrobial resistance. Epidemiological studies suggest meningococcal outer membrane vesicle (OMV) vaccines, eg 4CMenB (Bexsero), offer partial cross-protection, but immune correlates remain undefined. Methods: Using a murine genital tract infection model, we compared systemic and mucosal responses after immunization with Bexsero, gonococcal OMVs (Ng OMVs) with alum, or alum alone. Vaccinated mice were challenged intravaginally with N. gonorrhoeae. Serum bactericidal activity (SBA) was measured, and antigen-specific IgG responses were profiled using gonococcal protein microarrays. Murine responses were compared with high-risk Bexsero-immunized humans and patients with gonococcal infection. Results: Bexsero significantly accelerated bacterial clearance compared with Ng OMV or alum. Serum and vaginal IgG profiles were highly correlated, revealing distinct antigenic signatures between groups. Bexsero elicited responses to gonococcal orthologs of its recombinant antigens (GNA1030, GNA2091, NHBA), whereas Ng OMVs induced Opa, PilQ, and MtrE responses. SBA did not correlate with clearance; however, early PMN influx was associated with reduced bacterial load. Antigen-specific IgG patterns were concordant between Bexsero-immunized mice and humans. Conclusions: Protein microarrays with multivariate analysis identified antibody signatures associated with protection, supporting the translational value of this model for defining correlates of protection and guiding gonococcal vaccine development.