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Neisseria gonorrhoeae causes 82 million global cases of gonorrhoea annually. Multidrug-resistant gonococci threaten to make gonorrhoea untreatable. Meningococcal vaccines MeNZB and 4CMenB (Bexsero), containing Neisseria meningitidis group B detergent-extracted outer membrane vesicles (dOMV), cross-protect against gonorrhoea with 31–59% effectiveness. We hypothesised that gonococcal OMV-based vaccines would have greater efficacy against gonorrhoea than meningococcal vaccines. We developed native OMV (nOMV) candidate Neisseria vaccines from gonococcal strains GC_0817560 and FA1090, and meningococcal B strain NZ98/254. lpxL1 and rmp genes were deleted to reduce reactogenicity and minimise induction of unprotective or blocking antibodies. nOMV were characterised and formulated with aluminium hydroxide. Deletion of lpxL1 markedly reduced nOMV-induced IL-6 release from peripheral blood mononuclear cells. nOMV derived from GC_0817560 lpxL1 − rmp − and FA1090 lpxL1 − rmp − induced greater quantities of gonococcal-specific serum IgG and accelerated clearance of FA1090 from oestradiol-treated BALB/c mice significantly faster than 4CMenB and NZ98/254 lpxL1 − rmp − nOMV ( P  < 0.0001). Gonococcal nOMV-based vaccines represent promising candidates for further development.