Gonococcus (Gc), a bacterium resistant to most antibiotics and responsible for more than 80 million cases of gonorrhea annually, is a WHO high priority pathogen. Recently, new hopes for vaccine development were raised by studies reporting that OMV-containing MenB vaccines provided partial protection against Gc infection. To identify antigens responsible for cross-protection, peripheral blood mononuclear cells (PBMCs) were collected from 4CMenB vaccinated volunteers, and after single cell sorting of their memory B cells, we selected those producing antibodies killing Gc in a bactericidal assay. Nine different antibodies, all deriving from the IGHV4-34 germline carrying an unusually long HCDR3, recognized the PorB protein, four recognized the lipooligosaccharide (LOS), and four unknown antigens. One of the PorB antibodies, tested in an in vivo genital tract mouse model, provided protection from Gc infection. The identification of PorB and LOS as key antigens of gonococcal and meningococcal immunity provides a mechanistic explanation of the cross-protection observed in some observational real-world studies and shows that isolating human monoclonal antibodies from vaccinated people can be instrumental for bacterial antigen discovery.

Human monoclonal antibodies reveal subdominant gonococcal and meningococcal cross-protective antigens