Human monoclonal antibodies targeting subdominant meningococcal antigens confer cross-protection against gonococcus

Gonococcus, a bacterium resistant to most antibiotics, causes more than 80 million cases of gonorrhea annually and is considered a high-priority pathogen by the World Health Organization. Recently, vaccine development prospects were boosted by reports that licensed meningococcus serogroup B (MenB) vaccines provided partial protection against gonococcal infection. To determine antigens responsible for cross-protection, memory B cells isolated from 4CMenB-vaccinated volunteers were single cell-sorted to identify antibodies that kill gonococcus in a bactericidal assay. Nine different antibodies, all deriving from the IGHV4-34 germline and carrying an unusually long heavy-chain complementarity-determining region 3, recognized the PorB protein; four others recognized the lipooligosaccharide; and another four had unknown specificity. One of the PorB-specific antibodies provided protection in a mouse model of gonococcus infection. The identification of PorB and lipooligosaccharide as key antigens of gonococcal and meningococcal immunity provides a mechanistic explanation of the cross-protection observed in the clinic and shows that isolating human monoclonal antibodies from vaccinees can be instrumental for bacterial antigen discovery.