Neisseria gonorrhoeae (Ng) is the most prevalent sexually transmitted bacterial pathogen globally, and gonococcal antibiotic resistance continues to rise. Potentially untreatable gonorrhea is recognized as an urgent threat by WHO and the US CDC. Gonococcal vaccine development is critical to help stem the spread of antimicrobial resistant Ng. Because naturally-acquired infection does not result in immunity from subsequent infection, immune responses required for protection from infection have never been definitively established for N. gonorrhoeae. Recently, a vaccine has been developed for N. meningitidis (Nm) serogroup B, and mass vaccination campaigns with this outer membrane vesicle (OMV)-containing vaccine have demonstrated collateral reduction in gonorrhea rates. Nm-OMV vaccines also show protection in a mouse model of genital Ng infection. For the first time,we have the opportunity to study both human and murine immune responses to effective vaccines, and identify likely correlates of protection. Project 1 in the Gonorrhea Vaccine Cooperative Research Center (GV CRC) will (1) determine whether murine humoral immune responses to Nm-OMV- containing vaccines are important in protection from Ng infection; (2) identify murine cellular immune mechanisms induced by Nm-OMV-containing vaccines that contribute to protection from Ng infection; and (3) determine humoral and cellular immune responses to Ng antigens induced by Nm-OMV-containing vaccine in humans. Defining immunologic mechanisms that provide protection from Ng infection is critical to advancing Ng vaccine development.!We will engage with all 4 scientific cores of the GV CRC. Our studies will set the stage for clinical evaluation of Nm-OMV vaccines for protection from Ng and will inform vaccine development plans in other GV CRC projects.