Abstract: Rates of sexually transmitted infections are on the rise in the United States, including those caused by Neisseria gonorrhoeae. Antibiotic resistance in N. gonorrhoeae is also increasing and has been recognized as a serious emerging public health threat by WHO and the US CDC. A vaccine against N. gonorrhoeae could help combat the spread of antibiotic resistant N. gonorrhoeae, however, an effective vaccine for N. gonorrhoeae has thus far eluded discovery. Individuals infected with N. gonorrhoeae do not develop immunity to subsequent infection, limiting our understanding of the immune responses required for protection from infection. Mass vaccination campaigns in New Zealand and other countries with vaccines against N. meningitidis serogroup B made from outer membrane vesicles have been followed by reduced reported rates of N. gonorrhoeae infections in those countries. The US FDA-approved N. meningitidis serogroup B vaccine (4C-MenB) contains both N. meningitidis outer membrane vesicles and two recombinant antigens that are highly related to N. gonorrhoeae homologs of the antigens. Our research team currently uses a unique human experimental infection model to study N. gonorrhoeae in its natural host. Because the use of the 4C-MenB vaccine is not yet widespread within the US, there is a unique and time-sensitive opportunity to test the effectiveness of this vaccine in preventing N. gonorrhoeae using our human challenge model. The proposed clinical trial will also allow us to study immune responses to the 4C-MenB vaccine and determine which responses are essential to the protective effect of the vaccine. The current proposal requests support for the implementation of the proposed clinical trial, which represents an important step in the development of an effective N. gonorrhoeae vaccines.