Inhibition of <i>Neisseria gonorrhoeae</i> complement-mediated killing during acute gonorrhea is dependent upon the IgG2:IgG3 antibody ratio

The antigenic variation of <i>Neisseria gonorrhoeae</i> and a limited mechanistic understanding of immune responses to this bacterium have presented multiple challenges to generating a protective vaccine. Here, we use a collection of <i>N. gonorrhoeae</i> clinical isolates (<i>n</i> = 336) for a robust analysis of the host immune response to infection. We reveal a mechanism for serum resistance in which some isolates of <i>N. gonorrhoeae</i> drive the production of inhibitory IgG2 antibodies, which block the activity of IgG3 bactericidal antibodies. Importantly, an increased ratio of IgG2:IgG3 bound to the bacterium promotes serum resistance. Recently, there has been increased interest in developing a vaccine against <i>N. gonorrhoeae</i> given the observation that the licensed outer membrane vesicle-based vaccine against <i>Neisseria meningitidis</i> (MeNZB) generated some cross-protection against <i>N. gonorrhoeae</i>. Thus, the mechanism described here should guide the development of a vaccine that simultaneously prevents serum resistance and promotes serum killing of the gonococcus.