Meningococcal vaccine 4CMenB elicits a robust cellular immune response that targets but is not consistently protective against Neisseria gonorrhoeae during murine vaginal infection.

Retrospective epidemiological studies suggest that the licensed serogroup B meningococcal vaccine 4CMenB (Bexsero) provides some protection against the closely related pathogen Neisseria gonorrhoeae in humans. This result has been replicated in murine models of gonococcal colonization, with a gonococci-reactive humoral response and more rapid clearance of vaginal infection. However, immunization with 4CMenB consistently elicits a robust humoral response but does not protect all individuals; hence, the correlates of protection remain undefined. Herein, we exploit the fact that 4CMenB promotes gonococcal clearance in only a subset of immunized mice to perform a broad analysis of the adaptive response in animals that are or are not protected. We observe that 4CMenB vaccination induces high levels of anti-neisserial antibodies in both serum and the vaginal lumen, and a robust cellular response highlighted by an increase in both conventional naïve and memory populations as well as unconventional lymphocyte subsets. Multiplex and flow cytometry results show that 4CMenB vaccination generates a robust, multi-faceted cytokine response that spans numerous T cell subsets (T(H)1, T(H)2, T(reg), and T(H)17) and that non-T non-B lymphocytes play an important role in this response, as indicated by an unbiased principal component analysis. Together, this work provides the first comprehensive analysis of the robust humoral and complex cellular response to 4CMenB so as to reveal the effector mechanisms that may contribute to immunity against vaginal gonococcal infection.IMPORTANCEGonorrhea, a sexually transmitted infection caused by the human-specific pathogen Neisseria gonorrhoeae (Ngo), is a growing public health concern due to its rise in prevalence and increasing antibiotic resistance against first-line agents. There is currently no vaccine available for this important bacterium due, in part, to our lack of understanding of immune correlates of protection. Interestingly, a human-approved vaccine (4CMenB; Bexsero) against a related pathogen (N. meningitidis; a cause of meningitis) has demonstrated some protection against gonorrhea in epidemiologic studies. Herein, we provide the first detailed analysis of cellular and antibody-mediated immune responses to this vaccine in animals protected against gonococcal colonization. These findings provide new understanding regarding immune correlates of protection against N. gonorrhoeae, providing new insight into immune protection and helping guide the development of a much-needed vaccine.