Targeting the Host to Reverse Infection-induced Immune Suppression Affords a Novel Approach to Therapy and Vaccine Development against Neisseria gonorrhoeae

WHO estimates that there are >100 million new cases of gonorrhea worldwide every year, with the burden of morbidity falling mainly on women. However, gonococcal infection does not induce protective immunity, no vaccine is available, and Neisseria gonorrhoeae is becoming resistant to most available antibiotics. We have demonstrated in mice that the ability of N. gonorrhoeae to suppress Th1/Th2-governed adaptive responses can be reversed by intravaginal (i.vag.) treatment with IL-12 encapsulated in sustained-release biodegradable polymer microspheres (IL-12/ms), resulting in rapid elimination of the infection and protection against re-infection. This promotes Th1-driven responses including anti-gonococcal antibodies in serum and genital secretions, IFN-γ-secreting CD4+ T cells in the genital tract and iliac lymph nodes (ILN), and memory that can be recalled upon re-exposure to N. gonorrhoeae. Protection against re-infection persists for at least 6 months, and extends to antigenically distinct strains of N. gonorrhoeae. Protective immunity is not induced by IL-12/ms in the absence of gonococcal antigen, but gonococcal outer-membrane vesicles (OMV) can substitute for live N. gonorrhoeae to create a vaccine. I.vag. immunization with gonococcal OMV plus IL-12/ms induces similar responses, including serum (IgG) and vaginal (IgG and IgA) anti-gonococcal antibodies, secretion of IFN-γ and IL-17, but not IL-4, by CD4+ T cells isolated from the ILN, and protection against infection. The findings illuminate the mechanisms whereby a significant mucosal pathogen manipulates the host’s responses for its own benefit, and suggest new approaches both to treatment of antibiotic-resistant infections, and to developing an effective vaccine against gonorrhea.