Experimental vaccine induces Th1-driven immune responses and resistance to Neisseria gonorrhoeae infection in a murine model

Abstract

Female mice were immunized intravaginally with gonococcal outer membrane vesicles (OMV) plus microencapsulated IL-12, and challenged using an established model of genital infection with Neisseria gonorrhoeae. Whereas sham-immunized and control animals cleared the infection in 10–13 days, those immunized with OMV plus IL-12 cleared infection with homologous gonococcal strains in 6–9 days. Significant protection was also seen after challenge with antigenically distinct strains of N. gonorrhoeae, and protective anamnestic immunity persisted for at least 6 months after immunization. Serum and vaginal IgG and IgA antibodies were generated against antigens expressed by homologous and heterologous strains. Iliac lymph node CD4+ T cells secreted IFNγ, but not IL-4, in response to immunization, and produced IL-17 in response to challenge regardless of immunization. Antigens recognized by immunized mouse serum included several shared between gonococcal strains, including two identified by immunoproteomics approaches as EF-Tu and PotF3. Experiments with immunodeficient mice showed that protective immunity depended upon IFNγ and B cells, presumably to generate antibodies. The results demonstrated that immunity to gonococcal infection can be induced by immunization with a non-living gonococcal antigen, and suggest that efforts to develop a human vaccine should focus on strategies to generate Th1-driven immune responses in the genital tract.

Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays

“…Therefore, we predict that vaccine candidates selected from the FA1090 proteome will provide protection against heterologous strains. In support of our strategy, mice treated with interleukin-12 and immunized with membrane vesicles derived from FA1090 that contain proteins investigated in the current study (6) are protected against infection by both laboratory strains and clinical isolates (15).…”

“…Mice immunized with this treatment mount a type 1 T helper cell-driven immune response that accelerates the clearance of gonococcal infections and defends against subsequent infection for at least 6 months after immunization. Critically, vaccination with FA1090-derived membrane vesicles protects from challenges with the commonly used laboratory strains MS11 and FA19, as well as recent clinical isolates GC68 and GC69 (15). Using proteomics-based reverse vaccinology (16), we have investigated the composition of N. gonorrhoeae cell envelopes and naturally released membrane vesicles across common laboratory strains, including FA1090, MS11, and FA19 (6), as well as FA1090 cell envelopes under four different host-relevant growth conditions (5) to identify vaccine candidate targets.…”

Could Vaccination Against Neisseria Gonorrhoeae be on the Horizon?

“…Results obtained from immunization of mice indicate that both antibodies (IgG and/or IgA) and IFN-γ are required for immunity to N. gonorrhoeae [17], but the mechanism of protection is uncertain, and it cannot be assumed that findings from mice will necessarily apply to humans. Unfortunately, no other animal model is available for this exclusively human infection, as nonhuman primates (with the possible exception of chimpanzees) cannot be infected with N. gonorrhoeae.…”

“…Second, animal models have been developed for preclinical evaluation of vaccine candidates; it is noteworthy in this context that all previous attempts to create gonococcal vaccines lacked any such in vivo models in which to test candidates. The estradiol-treated female mouse model [16] has now been applied to this effort [17], and further refinements of the model using transgenic mice that express various human factors involved in gonococcal pathogenesis afford scope for more detailed analysis of the mechanisms whereby immune protection can be attained [10]. Third, efforts are now underway to apply proteomics technology to the discovery of novel, conserved surface antigens shared by different strains of N. gonorrhoeae [18].…”

Proof of principle for effectiveness of a gonorrhoea vaccine

“…Accordingly, many of the previously identified challenges might now be overcome. Since the failed early trials, we have considerably improved our understanding of gonococcal pathogenesis 5,6,8–10 . Studies have provided detailed information on some of the gonococcal vaccine candidate antigens, which might ideally be used in combination, for example targeting different essential steps or pathways of the pathogenesis.…”