Immune responses to Neisseria gonorrhoeae and implications for vaccine development

Abstract

Neisseria gonorrheoae is the causative agent of gonorrhea, a sexually transmitted infection responsible for a major burden of disease with a high global prevalence. Protective immunity to infection is often not observed in humans, possible due to high variability of key antigens, induction of blocking antibodies, or a large number of infections being relatively superficial and not inducing a strong immune response. N. gonorrhoeae is a strictly human pathogen, however, studies using mouse models provide useful insights into the immune response to gonorrhea. In mice, N. gonorrhoea appears to avoid a protective Th1 response by inducing a less protective Th17 response. In mouse models, candidate vaccines which provoke a Th1 response can accelerate the clearance of gonococcus from the mouse female genital tract. Human studies indicate that natural infection often induces a limited immune response, with modest antibody responses, which may correlate with the clinical severity of gonococcal disease. Studies of cytokine responses to gonococcal infection in humans provide conflicting evidence as to whether infection induces an IL-17 response. However, there is evidence for limited induction of protective immunity from a study of female sex workers in Kenya. A controlled human infection model (CHIM) has been used to examine the immune response to gonococcal infection in male volunteers, but has not to date demonstrated protection against re-infection. Correlates of protection for gonorrhea are lacking, which has hampered the progress towards developing a successful vaccine. However, the finding that the Neisseria meningitidis serogroup B vaccines, elicit cross-protection against gonorrhea has invigorated the gonococcal vaccine field. More studies of infection in humans, either natural infection or CHIM studies, are needed to understand better gonococcal protective immunity.

Characterization of protective immune responses against Neisseria gonorrhoeae induced by intranasal immunization with adhesion and penetration protein

“…Our results showed that the levels of cytokines IL-17A and IFN-γ were significantly increased after in vitro stimulation of splenocytes derived from respective immunized mice with Pa, Tr, and Pa + Tr, suggesting that Th17 and Th1 immune responses were activated [ 49 ]. Compared to the pCold-TF control group, neither the Pa and Tr groups nor the Pa + Tr group showed significantly increased IL-4 secretion after immunization, suggesting that Th2 cellular immune responses may not be significantly activated, possibly because activation of Th17 responses is partially dependent on TGF-β expression, which suppresses Th1 and Th2 responses [ 7 ]. Although there was a Th2 response bias in our lgG isotype results, which may also be related to the fact that Th2 responses can be induced using CTB adjuvants.…”

“…Ideally, the vaccine antigen should have good conservation and immunogenicity, induce functional antibodies, mediate bactericidal activity or phagocytosis, and effectively inhibit pathogen adherence [ 6 ]. The development of N. gonorrhoeae vaccine has been limited for many years due to the fact that N. gonorrhoeae is a strictly human pathogen and is characterized by high surface antigenic variability [ 7 ]. Fortunately, Jerse et al successfully established female mice treated with estradiol for N. gonorrhoeae infection of the reproductive tract, addressing the model constraints for gonococcal vaccine development [ 8 ].…”

Addressing Sexually Transmitted Infections Due to Neisseria gonorrhoeae in the Present and Future

“…Although they have moderate efficacy (31% in the case of MeNZB), mathematical models predict that they could have a significant impact on the prevalence of the disease in the population [110]; indeed, it has been observed that vaccination with these vaccines leads to a reduction in hospitalisation rates [111] and that they have a herd effect in the unvaccinated population [112]. As of 2019, new clinical trials are underway to evaluate the response to serotype B meningococcal vaccines against gonorrhoea [113].…”

“…Since then, advances in antigen purification and whole genome sequencing, the development of new proteomic, immunoproteomic, and bioinformatic techniques, the incorporation of an AI model (EDEN) [117] in the identification of protective antigens, as well as advances in the understanding of how the gonococcus is able to evade the immune response, have led to the proposal and investigation of a large pool of vaccine candidates, summarised in several reviews [106,113,[118][119][120][121][122]. The different approaches include the following vaccines: based on inactivated whole cells [123]; based on Nm OMV and Ng OMV, which require adjuvants that overcome N. gonorrhoeae-mediated immunosuppression such as IL-12 [124] (an inflammatory cytokine that stimulates Th-1-associated immunity and potentiates humoral or antibody-mediated immunity); in protein subunits involved in adhesion and invasion, such as PilQ, Opa, OpcA, OmpA, PorB, and NHBA [125]; based on nutrient acquisition and metabolisms, such as Tbps, Lbps, ZnuD, MtrE, MetQ, AniA, and phospholipase D; in the membrane biogenesis and LOS, such as BamA and LptD; or in immune evasions such as MtrCDE, SliC, PoB, ACP, NspA, MsrA/B [126], and MIP [127].…”