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.

Keywords: Neisseria; STI; gonococcus; gonorrhea; immunology; vaccines.

Figure 1

Different methods that have contributed to the field of gonococcal immunity. In vitro studies have been valuable in describing the interactions between gonococci and complement, for example. The murine female genital tract model is a transient infection model but is useful in describing the immune responses to gonococci and evasion mechanisms. Human studies of natural infection are valuable in studying gonococci in their natural host, while the controlled human infection model of gonococci can be used to describe the immune response to gonococci in the natural host in a controlled way, but only in males in a transient way.

Figure 2

Cytokine responses in the murine female genital tract model of gonococcal infection. Gonococcal infection in the female mouse leads to a mostly Th17 response, driven by interactions between gonococcal LOS and murine TLR4 as well as stimulation of TGF-β, which is partly driven by gonococcal Opa surface proteins. The consequences of a Th17 response is an influx of neutrophils in the murine genital tract and clearance of the gonococci. However, if TGF-β action is blocked, Th1 and Th2 responses are observed, which leads to accelerated clearance, memory and resistance to reinfection. On infection with gonococci, the female mouse also responds by secreting IL-10 through an as yet undiscovered mechanism. This stimulates the differentiation of Tr1 cells and the inhibition of protective Th1 and Th2 responses.

Figure 3

Evidence for protective immunity following gonococcal infection in a cohort of female commercial sex workers in Kenya. A cohort of 227 female sex workers in Kenya were followed in a longitudinal study over 16 months. Protective immunity in the cohort was said to be observed due to the findings supporting 4 hypotheses. These were: (A) the por-types of the infecting gonococci changed with time suggesting selective immune pressure; (B) HIV positive subjects were more likely to have gonococcal infections suggesting infection was associated with immune defects; (C) the likelihood of gonococcal infection decreased with the length of sex work suggesting a building-up of immunity with each exposure; and (D) subjects were unlikely to be re-infected with the same por-type suggesting at least por-type immunity is observed.