Vaccines against gonorrhea: current status and future challenges

Abstract

Gonorrhea occurs at high incidence throughout the world and significantly impacts reproductive health and the spread of human immunodeficiency virus. Current control measures are inadequate and seriously threatened by the rapid emergence of antibiotic resistance. Progress on gonorrhea vaccines has been slow; however, recent advances justify significant effort in this area. Conserved vaccine antigens have been identified that elicit bactericidal antibodies and, or play key roles in pathogenesis that could be targeted by a vaccine-induced response. A murine genital tract infection model is available for systematic testing of antigens, immunization routes and adjuvants, and transgenic mice exist to relieve some host restrictions. Furthermore, mechanisms by which Neisseria gonorrhoeae avoids inducing a protective adaptive response are being elucidated using human cells and the mouse model. Induction of a Th1 response in mice clears infection and induces a memory response, which suggests Th1-inducing adjuvants may be key in vaccine-induced protection. Continued research in this area should include human testing and clinical studies to confirm or negate findings from experimental systems and to define protective host factors.

Keywords: Antibodies; Gonococcal antigens; Immune regulation; Immunity; Innate defenses; T cells.

Fig. 1. Mechanisms of interaction of N. gonorrhoeae with cells of the immune system

Gc can interact with various immune cells to elicit innate inflammatory responses and suppress Th1/Th2-mediated specific immune responses. (A) Phagocytosis by macrophages results in activation of NLRP3 inflammasomes, the production of IL-1 and activation of PMNs, and activation of cathepsin B, which leads to pyronecrosis of APC [33]. (B) Interactions with DCs lead to up-regulation of PDL-1 and PDL-2, which induce apoptosis of cells bearing PD1. This up-regulation also causes release of IL-10 [32], which has immunoregulatory properties and stimulates type 1 regulatory T cells (Tr1). (C) Interaction with CD4+ T helper cells (or B cells) induces secretion of IL-10, TGF-β, and IL-6 [37, 100]. IL-10 and TGF- suppress the activation of Th1 and Th2 cells both directly, and through the activation of Tr1 cells. TGF-β and IL-6 drive the development of Th17 cells which secrete IL-17 and IL-22, leading to the recruitment or induction of innate defenses such as PMNs and anti-microbial peptides. Gc is able to resist destruction by PMNs and anti-microbial peptides while concomitantly suppressing the development of adaptive immune responses such as Gc-specific antibodies that could enhance phagocytosis and intracellular killing by phagocytes and bacteriolysis through the classical complement pathway [101]. Not shown is the expansion of IgD(+),CD27(+) B cells in response to gonococcal infection, which may contribute to a localized non-specific antibody response without immunologic memory in response to N. gonorrhoeae [42], or Opa-mediated B cell suppression[39] or killing [40], which are discussed in the text.

Fig. 2. Factors that may reduce susceptibility to gonorrhea

It is not understood why some individuals do not become infected following exposure to Gc. Differences in humoral (antibody, complement, antimicrobial peptides) or cellular factors (Th1 and Th17 cells, PMNs, macrophages) may affect the host’s ability to kill the organism or block infection. Polymorphisms in adherence or invasion receptors and innate immune receptors could also influence susceptibility to infection. In women, the stage of the reproductive cycle may affect host susceptibility based on well documented associations between positive culture rates and the estrogen-dominant phases of the menstrual cycle in women with gonorrhea [102, 103] and the temporal link between menses and the onset of pelvic inflammatory disease. The impact of reproductive hormones on susceptibility is also supported by differences in the kinetics of Gc colonization of normal and ovariectomized mice [104] and the effect of progesterone on Gc survival within cervical cells [105]. Potential soluble factors include complement components and antimicrobial peptides secreted by genital tract epithelial cells. Some commensal microbes may protect against Gc through competition for nutrients or adherence receptors, and the release of inhibitory factors. Reported associations between vaginal H₂O₂-producing lactobacilli and a reduced risk of gonorrhea [106] are countered by co-colonization studies in mice [107] and the demonstration that biofilms protect Gc from these commensals (Apicella, et al., 2012 IPNC abstract #0064). The vaginal microbiota of susceptible and uninfected women exposed to Gc could be comprehensively defined using modern genomic technology.