1. Introduction

Gonorrhea, a sexually transmitted infectious disease caused by the bacterium Neisseria gonorrhoeae (gonococcus), has remained an intractable global health problem despite continuing efforts to curtail its health impacts. The public health challenge posed by gonorrhea stems primarily from the large number of asymptomatic infected individuals, the ability of the gonococcus to undergo high levels of surface antigenic variation, and the progressive emergence of antibiotic-resistant gonococcal strains to recommended empiric monotherapies ^[1]. The World Health Organization (WHO) cited an increase in the number of new and untreated cases globally due to therapeutic failures and the asymptomatic nature of the disease ^[2]. According to the WHO, approximately 87 million people were diagnosed with gonorrhea out of the 376 million globally reported cases of sexually transmitted infections (STIs) that occurred among 15–49 year olds in 2016. Estimated global prevalence of urogenital gonorrhea was higher among females (0.9%) compared to males (0.7%) ^[3]. Additionally, the epidemiology of incident cases of gonorrhea varies widely by geographical WHO region, with the highest prevalence in the African region (women 1.9%; men 1.6%), the Americas (women 0.9%; men 0.8%), and the Western Pacific region (women 0.9%; men 0.7%), and the lowest prevalence in Europe (women 0.3%; men 0.3%) ^[3]. It is believed that these numbers likely underestimate the actual cases of gonorrhea globally ^[4]. Epidemiological STI surveillance and diagnostics are inadequate in most developing and resource-limited countries, where actual infection numbers are difficult to estimate. Differences in socioeconomic conditions, cultural perceptions of STIs, and access to quality STI education and prevention measures also likely contribute to this heterogeneity in country-specific prevalence data ^[5]. In 2018, a total of 583,405 gonorrheal cases were reported in the United States alone (i.e., a rate of 179.1 cases per 100,000 population), making gonorrhea the second most commonly reported STI ^[6]. According to the U.S. Centers for Disease Control and Prevention (CDC), the incidence of gonorrhea continues to rise annually ^[6]. Case reporting data indicated that the rate of U.S. gonococcal infections increased 5.0% during the period 2017–2018 and increased 82.6% since 2009, when reported gonorrhea cases declined to an historic low ^[6]. Regional, gender, and ethnicity disparities in rates of reported gonorrhea cases are also observed in the U.S. Surveillance data collected by the CDC revealed that the South had the highest rate of gonorrhea cases in 2018 (194.4 cases per 100,000 population) compared to the Northeast, which had the lowest rate (138.4 cases per 100,000 population) ^[6]. The rate of reported gonorrhea cases among males increased by a higher amount compared to females (6.0% versus 3.6%, respectively) in 2018. Finally, 2018 rates of reported gonococcal infections were the highest among Blacks (548.9 cases/100,000), American Indians/Alaska Natives (329.5 cases/100,000), Native Hawaiians/Other Pacific Islanders (181.4 cases/100,000), and Hispanics (115.9 cases/100,000), while rates remained the lowest among Whites (71.1 cases/100,000) and Asians (35.1 cases/100,000) ^[6]. U.S. rates of gonorrhea are also likely underestimated due to incomplete reporting. Furthermore, the majority of infected people are asymptomatic and constitute an important source of infection transmission [1,7]^[1][7].

N. gonorrhoeae is a human-restricted pathogen that infects the lower genital tract, pharynx, and rectum, with varying degrees of complication depending on the sex of the patient. The predominant site of infection is the cervix in females and the anterior urethra in males. Although gonorrhea is most commonly seen in young individuals 15–24 years of age, it can be present in any sexually active individual ^[6]. Symptoms of gonorrhea include cervical or urethral purulent discharge, discomfort, dysuria, urethritis, or cervicitis. Untreated cervical infection may result in ascension of the gonococcus to the upper genital tract and lead to serious reproductive health complications such as pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy, and tubal infertility [7,8]^[7][8]. Vertical transmission is a significant concern for pregnant women infected with N. gonorrhoeae and may lead to chorioamnionitis, septic abortion, premature rupture, preterm delivery, and sight-threatening neonatal conjunctivitis ^[9]. In males, rare disease complications and sequelae of untreated urethritis include penile edema, urethral stricture, epididymitis, or prostatitis ^[10]. Untreated urogenital gonorrhea infrequently disseminates to extragenital anatomic sites, causing septic arthritis, endocarditis, and skin manifestations in both genders. Moreover, N. gonorrhoeae infection facilitates the acquisition and transmission of other STIs, most notably HIV infection ^[11].

The lack of natural immunity in both symptomatic and asymptomatic patients has impeded development of an effective anti-gonococcal vaccine. Strain-specific antibodies directed against a number of gonococcal antigens (e.g., lipooligosaccharide [LOS], pili, and outer membrane proteins [PorB, Opa]) have been detected in the sera, seminal plasma, and cervical secretions of individuals infected with N. gonorrhoeae (reviewed in [7]). However, these humoral immune responses to N. gonorrhoeae tend to be modest, with antibody production in infected individuals characterized as only slightly increased compared to uninfected individuals and not protective against reinfection ^[12]. While in vitro evidence exists for some anti-gonococcal antibodies promoting either complement-mediated killing or opsonin-facilitated phagocytosis of the gonococcus [13^[13][14],14], the potential role of these antibodies in immunologic clearance of the pathogen from the host remains unclear. The persistence of gonococcal infections and the common occurrence of reinfection are consistent with evidence demonstrating that N. gonorrhoeae is capable of evading and actively suppressing the immune response to promote its survival in the host (reviewed in ^[15]). These evasion and suppression mechanisms include sialylation of the gonococcal LOS [16,17]^[16][17] and induction of anti-gonococcal Rmp (reduction-modifiable protein) antibodies that block the bactericidal activity of IgG antibodies directed against gonococcal LOS or porin protein ^[18]. In addition to non-protective humoral immune responses, N. gonorrhoeae infection manipulates the adaptive cell-mediated response away from Th1/Th2-based immunity and towards a Th17-driven neutrophilic inflammatory response by inducing localized TGF-β and IL-10 cytokine production [19,20]^[19][20]. This immunologic bias toward neutrophilic influx results in the cellular damage associated with serious clinical sequelae of gonorrhea and prevents the development of protective immunity (^[21]; reviewed recently in ^[8]).

In the absence of an effective vaccine and protective natural immunity against repeated infection, public health control of gonorrhea has depended exclusively upon effective and affordable antibiotic pharmacotherapy ^[15]. However, the continued resistance of gonococcal strains to all antimicrobial drugs introduced as first-line treatment since the 1930s points to the possibility of widespread, untreatable N. gonorrhoeae infections in the future. With N. gonorrhoeae assigned to ‘superbug’ status by the WHO, it is imperative that novel antibiotics are developed and new potential targets for vaccine design are identified in order to address the urgent need for prevention and treatment of gonorrhea. While a number of reviews have been published on gonorrhea over the years, including some that are recent [1^[1][5][15],5,15], there is a current need for a scholarly focus on potential novel therapeutics for the treatment of N. gonorrhoeae infection and on new approaches to antigen target discovery for vaccine development.

2. Update on Drug Treatment and Vaccine Development

Gonorrhea remains a challenging disease with wide-ranging clinical and social effects. For over 80 years, treatment of gonorrhea has evolved through changing antibiotic regimens as a result of N. gonorrhoeae resistance. Antibiotics such as penicillin, tetracyclines, quinolones, and macrolides, which previously were effective against N. gonorrhoeae, are no longer recommended as the first-line monotherapy due to widespread resistance among gonococci. Resistance to current extended-spectrum cephalosporin-based treatments has already emerged [76,77]^[22][23]. While antibiotic combinations will continue to offer limited options for gonorrhea treatment, there are currently no pipeline drugs in development to control multidrug-resistant N. gonorrhoeae infections. Although research may yield new therapeutic options, the genetic plasticity of the pathogen, coupled with its proficiency at acquiring genes encoding resistance determinants from the environment, will likely make the effectiveness of any new antibiotic short-lived.

It is therefore important that any long-term strategy designed to address the global burden of gonorrhea include vaccination. In a model-based epidemiological simulation study of vaccine efficacy, it was estimated that a 90% reduction in gonorrhea prevalence could be achieved in 20 years if a non-waning gonococcal vaccine of 50% effectiveness (or a 100% efficacy vaccine that wanes after 7.5 years) is administered to all 13 year olds [78]^[24]. There is currently no approved vaccine for protection against gonorrhea, and no candidate vaccine targets are at any advanced stage of clinical development. Potential gonorrhea vaccines have not progressed beyond the stages of discovery and preclinical evaluation to identify immune correlates and understand surrogates of protection. While there is a preponderance of scientific publications on gonorrhea, there is not much on vaccines. This can be attributed to historical failures at developing gonococcal vaccines.

A number of major challenges have been identified as limiting the successful development of vaccines against gonorrhea. One primary obstacle is that the infective mechanism and mode of drug resistance for this pathogen are not completely understood. Similarly, gonococcal mechanisms of host immune protection have not been clearly elucidated. Another challenge is that natural infection of N. gonorrhoeae does not confer immunity, nor does it protect against reinfection. Due to the ability of N. gonorrhoeae to suppress and divert host immune responses, only a transient and weak mucosal immune response is associated with gonorrheal infections. Most vaccine development is based on the principle of replicating the immunity of natural infection. Thus, conventional approaches such as the use of live-attenuated or inactivated N. gonorrhoeae will not be effective for gonococcal vaccination. Despite these limitations, the successful development of vaccines against human papilloma virus (HPV, the most common sexually transmitted infection), the development of vaccine technologies that employ antigen engineering, immune response optimization efforts, and enhanced targeted vaccine delivery have engendered optimism that development of a vaccine against N. gonorrhoeae is possible. Using the protein-based meningococcal vaccine as a prototype, for example, most vaccine optimists believe that an effective gonococcal vaccine can be developed. Other challenges to vaccine development include the observation that several strains of infective N. gonorrhoeae possess notable differences in their pathogenic behavior [24]^[25]. This heterogeneity implies the possibility of variation in the immune response depending on the strain and its associated virulence. Finally, perhaps the most relevant challenge to clinical vaccine development is the fact that N. gonorrhoeae is an obligate human pathogen, with the consequent absence of reliable test models for infection studies. The human-specific pathogenicity of N. gonorrhoeae renders typical animal models as poor estimations at best. Although animal models are still useful, they must be complemented with studies in human cells or clinical infections in order to produce meaningful data. Thus far, only female mice treated with 17-β estradiol have been reliably used as a small-animal model of lower genital tract infection [79,80]^[26][27]. Studies in this mice model have shown major reduction in the load and duration of gonococcal colonization with intraperitoneal administration of a multiantigenic peptide (MAP1) (a peptide mimic and an immunologic surrogate of the 2C7-OS epitope) [65]^[28], subcutaneously administered (and footpad-boosted) recombinant refolded porin delivered by virus replication particles (rrPorB-VRP) [81]^[29], and the nasally administered outer membrane vesicle (OMV) vaccine [82]^[30].

In the past 50 years, only three candidate gonococcal vaccines have progressed to clinical trials, with none offering reliable protection [29,30,31]^[31][32][33]. The experience and lessons learned from these trials suggest that a successful vaccine will need to be multivariate—capable of targeting multiple conserved epitopes. Moving forward, both new therapeutics and vaccines will need to be developed to keep pace with an evolving pathogen. There are only limited potential drug targets in N. gonorrhoeae, and the rate at which gonococci acquire resistance to existing drugs is cause for concern. Focusing on the non-variable host cell structures contacted by gonococci during adherence, colonization, and invasion may be a plausible approach for the development of new therapeutics. The success of maraviroc [83]^[34], an anti-attachment retroviral drug that targets host immune cells, may be a template in this regard. Other therapeutic options, including immunomodulators and monoclonal antibodies to enhance host immunity, may also be avenues of exploration for drug discovery scientists.