The future role of vaccination in prevention of Neisseria gonorrhoeae

Introduction

Gonococcal infection, caused by Neisseria gonorrhoeae, represents a significant global public health challenge due to its high prevalence, potential for severe health consequences and increasing resistance to antibiotics. Gonococcal infection rates have surged globally over the past two decades with an estimated 82.4 million (47.7 million–130.4 million) people newly infected with N. gonorrhoeae in 2020.¹ Resistance to azithromycin is increasing, and emerging resistance to ceftriaxone, the last-line treatment for N. gonorrhoeae, is concerning, with 74 countries reporting antimicrobial resistance (AMR) in N. gonorrhoeae.² This trend threatens the effectiveness of current treatment protocols, potentially leading to more difficult-to-treat infections and higher rates of complications such as infertility and neonatal health issues. Moreover, the escalation of resistant strains necessitates the urgent development of new antimicrobial agents and therapeutic strategies, increasing healthcare costs. Infections can range from symptomatic urogenital infections to asymptomatic cases, particularly in women. Extragenital infections, such as those in the oropharynx and rectum, are common in certain populations and often asymptomatic, acting as reservoirs for transmission, which makes controlling the spread of gonococcal infections challenging. High-risk populations include men who have sex with men (MSM), sex workers, people in prison, people living with human immunodeficiency virus (HIV), adolescents and young adults.³ Indigenous populations face complex social and cultural determinants, and barriers to healthcare with a five times higher risk for Aboriginal and Torres Strait Islander people in Australia.⁴ As natural infection with N. gonorrhoeae does not produce lasting immunity, recurrent infections are common.^5,6 Recurrent infections can significantly increase the risk of infertility in women, particularly due to the development of pelvic inflammatory disease, which can damage the fallopian tubes and lead to infertility.⁷ Gonococcal infection is associated with numerous adverse pregnancy and newborn outcomes, such as ectopic pregnancy, preterm birth, premature rupture of membranes, perinatal mortality, low birth weight and ophthalmia neonatorum.^8,9 Gonococcal infection can also promote the transmission and susceptibility to HIV by causing local inflammation, increasing the number of HIV target cells and disrupting mucosal barriers.¹⁰ Despite substantial efforts in prevention and treatment in high-income countries, gonococcal infection remains one of the most common sexually transmitted infections (STIs). Gonococcal infection notification rates in Australia increased by 127% from 2012 to 2019. This surge was followed by a decline of 23% during the COVID-19 pandemic restrictions in 2020 and 2021. The notifications in 2022 then returned to levels similar to those reported in 2019.¹¹ In low- and middle-income countries, the incidence of gonococcal infections has not significantly changed, largely due to limited access to testing and healthcare resources.¹² This paper aims to review gonococcal infection treatment options, vaccine development and current preventive measures, and highlight the research gaps in discovery science and vaccine programs.

Prevention and treatment

Prevention strategies primarily focus on sexual health promotion, including public health campaigns, sexual health education, behavioural counselling and consistent condom use. Adherence to condom use has waned in recent decades, partly due to the expansion of other HIV-prevention methods such as pre-exposure prophylaxis (PrEP).¹³ Prophylactic use of antibiotics (e.g. doxycycline) may reduce the incidence of bacterial STIs. The US Centers for Disease Control and Prevention (CDC) has recommended the use of doxycycline post-exposure prophylaxis (doxy PEP) for the prevention of bacterial STIs, including gonococcal infections, in gay, bisexual and other MSM, as well as for transgender women.¹⁴ However, it is important to note that the effectiveness of doxy PEP in reducing gonococcal infections has not been consistently observed in all studies. For example, studies conducted among MSM in France and women in Kenya did not find a significant decrease in gonococcal infections despite the use of doxy PEP.^15,16 Furthermore, antibiotic resistance is a growing concern when using doxy PEP or any antibiotic-based prevention strategy.

The current standard treatment for gonococcal infections involves a dual antimicrobial regimen of intramuscular ceftriaxone and oral azithromycin.¹² Treatment failure has been reported.¹⁷ This highlights the urgent need for new therapeutic options to combat the rising threat of AMR in gonococcal infections.¹²

Gonococcal vaccine development

The development of a vaccine against gonococcal infections has been challenging.¹² Neisseria gonorrhoeae exhibits antigenic and phase variation, meaning it can change its surface antigens over time, making it difficult for the immune system to recognise and target the bacterium consistently. Unlike some other infections, natural infection with N. gonorrhoeae does not confer lasting immunity. This lack of protective immunity complicates the development of a vaccine. There is currently no well-established immune correlate of protection against gonococcal infections. Therefore, it is challenging to determine which immune responses are essential for preventing infection. Neisseria gonorrhoeae primarily infects humans and has limited suitable animal models for studying infection and vaccine development.⁷

Early vaccines, primarily whole-cell or killed-bacteria formulations, showed limited efficacy.^18,19 Advances in molecular biology and immunology have shifted focus towards identifying specific antigens that could elicit a protective immune response. Multiple vaccine candidates are currently undergoing preclinical and clinical development stages, targeting various antigens and employing diverse delivery methods such as recombinant proteins and outer membrane vesicles (OMVs).^7,12 These approaches have demonstrated potential in stimulating immune responses. The N. gonorrhoeae-generalised modules for membrane antigens (GMMA) vaccine is the only candidate vaccine that has advanced to a Phase I or II clinical trial (NCT05630859).²⁰ The GMMA technology is a novel platform developed to design OMV-based vaccines.²¹

Cross-protection offered by meningococcal B outer membrane vesicle vaccines

Recent observational studies have suggested a potential reduction in the incidence of gonococcal infections with the use of meningococcal vaccines. As Neisseria meningitidis and N. gonorrhoeae share 80–90% genomic sequence identity, meningococcal vaccines containing OMVs with or without outer membrane proteins (OMPs) have been assessed for their protective effects against gonococcal infections. This potential for cross-protection provides valuable insights into the development of a targeted gonococcal vaccine. A notable study conducted in New Zealand demonstrated a meningococcal OMV vaccine, MenZB, offered moderate protection (31% vaccine effectiveness) against gonococcal infections, with additional supporting ecological evidence emerging from other meningococcal OMV vaccine studies in Cuba²² and Norway.²³ 4CMenB, an OMV-containing vaccine, incorporates OMVs from N. meningitidis serogroup B, along with three recombinant antigens (Neisseria adhesin A, FHbp, and Neisseria heparin binding antigen, NHBA) and two accessory proteins (GNA2091 fused with FHbp and GNA1030 fused with NHBA) to broaden immune responses.²⁴ NHBA antigen shares a 67% mean amino acid sequence similarity with N. gonorrhoeae, suggesting that its presence in the 4CMenB vaccine may confer an additional protective effect against gonococcal infections. Moreover, analysis of the antibody response in animals and humans following immunisation with 4CMenB has demonstrated the induction of cross-reactive antibodies specific to gonococcal infections.²⁵ Additionally, vaccination with 4CMenB has been shown to significantly reduce N. gonorrhoeae bacterial load and expedite clearance of infection after N. gonorrhoeae vaginal inoculation in the estradiol-treated mouse model.²⁶

4CMenB vaccine (Bexsero) is licensed in many countries and provided in funded programs in several, to protect against invasive meningococcal disease in infants and adolescents. Studies conducted in New Zealand, South Australia, Italy, France and the USA have assessed the vaccine effectiveness (VE) of meningococcal vaccines against gonococcal infections, examining various factors such as time points, doses and endpoint outcomes.^27–35 After removing overlapping data, eight studies evaluated VE of OMV vaccines against gonococcal infections^{27–29,31–35} including one for MenZB,³¹ six for 4CMenB,^{28,29,32–35} and one for a non-OMV vaccine, MenB-FHbp.²⁷ One study in New Zealand assessed VE against hospitalisation associated with gonococcal infections.³⁰

Among nine studies assessing VE of OMV vaccines, four case-control studies estimated the VE of complete meningococcal OMV vaccine series against gonococcal infections in adolescents and young people.^28,31,32,34 One observational cohort study²⁹ and one randomised control trial (RCT)³⁵ assessed the risks of gonococcal infections using hazard risk ratios in individuals receiving 4CMenB compared to non-recipients. Most of the included studies targeted the general population aged 15–30 years, whereas two studies including the RCT evaluated VE among adult MSM living with HIV.^32,35 To reduce potential healthy user bias most case-control studies used chlamydia as matched controls,^{27,28,31,32,34} including one study with patients diagnosed with syphilis, chlamydia or anal HPV as controls.³² One cohort study assessed the VE of 4CMenB against chlamydia as a negative control outcome in a separate analysis.²⁹ Adjusted VE for OMV vaccines against gonococcal infections ranged from 22 to 46%. This includes the RCT in France, which showed a VE of 22% (adjusted HR: 0.78; 95% CI: 0.60 to 1.01) after recruitment was prematurely stopped due to significant interim analysis results, with several gonococcal infections not included in the interim analysis.³⁵ MenB-FHbp did not show protection against gonococcal infections.

The studies conducted in the USA,²⁸ South Australia³⁴ and New Zealand³¹ investigated the duration of vaccine protection. In South Australia, VE estimates were reported to decrease from 35% (95% CI: 15 to 50%) to 23% (95% CI: −13 to 47%) in subgroup analyses after 36 months postvaccination.³⁴ A similar trend was observed in the MeNZB study, with VE estimates decreasing from 20 to 9% between 2004–2009 and 2010–2014.³¹ The US study explored assumptions regarding the duration of vaccine protection and found comparable VE estimates within a 3-year study period.²⁸

The study in South Australia estimated VE against recurrent infection in subgroup analyses.³⁴ The VE estimate in individuals with recurrent infection(s) was 23% (95% CI: −41 to 58%), whereas it was 37% (95% CI: 20 to 51%) in those with a single gonococcal infection. As co-infection with chlamydia is common, these three studies that investigated VE against co-infections had inconsistent results. The South Australian study observed no significant variation in VE between gonococcal patients with or without co-infections³⁴; the New Zealand study showed a reduced VE in patients with co-infections³¹; the US study reported that 4CMenB had no effectiveness against co-infections.²⁸

Ecological evidence from four studies demonstrated the impact of various meningococcal vaccine programs on gonococcal incidence across different global regions. Two studies investigated the impact of 4CMenB in Canada³⁶ and South Australia,³⁴ and one study assessed VA-MENGOC-BC in Cuba²² and another assessed MenBvac in Norway.²³ In South Australia, the vaccine impact of 4CMenB on gonococcal infections was assessed 3 years after the introduction of a state-funded vaccination program, showing a 30% reduction (95% CI: −14 to 57%) in gonococcal incidence among adolescents aged 15–17 years.³⁴ In Quebec, Canada, although the overall reduction in gonococcal infections was not significant, there was a decrease among individuals aged 14–20 years and an increase among those aged 21 and older.³⁶ In Cuba, following a vaccination campaign with VA-MENGOC-BC from 1988 to 1990, gonococcal cases notably declined.²² Similarly, in Norway, a reduction in gonococcal incidence rates was observed among vaccinated cohorts.²³

Social and economic impact of gonococcal vaccines

The introduction of a gonococcal vaccine would yield significant social and economic benefits. By reducing the burden of gonococcal infections, considerable reduction in healthcare costs could be achieved, while simultaneously decreasing morbidity and enhancing overall quality of life. Economic assessments suggest that vaccination may even result in cost savings, particularly in regions where gonococcal infections and AMR rates are high.³⁷ Although the specific settings may vary, modelling studies have consistently demonstrated the potential for significant reductions in gonococcal infections through 4CMenB or gonococcal specific vaccination, even with partial efficacy, moderate duration of protection and modest vaccine uptake.³⁸ However, existing modelling studies predominantly focus on heterosexual or MSM populations in high-income countries (e.g. the cost effectiveness of vaccinating MSM in England³⁷), with only one study considering a low- and middle-income country setting. Key and vulnerable populations are underrepresented, such as MSM, sex workers, transgender individuals, people living with HIV, incarcerated people and ethnic minorities.³⁸ Comprehensive epidemiological data, including age- and gender-specific prevalence and incidence, are needed to accurately estimate health and economic impact of a vaccine program. Improved surveillance of AMR, especially in low- and middle-income countries, is essential due to the ongoing problem of AMR.³⁹ Current models lack detailed data on sexual behaviour change, mixing between different sexual networks, and factors driving transmission.³⁸ More robust data on anatomical site-specific transmission, vaccine effectiveness against infection at different sites, vaccine effectiveness against asymptomatic or symptomatic infection,⁴⁰ and a better understanding of potential adverse sexual and reproductive outcomes of gonococcal infection,⁹ are needed to inform public health strategies and cost-effectiveness analyses. Such data would inform more accurate predictions regarding vaccine impact and guide future scientific and public health decision-making, including factors related to acquisition, transmission, and duration of infection, spanning multiple anatomical site.¹²

Conclusion

The escalating AMR in N. gonorrhoeae, with narrowing treatment options underscores the urgent need for a vaccine. Multiple vaccine candidates are currently undergoing preclinical and clinical development, and there is increasing evidence that meningococcal vaccines can protect against gonococcal infections. Vaccination has the potential to reduce spread of this infection, especially in regions and populations with high incidence rates and resistance patterns. Vigilant AMR surveillance is also crucial for assessing treatment efficacy and informing public health interventions. Ongoing research is imperative to address key knowledge gaps, including investigating the duration of vaccine-induced immunity, exploring vaccine effect on multiple anatomical infection sites, optimising delivery methods, and evaluating their impact on AMR. Collaborative efforts among researchers, public health authorities, and vaccine manufacturers are pivotal for advancing vaccine development.