Abstract
Background
Cross-protective immunity between Neisseria meningitidis (Nm) and Neisseria gonorrhoeae (Ng) may inform gonococcal vaccine development. Meningococcal serogroup B (MenB) outer membrane vesicle (OMV) vaccines confer modest protection against gonorrhea. However, whether urethral Nm infection protects against gonorrhea is unknown. We examined gonorrhea risk among men with US Nm urethritis clade (US_NmUC) infections.
Methods
We conducted a retrospective cohort study of men with urethral US_NmUC (n = 128) between January 2015 and April 2018. Using diagnosis date as the baseline visit, we examined Ng status at return visits to compute urethral Ng risk. We compared these data to 3 referent populations: men with urethral Ng (n = 253), urethral chlamydia (Ct) (n = 251), and no urethral Ng or Ct (n = 255). We conducted sensitivity analyses to assess varied approaches to censoring, missing data, and anatomical site of infection. We also compared sequences of protein antigens in the OMV-based MenB-4C vaccine, US_NmUC, and Ng.
Results
Participants were primarily Black (65%) and heterosexual (82%). Over follow-up, 91 men acquired urethral Ng. Men with urethral US_NmUC had similar Ng risk to men with prior urethral Ng (adjusted hazard ratio [aHR]: 1.27; 95% CI: .65–2.48). Men with urethral US_NmUC had nonsignificantly increased Ng risk compared with men with urethral Ct (aHR: 1.51; 95% CI: .79–2.88), and significantly increased Ng risk compared with men without urethral Ng or Ct (aHR: 3.55; 95% CI: 1.27–9.91). Most of the protein antigens analyzed shared high sequence similarity.
Conclusions
Urethral US_NmUC infection did not protect against gonorrhea despite substantial sequence similarities in shared protein antigens.
Keywords: Neisseria meningitidis, Neisseria gonorrhoeae, urethritis, vaccination, immunity
Cross-protective immunity between the gonococcus and the meningococcus may inform gonococcal vaccine development. In this study, we demonstrate that natural mucosal infection with a urethrotropic meningococcal clade does not protect against gonorrhea despite high sequence similarity in shared protein antigens.
Neisseria gonorrhoeae (Ng) is the pathogen that causes the sexually transmitted infection (STI) gonorrhea. Neisseria meningitidis (Nm), which shares 80–90% of its genome with Ng, can cause invasive infections such as meningitis [1]. Gonococcal infection subverts the host immune response, and efforts to develop an effective vaccine have so far failed [2–5]. However, an outer membrane vesicle (OMV)–derived meningococcal serogroup B vaccine from New Zealand (MeNZB) provided modest protection against gonorrhea [6]. Declines in Ng-related hospitalizations were also observed [7]. These results reinforce ecologic analyses documenting declines in gonorrhea in Norway and Cuba following meningococcal vaccination efforts [8, 9]. Vaccine-induced cross-protective immunity against gonorrhea has prompted interest in MenB-4C (Bexsero; GSK Vaccines, Italy), which contains the MeNZB OMV plus recombinant proteins Neisseria adhesin A (NadA), factor H binding protein (FHbp), and neisserial heparin binding antigen (NHBA), as a platform for Ng vaccine development [3–5, 10]. Semchenko et al. reported a core set of 22 proteins that constitute >90% of the MenB-4C OMV, most of which are also present in Ng [11, 12]. MenB-4C vaccination generates cross-reactive antibodies against Ng [11], and a study in Canada showed a nonsignificant decline in gonorrhea among vaccinees [13]. Mice immunized with MenB-4C also clear Ng from the genital tract faster than control mice [14]. Collectively, these findings support the notion of cross-protective immunity between Nm and Ng informing gonococcal vaccine development. Nevertheless, to our knowledge, no large studies have evaluated whether cross-protection against gonorrhea occurs following Nm infection of the urethral mucosa.
In 2015, clusters of phylogenetically linked urethritis cases among primarily Black, heterosexual men attending STI clinics were reported in the United States [15–17]. The cause was a novel Nm urethritis clade (the US_NmUC) belonging to the clonal complex 11, sublineage 11.2. The US_NmUC does not express a capsule (nongroupable phenotype), has acquired gonococcal alleles, and encodes for protein antigens targeted by MenB-4C (NadA, FHbp, and NHBA) [15–19]. Given the premise that cross-protective immunity may influence Ng infection risk, we aimed to assess whether men diagnosed with urethral US_NmUC infection had lower subsequent risk of urethral gonorrhea. Because high gonorrhea incidence is expected in STI clinic settings, we compared gonorrhea risk for men with baseline urethral US_NmUC infection with men with baseline urethral Ng, urethral Chlamydia trachomatis (Ct), and no urethral Ng or Ct infection. In addition, we compared sequences in the US_NmUC and Ng for the core OMV-derived and recombinant protein antigens in the MenB-4C vaccine [11].
METHODS
Study Design and Population
This retrospective cohort study used electronic medical record (EMR) data from male patients seeking care between 1 January 2015 and 30 April 2018 at a public STI clinic in Columbus, Ohio, USA. Males aged 13 years and older were eligible. We constructed a dataset in which each participant’s first selected visit during the study period was considered the baseline visit and we included 4 distinct groups categorized by infection status at the baseline visit: (1) urethral US_NmUC, (2) urethral Ng, (3) urethral Ct, and (4) no urethral Ng or Ct infection. We began by identifying males with confirmed urethral US_NmUC infection during the study period and then selected 2 men from each of the referent populations who visited the STI clinic within 2 days of the patient with urethral US_NmUC. Only the date and baseline infection status were used to select men in the referent groups; no additional matching variables were applied. We followed each man forward through the EMR, and extracted behavioral, clinical, and testing data from return visits to the same STI clinic, for all visits during the study period. Any follow-up visits within 30 days of a prior visit were excluded.
Data Sources
Clinical, Behavioral, and Demographic Data
Patient-reported symptoms, behaviors, and demographic information, and provider clinical observations, were extracted from the EMR using a standardized data-collection form. We obtained meningococcal vaccination history from ImpactSIIS, a voluntary statewide registry.
Laboratory Data
Per clinic protocol, men who came for STI care during the study period, regardless of symptoms, had urethral swabs collected to evaluate for the presence of gram-negative intracellular diplococci. Both the process of urethral Nm isolation and identification using culture, biochemical, and species-specific real-time-polymerase chain reaction (rt-PCR) testing, as well as US_NmUC identification by PCR detection of a signature IS1031-mediated insertion/deletion in the capsule locus and whole-genome sequencing, have been previously described [15, 17]. The men also provided urine samples for Ng and Ct nucleic acid amplification testing (NAAT) (APTIMA Combo2 Assay; Hologic, Inc, Marlborough, MA). Men who reported receptive anal sex in the last 12 months had rectal swabs collected for Ng and Ct NAAT. Those who reported oral sex in the last 12 months had oropharyngeal swabs collected for Ng culture. Finally, patients with presumed or confirmed infections received treatment according to Centers for Disease Control and Prevention (CDC) guidelines [20].
Data Management and Analysis
Demographic, clinical, and epidemiological characteristics were extracted from the EMR and analyzed using SAS (version 9.4; SAS Institute, Cary, NC). We used chi-square or Fisher’s exact tests to compare categorical variables and Mann-Whitney tests to compare medians of continuous variables between males with baseline urethral US_NmUC infection and those in whom urethral Ng, urethral Ct, or no urethral Ng or Ct infection was detected.
Primary Analysis
Our goal was to determine whether urethral US_NmUC infection confers protection against subsequent gonorrhea. The primary outcome was incident urethral gonorrhea. We performed hazard regression modeling with robust variance estimation to account for repeated visits. We censored after the first urethral Ng infection or after the final follow-up visit for men remaining Ng-negative. We ran separate models to produce hazard ratios (HRs) and 95% confidence intervals (CIs) for each comparison. For example, the HR comparing men with baseline urethral US_NmUC infection to men with baseline urethral Ng infection is the ratio of the hazard of incident gonorrhea among men with baseline urethral US_NmUC to the hazard of incident gonorrhea among men with baseline urethral Ng. We first specified unadjusted models, then adjusted for confounders selected using a directed acyclic graph [21]. Each adjusted model controlled for age, race, sexual identity, prior gonorrhea, and recent sexual behavior (number of partners, condom use, and oral sex).
Sensitivity Analyses
We conducted 3 sensitivity analyses to examine the robustness of the primary findings. First, we repeated the analysis but permitted multiple outcomes per participant (eg, no censoring after the first Ng infection). Second, we repeated the analysis but included urethral and extragenital gonorrhea, to determine whether any effect of urethral US_NmUC infection on Ng risk was different according to anatomical site. Third, we assessed the impact of missing data. In particular, men who fail to return for follow-up testing are probably less likely to be symptomatic. If there is a protective effect of urethral US_NmUC infection against subsequent gonorrhea, men with a history of urethral US_NmUC may return less often for testing. To assess the impact of these missing data, we assumed that all men who failed to return during the follow-up period—including men with baseline urethral US_NmUC infection as well as men in all 3 referent cohorts—were Ng-negative on the last day of the follow-up period. We then re-ran the unadjusted and adjusted models as specified above.
Sequence Analysis for Shared Protein Antigens
Relevant protein sequences were extracted from the genomes of NZ98/254 (Nm serogroup B strain from New Zealand, MenB-4C OMV source; ID# 59086), CNM3 (US_NmUC representative isolate; ID# 47233), FA1090 (Ng reference strain; ID# 2855), and M38556 (local urethral Ng isolate, 2015; ID# 39619) available in PubMLST (https://pubmlst.org/neisseria) [22]. For recombinant proteins, peptide variants included in MenB-4C were used for sequence comparison to those of CNM3. Pairwise alignments were performed with CLUSTAL W, MegAlign pro, DNASTAR lasergene 17, Madison, WI.
Ethical Approval
This study was approved by the institutional review board (IRB) at the Ohio State University. The requirement for written informed consent was waived because the project involved no direct patient contact and used previously collected EMR data.
RESULTS
The analysis included 128 men with urethral US_NmUC, 253 men with urethral Ng, 251 men with urethral Ct, and 255 men with no urethral Ng or Ct infection at baseline. We originally selected 2 men from each referent group per US_NmUC case, which would have led to 256 men in each referent population. However, we subsequently excluded 3 men (1%) selected for the Ng baseline cohort, 5 men (2%) for the Ct cohort, and 1 man (0%) for the no urethral Ng or Ct infection cohort due to errors in the database used to generate the sampling frame (eg, a man coded as having gonorrhea on a particular date who, upon review, was actually returning for treatment) or other factors leading to ineligibility per the IRB protocol (eg, patient who was subsequently incarcerated).
Participant Characteristics
Across the study population (N = 887), participants were primarily Black (65%) and heterosexual (82%) (Table 1). The median age was 28 years (interquartile range [IQR]: 23–36 years); however, age varied considerably by baseline infection: men with urethral Ct had a median age of 24 years (IQR: 21–29 years) and men with no urethral Ng or Ct had a median age of 33 years (IQR: 25–41 years). A substantial minority had documented prior history of gonorrhea, including 20% of men with baseline urethral US_NmUC, 23% of men with urethral Ng, 6% of men with urethral Ct, and 7% of men with no urethral Ng or Ct infection. Only 1 man (urethral Ct group) had documented prior MenB vaccination.
Table 1.
Characteristics of Included Participants, Overall and by Baseline Urethral Infection Status
| Characteristic | US_NmUC (n = 128) | Ng (n = 253) | Ct (n = 251) | No Ng or Ct (n = 255) | Total (N = 887) |
|---|---|---|---|---|---|
| Sexual orientation | |||||
| Heterosexual | 120 (93) | 183 (72) | 205 (82) | 220 (86) | 728 (82) |
| Gay | 4 (3) | 48 (19) | 18 (7) | 28 (11) | 98 (11) |
| Bisexual | 3 (2) | 8 (3) | 6 (2) | 6 (2) | 23 (3) |
| Missing | 1 (1) | 14 (6) | 22 (9) | 1 (<1) | 38 (4) |
| Relationship status | |||||
| Single | 91 (71) |
175 (69) | 170 (68) | 166 (65) | 602 (68) |
| Married/partnered | 15 (12) | 28 (11) | 21 (8) | 50 (20) | 114 (13) |
| Divorced/legally separated/widowed | 11 (9) | 12 (5) | 8 (3) | 21 (8) | 52 (6) |
| Missing | 11 (9) | 38 (15) | 52 (21) | 18 (7) | 119 (13) |
| Race/ethnicitya | |||||
| Black/African-American | 109 (85) | 173 (68) | 158 (63) | 135 (53) | 575 (65) |
| White | 115 (12) | 78 (31) | 84 (33) | 102 (40) | 279 (31) |
| Asian | 1 (1) | 1 (<1) | 6 (2) | 9 (4) | 17 (2) |
| American Indian or Alaska Native | 1 (1) | 4 (2) | 3 (1) | 5 (2) | 13 (1) |
| Native Hawaiian | 0 (0) | 1 (<1) | 2 (1) | 0 (0) | 3 (<1) |
| Other Pacific Islander | 2 (2) | 6 (2) | 8 (3) | 8 (3) | 24 (3) |
| Multiracial (not specified) | 5 (4) | 0 (0) | 5 (2) | 3 (1) | 13 (1) |
| Hispanic | 9 (7) | 11 (4) | 11 (4) | 15 (6) | 46 (5) |
| Missing | 1 (1) | 3 (1) | 6 (2) | 2 (1) | 12 (1) |
| Current smoker | 69 (54) | 113 (45) | 92 (37) | 104 (41) | 378 (43) |
| Lives with someone who smokes | 52 (41) | 93 (37) | 72 (29) | 81 (32) | 298 (34) |
| Educational level | |||||
| None/elementary/some high school | 10 (8) | 19 (8) | 27 (11) | 16 (6) | 72 (8) |
| High school graduate/GED | 61 (48) | 95 (38) | 68 (27) | 91 (36) | 315 (36) |
| Some college | 34 (27) | 58 (23) | 54 (22) | 53 (21) | 199 (22) |
| College graduate or higher | 17 (13) | 22 (9) | 39 (16) | 65 (25) | 143 (16) |
| Missing | 6 (5) | 59 (23) | 63 (25) | 30 (12) | 158 (18) |
| History of gonorrhea before baseline | 25 (20) | 57 (23) | 16 (6) | 19 (7) | 117 (13) |
| Nm serogroup B vaccination before baseline | 0 (0) | 0 (0) | 1 (<1) | 0 (0) | 1 (<1) |
| Age, median (IQR), y | 28 (24–36.5) | 28 (23–36) | 24 (21–29) | 33 (25–41) | 28 (23–36) |
| Number of people living in household, median (IQR) | 2 (1–3) | 2 (1–3) | 2 (1–3) | 2 (1–3) | 2 (1–3) |
N = 887.
Abbreviations: Ct, Chlamydia trachomatis; GED, General Educational Development; IQR, interquartile range; Ng, Neisseria gonorrhoeae; Nm, Neisseria meninigitidis; US_NmUC, US Nm urethritis clade.
aRace/ethnicity categories total >100% because participants could indicate >1 race.
Risk of Urethral Gonorrhea by Baseline Cohort
Fewer than half of the men (n = 378; 43%) returned to the STI clinic at least once during follow-up, and the proportion varied by baseline infection status: urethral US_NmUC (n = 73; 57%), urethral Ng (n = 124; 49%), urethral Ct (n = 89; 35%), and no urethral Ng or Ct infection (n = 92; 36%).
Among returning participants, we detected 135 cases of urethral Ng in 91 men, 13 cases of rectal Ng in 10 men, and 6 cases of oropharyngeal Ng in 6 men. Among men with baseline urethral US_NmUC, we observed no meaningful difference in the timing of Ng infection (eg, men were at similar risk in the period just after urethral US_NmUC infection as they were months or years after). Urethral Ng incident cases were not evenly distributed across baseline cohorts: proportionally more of the 91 Ng-positive men were found in those with baseline urethral US_NmUC (29%, even though they comprised only 19% of the follow-up sample) and baseline urethral Ng (44%, even though they comprised only 32% of the follow-up sample).
For the primary analysis, men with baseline urethral US_NmUC infection had similar urethral Ng risk during follow-up as men with baseline urethral Ng (unadjusted HR: 1.18; 95% CI: .70–1.99). Results were similar after controlling for age, race, sexual orientation, prior gonorrhea, and recent sexual behavior (adjusted HR: 1.27; 95% CI: .65–2.48). Men with baseline urethral US_NmUC had slight, but nonsignificant, increased urethral Ng risk during follow-up compared with men with baseline urethral Ct (adjusted HR: 1.51; 95% CI: .79–2.88). In contrast, men with baseline urethral US_NmUC had significantly increased urethral Ng risk during follow-up compared with men with no baseline urethral Ng or Ct infection (adjusted HR: 3.55; 95% CI: 1.27–9.91) (Table 2).
Table 2.
Unadjusted and Adjusted Hazard of Neisseria gonorrhoeae Infection by Baseline Urethral Infection Status
| Unadjusted HR | (95% CI) | Adjusteda HR | (95% CI) | |
|---|---|---|---|---|
| Primary analysis | ||||
| Permitting up to 1 event per participant | ||||
| US_NmUC vs Ng | 1.18 | (.70, 1.99) | 1.27 | (.65, 2.48) |
| US_NmUC vs Ct | 2.00 | (1.10, 3.61) | 1.51 | (.79, 2.88) |
| US_NmUC vs no Ng or Ct | 3.56 | (1.72, 7.40) | 3.55 | (1.27, 9.91) |
| Sensitivity analyses | ||||
| Permitting multiple events per participant | ||||
| US_NmUC vs Ng | 1.04 | (.60, 1.78) | 1.20 | (.69, 2.09) |
| US_NmUC vs Ct | 1.98 | (1.08, 3.61) | 1.58 | (.86, 2.90) |
| US_NmUC vs no Ng or Ct | 3.84 | (1.87, 7.91) | 3.42 | (1.35, 8.63) |
| Including urethral and extragenital Ng | ||||
| US_NmUC vs Ng | 1.14 | (.68, 1.90) | 1.13 | (.59, 2.17) |
| US_NmUC vs Ct | 2.03 | (1.12, 3.67) | 1.51 | (.79, 2.89) |
| US_NmUC vs no Ng or Ct | 3.27 | (1.60, 6.64) | 3.14 | (1.18, 8.41) |
| Assuming all men who failed to return were Ng-negative on the last day of follow-up | ||||
| US_NmUC vs Ng | 1.30 | (.77, 2.18) | 1.55 | (.83, 2.88) |
| US_NmUC vs Ct | 2.86 | (1.57, 5.20) | 1.70 | (.86, 3.34) |
| US_NmUC vs no Ng or Ct | 4.99 | (2.4, 10.21) | 2.92 | (.97, 8.73) |
Abbreviations: CI, confidence interval; Ct, Chlamydia trachomatis; HR, hazard ratio; Ng, Neisseria gonorrhoeae; US_NmUC, US Nm urethritis clade.
aAdjustment variables include age, race, sexual orientation, prior gonorrhea, and recent sexual behavior (number of partners in the last 3 months, condom use, and oral sex).
The robustness of the primary findings was confirmed through sensitivity analyses. All 3 sensitivity analyses showed similar patterns, including when permitting multiple events per participant, when the outcome included both urethral and extragenital gonorrhea, and when assuming that men who never returned after baseline were Ng-negative at the end of follow-up. Regardless of the analysis, the incident gonorrhea risk was approximately the same for men with baseline urethral US_NmUC as those with baseline urethral Ng, slightly but nonsignificantly elevated compared with those with baseline urethral Ct, and approximately 3 times as high compared with those with no baseline urethral Ng or Ct infection (Table 2).
Sequence Comparisons for Shared Protein Antigens
Comparisons of sequences (% amino acid similarity) in the US_NmUC (CNM3) and Ng (FA1090 and M38556) for the core OMV-derived and recombinant protein antigens in the MenB-4C vaccine [11] are shown in Supplementary Table 1). The median sequence similarities for shared OMV-derived proteins were as follows: MenB-4C (NZ98/254) to CNM3, 99.1% (range: 71.3–100%); CNM3 to FA1090, 97.0% (range: 74.2–99.4%); CNM3 to M38556, 97.2% (range: 72.7–99.4%); and FA1090 to M38556, 99.8% (range: 94.9–100%). In the gonococcus, the NadA gene is absent and FHbp is not surface-expressed, while NHBA is highly conserved and predicted to be surface-expressed [11, 23]. The NHBA sequence similarities were as follows: MenB-4C to CNM3 (77.9%), CNM3 to FA1090 (87.4%), CNM3 to M38556 (87.2%), and FA1090 to M38556 (95.8%).
DISCUSSION
Gonococcal infection does not confer protection against reinfection and repeat episodes of gonorrhea are well-known occurrences [2–5, 24–26]. In this study, we demonstrate that urethral US_NmUC infection does not reduce subsequent risk of urethral Ng infection, despite high sequence similarities in shared protein antigens. Regardless of the comparison population, the primary findings were robust to changes in model specification, site of infection, and methodological threats to validity, including missing data. Compared with men with a history of urethral Ng or Ct, men with a history of urethral US_NmUC had a similar risk of gonorrhea over the follow-up period. Men with prior urethral US_NmUC had a higher risk of acquiring urethral Ng than men who were baseline negative for urethral Ng and Ct, which was an expected finding given that STI history is a strong predictor of future STI acquisition [27].
There is great interest in understanding how cross-protective immunity between Nm and Ng could inform gonococcal vaccine development [2–5, 10]. In New Zealand, young adults who received the parenteral MeNZB vaccine had a 31% reduction in gonorrhea, and incidence was most reduced in the period just after vaccination, bolstering evidence for a causal effect [6]. The same temporal pattern was observed in Cuba following mass VA-MENGOC-BC vaccine administration [9]. Proteomic analysis of MenB-4C identified a core set of 22 OMV-derived proteins, most of which are also encoded by Ng [11]. Shared immunogenic proteins with 80% or higher predicted amino acid sequence similarity are proposed as potential drivers of cross-protection [23]. Except for PorB, many OMV-derived proteins shared between the US_NmUC and Ng had sequence similarities that exceeded this threshold (including those previously identified as potential gonococcal vaccine targets [2–4]). The same was observed for NHBA, which can facilitate gonococcal adherence to urogenital mucosa and may be a potential vaccine target [28, 29]. Of interest, the US_NmUC acquired a gonococcal norB-aniA cassette through homologous recombination [17]. AniA (nitrite reductase) is an outer membrane protein that is upregulated in Ng under microaerobic environments such as in the urethra [30] and has been identified as a potential gonococcal vaccine target [3, 4].
Although the present results differ from those observed in Nm OMV vaccine studies, the correlates of protective immunity against gonorrhea, including those related to natural infection and meningococcal vaccination, have not been fully defined [2–5, 10]. There is also evidence that Ng subverts the immune response to infection through a variety of previously described mechanisms (eg, suppression of T-helper [Th]-1 and Th2-driven adaptive response, generation of anti-Rmp blocking antibodies, complement inhibition, etc) [2, 3]. If or how these factors influence gonorrhea risk following urethral US_NmUC infection is not known. Furthermore, while immunization studies using gonococcal OMVs (mucosal administration) and the highly conserved 2C7-oligosaccharide epitope have shown promising results in mice [31–33], the optimal route of antigen delivery for a future vaccine in humans is not known [2–5, 10], and it is presently not clear if the murine model data will translate to humans. In the present study, if urethral US_NmUC infection elicited a cross-reactive immune response, it was not potent, durable, or specific enough to demonstrate meaningful protection against Ng acquisition. This hypothesis is supported by the discovery that, similar to gonorrhea [24–26], repeat episodes of US_NmUC urethritis can occur [34].
As a retrospective cohort study using EMR and surveillance data, the present analysis has important limitations. First, EMR data are not designed for epidemiological research, and key variables for the analysis were not available. For example, participants may have had infections for which the clinic does not routinely test (eg, Mycoplasma genitalium). Similarly, we had considerable missing data on participants’ Nm vaccination status, because we extracted this information from a voluntary statewide immunization database. Only 1 participant was identified as having a prior MenB vaccination. Although it is possible that other people in the study had undocumented vaccination, we expect that confounding by this variable is minimal since adult patients attending STI clinics generally do not meet MenB vaccination criteria [35] and thus overall vaccination rates are likely low. We may have missed gonorrhea in men who sought testing in other settings or extragenital infections in men who did not report behavioral risk and thus were not screened at extragenital sites. However, we do not expect these missing data to be differential by baseline infection status. Finally, we do not have immunological data from study participants to assess for cross-reactive immune responses to Ng following urethral US_NmUC infection. However, given that Nm nasopharyngeal colonization elicits cross-reactive antibodies against Ng [36], it seems plausible that the same could occur following urethral infection.
Despite these limitations, to our knowledge, this is the first study to analyze gonorrhea risk following urethral Nm infection in a large cohort of patients. While urethral Nm is not expected to be highly prevalent, it is also not routinely screened for, and can be easily misidentified as Ng on Gram stain [15]. Despite this, the occurrence of a large cluster of Nm urethritis cases provided the unique opportunity to examine the epidemiological consequence of infection with an urethrotropic Nm clade that has acquired gonococcal alleles and shares protein antigens with the MenB-4C vaccine and Ng [15–19].
Conclusions
We found that urethral US_NmUC infection did not reduce the risk of future urethral gonorrhea, despite substantial sequence similarities in shared protein antigens. However, research into how shared gonococcal and meningococcal antigens contribute to cross-protective immunity continues to gain traction. These discoveries have infused new momentum into decades-long gonococcal vaccine development efforts [2–5, 10]. Against a backdrop of increasing gonorrhea cases in the United States [37] and rise in antimicrobial resistance [38], additional studies should continue to explore how shared Neisseria antigens and their delivery in vaccines influence levels of immunity against gonorrhea.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments. The authors thank Devlin J. Prince, MA; Courtney Maierhofer, MPH; Melissa Ervin, MT (ASCP); Karen Fields, RN; Mysheika Roberts, MD, MPH; Tiffany Krauss, RN; and the clinical and laboratory personnel from the Sexual Health Clinic at Columbus Public Health for their support. The authors also thank Jennifer L. Edwards, PhD, from the Research Institute at Nationwide Children’s Hospital and the Ohio State University for her expert insight and review of the manuscript.
Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases/National Institutes of Health or the US Centers for Disease Control and Prevention.
Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant number R01AI127863 to A. N. T and J. A. B).
Potential conflicts of interest. A. N. T. reports contract and grant support from the Centers for Disease Control and Prevention (CDC), travel support from the American STD Association (ASTDA; ASTDA Board meeting, 2 times per year since 2017), serving as ASTDA Treasurer since 2019, and participation on the Data Safety Monitoring Board for a trial of zoliflodacin for treatment of uncomplicated gonorrhea for the Global Antibiotic Research & Development Partnership (GARDP), all outside the submitted work. A. C. reports contract support from the CDC, outside the submitted work. A. C. R. reports receiving salary and travel support from the CDC. J. A. B. reports contract and grant support from the CDC, outside the submitted work. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Contributor Information
Abigail Norris Turner, Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Alexandria M Carter, Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Yih-Ling Tzeng, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
David S Stephens, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Morgan A Brown, Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Brandon M Snyder, Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Adam C Retchless, Meningitis and Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Xin Wang, Meningitis and Vaccine Preventable Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Jose A Bazan, Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA; Sexual Health Clinic, Columbus Public Health, Columbus, Ohio, USA.
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