Abstract
Background
A publicly funded 4CMenB program has been implemented in South Australia since 2018. We aimed to evaluate vaccine effectiveness (VE) and vaccine impact on invasive meningococcal B (MenB) disease and gonococcal infections 5 years after the program introduction.
Methods
Vaccine impact was assessed using a Poisson or negative binomial regression model, and VE was estimated using both cohort screening and case-control methods. VE against the subsequent gonococcal infection was measured using a Cox regression model.
Results
Relative reductions of 72.7% (95% confidence interval [CI], 38.0%–88.0%) and 76.2% (41.6%–90.3%) in the incidence of MenB disease were observed in infants aged <1 year and adolescents aged 15–18 years, respectively. VE against MenB disease for the 3-dose schedule was 98.5% (95% CI, 81.9%–99.9%) in children and 92.3% (34.3%–99.1%) for the 2-dose vaccination in adolescents. VE for 2-dose vaccination against gonococcal infections in adolescents was 39.1% (95% CI, 31.3%–46.0%). Lower VE estimates were demonstrated in those >5 years compared to within 5 years since vaccination (−6.3% (95% CI, −44.5% to 21.8%) vs 41.8% (34.0%–48.7%). The VE against the subsequent gonococcal infection was 27.0% (adjusted hazard ratio, 0.730 [95% CI, .540–.988]), comparing fully vaccinated with unvaccinated case patients.
Conclusions
4CMenB demonstrates high protection against MenB disease in children and adolescents at 5 years. Moderate protection against the first and subsequent gonococcal infections in adolescents was observed up to 5 years after vaccination, with waning evident after 5 years.
Keywords: 4CMenB, MenB vaccine, vaccine effectiveness, vaccine impact, gonococcal and meningococcal infections
The continuation of the publicly funded childhood and adolescent 4CMenB programs over 5 years has created a unique opportunity to investigate long-term vaccine protection against meningococcal B and gonococcal infections and the vaccine effect on subsequent gonococcal infections.
Invasive meningococcal disease caused by Neisseria meningitidis and gonococcal infection caused by Neisseria gonorrhoeae both pose substantial public health challenges. Although meningococcal disease is relatively rare, it is associated with high mortality rates and severe long-term sequelae, even with timely antibiotic treatment [1]. In contrast, gonococcal infection is highly prevalent, with a rising incidence observed following the coronavirus disease 2019 pandemic, a growing threat of antibiotic resistance, and the potential to cause infertility in women [2].
The most frequently used vaccine for meningococcal B (MenB) disease prevention, 4CMenB (Bexsero; GSK), contains 3 recombinant proteins and an outer membrane vesicle. 4CMenB has shown strong protection against MenB disease in the United Kingdom [3–5], Canada [6, 7], Australia [8–11], Spain [12], Italy [13, 14], and Portugal [15], as well as in outbreak control in the United States [16], with high vaccine effectiveness (VE) observed [17]. Therefore, real-world evidence on the effectiveness of 4CMenB, especially long-term protection, is crucial to inform public funding decisions.
Real-world evidence suggests that MenB vaccines with outer membrane vesicle–based antigens offer moderate protection against gonococcal infections in New Zealand [18, 19], Norway [20], Cuba [21], Italy [22], France [23], Australia [9–11], and the United States [17, 24–28]. N. gonorrhoeae and N. meningitidis are genetically closely related, sharing 80%–90% genome sequence identity [29], and there are very high genomic similarities between the 4CMenB antigens and N. gonorrhoeae protein sequences [29]. In the United Kingdom, the Joint Committee on Vaccination and Immunisation has recommended the use of 4CMenB to prevent gonorrhea among individuals at higher risk of gonococcal infection attending sexual health services [30].
A publicly funded 4CMenB program was introduced in South Australia based on observed epidemiological peaks, commencing for children on 1 October 2018 and for adolescents and young adults on 1 February 2019.
METHODS
Data Source
MenB disease, gonococcal infection, and chlamydia are notifiable diseases in Australia, requiring mandatory reporting to health authorities. All notification data were obtained from the Communicable Disease Control Branch of SA Health. MenB immunization records were obtained from the South Australian subset of the Australian Immunization Register (AIR). The residential postcode was used to assess socioeconomic status, using the Socio-Economic Indexes for Areas, Australia, 2021 [31].
VE of 4CMenB Against MenB Disease
MenB case patients included were those eligible to receive the 3-dose 4CMenB through the ongoing childhood program (those born after 1 October 2017 who were still <12 months of age when the program commenced on 1 October 2018) or the 2-dose 4CMenB through a catch-up program (born between 1 October 2014 and 30 September 2017), with a MenB notification date between 1 October 2018 and 30 September 2023.
The ongoing 4CMenB adolescent program was offered to year 10 students in high schools through the School Immunisation Program. Since the annual cutoff birth date for school entry in Australia is 1 May, 30 April was used to approximate eligibility for free 4CMenB based on the school year. The analysis included all MenB case patients who were eligible to receive free 4CMenB through the ongoing and catch-up programs (born between 31 January 1998 and 30 April 2008) with a MenB notification date between 1 February 2019 and 31 January 2024.
For estimates of VE, a vaccine dose was considered valid if received ≥14 days before MenB disease onset. VE against MenB disease was assessed using 2 previously published methods: the cohort screening [3, 5] and case-control [32] methods. For the screening method, logistic regression was used, with the child's vaccination status as the binary outcome variable. The model included only a constant term and an offset for the log odds of the matched coverage. For the case-control method, 20 controls matched by date of birth were selected from AIR records. Conditional logistic regression was performed with the case patient's vaccination status as the categorical exposure variable, adjusted for age, sex, socioeconomic status, and Aboriginal background. For both the cohort screening and case-control methods, VE was calculated as 1 minus the odds ratio (OR) estimated from the model.
Since the childhood catch-up program provided 2 doses of 4CMenB without a booster dose for all children aged >12 months and <4 years, a subgroup VE analysis using the case-control method was conducted. Three categories were used for children born between 1 October 2014 and 30 September 2017: complete vaccination (2 doses), partial vaccination (1 dose), and unvaccinated (reference group). A separate subgroup analysis was performed for children born on or after 1 October 2017, who were eligible for 2 primary doses and a booster dose, using different categories: complete vaccination (3 doses), partial vaccination (1 or 2 doses), and unvaccinated (reference group).
VE of 4CMenB Against Gonococcal Infection
The published case-control method [19] was used, and controls matched for date of birth (±28 days) were selected from the chlamydia notification database. Patient-level data were used in the analysis. Gonococcal case patients were included if they were born between 31 January 1999 and 31 January 2009, with a gonococcal notification date between 1 February 2019 and 31 January 2024. As gonococcal infection may persist for months before diagnosis, a 3-month lag time was considered for vaccination status, and vaccine doses were counted if disease onset occurred ≥3 months after the dose.
The first recorded diagnosis after the MenB vaccination was used to define the index infection in gonococcal case patients with repeated gonococcal infections and chlamydia controls with repeated chlamydia infections. Gonococcal infection with chlamydia coinfections were common. Individuals with gonococcal infection coinfected with chlamydia were classified as gonococcal case patients. All chlamydia controls were individuals with chlamydia only, without any gonococcal coinfections. Logistic regression was performed, with standard errors clustered by person; analysis included covariates for age, sex, and socioeconomic status. Aboriginal background was not included because these data were missing in 22.6% of gonococcal case patients and chlamydia controls.
Subgroup analyses were performed to explore the effect of coinfection with chlamydia, the duration of protection against gonococcal infections, and differences by sex. For coinfection, 2 subgroup analyses were performed: (1) comparing gonococcal case patients with coinfection with chlamydia-only controls and (2) comparing gonococcal-only case patients with chlamydia-only controls. To assess VE over time, we evaluated VE in 2 subgroups of gonococcal case patients, those who had received 4CMenB ≤60 versus >60 months before the index infection.
A time-to-event analysis using a Cox regression model was conducted to estimate the vaccine effect on subsequent gonococcal infections (first repeated infection) adjusted for sex, socioeconomic status with stratification by age. Exposure was defined as vaccination status at the time of gonococcal notification (0, 1, or 2 doses). The assumption for the proportional hazards was examined.
Vaccine Impact on MenB Disease and Gonococcal Infection
The vaccine impact (VI) was calculated by comparing the MenB or gonococcal case patients reported in the prevaccine program years to those reported after the 4CMenB programs commenced. To obtain the adjusted incidence rate ratios (aIRRs), Poisson and negative binomial regression models were applied to evaluate VI on MenB disease and gonococcal infections, respectively.
The study protocol and methods have been published elsewhere [9–11, 33]. The study was approved by the SA Department for Health and Wellbeing Human Research Ethics Committee (HREC/19/SAH/59; 2022/HRE00308).
RESULTS
A total of 334 743 doses of 4CMenB were administered to 137 502 children eligible to receive 4CMenB through ongoing/catch-up childhood programs during the 5 program years. The 3-dose vaccine coverage in children who were born on or after 1 October 2018 was 81.43% (62 994 of 77 358; 95% confidence interval [CI], 81.16%–81.70%). A total of 191 012 doses of 4CMenB were administered to 102 624 individuals born between 1998 and 2010. The highest vaccine coverage of 68.36% (15 140 of 22 147; 95% CI, 67.75%–68.97%) was observed among adolescents born in 2005.
VE Against MenB Disease
A total of 16 children were reported to have MenB disease at age <5 years. Seven cases occurred in children <1 year of age (age range: 5–51 weeks). One child was too young to receive the first dose (aged 5 weeks), and another did not receive the first dose within the recommended time frame, with MenB disease developing at 7 weeks old. Three children were vaccinated with 2 doses and were too young to receive the third (age range, 32–51 weeks), and 1 child was unvaccinated (aged 25 weeks). Among children aged 1–4 years, 2 were fully vaccinated: 1 completed the full 2-dose schedule under the catch-up program (aged 4 years), and the other received the full 3-dose schedule under the ongoing infant program (aged 2 years).
Using the case-control method with 20 AIR controls and for all children who were eligible to receive 2-dose 4CMenB through the catch-up program and 3-dose 4CMenB through the ongoing program, the 2-dose VE estimate was 64.2% (95% CI, 7.4%–86.1%; adjusted OR [aOR], 0.358 [.139–.926]; P = .03) and the 3-dose VE, 98.5% (81.9%–99.9%; aOR, 0.015 [.001–.181]; P = .001). The estimates of VE were 52.1% (95% CI, −88.4% to 87.8%; aOR, 0.479 [.122–1.884]; P = .29) for 2-dose 4CMenB and 64.0% (−662.5% to 98.3%; aOR, 0.360 [.017–7.625], P = .51) for 3-dose 4CMenB, using the screening method.
In the subgroup analysis using the case-control method with 20 AIR controls, for children who were eligible only for 2-dose 4CMenB through the catch-up program (born between 1 October 2014 and 30 September 2017), the VE for complete vaccination (2 doses) was 81.9% (95% CI, 3.5%–96.6%; aOR, 0.181 [.034–.965]; P = .045). For children who were eligible for the 3 doses of 4CMenB through the ongoing program (born after or on 1 October 2017), the VE for complete vaccination (3 doses) was 98.8% (95% CI, 83.8%–99.9%; aOR, 0.012 [.001–.162]; P = .001).
In total, 19 adolescents and young adults had MenB disease diagnosed during the 5 program years. The 2-dose VE was 92.3% (95% CI, 34.3%–99.1%; aOR, 0.077 [.009–.657)]; P = .02) with the case-control method and 89.7% (15.9%–98.7%; aOR, 0.103 [.013–.841]; P = .03) with the screening method.
VI on MenB Disease
Five years after the implementation of the 4CMenB program, a relative reduction of 72.7% was observed in the incidence of MenB disease among infants aged 12 weeks to 11 months (aIRR, 0.273 [95% CI, .120–620]) (Tables 1 and 2). No significant reduction was observed among children aged 3–8 years, who were partially eligible for the ongoing and catch-up childhood programs and had lower vaccine coverage than the infant cohort. A relative reduction of 76.2% in the MenB incidence among adolescents aged 15–18 years was observed 5 years after the introduction of the ongoing adolescent program (aIRR, 0.238 [95% CI, .097–.584).
Table 1.
Incidence of Meningococcal B Disease Before and 5 Years After the Implementation of the Childhood Ongoing and Catch-up Programs in September 2023
| Age Group | Prevaccination Perioda | Postvaccination Perioda | IRR (95% CI) [P Value] | |||
|---|---|---|---|---|---|---|
| Unadjustedb | Adjustedc | |||||
| Average Annual No. of MenB Cases | Annual Incidence of MenB Disease (per 100 000 Population) | Average Annual No. of MenB Cases | Annual Incidence of MenB Disease (per 100 000 Population) | Post- vs Prevaccination Period | Post- vs Prevaccination Period | |
| 0–12 wkd | 0 | 0 | 0.4 | 9.059 | 0 (Not calculable) | … |
| 12 wk to 1 y | 2.667 | 17.198 | 1 | 6.794 | 0.395 (.196–.798) [.01] | 0.273 (.120–.620) [.002] |
| 1 y | 1.333 | 6.569 | 0.4 | 2.073 | 0.316 (.046–2.170) [.24] | 0.219 (.026–1.840) [.16] |
| 2 y | 1.333 | 6.571 | 0.8 | 4.067 | 0.618 (.196–1.959) [.41] | 0.430 (.121–1.529) [.19] |
| 3–8 y | 1.333 | 1.091 | 0.8 | 0.640 | 0.587 (.136–2.540) [.48) | 0.408 (.076–2.178) [.29] |
| 9–14 yd | 0.333 | 0.284 | 1.8 | 1.415 | 4.985 (1.326–18.734) [.02] | … |
Abbreviations: CI, confidence interval; IRR, incidence rate ratio; MenB, meningococcal B.
aThe prevaccination period for these programs was October 2012 to September 2018, and the postvaccination period, October 2018 to September 2023.
bThese IRRs were estimated in separate models for each age cohort and adjusted only to account for changes in the population denominators.
cThese IRRs were adjusted according to changes in the incidence of MenB disease in the age cohorts of children/adolescents who were not eligible to receive the free MenB vaccine.
dAge cohorts not eligible for the state MenB program were included but were not compared between the prevaccination and vaccination periods in the vaccine eligibility–adjusted regression model.
Table 2.
Incidence of Meningococcal B Disease Before and 2 Years After Implementation of the Adolescent Ongoing and Adolescent/Young Adult Catch-up Programs
| Age Group, y | Prevaccination Perioda | Postvaccination Perioda | IRR (95% CI) [P Value] | |||
|---|---|---|---|---|---|---|
| Unadjustedb | Adjustedc | |||||
| Average Annual No. of MenB Cases | Annual Incidence of MenB Disease (per 100 000 Population) | Average Annual No. of MenB Cases | Annual Incidence of MenB Disease (per 100 000 Population) | Post- vs Prevaccination Period | Post- vs Prevaccination Period | |
| 15–18 | 4 | 4.846 | 1.2 | 1.460 | 0.301 (.154–.591) [<.001] | 0.238 (.097–.584) [.002) |
| 19–21 | 3.875 | 5.738 | 1.6 | 2.446 | 0.426 (.180–1.007) [.052] | 0.337 (.105–1.083) [.07] |
| 22–25 | 1.25 | 1.342 | 0.8 | 0.849 | 0.633 (.160–2.505) [.51] | 0.501 (.130–1.933) [.32] |
Abbreviations: CI, confidence interval; IRR, incidence rate ratio; MenB, meningococcal B.
aThe prevaccination period for these programs was February 2011 to January 2019, and the postvaccination period, February 2019 to January 2024.
bThese IRRs were estimated in separate models for each age cohort and adjusted only to account for changes in the population denominators.
cThese IRRs were adjusted according to changes in the incidence of MenB disease in the age cohorts of adolescents/young adults who were not eligible to receive the free MenB vaccine. Age cohorts of adolescents/young adults who were not eligible to receive the vaccine were included but not compared between pre- and postvaccination periods in the adjusted model.
VE Against Gonococcal Infections
The analysis included 1637 gonococcal and 7724 chlamydia patients (Table 3). Using chlamydia controls, the VE was 39.1% for people who received 2 doses compared with those who were unvaccinated (95% CI, 31.3%–46.0%), after adjustment for age, sex, and socioeconomic status (Table 4).
Table 3.
Characteristics of Gonococcal Case Patients and Chlamydia Controls
| Characteristic | No. (%)a | ||
|---|---|---|---|
| Gonococcal Case Patients (n = 1637) |
Chlamydia Controls (n = 7724) |
Total (N = 9361) |
|
| Age, mean (SD), y | 19.34 (2.30) | 19.58 (1.90) | 19.54 (1.98) |
| Sex | |||
| Female | 840 (51.31) | 5080 (65.77) | 5920 (63.24) |
| Male | 797 (48.69) | 2632 (34.08) | 3429 (36.63) |
| Not stated | 0 | 12 (.16) | 12 (0.13) |
| Aboriginal background | |||
| No | 1171 (71.53) | 5211 (67.47) | 6382 (68.18) |
| Aboriginal and/or Torres Strait Islander | 459 (28.04) | 403 (5.22) | 862 (9.21) |
| Not stated | 6 (0.37) | 2104 (27.24) | 2110 (22.54) |
| Missing | 1 (0.06) | 6 (0.08) | 7 (0.07) |
| Socioeconomic status | |||
| Low | 985 (60.17) | 3627 (46.96) | 4612 (49.27) |
| Middle | 350 (21.38) | 2006 (25.97) | 2356 (25.17) |
| High | 287 (17.53) | 2023 (26.19) | 2310 (24.68) |
| Missing | 15 9 (0.92) | 68 (0.88) | 83 (0.89) |
| Doses of 4CMenB | |||
| 0 | 1048 (64.02) | 3867 (50.06) | 4915 (52.51) |
| 1 | 83 (5.07) | 493 (6.38) | 576 (6.15) |
| 2 | 498 (30.42) | 3329 (43.10) | 3827 (40.88) |
| 3 | 6 (0.37) | 25 (0.32) | 31 (0.33) |
| 4 | 2 (0.12) | 10 (0.13) | 12 (0.13) |
| Months since receipt of 2nd vaccine dose | |||
| No 2nd dose or <3 m | 1131 (69.09) | 4360 (56.45) | 5491 (58.66) |
| 3–36 m | 207 (12.65) | 1547 (20.03) | 1754 (18.74) |
| 37–48 m | 160 (9.77) | 912 (11.81) | 1072 (11.45) |
| 49–60 m | 80 (4.89) | 553 (7.16) | 633 (6.76) |
| >60 m | 59 (3.60) | 352 (4.56) | 411 (4.39) |
| Chlamydia coinfection at time of 1st gonococcal diagnosis | |||
| Yes | 526 (32.13) | 0 | 526 (5.62) |
| No | 1111 (67.87) | 7724 (100) | 8835 (94.38) |
| Repeated infections | Repeated gonococcal infections | Repeated chlamydia infections | |
| Yes | 249 (15.21) | 1278 (16.55) | 1527 (16.31) |
| No | 1388 (84.79) | 6446 (83.45) | 7834 (83.69) |
aData represent no. (%) of case patients or controls, unless otherwise specified. Gonococcal case patients include individuals who had gonococcal infections, with or without chlamydia coinfections. Chlamydia controls include individuals with chlamydia only, without gonococcal coinfections.
Table 4.
Adjusted Odds Ratios and Vaccine Effectiveness for 2-Dose 4CMenB Vaccination Against Gonococcal Infections in Primary and Sensitivity Analyses
| Analysis | aOR (95% CI) [P Value] | VE (%) (95% CI), % |
|---|---|---|
| Primary analysis: vaccinated (within >3 m) with 2-dose 4CMenB vs unvaccinateda | 0.609 (.540–.687) [<.001] | 39.1 (31.3 –46.0) |
| Subgroup analysis by duration of protection | ||
| Vaccinated within 3–60 mb | 0.582 (.513–.660) [<.001] | 41.8 (34.0–48.7) |
| Vaccinated within >60 mc | 1.063 (.782–1.445) [.70] | −6.3 (−44.5 to 21.8) |
| Subgroup analysis by sex at birth | ||
| Femaled | 0.596 (.507–.699) [<.001] | 40.4 (30.1–49.3) |
| Malee | 0.630 (.525–.755) [<.001] | 37.0 (24.5–47.5) |
| Subgroup analysis by chlamydia coinfection status | ||
| Gonococcal case patients with chlamydia coinfection vs chlamydia controlsf | 0.525 (.430–.643) [<.001] | 47.5 (35.7–57.0) |
| Gonococcal case patients without coinfection vs chlamydia controlsg | 0.653 (.568–.751) [<.001] | 34.7 (24.9–43.2) |
Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; VE, vaccine effectiveness
aFor the primary analysis, 1613 gonococcal case patients (cases) were included, and 7609 chlamydia controls were matched to gonococcal cases with replacement (283 455 chlamydia controls included after matching).
bFor 1556 gonococcal cases included, 7266 chlamydia controls were matched to gonococcal cases with replacement (258 097 chlamydia controls included after matching).
cFor 1175 gonococcal cases included, 4635 chlamydia controls were matched to gonococcal cases with replacement (137 989 chlamydia controls included after matching).
dFor 833 gonococcal cases included, 5028 chlamydia controls were matched to gonococcal cases with replacement (91 764 chlamydia controls included after matching).
eFor 773 gonococcal cases included, 2574 chlamydia controls were matched to gonococcal cases with replacement (50 400 chlamydia controls included after matching).
fFor 516 gonococcal cases included, 7602 chlamydia controls were matched to gonococcal cases with replacement (86 670 chlamydia controls included after matching).
gFor 1097 gonococcal cases included, 7608 chlamydia controls were matched to gonococcal cases with replacement (196 785 chlamydia controls included after matching).
In the sensitivity analyses, lower VE estimates were demonstrated beyond 60 months after vaccination (−6.3% [95% CI, −44.5% to 21.8%]), and VE estimates were higher 3–60 months after vaccination (41.8% [34.0%– 48.7%]) (Tables 4 and 5). The VE estimates increased when comparing gonococcal case patients coinfected with chlamydia and chlamydia controls and decreased when patients with coinfection were excluded. However, the CIs overlapped. Although the VE estimate was higher in female than in male patients, no statistically significant difference was observed between the 2 subgroups, as indicated by the substantial overlap of CIs.
Table 5.
Adjusted Odds Ratios and Vaccine Effectiveness for 2-Dose 4CMenB Vaccination Against Gonococcal Infections in Sensitivity Analyses by Months Since Vaccination (Sensitivity Analyses)a
| Time Since Vaccination With 2-Dose 4CMenB, m | aOR (95% CI) [P Value] |
VE (95% CI), % |
|---|---|---|
| 3–12b | 0.667 (.459–.971) [.04] | 33.3 (2.9–54.1) |
| >12c | 0.605 (.536–.684) [<.001] | 39.5 (31.6–46.4) |
| 3–24d | 0.463 (.367–.585) [<.001] | 53.7 (41.5–63.3) |
| >24e | 0.663 (.584–.754) [<.001] | 33.7 (24.6–41.6) |
| 3–36f | 0.470 (.396–.557) [<.001] | 53.0 (44.3–60.4) |
| >36g | 0.801 (.692–.927) [.003] | 19.9 (7.3–30.8) |
| 3–48h | 0.569 (.496–.652) [<.001] | 43.1 (34.8–50.4) |
| >48i | 0.838 (.682–1.029) [.09] | 16.2 (−2.9 to 31.8) |
| 37–60j | 0.774 (.661–.906) [.001] | 22.6 (9.4–33.9) |
Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; VE, vaccine effectiveness.
aAnalyses comparing completely vaccinated (2-dose 4CMenB) with unvaccinated case patients.
bFor 1157 gonococcal case patients (cases) included, 4473 chlamydia controls were matched to gonococcal cases with replacement (126 438 chlamydia controls included after matching).
cFor 1574 gonococcal cases included, 7428 chlamydia controls were matched to gonococcal cases with replacement (272 743 chlamydia controls included after matching).
dFor 1217 gonococcal cases included, 4995 chlamydia controls were matched to gonococcal cases with replacement (143 505 chlamydia controls included after matching).
eFor 1514 gonococcal cases included, 6906 chlamydia controls were matched to gonococcal cases with replacement (248 470 chlamydia controls included after matching).
fFor 1319 gonococcal cases included, 5819 chlamydia controls were matched to gonococcal cases with replacement (175 125 chlamydia controls included after matching).
gFor 1412 gonococcal cases included, 6082 chlamydia controls were matched to gonococcal cases with replacement (209 955 chlamydia controls included after matching).
hFor 1479 gonococcal cases included, 6720 chlamydia controls were matched to gonococcal cases with replacement (224 980 chlamydia controls included after matching).
iFor 1252 gonococcal cases included, 5181 chlamydia controls were matched to gonococcal cases with replacement (164 057 chlamydia controls included after matching).
jFor 1355 gonococcal cases included, 5739 chlamydia controls were matched to gonococcal cases with replacement (187 685 chlamydia controls included after matching).
In the adjusted Cox regression model, the risk of the subsequent gonococcal infection in vaccinated case patients with 2-dose 4CMenB was lower than in unvaccinated case patients (adjusted hazard ratio, 0.730 [95% CI, .540 to .988]; P = .04). The average follow-up duration was 1639.7 days (range, 115–1825 days).
VI on Gonococcal Infections
The negative binomial regression model showed a 35.5% relative reduction (aIRR, 0.645 [95% CI, .436–.955]) in the incidence of gonococcal infections in adolescents aged 15–17 years 5 years after the implementation of the state MenB program (Table 6).
Table 6.
Incidence of Gonococcal Infection Before and After the Implementation of the Adolescent Ongoing and Adolescent/Young Adult Catch-up Programs
| Age Group, y | Average Annual No. of Gonococcal Notifications (Annual Incidence of Gonococcal Notifications per 100 000 Population) | aIRRa (95% CI) (Postvaccination vs Prevaccination Period) | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2/2011–1/2012 | 2/2012–1/2013 | 2/2013–1/2014 | 2/2014–1/2015 | 2/2015–1/2016 | 2/2016–1/2017 | 2/2017–1/2018 | 2/2018–1/2019 | 2/2019–1/2020 | 2/2020–1/2021 | 2/2021–1/2022 | 2/2022–1/2023 | 2/2023–1/2024 | 2/2017–1/2018 | 2/2018–1/2019 | 2/2019–1/2020 | 2/2020–1/2021 | 2/2021–1/2022 | 2/2022–1/2023 | 2/2023–1/2024 | |
| 15–17 | 48.5 (78.769) (Prevaccination period 2011–2017) | 45.5 (75.693) (“B Part of It” study periodb) | 76.8 (124.525) (Postvaccination period 2019–2024) | 0.600 (.402–.894) [.01] (“B Part of It” study periodb) | 0.645 (.436–.955) [.03] (Postvaccination period 2019–2024) | |||||||||||||||
| 18–20 | 110.5 (167.762) (Prevaccination period 2011–2019) | 193.2 (303.748) (Postvaccination period 2019–2024] | 0.862 (.606–1.227) [.41] (Postvaccination period 2019–2024) | |||||||||||||||||
| 21–26c | 291 (208.632) (Prevaccination period 2011–2020) | 440 (312.876) (Postvaccination period 2020–2024) | 0.769 (.535–1.106) [.16] (Postvaccination period 2020–2024) | |||||||||||||||||
Abbreviations: aIRR, adjusted incidence rate ratio; CI, confidence interval.
aThe aIRRs, comparing postvaccination versus prevaccination periods, were adjusted according to changes in the incidence of gonococcal notifications in all 3 age cohorts of adolescents/young adults who were not eligible to receive the free 4CMenB vaccine.
bThe impact of the “B Part of It” study was accounted for in the adjusted model, as this was a state-wide vaccination initiative. The 4CMenB vaccinations were administered in 237 schools and campuses across metropolitan Adelaide and rural and remote South Australia, representing 96.1% of enrolled senior school students.
cThe cohort of young adults, ranging in age from 21 to 26 years, did not meet the criteria for the state meningococcal B (MenB) immunization program in 2019. As those who were <21 years old in 2019 advanced in age and transitioned into the 21–26-year age group in 2020, this cohort became partially eligible for the state MenB immunization program after 2020, with low vaccine coverage.
DISCUSSION
The real-world evidence for long-term protection of 4CMenB against MenB in infants, children and adolescents is strong. Moderate protection against gonorrhea in adolescents appears to wane about 4–5 years after vaccination.
Our results of VE against MenB align with estimates from other studies that used similar methods. VE estimates in the United Kingdom [3, 5], Italy [13, 14], Portugal [15], Spain [12], and Canada [6, 7] ranged from 55% to 100% [17]. At the 5-year evaluation, 2 MenB cases were observed in individuals fully vaccinated for their age: 1 with 2 primary doses and 1 booster dose and the other with 2 primary doses received through the childhood catch-up program. For older children eligible only for the 2-dose catch-up program, the point estimate for VE was 82%. For younger children eligible for the 3-dose schedule, the VE was 99%. Moreover, half of the MenB cases in children were reported in infants <1 year of age, with 2 being too young to receive vaccination. In the United Kingdom, following the introduction of 4CMenB, a shift in the peak age of MenB cases from 5–6 months to 1–3 months was observed [4].
The results of VI on MenB are within the range reported in studies in other countries and consistent with results in our previous evaluations [17, 28]. The estimates of VI in previous studies have a wide range of 50% to 100%, depending on study design, 4CMenB dosing schedule, targeting populations and statistical methods [28]. The VI results demonstrate a relative reduction associated with the 4CMenB program and are generally easy to understand and communicate to the public. However, the analysis does not account for vaccine uptake and may be susceptible to confounding factors (eg, sexual behavior risk and Aboriginal status) due to trends unrelated to the intervention [34].
Our results confirm the moderate protection provided by 4CMenB against gonococcal infection. The VE estimate is consistent with findings from our previous evaluations and most studies conducted in the United States [25–27], Italy [22], and New Zealand [18, 19], with VE ranging from 31% to 47%, despite the use of different methods in those studies [17]. One study conducted in France showed insignificant lower VE estimate (adjusted hazard ratio, 0.78 [95% CI, .60–1.01]; P = .06) against gonococcal infection in an open-label randomized trial [23]. The French study was prematurely discontinued before reaching the required sample size.
Another observational study conducted in Northern California showed 23% protection (adjusted prevalence ratio, 0.77 [95% CI, .64–.99]) in a limited mode but no significant effect in the expanded model [35]. In this observational study, vaccine coverage was extremely low, with a 2-dose vaccination rate of 0.2% among all individuals. With such low vaccine coverage, there may not be enough vaccinated individuals among the case patients (0.1% of gonococcal case patients fully vaccinated with 2-dose 4MenB) or controls (0.2% of chlamydia controls fully vaccinated) to reliably estimate the vaccine effect [36]. Given the low vaccination coverage, it is challenging to draw definitive conclusions from the gonococcal data, particularly as the CIs are wide. As such, it was difficult to determine whether the intervention provides moderate protection. All other observational studies were conducted in populations or high-risk groups with a much higher vaccine coverage.
Our findings suggest that protection against gonococcal infection may wane by 4–5 years after the 2-dose 4CMenB vaccination series. However, due to limited case numbers and follow-up duration, we are unable to precisely determine the optimal timing for a booster dose. Further longitudinal studies incorporating immunogenicity data are necessary to identify the most effective booster schedule to maintain or enhance vaccine-induced protection against gonorrhea. Using 4CMenB to protect against gonococcal infection in high-risk groups as recommended in the United Kingdom may require a booster dose at 4–5 years [17]. The Cox regression model showed 2-dose 4CMenB significantly reduced the risk of the subsequent gonococcal infection in fully vaccinated compared to unvaccinated gonococcal case patients. This is important evidence to support programs in high-risk groups, such as the UK recommendation.
Previous research has shown that N. gonorrhoeae can evade or resist host immune responses to natural infection. Further studies are needed to investigate the cellular and humoral responses against N. gonorrhoeae following 4CMenB vaccination, in order to fully understand both natural immunity and the potential for vaccine-mediated immunity to N. gonorrhoeae infection [37]. Consistent with our previous evaluation results, no significant difference in VE was found in gonococcal case patients with or without coinfection with chlamydia, which contrasts with findings from the studies conducted in New Zealand [19] and the United States [25].
The major strengths of this study include a large-scale cohort with high vaccine coverage and the well-established AIR, which records vaccinations for all individuals in Australia. However, our study has limitations. MenB case patients received 4CMenB at various time points during the evaluation period, and the small sample size limits our ability to estimate VE at specific postvaccination intervals (eg, 2, 3, or 5 years after vaccination). The sustained protection provided by the vaccine likely contributed to the low number of MenB case patients, further limiting our ability to assess potential waning of effectiveness over time. We were also unable to incorporate genomic surveillance data into our analysis, so it remains unclear whether the fully vaccinated MenB case patients resulted from suboptimal immune response or from exposure to strains not covered by 4CMenB. However, previous work using the Meningococcal Antigen Typing System (MATS) estimated that approximately 90% of circulating MenB strains in South Australia would be covered by 4CMenB [38]. Clinical outcomes and severity of meningococcal disease were not included in the evaluation, so we were also unable to assess VE against severe disease.
Another limitation is the reliance on routinely collected notifiable disease data. Although reporting of meningococcal disease is likely to be complete due to its clinical severity, mandatory reporting requirements, and laboratory confirmation, underascertainment may still occur for more frequently underdiagnosed conditions, such as gonorrhea and chlamydia. Asymptomatic infections, variations in healthcare-seeking behavior, and differences in testing practices may lead to incomplete case capture. These factors may introduce misclassification bias and influence the observed estimates of VE.
Our evaluations have provided definitive data on the potential waning of immunity against gonococcal infections, supporting the consideration of booster vaccinations to ensure adequate protection against both diseases with a single vaccine.
Notes
Author contributions. J. W. and H. M. led the project. B. W., P. A., M. M., L. F., J. W., and H. M. designed the study protocol. R. B. and C. B. were involved in the design of the study. B. W. and L. G. performed the analysis. B. W. wrote the first draft. R. B., S. A., N. L., C. B., and L. F. organized or were involved in data collection. All named authors were involved in the interpretation of data and critical review of the content and have approved the final version for publication. B. W. and L. G. accessed and verified all the data. H. M. had final responsibility for the decision to submit the manuscript for publication.
Disclaimer. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the publication.
Data sharing. All analyses were performed using deidentified disease notification data provided by the Communicable Disease Control Branch of SA Health, Government of South Australia, and immunization records provided by the Australian Immunisation Register. The deidentified individual disease notification data with the serogroup B meningococcal disease vaccination history, and a data dictionary defining each field in the set can be made available to others on the approval of the Commonwealth Department of Health and the South Australia Department for Health and Wellbeing Human Research Ethics Committee. The study protocol has been published in a peer-reviewed journal. The full study protocol and statistical analysis plan can be made available on request, by contacting B. W. or H. M.
Financial support . The study is funded by Australian Government Department of Health and Aged Care (Blood Borne Viruses and Sexually Transmissible Infections Research Grant GO5055).
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
Bing Wang, Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia; Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
Lynne Giles, Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; School of Public Health, The University of Adelaide, Adelaide, South Australia, Australia.
Prabha Andraweera, Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia; Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
Mark McMillan, Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia; Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
Rebecca Beazley, Communicable Disease Control Branch, SA Health, Adelaide, South Australia, Australia.
Sara Almond, Communicable Disease Control Branch, SA Health, Adelaide, South Australia, Australia.
Noel Lally, Communicable Disease Control Branch, SA Health, Adelaide, South Australia, Australia.
Charlotte Bell, Communicable Disease Control Branch, SA Health, Adelaide, South Australia, Australia.
Louise Flood, Communicable Disease Control Branch, SA Health, Adelaide, South Australia, Australia.
James Ward, UQ Poche Centre for Indigenous Health, University of Queensland, Brisbane, Queensland, Australia.
Helen Marshall, Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia; Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
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