Comprehensive observational study evaluating the enduring effectiveness of 4CMenB, the meningococcal B vaccine against gonococcal infections in the Northern Territory and South Australia, Australia: study protocol.

INTRODUCTION: The effectiveness of antibiotics for treating gonococcal infections is compromised due to escalating antibiotic resistance; and the development of an effective gonococcal vaccine has been challenging. Emerging evidence suggests that the licensed meningococcal B (MenB) vaccine, 4CMenB is effective against gonococcal infections due to cross-reacting antibodies and 95% genetic homology between the two bacteria, Neisseria meningitidis and Neisseria gonorrhoeae, that cause the diseases. This project aims to undertake epidemiological and genomic surveillance to evaluate the long-term protection of the 4CMenB vaccine against gonococcal infections in the Northern Territory (NT) and South Australia (SA), and to determine the potential benefit of a booster vaccine doses to provide longer-term protection against gonococcal infections. METHODS AND ANALYSES: This observational study will provide long-term evaluation results of the effectiveness of the 4CMenB vaccine against gonococcal infections at 4-7 years post 4CMenB programme implementation. Routine notifiable disease notifications will be the basis for assessing the impact of the vaccine on gonococcal infections. Pathology laboratories will provide data on the number and percentage of N. gonorrhoeae positive tests relative to all tests administered and will coordinate molecular sequencing for isolates. Genome sequencing results will be provided by SA Pathology and Territory Pathology/New South Wales Health Pathology, and linked with notification data by SA Health and NT Health. There are limitations in observational studies including the potential for confounding. Confounders will be analysed separately for each outcome/comparison. ETHICS AND DISSEMINATION: The protocol and all study documents have been reviewed and approved by the SA Department for Health and Well-being Human Research Ethics Committee (HREC/2022/HRE00308), and the evaluation will commence in the NT on receipt of approval from the NT Health and Menzies School of Health Research Human Research Ethics Committee. Results will be published in peer-reviewed journals and presented at scientific meetings and public forums.

THE ROLE OF SCHOOLS IN MENINGOCOCCAL CARRIAGE AMONG ADOLESCENTS AND YOUNG ADULTS IN SOUTH AUSTRALIA.

Neisseria meningitidis carriage peaks in adolescents. This secondary analysis of a randomized controlled trial (NCT03089086) assessing 4CMenB herd protection in South Australia ("B-Part-of-It" study) explored school attributes linked to baseline carriage in 34,489 adolescents prevaccination. Carriage was higher in students attending single-sex [adjusted odds ratio (aOR): 1.49; 95% confidence interval (CI): 1.14-1.93], boarding (aOR: 1.92; 1.13-3.27) and government schools (aOR: 1.32, 1.09-1.61).

Longitudinal study of meningococcal carriage in adolescents and young adults in South Australia 2017-2020.

BACKGROUND: This analysis investigated longitudinal changes in meningococcal carriage in adolescents in South Australia over 4 years. METHODS: Data from the "B Part of It" study, which included a state-wide cluster randomized controlled trial in secondary-school students (n = 34,489 in 2017 and 2018) and serial cross-sectional studies in school leavers aged 17-25 years (n = 4028 in 2019-2020). Individuals had oropharyngeal swabs collected annually. This study included two unique cohorts: (1) individuals enrolled in 2019, with three consecutive annual swabs taken in 2017, 2018 and 2019; and (2) individuals enrolled in 2020, with swabs taken in 2017, 2018, and 2020. Disease-associated N. meningitidis genogroups were identified using PCR and whole genome sequencing. Univariate analysis identified risk factors for recurrent carriage (≥2). RESULTS: Among school leavers, 50 (1.7%, total n = 2980) had carriage detected at successive visits. In participants with meningococcal carriage at successive visits, 38/50 (76.0%) had the same genogroup detected by porA PCR. Of those, 19 had the same MLST type and demonstrated minimal variation, indicating they most likely had sustained carriage of the same isolate (range 226 to 490 days, mean duration 352 [SD 51] days). In the 2019 school leaver cohort, 6.7% acquired carriage in their first year out of school compared to 3.3% in their final school year. Compared to single carriage detection, recurrent carriage was potentially more likely in older adolescents (16 compared to ≤15 years; OR = 1.97 (95%CI 1.0, 3.86); p = 0.048). CONCLUSION: Whilst carriage is typically transient, some adolescents/young adults may have persistent carriage and are likely to be an important group in the transmission of meningococci.

The genomic epidemiology of Neisseria meningitidis carriage from a randomised controlled trial of 4CMenB vaccination in an asymptomatic adolescent population.

Background: Oropharyngeal carriage of Neisseria meningitidis is frequent during adolescence, representing a major source of invasive meningococcal disease. This study examined the impact of a serogroup B vaccination (Bexsero, GSK 4CMenB) programme on adolescent N. meningitidis carriage using genomic data. Methods: A total 34,489 oropharyngeal samples were collected as part of a state-wide cluster randomised-controlled trial in South Australia during 2017 and 2018 (NCT03089086). Samples were screened for the presence of N. meningitidis DNA by porA PCR prior to culture. Whole genome sequencing was performed on all 1772 N. meningitidis culture isolates and their genomes were analysed. Findings: Unencapsulated meningococci were predominant at baseline (36.3% of isolates), followed by MenB (31.0%), and MenY (20.5%). Most MenB were ST-6058 from hyperinvasive cc41/44, or ST-32 and ST-2870 from cc32. For MenY, ST-23 and ST-1655 from cc23 were prevalent. Meningococcal carriage was mostly unchanged due to the vaccination programme; however, a significant reduction in ST-53 capsule-null meningococci prevalence was observed in 2018 compared to 2017 (OR = 0.52; 95% CI: 0.30-0.87, p = 0.0106). This effect was larger in the vaccinated compared to the control group (OR = 0.37; 95% CI: 0.12-0.98, p = 0.0368). Interpretation: While deployment of the 4CMenB vaccination did not alter the carriage of hyperinvasive MenB in the vaccinated population, it altered the carriage of other N. meningitidis sequence types following the vaccination program. Our findings suggest 4CMenB vaccination is unlikely to reduce transmission of hyperinvasive N. meningitidis strains and therefore ongoing targeted vaccination is likely a more effective public health intervention. Funding: This work was funded by GlaxoSmithKline Biologicals SA.

Geographical distribution of invasive meningococcal disease and carriage: A spatial analysis.

Little information exists concerning the spatial relationship between invasive meningococcal disease (IMD) cases and Neisseria meningitidis (N. meningitidis) carriage. The aim of this study was to examine whether there is a relationship between IMD and asymptomatic oropharyngeal carriage of meningococci by spatial analysis to identify the distribution and patterns of cases and carriage in South Australia (SA). Carriage data geocoded to participants' residential addresses and meningococcal case notifications using Postal Area (POA) centroids were used to analyse spatial distribution by disease- and non-disease-associated genogroups, as well as overall from 2017 to 2020. The majority of IMD cases were genogroup B with the overall highest incidence of cases reported in infants, young children, and adolescents. We found no clear spatial association between N. meningitidis carriage and IMD cases. However, analyses using carriage and case genogroups showed differences in the spatial distribution between metropolitan and regional areas. Regional areas had a higher rate of IMD cases and carriage prevalence. While no clear relationship between cases and carriage was evident in the spatial analysis, the higher rates of both carriage and disease in regional areas highlight the need to maintain high vaccine coverage outside of the well-resourced metropolitan area.

4CMenB sustained vaccine effectiveness against invasive meningococcal B disease and gonorrhoea at three years post programme implementation.

OBJECTIVES: To evaluate persistence of vaccine effectiveness (VE) and vaccine impact (VI) on invasive meningococcal B (MenB) disease and gonorrhoea at three years after implementation of a state funded 4CMenB programme for infants, children, adolescents and young people in South Australia. METHODS: VI was assessed using a Poisson or negative binomial regression model, and VE was estimated using screening and case-control methods. Chlamydia controls were used to estimate VE in the primary analysis to control potential confounding effects such as high-risk sexual behaviour associated with sexually transmitted infections. RESULTS: During the three-year programme, reductions of 63.1% (95%CI 29.0-80.9%) and 78.5% (95%CI 33.0-93.1%) in incidence of MenB disease were observed in infants and adolescents, respectively. There were no cases in infants who had received three doses of 4CMenB. Two-dose VE against MenB disease was 90.7% (95%CI 6.9-99.1%) for the childhood programme and 83.5% (95%CI 0-98.2%) for the adolescent programme. Two-dose VE against gonorrhoea in adolescents was 33.2% (95%CI 15.9-47.0%). Lower VE estimates were demonstrated after 36 months post-vaccination (23.2% (95%CI 0-47.5%)> 36 months post-vaccination compared to 34.9% (95%CI 15.0-50.1%) within 6-36 months). Higher VE estimates were found after excluding patients with repeat gonorrhoea infections (37.3%, 95%CI 19.8-51.0%). For gonorrhoea cases co-infected with chlamydia VE was maintained (44.7% (95%CI 17.1-63.1%). CONCLUSION: The third-year evaluation results show persistent vaccine effectiveness of 4CMenB against MenB disease in infants and adolescents. As this is the first ongoing programme for adolescents, moderate vaccine protection against gonorrhoea with waning effectiveness three years post-vaccination was demonstrated in adolescents and young adults. The additional protection of 4CMenB vaccine against gonorrhoea, likely through cross-protection should be considered in cost-effectiveness analyses. A booster dose may need to be further evaluated and considered in adolescents due to waning protection against gonorrhoea demonstrated after 36 months post-vaccination.

Neonatal Group B Streptococcal Infection in Australia: A Case-control Study.

BACKGROUND: To determine maternal and neonatal risk factors for, and incidence of, neonatal early-onset group B streptococcus (EOGBS) and late-onset (LOGBS) infection in South Australia (SA) and the Northern Territory (NT). METHODS: A case-control study with 2:1 matched controls to cases. The study included tertiary hospitals in South Australia and the Northern Territory, Australia. Retrospective data were collected from a 16-year epoch (2000-2015). RESULTS: Of a total of 188 clinically suspected or confirmed cases, 139 were confirmed, of which 56.1% (n = 78) were EOGBS and 43.9% (n = 61) were LOGBS. The incidence of clinically suspected and confirmed cases of EOGBS was 0.26/1000 live births in SA and 0.73/1000 live births in the NT, and the incidence of confirmed cases was 0.19/1000 for SA and 0.36/1000 for the NT. The incidence of clinically suspected or confirmed LOGBS was 0.18/1000 live births in SA and 0.16/1000 for the NT. The majority of infants with GBS presented with sepsis, pneumonia, or meningitis. Developmental delay was the most commonly recorded long-term complication at 1 year old. Risk factors for EOGBS included maternal GBS carriage, previous fetal death, identifying as Aboriginal and/or Torres Strait Islander, and maternal fever in labor/chorioamnionitis. CONCLUSIONS: GBS remains a leading cause of neonatal morbidity and mortality. Adding previous fetal death to GBS screening guidelines would improve GBS prevention. The introduction of maternal GBS vaccination programs should be guided by country-specific disease epidemiology.

A Systematic Review and Meta-Analysis on the Real-World Effectiveness of COVID-19 Vaccines against Infection, Symptomatic and Severe COVID-19 Disease Caused by the Omicron Variant (B.1.1.529).

Real-world data on the effectiveness of COVID-19 vaccines against the Omicron variant (B.1.1.529) is limited. This systematic review aimed to investigate the real-world effectiveness and durability of protection conferred by primary course and booster vaccines against confirmed Omicron infection, and severe outcomes. We systematically searched literature up to 1 August 2022. Meta-analysis was performed with the DerSimonian-Laird random-effects model to estimate the pooled vaccine effectiveness (VE). Overall, 28 studies were included representing 11 million individuals. The pooled VE against Omicron infection was 20.4% (95%CI: 12.1-28.7%) and 23.4% (95%CI: 13.5-33.3%) against symptomatic infection with variation based on vaccine type and age groups. VE sharply declined from 28.1% (95%CI: 19.1-37.1%) at three months to 3.9% (95%CI: -24.8-32.7%) at six months. Similar trends were observed for symptomatic Omicron infection. A booster dose restored protection against Omicron infection up to 51.1% (95%CI: 43.8-58.3%) and 57.3% (95%CI: 54.0-60.5%) against symptomatic infection within three months; however, this waned to 32.8% (95%CI: 16.8-48.7%) within six months. VE against severe Omicron infection following the primary course was 63.6% (95%CI: 57.5-69.7%) at three months, decreased to 49% (95%CI: 35.7-63.4%) within six months, and increased to 86% after the first or second booster dose.

Impact of COVID-19 Containment Strategies and Meningococcal Conjugate ACWY Vaccination on Meningococcal Carriage in Adolescents.

OBJECTIVES: To examine if COVID-19 containment strategies were associated with reduced pharyngeal carriage of meningococci in adolescents. Also, to observe if carriage prevalence of meningococcal A, C, W and Y differed in meningococcal conjugate ACWY vaccinated and unvaccinated adolescents. DESIGN: Repeat cross-sectional study of pharyngeal carriage. SETTING: In 2020, recruitment commenced from February to March (pre-COVID-19) and recommenced from August to September (during COVID-19 measures) in South Australia. PARTICIPANTS: Eligible participants were between 17 and 25 years of age and completed secondary school in South Australia in 2019. RESULTS: A total of 1338 school leavers were enrolled in 2020, with a mean age of 18.6 years (standard deviation 0.6). Pharyngeal carriage of disease-associated meningococci was higher during the COVID-19 period compared with the pre-COVID-19 period (41/600 [6.83%] vs. 27/738 [3.66%]; adjusted odds ratio [aOR], 2.03; 95% CI: 1.22-3.39; P = 0.01). Nongroupable carriage decreased during COVID period (1.67% vs. 3.79%; aOR, 0.45; 95% CI: 0.22-0.95). Pharyngeal carriage of groups A, C, W and Y was similar among school leavers vaccinated with meningococcal conjugate ACWY (7/257 [2.72%]) compared with those unvaccinated (29/1081 [2.68%]; aOR, 0.86; 95% CI: 0.37-2.02; P = 0.73). Clonal complex 41/44 predominated in both periods. CONCLUSIONS: Meningococcal carriage prevalence was not impacted by public health strategies to reduce severe acute respiratory syndrome coronavirus 2 transmission and is unlikely to be the mechanism for lower meningococcal disease incidence. As international travel resumes and influenza recirculates, clinicians must remain vigilant for signs and symptoms of meningococcal disease. Vaccinating people at the highest risk of invasive meningococcal disease remains crucial despite containment strategies.

Effectiveness and impact of the 4CMenB vaccine against invasive serogroup B meningococcal disease and gonorrhoea in an infant, child, and adolescent programme: an observational cohort and case-control study.

BACKGROUND: A programme of vaccination with the four-component serogroup B meningococcal (4CMenB) vaccine was introduced in South Australia for infants and children aged 0-3 years on Oct 1, 2018, and for senior school students in school years 10 and 11 (aged 15-16 years) and young adults aged 17-20 years on Feb 1, 2019. We aimed to evaluate vaccine effectiveness and impact on serogroup B meningococcal disease and gonorrhoea 2 years after implementation of the programme. METHODS: We did a cohort and case-control study among those targeted by the South Australia 4CMenB vaccination programme. We obtained disease notification data from SA Health, Government of South Australia, and vaccine coverage data from the South Australian records of the Australian Immunisation Register. Vaccine effectiveness was estimated as the reduction in the odds of infection using the screening and case-control methods. Vaccine impact was estimated as incidence rate ratios (IRRs), obtained by comparing case numbers in each year following the start of the vaccination programme with cases in the equivalent age cohort during the pre-vaccination programme years. We used Poisson or negative binomial models, as appropriate, with adjustment for changes in the incidence of serogroup B meningococcal disease in age cohorts not eligible for vaccination through the state programme. FINDINGS: 4CMenB vaccine coverage 2 years after introduction of the childhood vaccination programme was 94·9% (33 357 of 35 144 eligible individuals) for one dose, 91·4% (26 443 of 28 922) for two doses, and 79·4% (15 440 of 19 436) for three doses in infants. The one-dose (77·1%, 16 422 of 21 305) and two-dose (69·0%, 14 704 of 21 305) coverage was highest in adolescents born in 2003 (approximately year 10 students). 2 years after implementation of the childhood vaccination programme, incidence of serogroup B meningococcal disease was significantly reduced compared with before programme implementation in infants aged 12 weeks to 11 months (adjusted IRR [aIRR] 0·40 [95% CI 0·23-0·69], p=0·0011), but not in those aged 1 year (0·79 [0·16-3·87], p=0·77), 2 years (0·75 [0·18-3·14], p=0·70), or 4 years (3·00 [0·47-18·79], p=0·24). aIRRs were not calculable in those aged 3 or 5 years because of no cases occurring after programme implementation. aIRR for serogroup B meningococcal disease was 0·27 (0·06-1·16, p=0·078) in adolescents aged 15-18 years 2 years after implementation of the adolescent and young adult programme, and 1·20 (0·70-2·06, p=0·51) in those aged 19-21 years in the first year. Two-dose vaccine effectiveness against serogroup B meningococcal disease was estimated to be 94·2% (95% CI 36·6-99·5) using the screening method and 94·7% (40·3-99·5) using the case-control method in children, and 100% in adolescents and young adults (no cases reported after implementation). Estimated two-dose vaccine effectiveness against gonorrhoea in adolescents and young adults was 32·7% (8·3-50·6) based on the case-control method using age-matched individuals with chlamydia infection as controls. INTERPRETATION: 4CMenB vaccine shows sustained effectiveness against serogroup B meningococcal disease 2 years after introduction in infants and adolescents, and moderate effectiveness against gonorrhoea in adolescents. The high vaccine effectiveness against serogroup B meningococcal disease is likely due to high coverage in the target age groups and close antigenic match between the 4CMenB vaccine and the disease-associated serogroup B meningococcal strains circulating in South Australia. COVID-19-related physical distancing policies might have contributed to further declines in serogroup B meningococcal disease cases during the programme's second year. FUNDING: SA Health, Government of South Australia.

Social and behavioral predictors of two-doses 4CMenB vaccine series among adolescents enrolled in a cluster randomized controlled trial in Australia.

This study aimed to determine social and behavioral predictors of completing a course of 4CMenB vaccine in adolescents in a parallel cluster randomized controlled trial enrolling secondary school students (approximately 15-18 years of age) in South Australia. Participating schools were randomized to vaccination at baseline (intervention) or 12 months (control). Students assigned to the intervention group were excluded because they have received the first dose of 4CMenB vaccine at baseline. Logistic regression models examined factors associated with non-vaccination or incomplete 4CMenB doses. The study population comprised 11391 students. Overall, 8.3% (n = 946) received no doses and 91.7% (n = 10445) at least one dose. Of 10445 students who initiated their primary dose, 1334 (12.8%) did not complete the two-dose course. The final adjusted model indicated factors associated with non-vaccination in school students were older age (adjusted odds ratio; aOR 7.83, 95% CI: 4.13-14.82), smoking cigarettes (aOR 3.24, 95% CI: 1.93-5.44), exposure to passive smoke (aOR 2.64, 95% CI: 1.48-4.71), Aboriginal or Torres Strait Islander (aOR 1.77, 95% CI: 1.23-2.55), smoking water pipes (aOR 1.94, 95% CI:1.28-2.92), low socioeconomic status (aOR 1.77, 95% CI:1.21-2.60), attending government schools (aOR 1.76, 95% CI: 1.28, 2.43) and participating in intimate kissing (aOR 1.40, 95% CI:1.10-1.79). Multivariable analysis for incomplete vaccination yielded similar findings. Social and behavioral predictors of non-vaccination or incomplete MenB doses were also known risk factors for carriage of Neisseria meningitidis. Immunization strategies to improve MenB vaccination completion need to be tailored to social behavior of adolescents.

4CMenB vaccine and its role in preventing transmission and inducing herd immunity.

INTRODUCTION: Vaccination is the most effective method of protecting people from invasive meningococcal disease (IMD). Of all the capsular groups, B is the most common cause of invasive meningococcal disease in many parts of the world. Despite this, adolescent meningococcal B vaccine programs have not been implemented globally, partly due to the lack of evidence for herd immunity afforded by meningococcal B vaccines. AREAS COVERED: This review aims to synthesize the available evidence on recombinant 4 CMenB vaccines' ability to reduce pharyngeal carriage and therefore provide indirect (herd) immunity against IMD. EXPERT OPINION: There is some evidence that the 4CMenB vaccine may induce cross-protection against non-B carriage of meningococci. However, the overall body of evidence does not support a clinically significant reduction in carriage of disease-associated or group B meningococci following 4CMenB vaccination. No additional cost-benefit from herd immunity effects should be included when modeling the cost-effectiveness of 4CMenB vaccine programs against group B IMD. 4CMenB immunization programs should focus on direct (individual) protection for groups at greatest risk of meningococcal disease. Future meningococcal B and combination vaccines being developed should consider the impact of the vaccine on carriage as part of their clinical evaluation.

B Part of It School Leaver Study: A Repeat Cross-Sectional Study to Assess the Impact of Increasing Coverage With Meningococcal B (4CMenB) Vaccine on Carriage of Neisseria meningitidis.

BACKGROUND: Recombinant protein-based vaccines targeting serogroup B meningococci protect against invasive disease but impacts on carriage are uncertain. This study assessed carriage prevalence of disease-associated meningococci in 2018-2020 as the proportion of vaccinated adolescents increased following introduction of a school-based 4CMenB immunization program. METHODS: Eligible participants who completed high school (aged 17-25) in South Australia in the previous year had an oropharyngeal swab taken and completed a risk factor questionnaire. Disease-associated meningococci (genogroups A, B, C, W, X, Y) were detected by meningococcal and genogroup-specific polymerase chain reaction. RESULTS: The analysis included 4104 participants in 2018, 2690 in 2019, and 1338 in 2020. The proportion vaccinated with 4CMenB increased from 43% in 2018, to 78% in 2019, and 76% in 2020. Carriage prevalence of disease-associated meningococci in 2018 was 225/4104 (5.5%). There was little difference between carriage prevalence in 2019 (134/2690, 5.0%; adjusted odds ratio [aOR], 0.82; 95% confidence interval [CI], .64-1.05) and 2020 (68/1338, 5.1%; aOR, 0.82; 95% CI, .57-1.17) compared to 2018. CONCLUSIONS: Increased 4CMenB uptake in adolescents was not associated with decline in carriage of disease-associated meningococci. 4CMenB immunization programs should focus on direct (individual) protection for groups at greatest risk of disease. CLINICAL TRIALS REGISTRATION: NCT03419533.

A rapid global review of strategies to improve influenza vaccination uptake in Australia.

This study aimed to identify effective strategies for improving the uptake of influenza vaccination and to inform recommendations for influenza vaccination programs in Australia. A rapid systematic review was conducted to assimilate and synthesize peer-reviewed articles identified in PubMed. The National Health and Medical Research Council (NHMRC) Hierarchy of Evidence was used to appraise the quality of evidence. A systematic search identified 4373 articles and 52 that met the inclusion criteria were included. The evidence suggests influenza vaccination uptake may be improved by interventions that (1) increase community/patient demand and access to influenza vaccine and overcome practice-related barriers; (2) reinforce the critical role healthcare providers play in driving influenza vaccination uptake. Strategies such as standing orders, reminder and recall efforts were successful in improving influenza vaccination rates. Community pharmacies, particularly in regional/remote areas, are well positioned to improve influenza vaccine coverage. The findings of this rapid review can be utilized to improve the performance of influenza immunization programs in Australia and other countries with comparable programs; and recommend priorities for future evaluation of interventions to improve influenza vaccination uptake.

Impact of Meningococcal B Vaccine on Invasive Meningococcal Disease in Adolescents.

BACKGROUND: From 2017, a statewide cluster randomized trial was conducted in South Australia to assess the impact of the meningococcal B vaccine 4CMenB on pharyngeal Neisseria meningitidis carriage in adolescents. Senior schools were randomized to receive the vaccine in 2017 (intervention) or 2018 (control). In this study we report the vaccine impact of 4CMenB on serogroup B invasive meningococcal disease (IMD) in 16- to 19-year-old adolescents in South Australia. METHODS: This observational time series analysis of serogroup B IMD cases compares the 14 years prior to the commencement of the trial (2003-2016) with the 2 years following 4CMenB vaccination of the 2017 adolescent cohort. RESULTS: Approximately 62% of year 10 and 11 students (15-16 years old) in South Australia enrolled in the trial. A total of 30 522 year 10-12 students received at least 1 dose of 4CMenB. The number of serogroup B IMD cases in 16- to 19-year old adolescents in South Australia increased on average by 10% per year from 2003 to 2016 (95% confidence interval [CI], 6%-15%, P < .001), peaking with 10 cases in 2015. Serogroup B IMD cases reduced to 5 in 2017-2018 and 1 in 2018-2019, below the expected numbers of 9.9 (95% prediction interval [PI], 3.9-17.5) and 10.9 (95% PI, 4.4-19.1), respectively. This translated to an overall reduction in the number of serogroup B IMD cases of 71% (95% CI, 15%-90%, P = .02). There were no serogroup B IMD cases in vaccinated adolescents. CONCLUSIONS: Vaccinating adolescents with 4CMenB was associated with a reduction in group B meningococcal disease in South Australia. CLINICAL TRIALS REGISTRATION: NCT03089086.

Evaluating the effectiveness of the 4CMenB vaccine against invasive meningococcal disease and gonorrhoea in an infant, child and adolescent program: protocol.

Invasive meningococcal disease causes significant morbidity and mortality worldwide, with serogroup B being one of the predominant serogroups in Australia for many years. The South Australian (SA) State Government recently funded the introduction of a 4CMenB vaccination program for infants, children and adolescents. In addition to protecting against invasive meningococcal disease, emerging evidence suggests the 4CMenB vaccine may also be effective against gonorrhoea due to genetic similarities between Neisseria meningitidis and Neisseria gonorrhoeae. The proposed project aims to evaluate the effectiveness of the SA 4CMenB vaccination program against invasive meningococcal disease and gonorrhoea through a combination of observational studies using routine surveillance and research data. The main methodological approaches involve an interrupted time series regression model, screening, and case-control analyses with different sets of controls to estimate vaccine impact and effectiveness. These analyses are designed to minimize potential biases inherent in all observational studies and to provide critical data on the effectiveness of the 4CMenB vaccine against two diseases of major global public health concern.

Impact of Meningococcal B (4CMenB) Vaccine on Pharyngeal Neisseria meningitidis Carriage Density and Persistence in Adolescents.

BACKGROUND: Higher density of Neisseria meningitidis carriage may be associated with transmission of the meningococcus. Our aim was to establish the impact of meningococcal B (4CMenB) vaccine on N. meningitidis carriage density. METHODS: We compared 4CMenB vaccine to control among 913 South Australian students aged approximately 15-18 years in a cluster randomized trial who had N. meningitidis carriage at 12 months. Oropharyngeal swabs were collected at baseline and 12 months later to detect N. meningitidis carriage. Colony-forming units per milliliter (CFU/mL) were estimated by generating a standard curve that plotted quantitative polymerase chain reaction cycle threshold values against log-normalized CFU. RESULTS: Among the 913 students with N. meningitidis carriage at 12 months, there was no difference in mean carriage density between the vaccinated (n = 434; 3.80 log CFU/mL [standard deviation {SD}, 1.29]) and control group (n = 479; 3.73 log CFU/mL [SD, 1.30]; P = .51). Higher N. meningitidis carriage density at baseline was associated with an increase in the odds of persistent carriage at 12 months (n = 504; odds ratio [OR] per 1.0 log CFU/mL increase in density, 1.36 [95% confidence interval {CI}, 1.17-1.58]; P < .001). Students with baseline carriage who were vaccinated had decreased persistent N. meningitidis carriage at 12 months compared to unvaccinated students (81/260 [31%] vs 105/244 [43%]; OR, 0.60 [95% CI, .40-.90]; P = .01). CONCLUSIONS: 4CMenB vaccine did not reduce carriage density of N. meningitidis 12 months postvaccination, despite increased carriage clearance. Higher carriage density is likely to enable transmission through prolonged periods of population exposure. CLINICAL TRIALS REGISTRATION: NCT03089086.

Effectiveness of Meningococcal Vaccines at Reducing Invasive Meningococcal Disease and Pharyngeal Neisseria meningitidis Carriage: A Systematic Review and Meta-analysis.

BACKGROUND: Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, leads to significant morbidity and mortality worldwide. This review aimed to establish the effectiveness of meningococcal vaccines at preventing IMD and N. meningitidis pharyngeal carriage. METHODS: A search within PubMed, Embase, Scopus, and unpublished studies up to 1 February 2020 was conducted. RESULTS: After removal of duplicates, 8565 studies were screened and 27 studies included. Protection was provided by meningococcal C vaccines for group C IMD (odds ratio [OR], 0.13 [95% confidence interval {CI}, .07-.23]), outer membrane vesicle (OMV) vaccines against group B IMD (OR, 0.35 [95% CI, .25-.48]), and meningococcal A, C, W, Y (MenACWY) vaccines against group ACWY IMD (OR, 0.31 [95% CI, .20-.49]). A single time series analysis found a reduction following an infant 4CMenB program (incidence rate ratio, 0.25 [95% CI, .19-.36]). Multivalent MenACWY vaccines did not reduce carriage (relative risk [RR], 0.88 [95% CI, .66-1.18]), unlike monovalent C vaccines (RR, 0.50 [95% CI, .26-.97]). 4CMenB vaccine had no effect on group B carriage (RR, 1.12 [95% CI, .90-1.40]). There was also no reduction in group B carriage following MenB-FHbp vaccination (RR, 0.98 [95% CI, .53-1.79]). CONCLUSIONS: Meningococcal conjugate C, ACWY, and OMV vaccines are effective at reducing IMD. A small number of studies demonstrate that monovalent C conjugate vaccines reduce pharyngeal N. meningitidis carriage. There is no evidence of carriage reduction for multivalent MenACWY, OMV, or recombinant MenB vaccines, which has implications for immunization strategies. CLINICAL TRIALS REGISTRATION: CRD42018082085 (PROSPERO).

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

BACKGROUND: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain. METHODS: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing Neisseria meningitidis (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for PorA (encoding porin protein A) and N. meningitidis genogroups. Secondary outcomes included carriage prevalence and acquisition of all N. meningitidis and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline. RESULTS: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing N. meningitidis between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing N. meningitidis included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified. CONCLUSIONS: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).

Deep Learning Based Prediction of Atrial Fibrillation Disease Progression with Endocardial Electrograms in a Canine Model.

OBJECTIVE: We sought to determine whether electrical patterns in endocardial wavefronts contained elements specific to atrial fibrillation (AF) disease progression. METHODS: A canine paced model (n=7, female mongrel, 29±2 kg) of persistent AF was endocardially mapped with a 64-electrode basket catheter during periods of AF at 1 month, 3 month, and 6 months post-implant of stimulator. A 50-layer residual network was then trained to map half-second electrogram samples to their source timepoint. RESULTS: The trained network achieved final validation and testing accuracies of 51.6 and 48.5% respectively. Per class F1 scores were 24%, 59%, and 53% for 1 month, 3 month, and 6 month inputs from the testing dataset. CONCLUSION: Differentiation of AF based on its time progression was shown to be feasible with a deep learning method. This is promising for differentiating treatment based on disease progression though low accuracy with earlier timepoints may be an obstacle to identifying nascent AF.