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In Western Europe, many countries have robust and well-established surveillance systems and case reporting mechanisms. IMD incidence across Western Europe is low with a predominance of meningococcal serogroup B (MenB). Case confirmation and antimicrobial susceptibility testing is often standardised in this region, with many countries also having robust vaccination programmes in place. Both MenB and MenACWY vaccines form part of National Immunisation Programmes (NIPs) in most European countries, with Sweden only offering vaccination in special circumstances. Despite these established programmes, there remains a critical need for advocacy efforts in affecting change in diagnosis, testing, and treatment. Recent campaigns, such as the World Meningitis Day digital toolkit, have helped raise awareness and draw attention to meningococcal disease. Awareness around antibiotic resistance has also led to the identification of antibiotic-resistant meningococcal strains, with an increase, albeit small, in these strains noted across the region. Countries such as Spain, Portugal, Germany, Switzerland, and France have either reported strains resistant to penicillin, ciprofloxacin and/or isolates with a reduced susceptibility to third-generation cephalosporins., Competing Interests: Declaration of Competing Interest Ray Borrow performs contract research on behalf of UKHSA for GSK, PATH, Pfizer and Sanofi. Heike Claus has received personal fee for scientific presentation for Sanofi. Ener Cagri Dinleyici performs contract work for the Eskisehir Osmangazi University funded by GSK, Sanofi Pasteur and Pfizer. Lee Harrison has served on advisory boards and/or made scientific presentations for GSK, Pfizer, Sanofi, and Merck, for which he does not receive any personal fees. William P. Hausdorff has served on advisory boards for Sanofi, Merck, and Vaxcyte, for which he does not receive any personal fees or reimbursement. Corinne Levy reports personal fees for advisory board and scientific presentations for MSD and Pfizer. Wesley Mattheus reports research grants funded by GSK and Pfizer. Marco A. P. Sáfadi reports research grants and personal fees for advisory boards from GSK, Pfizer, and Sanofi. Vinny Smith works for Meningitis Research Foundation that receives income from grants, sponsorship and consultancy income from GSK, MSD, Pfizer, Sanofi and Serum Institute of India. M.K. Taha performs contract work for the Institut Pasteur funded by GSK, Pfizer and Sanofi. M.K. Taha and A-E Deghmane have a patent NZ630133A Patent with GSK “Vaccines for serogroup X meningococcus” issued. Georgina Tzanakaki reports contract work on behalf of the University of West Attica as participation on advisory boards and scientific presentations for Pfizer, Sanofi and Merck. J.A. Vázquez performs contract work for the Institute of Health Carlos III funded by GSK and Pfizer and he has received personal fees from Pfizer and Sanofi. Nina van Sorge receives fee for service and presentations (directly paid to the institution) from MSD and GSK. Finnish Institute for Health and Welfare has received research funding from Pfizer and GSK for projects in which Maija Toropainen has acted as a researcher without personal remuneration., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Objectives: We aimed to describe cases of acute bacterial meningitis (ABM) without cerebrospinal fluid (CSF) pleocytosis and the clinical and biological characteristics of affected children., Methods: We analyzed results of a nation-wide population-based prospective surveillance study of acute ABM in children aged 3 months to 15 years in France. Absence of CSF pleocytosis was defined as CSF leukocyte count ≤5/mm 3 ., Results: We included 4754 cases of acute ABM from 2001 to 2022: 173 patients (3.6%) did not have CSF pleocytosis. ABM cases without CSF pleocytosis were mainly related to meningococcus (70% vs 44% with CSF pleocytosis, P <0.001). When performed in CSF with normal leukocyte count, Gram staining results were positive for 33%, culture for 80%, polymerase chain reaction results for 41%, and antigen detection for 20% of cases. Case fatality rate was higher for cases without than those with CSF pleocytosis (18% vs 6%, P <0.001). On multivariate analysis, absence of CSF pleocytosis was associated only with seizures before hospital arrival (adjusted odds ratio 2.3, 95% confidence interval 1.2-4.6, P <0.01)., Conclusions: ABM without CSF pleocytosis is infrequent but not exceptional, particularly in children with seizures before hospital arrival. Extended vaccination against meningococcus could prevent this clinical form with a high case fatality rate., Competing Interests: Declarations of competing interest Corinne Levy received grants from Pfizer during the conduct of the study, personal fees from Pfizer and MSD, and nonfinancial support from Pfizer outside the submitted work. Emmanuelle Varon received grants from the French Public Health Agency during the conduct of the study, and from Pfizer and MSD outside the submitted work. Muhamed Kheir Taha performs contract work for the Institut Pasteur funded by GSK, Pfizer, and Sanofi Pasteur, and has a patent with GSK (“Vaccines for serogroup X meningococcus”; NZ630133A Patent). Naïm Ouldali received grants from Pfizer to his institution during the conduct of the study and travel grants from Pfizer, Sanofi, and GlaxoSmithKline outside the submitted work. François Angoulvant received personal fees from MSD, Sanofi, and AstraZeneca outside the submitted work. Robert Cohen received personal fees from Sanofi, Pfizer, MSD, Viatris, and GSK; travel grants from Sanofi, Pfizer, and MSD; and grants from Sanofi, Pfizer, MSD, and GSK outside the submitted work. Alexis Rybak received personal fees from MSD and Pfizer outside the submitted work and nonfinancial support from Pfizer and AstraZeneca. The remaining authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To monitor the spread of invasive meningococcal disease due to group C of the clonal complex 10217 isolates beyond the sub-Saharan African meningitis belt., Methods: Cases were confirmed by real-time polymerase chain reaction in blood or cerebrospinal fluid samples and further characterized by multi-locus sequence typing that defined sequence type and clonal complexes. Sequencing of penA gene (encoding the penicillin-binding protein 2) was also used to predict susceptibility to β-lactams., Results: Between July and December 2023, we identified four cases of invasive meningococcal disease among adults, with two fatal cases in Algeria. Three cases were among subjects who recently arrived in Algeria from sub-Saharan African countries and one case was reported in an autochthonal subject. A case was also detected in France in 2018 in a subject who traveled to Cameroon. All five cases were provoked by group C isolates and belonged to the clonal complex cc10217 with identical PorA (P1.21-15,16) and FetA (F1-7) markers. The penA sequencing revealed a wildtype allele that is correlated to susceptibility to β-lactams., Conclusions: Our results suggest that serogroup C isolates belonging to cc10217 are spreading beyond the meningitis belt. The data underscore the need for enhanced surveillance to inform vaccination strategies., Competing Interests: The corresponding author, HTM, has full access to all the data in the study and had final responsibility for the decision to submit for publication. MKT also performs contract works for the Institut Pasteur funded by GSK and Pfizer outside the submitted manuscript, and MKT and AED have a patent with GSK, 630133. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject., (© 2024 The Authors.)

Neisseria meningitidis is a human-restricted bacteria that is a normal nasopharyngeal resident, yet it can also disseminate, causing invasive meningococcal disease. Meningococci are highly adapted to life in humans, with human-specific virulence factors contributing to bacterial adhesion, nutrient acquisition and immune evasion. While these factors have been explored in isolation, their relative contribution during infection has not been considered due to their absence in small animal models and their expression by different human cell types not readily combined in either in vitro or ex vivo systems. Herein, we show that transgenic expression of the iron-binding glycoproteins human transferrin and lactoferrin can each facilitate N. meningitidis replication in mouse serum but that transferrin was required to support infection-induced sepsis. While these host proteins are insufficient to allow nasopharyngeal colonization alone, mice co-expressing these and human CEACAM1 support robust colonization. In this case, meningococcal colonization elicits an acute elevation in both transferrin and lactoferrin levels within the upper respiratory mucosa, with transferrin levels remaining elevated while lactoferrin returns to basal levels after establishment of infection. Competitive infection of triple transgenic animals with transferrin- and lactoferrin- binding protein mutants selects for bacteria expressing the transferrin receptor, implicating the critical contribution of transferrin-based iron acquisition to support colonization. These transgenic animals have thus allowed us to disentangle the relative contribution of three virulence factors during colonization and invasive disease, and provides a novel in vivo model that can support extended meningococcal colonization, opening a new avenue to explore the meningococcal lifestyle within its primary niche.

The 4-component meningococcal serogroup B (MenB) vaccine, 4CMenB, the first broadly protective, protein-based MenB vaccine to be licensed, is now registered in more than 50 countries worldwide. Real-world evidence (RWE) from the last decade confirms its effectiveness and impact, with infant immunization programs showing vaccine effectiveness of 71-95% against invasive MenB disease and cross-protection against non-B serogroups, including a 69% decrease in serogroup W cases in 4CMenB-eligible cohorts in England. RWE from different countries also demonstrates the potential for additional moderate protection against gonorrhea in adolescents. The real-world safety profile of 4CMenB is consistent with prelicensure reports. Use of the endogenous complement human serum bactericidal antibody (enc-hSBA) assay against 110 MenB strains may enable assessment of the immunological effectiveness of multicomponent MenB vaccines in clinical trial settings. Equitable access to 4CMenB vaccination is required to better protect all age groups, including older adults, and vulnerable groups through comprehensive immunization policies.

Infections due to Haemophilus influnezae require prompt treatment using beta-lactam antibiotics. We used a collection of 81 isolates obtained between 1940 and 2001 from several countries. Whole genome sequencing showed the high heterogeneity of these isolates but allowed us to track the acquisition of beta-lactamase, which was first detected in 1980. Modifications of the ftsI gene encoding the penicillin-binding protein 3, PBP3, also involved in resistance to beta-lactams, appeared in 1991. These modifications (G490E, A502V, R517H, and N526K) were associated with resistance to amoxicillin that was not relieved by a beta-lactamase inhibitor (clavulanic acid), but the isolates retained susceptibility to third-generation cephalosporins (3GC). The modeling of the PBP3 structure suggested that these modifications may reduce the accessibility to the PBP3 active site. Other modifications appeared in 1998 and were associated with resistance to 3GC (S357N, M377I, S385T, and L389F). Modeling of the PBP3 structure suggested that they lie near the S379xN motif of the active site of PBP3. Overall resistance to amoxicillin was detected among 25 isolates (30.8%) of this collection. Resistance to sulfonamides was predicted by a genomic approach from the sequences of the folP gene (encoding the dihydropteroate synthase) due to difficulties in interpreting phenotypic anti-microbial testing and found in 13 isolates (16.0%). Our data suggest a slower spread of resistance to sulfonamides, which may be used for the treatment of H. influnezae infections. Genomic analysis may help in the prediction of antibiotic resistance, inform structure-function analysis, and guide the optimal use of antibiotics.

A 13-year-old boy was admitted with severe meningococcal meningitis. Immunologic workup revealed a properdin deficiency, and genetic sequencing of CFP identified a novel, private and predicted pathogenic variant in exon 8. The patient received broad immunizations and penicillin prophylaxis. Children with invasive meningococcal disease should be tested for complement deficiency., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Invasive meningococcal disease (IMD) cases declined upon the implementation of non-pharmaceutical interventions (NPI) (social distancing and mask wearing) to control the COVID-19 pandemic but rebounded in 2022 in numbers with genotypical changes of the strains. We explored here associated modifications in the clinical presentations of IMD., Methods: We conducted a retrospective descriptive study using the Database of the French National Reference Centre for meningococci and Haemophilus influnezae for IMD cases between 2015 and 2022. We scored serogroups, sex, age groups, clinical presentations and clonal complexes of the corresponding patients and isolates., Findings: Non-meningeal forms of IMD increased significantly upon easing of NPI, such as bacteremic meningococcal pneumonia and bacteremic abdominal forms. They represented 6% and 8% of all IMD forms and were significantly linked to serogroups Y and W respectively, to older adults for bacteremic pneumonia and to young adults for bacteremic abdominal presentations. These forms were significantly associated with more early mortality and clonal complexes 23, 11 and 9316., Interpretation: The increase in atypical IMD forms may lead to higher burden of IMD due to delayed diagnosis and management. Updating prevention may be needed through by adapting the current vaccination strategies to epidemiological changes., (© 2024. The Author(s).)

Biofilm formation has been suggested to be associated with phenotype changes compared with the planktonic form. We screened 1092 Haemophilus influenzae isolates for their genetic relationships and then selected 29 isolates from different genotypes and phenotypes and tested their ability to form biofilm. Our data showed a higher capacity of nontypable isolates, particularly isolates from respiratory and genital infections to form biofilm, compared with typable isolates. This ability to form biofilm was also correlated with reduced deposition of the complement component C3b on biofilm-involved bacteria. These data suggest that the biofilm formation contributes to the virulence of nontypable H. influenzae., Competing Interests: Potential conflict of interest. All authors: No reported 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Invasive meningococcal disease (IMD), caused by infection with the bacterium Neisseria meningitidis, usually manifests as meningitis or septicemia and can be severe and life-threatening (1). Six serogroups (A, B, C, W, X, and Y) account for most cases (2). N. meningitidis is transmitted person-to-person via respiratory droplets and oropharyngeal secretions. Asymptomatic persons can carry N. meningitidis and transmit the bacteria to others, potentially causing illness among susceptible persons. Outbreaks can occur in conjunction with large gatherings (3,4). Vaccines are available to prevent meningococcal disease. Antibiotic prophylaxis for close contacts of infected persons is critical to preventing secondary cases (2)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jay Lucidarme, Stephen A. Clark, and Ray Borrow report performing contract research on behalf of the UK Health Security Agency (UKHSA) for GSK, Pfizer, and Sanofi. Muhamed-Kheir Taha reports performing contract research on behalf of the Institut Pasteur for GSK, Pfizer, and Sanofi. Shamez N. Ladhani reports performing contract research on behalf of the UKHSA and St. George’s University of London for GSK, Pfizer, Merck Sharp & Dohme, and Sanofi. Helen Campbell and Mary Ramsay report receipt of a recovery charge by the Immunisation and Vaccine Preventable Diseases Division at UKHSA for provision to vaccine manufacturers (GSK, Pfizer, and Sanofi) of postmarketing surveillance reports on meningococcal, Haemophilus influenzae, and pneumococcal infections, which are required by the U.K. Licensing Authority in compliance with their risk management strategy. Jennifer Zipprich reports that her spouse is employed by Pfizer. No other potential conflicts of interest were disclosed.

Purpose: Invasive meningococcal disease (IMD) is a devastating condition. While most attention is directed towards disease in children and adolescents, IMD poses an important cause of morbidity and mortality in adults ≥60 years. While immunization is a critical component of healthy ageing strategies, meningococcal immunization is not routinely offered to older adults. The aim of this review was to summarize clinical and epidemiological aspects of IMD and available immunization strategies, with a particular focus on disease in older individuals, to emphasize the importance of this rather neglected area., Methods: An expert working group was established to evaluate clinical and epidemiological data to raise awareness of IMD in older individuals, and develop suggestions to improve the existing burden., Results: Routine child and adolescent meningococcal immunization has substantially reduced IMD in these targeted populations. Consequently, prevalence and proportion of IMD among those ≥60 years, mostly unvaccinated, is increasing in developed countries (accounting for up to 25% of cases). IMD-related mortality is highest in this age-group, with substantial sequelae in survivors. IMD due to serogroups W and Y is more prevalent among older adults, often with atypical clinical features (pneumonia, gastrointestinal presentations) which may delay timely treatment., Conclusions: IMD in older adults remains overlooked and greater awareness is required at clinical and societal levels. We encourage clinicians and immunization policy makers to reconsider IMD, with a call for action to remedy existing inequity in older adult access to protective meningococcal immunization., (© 2024. The Author(s).)

Background: The Banalia health zone in the Democratic Republic of Congo reported a meningitis epidemic in 2021 that evolved outside the epidemic season. We assessed the effects of the meningitis epidemic response., Methods: The standard case definition was used to identify cases. Care was provided to 2651 in-patients, with 8% of them laboratory tested, and reactive vaccination was conducted. To assess the effects of reactive vaccination and treatment with ceftriaxone, a statistical analysis was performed., Results: Overall, 2662 suspected cases of meningitis with 205 deaths were reported. The highest number of cases occurred in the 30-39 years age group (927; 38.5%). Ceftriaxone contributed to preventing deaths with a case fatality rate that decreased from 70.4% before to 7.7% after ceftriaxone was introduced ( p = 0.001). Neisseria meningitidis W was isolated, accounting for 47/57 (82%), of which 92% of the strains belonged to the clonal complex 11. Reactive vaccination of individuals in Banalia aged 1-19 years with a meningococcal multivalent conjugate (ACWY) vaccine (Menactra ® ) coverage of 104.6% resulted in an 82% decline in suspected meningitis cases (incidence rate ratio, 0.18; 95% confidence interval, 0.02-0.80; p = 0.041)., Conclusion: Despite late detection (two months) and reactive vaccination four months after crossing the epidemic threshold, interventions implemented in Banalia contributed to the control of the epidemic.

Objectives: Haemophilus parainfluenzae is an opportunistic pathogen causing respiratory tract infection and sexually transmitted diseases. The emergence of multidrug resistance in this species is particularly worrisome, especially since the recent description of CTX-M-15 ESBL-producing isolates in Spain. The aim of this study was to characterize a CTX-M-15-producing H. parainfluenzae clinical isolate, HP01, obtained from a urethral swab., Methods: MICs were determined with gradient strips for this isolate. Hydrolysis assays were performed with the β LACTA test. Genomic DNA from HP01 was subjected to Illumina and Oxford Nanopore sequencing to investigate the genetic environment of blaCTX-M-15. Phylogenetic analysis was performed with available H. parainfluenzae genomes from the NCBI database, including CTX-M-15 producers., Results: HP01, an XDR isolate, was resistant to penicillin, third-generation cephalosporins, fluoroquinolones, macrolides, cyclines and co-trimoxazole and susceptible only to carbapenems and rifampicin. HP01 carried blaTEM-1, blaCTX-M-15, tet(M), catS and mef(E)/mel and harboured amino acid substitutions in PBP3, PBP5, GyrA, ParC and FolA implicated in resistance. Genomic analysis revealed that blaCTX-M-15 was carried by a Tn3-like transposon inserted into a novel integrative and conjugative element (ICE), ICEHpaSLS, present on the chromosome and belonging to the ICEHin1056 family described in Haemophilus influenzae. The tet(M)-MEGA element was also detected on the chromosome. No plasmid was found. The phylogenetic analysis showed that four H. parainfluenzae producing CTX-M-15 clustered in the same clade., Conclusions: Here we report the description of an XDR H. parainfluenzae producing blaCTX-M-15 isolated from a urethral swab. The blaCTX-M-15 gene was inserted into an ICE structure similar to those recently described in CTX-M-15 producers in Spain. The emergence of XDR H. parainfluenzae producing blaCTX-M-15 is a matter of great concern. Careful surveillance is required to prevent its spread., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This review details recent findings from the Global Meningococcal Initiative's (GMI) recent meeting on the surveillance and control strategies for invasive meningococcal disease in the Middle East. The nature of case reporting and notification varies across the region, with many countries using bacterial meningitis as an IMD case definition in lieu of meningitis and septicaemia. This may overlook a significant burden associated with IMD leading to underreporting or misreporting of the disease. Based on these current definitions, IMD reported incidence remains low across the region, with historical outbreaks mainly occurring due to the Hajj and Umrah mass gatherings. The use of case confirmation techniques also varies in Middle Eastern countries. While typical microbiological techniques, such as culture and Gram staining, are widely used for characterisation, polymerase chain reaction (PCR) testing is utilised in a small number of countries. PCR testing may be inaccessible for several reasons including sample transportation, cost, or a lack of laboratory expertise. These barriers, not exclusive to PCR use, may impact surveillance systems more broadly. Another concern throughout the region is potentially widespread ciprofloxacin resistance since its use for chemoprophylaxis remains high in many countries., Competing Interests: Declaration of Competing Interest Xilian Bai performs contract research on behalf of UKHSA for GSK, PATH, Pfizer and Sanofi Pasteur. Ray Borrow performs contract research on behalf of UKHSA for GSK, PATH, Pfizer and Sanofi Pasteur. Ener Cagri Dinleyici performs contract work for the Eskisehir Osmangazi University funded by GSK, Sanofi Pasteur and Pfizer. Jay Lucidarme performs contract research on behalf of UKHSA for GSK, PATH, Pfizer and Sanofi Pasteur. Marco A. P. Sáfadi reports research grants and personal fees for advisory boards from GSK, Pfizer, and Sanofi. Vinny Smith and Claire Wright work for the MRF that receives grants and/or sponsorship from GSK, PATH, Pfizer, Sanofi, Bill and Melinda Gates Foundation, and Serum Institute of India. M.K. Taha performs contract work for the Institut Pasteur funded by GSK, Pfizer and Sanofi Pasteur. M.K. Taha and A.E. Deghmane has a patent NZ630133A Patent with GSK “Vaccines for serogroup X meningococcus” issued. J.A. Vázquez performs contract work for the Institute of Health Carlos III funded by GSK and Pfizer and he has received personal fees from Pfizer and Sanofi Pasteur., (Copyright © 2023. Published by Elsevier Ltd.)

Background: In France, vaccination has been implemented against Hi serotype b (Hib), pneumococcus with pneumococcal conjugate vaccines (PCV), and Neisseria meningitidis serogroup C (MenC). These interventions with different coverage and uptake have disrupted the epidemiology of vaccine-preventable acute bacterial meningitis (ABM)., Methods: We analyzed data from a French prospective surveillance network of ABM in children ≤15 years old enrolled by 259 pediatric wards (estimated national coverage: 61%). From 2001 to 2020, the effect of vaccine implementation was estimated with segmented linear regression., Results: We analyzed 7,186 cases, mainly due to meningococcus (35.0%), pneumococcus (29.8%), and Hi (3.7%). MenC ABM incidence decreased (-0.12%/month, 95% CI: -0.17 to -0.07, P < 0.001) with no change for the overall meningococcal ABM when comparing the pre-MenC vaccination and the post-MenC vaccination trends. Despite a decreasing MenB ABM incidence without a vaccination program (-0.43%/month, 95% CI: -0.53 to -0.34, P < 0.001), 68.3% of meningococcal ABM involved MenB. No change in pneumococcal ABM incidence was observed after the PCV7 recommendation. By contrast, this incidence significantly decreased after the switch to PCV13 (-0.9%/month, 95% CI: -1.6 to -0.2%, P = 0.01). After May 2014, a rebound occurred (0.5%/month, 95% CI: 0.3-0.8%, P < 0.001), with 89.5% of non-PCV13 vaccine serotypes. Hib ABM incidence increased after June 2017., Conclusions: PCV7 and MenC vaccine introduction in France, with slow vaccine uptake and low coverage, had no to little impact as compared to the switch from PCV7 to PCV13, which occurred when coverage was optimal. Our data suggest that MenB and next-generation PCVs could prevent a large part of the ABM incidence in France., Competing Interests: A.R. reports personal fees from MSD outside the submitted work and nonfinancial support from Pfizer and AstraZeneca. N.O. reported receiving grants from Pfizer to his institution during the conduct of the study and travel grants from Pfizer, Sanofi, and GlaxoSmithKline outside the submitted work. E.V. reports grants from a French public health agency, during the conduct of the study, grants from Pfizer and from MSD, outside the submitted work. M.K.T. performs contract work for the Institut Pasteur funded by GSK, Pfizer and Sanofi Pasteur. M.K.T. has a patent NZ630133A Patent with GSK “Vaccines for serogroup X meningococcus” issued. F.A. reports receiving personal fees from MSD, Sanofi, and AstraZeneca outside the submitted work. R.C. reported receiving personal fees from Sanofi, Pfizer, MSD, and GSK; travel grants from Pfizer and MSD, and grants from Sanofi, Pfizer, MSD, and GSK outside the submitted work. C.L. reported receiving grants from Pfizer during the conduct of the study, personal fees from Pfizer and MSD, and nonfinancial support from Pfizer outside the submitted work. The other authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Invasive meningococcal disease (IMD) is a life-threatening disease caused by Neisseria meningitidis and has high mortality rates. Survivors often exhibit long-term sequelae and reduced life expectancy. Disease incidence is highest in infants and toddlers, with a resurgence of cases in adolescents and older adults (>50 years of age). Substantial heterogeneity exists in the recommendations of meningococcal vaccines included in National Immunization Programs (NIPs) across countries. Recommendations are usually based on infant/toddler immunization, with some countries recommending immunization only for toddlers. While existing recommendations have led to a reduced incidence of IMD in children <5 years of age, there has been an increase in cases among adolescents and older adults. Currently, older adults are not included in the recommendations. The higher healthcare burden and the economic costs associated with IMD in these age groups suggest that it is time to consider including adolescents and older adults in NIPs to protect against IMD caused by the five most prevalent serogroups. Currently, the lack of equity of access to vaccines in the immunization programs is a glaring gap in the betterment of public health, and a broader meningococcal strategy is recommended to provide optimal protection for all age groups.

The rebound of invasive meningococcal disease cases in France since the fall of 2022 was accompanied by an increase in adult epiglottitis. These cases were provoked mainly by isolates of serogroup W belonging to the clonal complex 11 of Neisseria meningitidis. Awareness and surveillance should be reinforced., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Invasive meningococcal disease (IMD) cases declined upon the implementation of non-pharmaceutical measures to control the COVID-19 pandemic. A rebound in IMD cases was feared upon easing these measures., Methods: We conducted a retrospective descriptive study using the French National Reference Center Database for meningococci between 2015 and 2022. We scored serogroups, sex, age groups, and clonal complexes of the corresponding isolates., Findings: Our data clearly show a decline in the number of IMD cases for all serogroups and age groups until 2021. This decline was mainly due to a decrease in IMD cases provoked by the hyperinvasive ST-11 clonal complex. However, since the fall of 2021, there has been an increase in IMD cases, which accelerated in the second half of 2022. This rebound concerned all age groups, in particular 16-24 years. The increase in cases due to serogroups B, W, and Y were mainly due to the expansion of isolates of the ST-7460, the clonal complex ST-9316 and the clonal complex ST-23, respectively., Interpretation: IMD epidemiology changes constantly and profound epidemiological changes have been recently observed. The surveillance of IMD needs to be enhanced using molecular tools. Additionally, vaccination strategies need to be updated to acknowledge recent epidemiological changes of these vaccine-preventable serogroups., Competing Interests: Declaration of Competing Interest MKT performs contract works for the Institut Pasteur funded by GSK, Sanofi and Pfizer outside the submitted manuscript, and MKT and AED have a patent with GSK, 630133. ST was a recipient of a fellowship from Pfizer that had no role in the data collection, interpretation, or writing of the manuscript. The other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Our goal was to describe Invasive Meningococcal Disease (IMD) in Southern Vietnam over the last 10 years. We characterized 109 Neisseria meningitidis strains in Southern Vietnam isolated between 1980s to 2021, that were collected from IMD (n = 44), sexually transmitted infections (n = 2), and healthy carriage (n = 63)., Methods: IMD were confirmed by bacterial culture and/or real-time polymerase chain reaction at the national reference laboratory in Pasteur Institute of Ho Chi Minh City (PIHCM). Antimicrobial resistance was determined on 31 IMD and two sexually transmitted infection isolates with E-test for chloramphenicol (CHL), penicillin (PEN), ciprofloxacin (CIP), ceftriaxone (CRO), and rifampicin (RIF). Sequencing was performed for analyzing of multilocus-sequence-typing (MLST), porA, fetA , and antibiotic resistance genes, including gyrA, penA , and rpoB ., Results: The incidence rate during this period was 0.02 per 100,000 persons/year. Serogroup B accounted for over 90% of cases (50/54). ST-1576 were mainly responsible for IMD, 27/42 MLST profiles, and associated with CHL resistance. Resistance was prevalent among IMD isolates. Thirteen were resistant to CHL (minimum inhibitory concentration [MIC] ≥16 mg/l), 12 were intermediate to PEN (MIC between 0.19 and 0.5 mg/l), and five were CIP-resistant (MIC between 0.19 and 0.5 mg/l). Particularly, one was non-susceptible to CRO (MIC at 0.125 mg/l), belonging to ST-5571 lineage. The resistance was due to carrying resistant alleles of penA and gyrA genes, and catP gene. Notably, seven isolates were resistant/non-susceptible to two or more antibiotics., Conclusion: Our results suggest the persistence of the circulating ST-1576 in Southern Vietnam, with a spread of antimicrobial resistance across the community., Competing Interests: The authors have no competing interests to declare., (© 2023 The Authors.)

Competing Interests: We declare no competing interests.

Introduction: Invasive meningococcal disease (IMD) due to serogroup W meningococci (MenW) is consistently reported with atypical clinical manifestations, including gastrointestinal symptoms, bacteremic pneumonia, and septic arthritis. We undertook a systematic review of the literature for a comprehensive assessment of the clinical presentation of IMD caused by MenW., Methods: PubMed and Embase databases were searched from inception to June 2022 using a combination of MeSH terms and free text for articles that reported symptoms and signs of MenW IMD, and associated manifestations., Results: The most commonly reported symptoms identified included: fever (range 36-100% of cases), nausea and/or vomiting (range 38-47%), vomiting (range 14-68%), cough (range 7-57%), sore throat (range 13-34%), headache (range 7-50%), diarrhea (range 8-47%), altered consciousness/mental status (range 7-38%), stiff neck (range 7-54%), and nausea (range 7-20%). Sepsis (range 15-83% of cases) was the most commonly reported manifestation followed by meningitis (range 5-72%), sepsis and meningitis (range 6-74%), bacteremic pneumonia (range 4-24%), arthritis (range 1-15%), and other manifestations (e.g., pharyngitis/epiglottitis/supraglottitis/tonsillitis/conjunctivitis; range 1-24%). The case fatality rates ranged from 8-40%, and among the survivors 4-14% had long-term sequelae., Conclusions: Clinicians need to be aware of the nonspecific symptoms and signs of IMD, as well as of the atypical manifestations in regions where MenW is known to circulate to ensure timely diagnoses and treatment., (© 2023. The Author(s).)

Background: The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic., Methods: For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere., Findings: Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories., Interpretation: COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies., Funding: Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization., Competing Interests: Declaration of interests The UK Health Security Agency's Immunisation and Vaccine Preventable Diseases Division has provided vaccine manufacturers (GSK, Pfizer, and Sanofi) with post-marketing surveillance reports, which the Marketing Authorization Holders are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports. The UK Health Security Agency's Respiratory and Vaccine Preventable Bacteria Reference Unit has received unrestricted research grants from Pfizer to participate in pneumococcal surveillance projects. CHI de Créteil (France) received research grants from the French Public Health Agency, Pfizer, and MSD. University Hospitals Leuven (Belgium) received research grants from Merck-MSD and Pfizer, and consulting fees from Merck-MSD. SD received personal payments or honoraria from Pfizer. The Swiss National Reference Center for Invasive Pneumococci received funding from the Federal Office of Public Health. MH has received grants from Pfizer and personal fees (for being on an advisory board) from Pfizer and Merck Sharp & Dohme. The National Medicines Institute (Warsaw, Poland) received funding from the Polish Ministry of Health, the Polish Ministry of Science and Higher Education, Pfizer, and MSD. AS received payments from MSD and Pfizer for lectures, and from MSD, Pfizer, and Sanofi Pasteur for participation in advisory boards. AS is the unpaid Vice President of the European Meningococcal and Haemophilus Disease Society. The Finnish Institute for Health and Welfare (Finland) received research funding from Pfizer. ABB is an unpaid adviser to WHO, providing expertise related to vaccines and antimicrobial resistance. ABB is an unpaid General Assembly member (2022 onwards), and has been a board member (2016–22) and Secretary (2018–22), of the International Society of Pneumonia and Pneumococcal Diseases (ISPPD). MD has received financial support from Pfizer to attend national scientific meetings. MdP received grant funding from the National Research Foundation (South Africa) and the Bill & Melinda Gates Foundation to support the International Pathogenic Neisseria Conference (IPNC) 2022 meeting. MdP received personal support from the ISPPD to participate in the ISPPD conference in 2022, and was a member of the organising and scientific committee for the IPNC meeting in 2022. HH and MC received a grant from Pfizer (W1243730) to investigate Irish pneumococcal serotypes by whole-genome sequencing. HH received payment from Scottish Hospitals Enquiry for expert testimony. HH was the President of the Healthcare Infection Society (2018–22). KAJ received personal royalties from GlaxoSmithKline, and personal honoraria from the Wellcome Trust. SL performs contract research on behalf of St George's University of London for pharmaceutical companies (GlaxoSmithKline, Pfizer, and Sanofi), including vaccine manufacturers, but does not receive any personal remuneration. T-TL received consulting fees from the Trond Mohn Foundation. T-TL is an unpaid board member of the European Meningococcal and Haemophilus Disease Society and the German Society for Hygiene and Microbiology, committee for microbial systematics, population genetics and infection epidemiology. SM participated on an unpaid advisory board for Pfizer for the meningococcal type B vaccine in South Africa in 2020. WM received funding from GlaxoSmithKline and Pfizer for investigator-initiated research on meningitis B (MenB) strain vaccine coverage. CS received financial support for flights, accommodation, and registration to attend the 2022 ISPPD meeting in Canada. H-CS received funding from Pfizer for a pneumococcal carriage project. H-CS received funding for participation on a data safety monitoring board or advisory board for MSD. LS received personal support from the European Centre for Disease Prevention and Control for attending the European Scientific Conference on Applied Infectious Disease Epidemiology in 2022. MPGvdL received consulting fees from Pfizer, Merck, and GlaxoSmithKline; payment or honoraria from Pfizer and Merck; and support for attending meetings or travel, or both, from Pfizer. AvG is the chairperson for the National Advisory Group on Immunization of South Africa. NMvS received fees for services and consulting fees from MSD and GlaxoSmithKline, and research funding from the Dutch Health Counsel, US National Institutes of Health, and Amsterdam University Medical Centers, and from MSD and GlaxoSmithKline, which are all directly paid to the institution. NMvS holds a patent (WO 2013/020090 A3) on vaccine development against Streptococcus pyogenes. NMvS is an unpaid scientific adviser to the ItsME foundation, and a scientific adviser to the StrepAotearoa New Zealand project but fees are paid to the University of Amsterdam. NMvS holds personal stocks in Genmab. JY received payments for lectures given at scientific meetings organised by MSD and Pfizer; received support from MSD and Pfizer to attend national and international scientific meetings; and participated in advisory boards for MSD and Pfizer. DS is supported by an Oxford Clarendon Scholarship. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Beta-lactams are the main antibiotics for the treatment of invasive meningococcal disease. However, reduced susceptibility to penicillin G is increasingly reported in Neisseria meningitidis and reduced susceptibility to third-generation cephalosporines (3GC) and the rare acquisition of ROB-1 beta-lactamase were also described. Modifications of penicillin-binding protein 2 (PBP2) encoded by the penA gene are the main described mechanism for the reduced susceptibility to penicillin and to other beta-lactams. penA modifications were analyzed using the sequences of all penA genes from cultured isolates between 2017-2021 in France ( n = 1255). Data showed an increasing trend of reduced susceptibility to penicillin from 36% in 2017 to 58% in 2021. Reduced susceptibility to 3GC remained limited at 2.4%. We identified 74 different penA alleles and penA1 was the most frequent wild-type allele and represented 29% of all alleles while penA9 was the most frequently altered allele and represented 17% of all alleles. Reduced susceptibility to 3GC was associated with the penA327 allele. The amino acid sequences of wild-type and altered PBP2 were modeled. The critical amino acid substitutions were shown to change access to the active S310 residue and hence hinder the binding of beta-lactams to the active site of PBP2.

Working in the era of the novel coronavirus disease 2019 can predispose to cognitive bias. We present a case of life-threatening bacterial infection misdiagnosed as multisystem inflammatory syndrome in children. While multisystem inflammatory syndrome in children-related myocardial dysfunction is now a well-recognized complication of coronavirus disease 2019, a rigorous differential diagnosis approach, notably for infectious etiologies, is paramount., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The highest incidence of invasive meningococcal disease (IMD) is observed in infants. However, its prevalence in neonates (≤28 days of age) and the characteristics of the corresponding isolates are less described. This report aimed to analyze meningococcal isolates from neonates., Methods: We first screened the database of the national reference center for meningococci in France for confirmed neonatal IMD cases between 1999 and 2019. We then performed whole-genome sequencing on all cultured isolates, and we evaluated their virulence in a mouse model., Results: Fifty-three neonatal cases of IMD (mainly bacteremia) were identified (50 culture-confirmed cases and 3 PCR-confirmed cases) of a total of 10,149 cases (0.5%) but represented 11% of cases among infants of under 1 year of age. Nine cases (17%) occurred among neonates of 3 days of age and younger (early onset). The neonate isolates were often of serogroup B (73.6%) and belonged to the clonal complex CC41/44 (29.4%) with at least 68.5% of coverage by vaccines against serogroup B isolates. The neonatal isolates were able to infect mice although to variable levels., Conclusion: IMD in neonates is not rare and can be of early or late onsets suggesting that anti-meningococcal vaccination can target women planning to have a baby., (© 2023 S. Karger AG, Basel.)

Invasive meningococcal disease (IMD) carries a high burden in terms of mortality, long-term complications, and cost, which can be significantly reduced by vaccination. The objectives of this case-control study were to document the care pathways of patients with IMD before, during, and after hospitalization and to assess in-hospital complications and long-term sequelae. Cases consisted of all people hospitalized for IMD in France between 2012 and 2017. Controls were matched by age, gender, and district of residence. Data were extracted from the French national public health insurance database on demographics, hospitalizations, mortality and potential sequelae of IMD. Overall, 3,532 cases and 10,590 controls were assessed and followed up for 2.8 years (median). During hospitalization, 1,577 cases (44.6%) stayed in an intensive care unit, 1,238 (35.1%) required mechanical ventilation, and 43 (1.2%) underwent amputation; 293 cases (8.3%) died in hospital and a further 163 (4.6%) died following discharge; 823 cases (25.4% of survivors) presented ≥1 sequela and 298 (9.2%) presented multiple sequelae. The most frequently documented sequelae were epilepsy (N = 205; 5.8%), anxiety (N = 196; 5.5%), and severe neurological disorders (N = 193; 5.5%). All individual sequelae were significantly more frequent ( p < .0001) in cases than controls. Hearing/visual impairment and communication problems were conditions that presented the highest risk for cases compared to controls (risk ratios >20 in all cases). In conclusion, this study highlights the importance of providing optimal medical care for patients with IMD, of minimizing the delay before hospitalization, and of effective prevention through comprehensive vaccination programs.

Bexsero® is a multicomponent vaccine composed of four major proteins of Neisseria meningitidis : the fHbp, NHBA, NadA and PorA. This vaccine was licensed against invasive meningococcal disease (IMD) due to serogroup B isolates. When administered alone, Bexsero® showed a safety profile similar to other childhood vaccines. It provides an excellent immunogenicity but that requires booster doses in infants and young children. Although the vaccine does not seem to impact on acquisition of carriage of serogroup B isolates, it confers protection against isolates of serogroup B harboring distinct but cross-reactive variants of fHbp, NadA and NHBA. Primary vaccination schemes in infancy underwent a rapid increase after a toddler booster suggesting an anamnestic response and the establishment of a memory response. As Bexsero® targets sub-capsular proteins that can be conserved regardless the capsule, the vaccine can be effective against non-B isolates such as isolates of serogroups W and X.

Objectives: Despite a high risk of invasive meningococcal (Men) disease, there is no published data on any MenB vaccine after hematopoietic cell transplantation (HCT). We investigated the immunogenicity and safety of the 4CMenB recombinant vaccine (Bexsero) in adult HCT recipients., Methods: Patients were eligible from 6 months post-HCT to receive 2 4CMenB doses at 2-month intervals. Sera were collected at baseline, 1 month after the second dose, and 12 months after enrolment. The serum bactericidal activity (SBA) using human complement (hSBA) was assessed against fHbp, NadA, PorAP1.4, and NHBA antigens. The vaccine response was defined by one criterion for one vaccine antigen: (1) in patients with a hSBA titer <4 at baseline: a titer ≥4; (2) in patients with a hSBA titer ≥4 at baseline: at least a 4 time increase., Results: Forty (40) patients were included at a median of 2.14 (0.57-13.03) years posttransplant. At baseline, most patients (32/40, 80%) had hSBA titers <4 for all vaccine antigens. After 2 vaccine doses, the proportion of patients with a titer ≥4 was significantly increased for fHbp (23/40, 57.5%), NadA (25/40, 62.5%), and PorA (31/40, 77.5%) but not for NHBA for which only 6 of 40 (15%) patients responded. Of patients, 36 out of 0 (90%) were responders to ≥1 antigen. However, 9 months later, only 23 out of 37 (62.2%) patients were still seroprotected. No severe adverse event was observed., Discussion: The response rate of 90% for ≥1 vaccine antigen and our safety data supports the 4CMenB vaccination of HCT recipients from 6 months after transplant with 2 doses., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Haemophilus influenzae is a prevalent agent of respiratory infections, including acute otitis media (AOM), that lead to high antibiotic prescription and may contribute to the development of bacterial resistance to antibiotics. The objective of this work was to describe and analyse antibiotic resistance of H. influenzae from 2017 to 2021 in France., Methods: We characterized H. influenzae isolates transmitted to the French national reference centre for H. influenzae between 2017 and 2021. We included all the 608 non-invasive respiratory isolates. Resistance rates to the main antibiotics were described. The relationship between resistance rate, age, and sex of patients and germ serotype was investigated., Results: Isolates were mainly from alveolar lavage (29.3%), expectoration (22.9%), or sputum (15%). Resistance to amoxicillin (61.4%), amoxicillin/clavulanic acid (47.4%), and cefotaxime (39.3%) was high and correlated with the presence of β-lactamase and/or modifications of the ftsI gene encoding penicillin-binding protein 3. Resistance to sulfamethoxazole/trimethoprim (33.2%) was more moderate. There were no significant differences according to serotype, age, or gender., Conclusions: The benefit/risk balance of first choice use of amoxicillin and even of amoxicillin/clavulanic acid in AOM is questionable in view of the significant resistance to H. influenzae. The use of sulfamethoxazole/trimethoprim could be an alternative but may still need further evaluation., Competing Interests: Competing interests None declared, (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of β-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI., (Copyright © 2022. Published by Elsevier Ltd.)

Since January 2018, mandatory vaccination against meningococci serogroup C has been implemented in France for children <2 years with a recommended catch-up vaccination until the age of 24 years. We aimed to analyse the impact of mandatory vaccination on populations not targeted by it (2-24 years old). We used the database of the national reference centre for meningococci to collect the number of invasive meningococcal disease (IMD) cases before (2016-2017) and after (2018-2019) the mandatory vaccination. The cultured isolates were sequenced and submitted for genomic comparison. The total number of cases was 1706, including 376 cases of IMD serogroup C. Mandatory vaccination correlated with a significant decrease among the <2 years old and a decreasing trend among the 2-14 years old group but not among 15-25 years of age. This observation may be explained by the vaccine coverage that is still low among adolescents and young adults. Moreover, the genomic analysis revealed the co-circulation of two major genotypes belonging to the clonal complex ST-11 whose distribution differed across the age groups in accord with cyclic variations of genotypes. It is important to increase specific knowledge on meningococcal epidemiology and vaccination to involve them in establishing the vaccination strategy., (© 2022. The Author(s).)

Introduction: Recombinant surface protein meningococcal serogroup B (MenB) vaccines are available but with different antigen compositions, leading to differences between vaccines in their immunogenicity and likely breadth of coverage. The serology and breadth of coverage assessment for MenB vaccines are multifaceted areas, and a comprehensive understanding of these complexities is required to appropriately compare licensed vaccines and those under development., Areas Covered: In the first of two companion papers that comprehensively review the serology and breadth of coverage assessment for MenB vaccines, the history of early meningococcal vaccines is considered in this narrative review to identify transferable lessons applicable to the currently licensed MenB vaccines and those under development, as well as their serology., Expert Opinion: Understanding correlates of protection and the breadth of coverage assessment for meningococcal surface protein vaccines is significantly more complex than that for capsular polysaccharide vaccines. Determination and understanding of the breadth of coverage of surface protein vaccines are clinically important and unique to each vaccine formulation. It is essential to estimate the proportion of MenB cases that are preventable by a specific vaccine to assess its overall potential impact and to compare the benefits and limitations of different vaccines in preventing invasive meningococcal disease.

Introduction: COMBAT is a prospective, multicentre cohort study that enrolled consecutive adults with community-acquired bacterial meningitis (CABM) in 69 participating centres in France between February 2013 and July 2015 and followed them for 1 year., Methods: Patients aged at least 18 years old, hospitalised with CABM were followed during their hospitalisation and then contacted by phone 12 months after enrolment. Here we present the prevalence of sequelae at 12 months in a subgroup of patients with meningococcal meningitis., Results: Five of the 111 patients with meningococcal meningitis died during initial hospitalisation and two died between discharge and 12 months, leaving 104 patients alive 1 year after enrolment, 71 of whom provided 12-month follow-up data. The median age was 30.0 years and 54.1% of the patients had no identified risk factor for meningitis. More than 30% reported persistent headache, more than 40% were not satisfied with their sleep and 10% had concentration difficulties. Hearing loss was present in about 15% of the patients and more than 30% had depressive symptoms. About 13% of the patients with a previous professional activity had not resumed work. On the SF-12 Health Survey, almost 50% and 30% had physical component or mental component scores lower than the 25th percentile of the score distribution in the French general population. There was a non-significant improvement in the patients' disability scores from hospital discharge to 12 months (p = 0.16), but about 10% of the patients had residual disability., Conclusions: Although most patients in our cohort survive meningococcal meningitis, the long-term burden is substantial and therefore it is important to ensure a prolonged follow-up of survivors and to promote preventive strategies, including vaccination., Trial Registration: ClinicalTrial.Gov identification number NCT01730690., (© 2022. The Author(s).)

Introduction: Invasive meningococcal disease (IMD) is still an important cause of mortality in children and survivors can have significant long-term disabling sequelae. There are few prospective studies looking at the long term neuropsychological and developmental consequences of IMD in surviving children, and the rate of sequelae may be underestimated. The SEINE study aims to have a more reliable estimate of the real rate of sequelae by assessing the long-term physical, neuropsychological, learning disorders and sensory sequelae of IMD in children and adolescents and by assessing the post-traumatic stress in parents., Methods and Analysis: The SEINE study is a multicentre, prospective, non-randomized, interventional study based on the French bacterial meningitis surveillance network. The study will include 100 children aged from birth to 15 years old, hospitalized in a Paris area paediatric ward for a meningococcal meningitis or a purpura fulminans between 2010 and 2019. The first outcome will assess long-term sequelae (physical, neurological, or sensory) measured by a general clinical and neurological examination, a neurocognitive assessment, learning development, a pure tone audiometry and an ophthalmic examination. The second outcome will assess the long-term post-traumatic stress in parents measured by the Impact of Event Scare Revised questionnaire., Perspectives: By providing a better estimation of the rate of sequelae in children and offering an adapted follow-up of these children, we believe that the SEINE study will help to improve the management of patients surviving IMD., Trial Registration Number: NCT04685850., Competing Interests: RC and CL received personal fees and non-financial support from Pfizer outside the submitted work. RC reports personal fees from AstraZeneca, GSK, Merck, Pfizer and Sanofi outside the submitted work. MKT reported institutional fees from the GSK group of companies, Pfizer and Sanofi-Pasteur for activities outside the presented work and a patent 630133 issued (with GSK group of companies) CJ reports personal fees from MSD and Nestlé outside the submitted work. AB received personal fees and non-financial support from Sanofi outside the submitted work. All other authors declare no competing interests for this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Social deprivation is associated with poorer healthcare access. Vaccination is among the most effective public health interventions and achieving equity in vaccination access is vitally important. However, vaccines are often reimbursed by public funds only when recommended in national immunization programs (NIPs), which can increase inequity between high and low socioeconomic groups. Invasive meningococcal disease (IMD) is a serious vaccination-preventable disease. This review focuses on vaccination strategies against IMD designed to reduce inequity., Areas Covered: We reviewed meningococcal epidemiology and current vaccination recommendations worldwide. We also reviewed studies demonstrating an association between social deprivation and risk of meningococcal disease, as well as studies demonstrating an impact of social deprivation on uptake of meningococcal vaccines. We discuss factors influencing inclusion of meningococcal vaccines in NIPs., Expert Opinion: Incorporating meningococcal vaccines in NIPs is necessary to reduce inequity, but insufficient alone. Inclusion provides clear guidance to healthcare professionals and helps to ensure that vaccines are offered universally to all target groups. Beyond NIPs, cost of vaccination should be reimbursed especially for disadvantaged individuals. These approaches should help to achieve optimal protection against IMD, by increasing access and immunization rates, eventually reducing social inequities, and helping to protect those at greatest risk.

BackgroundSince the appearance of COVID-19 in January 2020, invasive bacterial infections have decreased significantly worldwide. However, alterations in age and sex distributions, clinical forms, phenotypes, and genotypes of isolates have not been analyzed. Our goal is to present and discuss these data considering the current COVID-19 pandemic situation. Methods: The data of the national reference center for meningococci and Haemophilus influenzae in France were mined to examine the above aspects of invasive bacterial infection before (2018−2019) and after (2020−2021) the COVID-19 pandemic. Detailed epidemiological, clinical, and microbiological data were collected, and whole genome sequencing was carried out on meningococcal isolates (n = 1466). Results: In addition to the overall decline in the number of cases, various changes in age, sex, and phenotypes of isolates were also noted. As for N. meningitidis, more cases were observed in adults, as well as more invasive pneumopathies. Furthermore, fewer hyperinvasive meningococcal genotypes have circulated since COVID-19 emerged. The situation has been different for H. influenzae, as the number of invasive cases among adults decreased due to a reduction in non-typeable isolates. In contrast, cases due to serotypeable isolates, particularly serotypes a and b, increased in children <5 years-old. Conclusions: It is possible that measures implemented to stop COVID-19 may have reduced the circulation of N. meningitidis and H. influenzae isolates, but to a variable extent. This may be due to differences in circulation between these two species according to age groups. Vaccination schedules against these two species may have also influenced the evolution of these invasive bacterial infections since the emergence of the COVID-19 pandemic.

Recent reports have indicated a rise of invasive disease caused by Haemophilus influenzae serotype a (Hia) in North America and some European countries. The whole-genome sequences for a total of 410 invasive Hia isolates were obtained from 12 countries spanning the years of 1998 to 2019 and underwent phylogenetic and comparative genomic analysis in order to characterize the major strains causing disease and the genetic variation present among factors contributing to virulence and antimicrobial resistance. Among 410 isolate sequences received, 408 passed our quality control and underwent genomic analysis. Phylogenetic analysis revealed that the Hia isolates formed four genetically distinct clades: clade 1 ( n = 336), clade 2 ( n = 13), clade 3 ( n = 3) and clade 4 ( n = 56). A low diversity subclade 1.1 was found in clade 1 and contained almost exclusively North American isolates. The predominant sequence types in the Hia collection were ST-56 ( n = 125), ST-23 ( n = 98) and ST-576 ( n = 51), which belonged to clade 1, and ST-62 ( n = 54), which belonged to clade 4. Clades 1 and 4 contained predominantly North American isolates, and clades 2 and 3 predominantly contained European isolates. Evidence of the presence of capsule duplication was detected in clade 1 and 2 isolates. Seven of the virulence genes involved in endotoxin biosynthesis were absent from all Hia isolates. In general, the presence of known factors contributing to β-lactam antibiotic resistance was low among Hia isolates. Further tests for virulence and antibiotic susceptibility would be required to determine the impact of these variations among the isolates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Topaz, Tsang, Deghmane, Claus, Lâm, Litt, Bajanca-Lavado, Pérez-Vázquez, Vestrheim, Giufrè, Van Der Ende, Gaillot, Kuch, McElligott, Taha and Wang.)

Invasive meningococcal disease (IMD) is a life-threatening, unpredictable condition. Vaccines are available against 5 of the 6 meningococcal serogroups (Men) accounting for nearly all IMD cases worldwide; conjugate monovalent MenC, quadrivalent MenACWY, and protein-based MenB vaccines are commonly used. We provide a comprehensive overview of the evolution of meningococcal vaccination strategies employed in national immunization programmes (NIPs) and their impact on IMD incidence in Europe. A more in-depth description is given for several countries: the United Kingdom (UK), the Netherlands, Greece, Italy, and Ireland. We searched European health authorities' websites and PubMed. Various vaccines and immunization schedules are used in 21 NIPs. Most countries implement MenC vaccination in infants, MenACWY in adolescents, and a growing number, MenB in infants. Only Malta has introduced MenACWY vaccination in infants, and several countries reimburse immunization of toddlers. The UK, Italy, Ireland, Malta, Andorra, and San Marino recommend MenB vaccination in infants and MenACWY vaccination in adolescents, targeting the most prevalent serogroups in the most impacted age groups. Main factors determining new vaccination strategies are fluctuating IMD epidemiology, ease of vaccine implementation, ability to induce herd protection, favorable benefit-risk balance, and acceptable cost-effectiveness. Since 1999, when the UK introduced MenC vaccination, the reduction in IMD incidence has been gradually enhanced as other countries adopted routine meningococcal vaccinations. Meningococcal vaccination strategies in each country are continually adapted to regional epidemiology and national healthcare priorities. Future strategies may include broader coverage vaccines when available (e.g., MenABCWY, MenACWY), depending on prevailing epidemiology.

This review article incorporates information from the 4th Global Meningococcal Initiative summit meeting. Since the introduction of stringent COVID-19 infection control and lockdown measures globally in 2020, there has been an impact on IMD prevalence, surveillance, and vaccination compliance. Incidence rates and associated mortality fell across various regions during 2020. A reduction in vaccine uptake during 2020 remains a concern globally. In addition, several Neisseria meningitidis clonal complexes, particularly CC4821 and CC11, continue to exhibit resistance to antibiotics, with resistance to ciprofloxacin or beta-lactams mainly linked to modifications of gyrA or penA alleles, respectively. Beta-lactamase acquisition was also reported through horizontal gene transfer (bla ROB-1 ) involving other bacterial species. Despite the challenges over the past year, progress has also been made on meningococcal vaccine development, with several pentavalent (serogroups ABCWY and ACWYX) vaccines currently being studied in late-stage clinical trial programmes., (Copyright © 2021. Published by Elsevier Ltd.)

Background: In April-May, 2013, France modified its pertussis vaccination schedule, which uses the acellular pertussis vaccine, from three primary doses at 2, 3, and 4 months of age and a first booster at 16-18 months of age (former schedule) to two primary doses at 2 and 4 months of age and a first booster at 11 months of age (new schedule). We aimed to assess the subsequent effect of the vaccine schedule change on pertussis epidemiology in France., Methods: In this modelling study, using data collected between Jan 1, 2012, and Dec 31, 2019, from French national surveillance sources, we analysed the PCR test results of nasopharyngeal swabs collected from symptomatic outpatients aged 2-20 years with suspected pertussis. We developed a negative binomial regression model for the number of confirmed pertussis cases by year and age to assess the relative risks of pertussis depending on vaccine schedule. The linear predictor included the year, the age group, the population size, and a proxy of waning immunity. We tested different models in which waning immunity could vary with vaccine schedule and type of primary vaccine. The models were fitted to the 2012-18 data via Bayesian Markov chain Monte Carlo sampling, and the 2019 data were left out for external model validation. We also compared the anti-pertussis toxin (PT) antibody concentrations in leftover sera from children not tested for pertussis or recent respiratory tract infection aged 2-5 years born before and after the vaccine schedule change., Findings: We collected data on 7493 confirmed cases of pertussis. The model that best fitted the 2012-18 epidemiological data supported a faster waning of immunity following vaccination with the new vaccine schedule. 3 years after vaccination, the risk of developing pertussis was 1·7 (95% CI 1·4-2·0) times higher for children vaccinated according to the new schedule than those vaccinated according to the former schedule. The model correctly predicted the age distribution of cases in 2019. Geometric mean concentrations (GMC) of anti-PT IgG were 50% lower in children aged 2 years vaccinated with the new schedule (GMC=5·85 IU/mL [95% CI 4·08-8·39]) than in children of the same age vaccinated with the former schedule (GMC=11·62 IU/mL [95% CI 9·05-14·92]; p=0·0016), and 43% lower in children aged 3 years vaccinated with the new schedule (GMC=3·88 IU/mL [95% CI 2·82-5·34]) than those with the former schedule (GMC=6·80 IU/mL [95% CI 4·77-9·70]; p=0·026)., Interpretation: A shorter-lived protection induced by the new vaccine schedule recommended in France since 2013 is associated with an increase of pertussis cases in children aged 2-5 years. If similar findings are observed in other countries and clinical trials, these findings should be considered in future pertussis vaccination policies., Funding: INCEPTION, Labex-IBEID, Institut Pasteur, and Santé Publique France., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We implemented a project named MENINGSTOP in three countries of North Africa (Algeria, Morocco and Tunisia). The main objective was to use real-time PCR to detect, identify and type the three main agents (Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae) responsible for invasive bacterial infections (IBI)., Methods: The protocol of WHO and US CDC for real-time PCR was used to detect and type the three bacterial agents in clinical samples. We also designated two quality exercises using an external interlaboratory study and cross-testing of 10% of randomly selected samples., Results: Among the 752 samples tested, 18% were positive for one of the three agents. N. meningitidis was the most frequent globally reaching 9% of all samples (7% to 17% range) followed by S. pneumoniae 8% of all samples (6% to 15%). Group B meningococci was the most frequent (74% of all positive samples for meningococci and ranging from 50% to 90%). Quality assurance showed >85% correlation scores., Conclusions: Real-time PCR can help improving epidemiological surveillance. Data confirm the prevalence of meningococci B. Our project adds a reliable tool to enhance surveillance and to help decision making in vaccination strategies against IBI., Competing Interests: Declaration of Competing Interest This collaborative work was in part funded by Sanofi Pasteur but the latter was not responsible for data collection, data interpretation, and writing of the report. The corresponding author, MKT, had full access to all the data in the study and had final responsibility for the decision to submit for publication. MKT also performs contract works for the Institut Pasteur funded by GSK and Pfizer outside the submitted manuscript, and MKT and AED have a patent with GSK, 630133. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject. AA and MK are Sanofi employees and may hold shares and/or stock options in the company., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neisseria meningitidis (the meningococcus) causes significant morbidity and mortality worldwide through an epidemic or sporadic invasive infections. The epidemiology of N. meningitidis is changing and unpredictable. Certain emerging meningococcal genotypes seem to be associated with increasing unusual clinical presentations. Indeed, early symptoms may vary and are frequently non-specific. However, atypical clinical forms including abdominal presentations, septic arthritis, and bacteremic pneumonia may lead to misdiagnosis and some are usually associated with higher case fatality rates due to delayed optimal management. Improving awareness of clinicians and public health specialists about these unusual but potentially severe presentations should help establish prompt diagnoses and provide appropriate management of cases. In this review, we described unusual panels of clinical presentations of invasive meningococcal disease linked to the recent changes in meningococcal epidemiology.

The 4CMenB, a protein-based vaccine, was licensed in Europe in 2013 against invasive meningococcal disease caused by serogroup B and is currently implemented in several countries although according to different national strategies. Isolate coverage estimation is required as vaccine-targeted antigens may vary among isolates over time. Several phenotypic and genotypic methods have been developed to predict strain coverage by scoring the expression and cross-reactivity of vaccine antigens using the Meningococcal Antigen Typing system (MATS), by the genetic correlation of alleles encoding these antigens and MATS expression data (gMATS) and by the Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR). We applied these approaches on meningococcal B isolates in France and compared two epidemiological years, 2013-2014 and 2018-2019. A strong correlation was observed between MATS data that were generated for the year 2013-2014 and the gMATS data extracted from whole genome sequencing. gMATS and MenDeVAR were next used to compare the two years. Using gMATS, the overall coverage was 77.2% (lower limit (LL)-upper limit (UL) 66.7-87.7) and 70.7% (LL-UL 61.5-80.0) for the two years, respectively. The reduction in coverage between the two years is mainly driven by the reduction of alleles exactly matching the vaccine antigens. A high number of unpredictable isolates was observed using the MenDeVAR and was due to lack of MATS information for new or rare alleles in particular for the year 2018-2019. Our data underline the need of continuous surveillance of strain coverage and the importance of generating phenotypic MATS data to update the genetic approaches of prediction.