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Background Meningococcal serogroup C (MenC) vaccination was introduced for 14-month-olds in the Netherlands in 2002, alongside a mass campaign for 1–18 year-olds. Due to an outbreak of serogroup W disease, MenC vaccination was replaced for MenACWY vaccination in 2018, next to introduction of a booster at 14 years of age and a catch-up campaign for 14–18 year-olds. We assessed meningococcal ACWY antibodies across the Dutch population in 2016/17 and 2020. Methods In a nationwide cross-sectional serosurvey in 2016/17, sera from participants aged 0–89 years (n = 6886) were tested for MenACWY-polysaccharide-specific (PS) serum IgG concentrations, and functional MenACWY antibody titers were determined in subsets. Moreover, longitudinal samples collected in 2020 (n = 1782) were measured for MenACWY-PS serum IgG concentrations. Results MenC antibody levels were low, except in recently vaccinated 14–23 month-olds and individuals who were vaccinated as teenagers in 2002, with seroprevalence of 59% and 20–46%, respectively. Meningococcal AWY antibody levels were overall low both in 2016/17 and in 2020. Naturally-acquired MenW immunity was limited in 2020 despite the recent serogroup W outbreak. Conclusions This study demonstrates waning of MenC immunity 15 years after a mass campaign in the Netherlands. Furthermore, it highlights the lack of meningococcal AWY immunity across the population and underlines the importance of the recently introduced MenACWY (booster) vaccination.

Background In response to the recent serogroup W invasive meningococcal disease (IMD-W) epidemic in the Netherlands, meningococcal serogroup C (MenC) conjugate vaccination for children aged 14 months was replaced with a MenACWY conjugate vaccination, and a mass campaign targeting individuals aged 14–18 years was executed. We investigated the impact of MenACWY vaccination implementation in 2018–2020 on incidence rates and estimated vaccine effectiveness (VE). Methods We extracted IMD cases diagnosed between July 2014 and December 2020 from the national surveillance system. We calculated age group–specific incidence rate ratios by comparing incidence rates before (July 2017–March 2018) and after (July 2019–March 2020) MenACWY vaccination implementation. We estimated VE in vaccine-eligible cases using the screening method. Results Overall, the IMD-W incidence rate declined by 61% (95% confidence interval [CI], 40 to 74). It declined by 82% (95% CI, 18 to 96) in the vaccine-eligible age group (individuals aged 15–36 months and 14–18 years) and by 57% (95% CI, 34 to 72) in vaccine-noneligible age groups. VE was 92% (95% CI, –20 to 99.5) in vaccine-eligible toddlers (aged 15–36 months). No IMD-W cases were reported in vaccine-eligible teenagers after the campaign. Conclusions The MenACWY vaccination program was effective in preventing IMD-W in the target population. The IMD-W incidence reduction in vaccine-noneligible age groups may be caused by indirect effects of the vaccination program. However, disentangling natural fluctuation from vaccine effect was not possible. Our findings encourage the use of toddler and teenager MenACWY vaccination in national immunization programs.

BackgroundComplement-mediated killing is critical in the defense against meningococci. During a recent outbreak of invasive meningococcal serogroup W disease (IMD-W) in the Netherlands, the predominant isolates belonged to clonal complex (cc) 11, which may suggest a role for cc11-assocated traits in complement resistance. We investigated complement resistance of invasive and carriage meningococcal isolates of different serogroups and lineages. In addition, we investigated whether vaccine-induced antibodies can overcome resistance to complement-mediated killing.MethodsWe analyzed IMD isolates (n=56) and carriage isolates (n=19) of different serogroups and clonal lineages in the serum bactericidal antibody (SBA) assay using pooled serum from unvaccinated and vaccinated individuals. Furthermore, we determined meningococcal serogroup W geometric mean titers (GMTs) and protection levels with the routinely-used non-cc11 isolate and hyperinvasive cc11 isolates using individual serum samples from adolescents and adults 5 years postvaccination.ResultsThe hyperinvasive IMD isolates showed high variation in their resistance to complement-mediated killing when pooled serum from unvaccinated individuals was used (median 96, range 2-1,536). When pooled sera from vaccinated individuals was used, all isolates were killed. The minimum spanning tree revealed moderate clustering of serogroup and cc, while complement resistance did not. While a significantly lower GMT was observed against cc11 meningococcal serogroup W (MenW) compared to a non-cc11 MenW isolate in vaccinated adults but not in adolescents, we found no differences in the proportion protected between these isolates.ConclusionsThese data show that vaccine-induced antibodies are effectively inducing complement-mediated killing of complement-resistant hyperinvasive and carriage meningococcal isolates.Short summaryMeningococcal isolates of hyperinvasive lineages are resistant to complement-mediated killing but vaccine-induced antibodies effectively kill these invasive isolates.

Neisseria meningitidis is often asymptomatically carried in the nasopharynx but may cause invasive meningococcal disease, leading to morbidity and mortality. Meningococcal conjugate vaccinations induce functional protective antibodies against capsular antigens, but seroprotection wanes over time. We measured functional antibody titers five years after administration of a single dose of the meningococcal ACWY-polysaccharide-specific tetanus toxoid-conjugated (MenACWY-TT) vaccine in adolescents and middle-aged adults in the Netherlands, using the serum bactericidal antibody with baby rabbit complement (rSBA) assay. Protection was defined as rSBA titer &ge, 8. The meningococcal ACWY-specific serum IgG concentrations were measured with a multiplex immunoassay. Duration of protection was estimated by a bi-exponential decay model. Sufficient protection for MenC, MenW, and MenY was achieved in 94&ndash, 96% of the adolescents five years postvaccination, but, in middle-aged adults, only in 32% for MenC, 65% for MenW and 71% for MenY. Median duration of protection for MenCWY was 4, 14, and 21 years, respectively, in middle-aged adults, while, in adolescents, it was 32, 98, and 33 years. Our findings suggest that adolescents, primed in early childhood with MenC conjugate vaccination, remain sufficiently protected after a single dose of MenACWY-TT vaccine. Middle-aged adults without priming vaccination show fast waning of antibodies, particularly MenC, for which protection is lost after four years.

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p

Background: Dysembryoplastic neuroepithelial tumors (DNETs) are benign developmental brain tumors associated with intractable, drug-resistant epilepsy. Distinguishing this entity from other low-grade ganglioneuronal tumors is challenging for neuro-pathologists. We set out to identify the genetic causes of DNETs and to clarify the molecular mechanisms underlying this condition. Experimental procedures: We collected a family with three individuals with seizures and multinodular DNETs together with 100 sporadic tumors from 96 persons referred to us as DNETs. Whole-exome sequencing was performed on 46 tumours and targeted sequencing for hotspot FGFR1 mutations and BRAFp.V600E was used on the remaining samples. Blind neuropathology review and molecular characterization were performed. FISH, Copy Number Variation assays and Sanger sequencing were used to validate the findings. Supporting evidence for functional defects was obtained by in silico modelling of novel FGFR1p.R661P variant. Functional impact of this and other FGFR1 mutations were assessed using Flow Cytometry and β-galactosidase staining in HEK293 cells. Results: We identified a novel germline FGFR1 mutation, p.R661P, in a father and his two children with DNETs. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in cis in the tumors with the germline mutation. Pathology review distinguished DNETs (WHO grade I) (45%) from DNET-like tumors (55%). FGFR1 alterations, mainly intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis, characterized DNETs (25/43;58.1%) whereas FGFR1 mutations (10/53;19%) (p < 0.0001) and hotspot BRAFp.V600E (12/53;22.6%) (p < 0.001) were identified in DNET-like tumors. Phospho-ERK overexpression in FGFR1p.R661P and p.N546K mutant cells support enhanced MAPK/ERK activation in this condition. Conclusions: This study identifies constitutional and somatic FGFR1 alterations and hotspot BRAFV600E as key events in DNETs and DNET-like tumors respectively. The final common effect of these alterations appears to be a balanced level of signalling that results in benign rather than malignant tumors. The integrated pathology and molecular characterization performed here reveals the key role of the MAP-Kinase pathway in these epileptogenic low-grade glioneuronal tumors, pointing the way towards existing targeted therapies. Citation Format: Barbara Rivera, Tenzin Gayden, Jian Zhang, Javad Nadaf, Talia Boshari, Damien Faury, Michele Zeinieh, Romeo Blanc, David Burk, Somayyeh Fahiminiya, Eric Bareke, Ulrich Schueller, Camelia M. Monoranu, Ronald Sträter, Kornelius Kerl, Thomas Niederstadt, Gerhard Kurlemann, Benjamin Ellezam, Zuzanna Michalak, Maria Thom, Paul Lockhart, Richard Leventer, Milou Ohm, Duncan McGregor, David Jones, Jason Karamchandani, Celia Greenwood, Albert Berghuis, Susanne Bens, Reiner Siebert, Magdalena Zakrzewska, Pawel Liberski, Krzysztof Zakrzewski, Sanjay Sisodiya, Werner Paulus, Steffen Albrecht, Martin Hasselblatt, Nada Jabado, William D. Foulkes, Jacek Majewski. FGFR1 abnormalities in seizure-associated familial and sporadic dysembryoplastic neuroepithelial tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-019.