4CMenB journey to the 10-year anniversary and beyond.

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.

Invasive meningococcal disease, caused by the bacterium Neisseria meningitidis(meningococcus), is rare but often devastating and can be deadly. Effective vaccines are available, including vaccines against meningococcal serogroup B disease. In 2013, the 4-component meningococcal serogroup B vaccine, 4CMenB, became the first broadly protective, protein-based vaccine against serogroup B to be licensed, with the second (bivalent vaccine, MenB-FHbp) licensed the following year. 4CMenB is now registered in more than 50 countries, in the majority, for infants and all age groups. In the US, it is approved for individuals aged 10­25 years. Evidence from immunization programs in the last decade, comparing vaccinated and unvaccinated individuals and the same population before and after vaccination, confirms the effectiveness and positive impact of 4CMenB against serogroup B disease. This also demonstrates that 4CMenB can provide protection against invasive diseases caused by other meningococcal serogroups. Furthermore, N. meningitidis is closely related to the bacterium that causes gonorrhea, N. gonorrhoeae, and emerging real-world evidence suggests that 4CMenB provides additional moderate protection against gonococcal disease. The safety of 4CMenB when given to large numbers of infants, children, adolescents, and adults is consistent with the 4CMenB safety profile reported before licensure.For the future, it would be beneficial to address differences among national guidelines for the recommended administration of 4CMenB, particularly where there is supportive epidemiological evidence but no equitable access to vaccination. New assays for assessing the potential effectiveness of meningococcal serogroup B vaccines in clinical trials are also required because serogroup B strains circulating in the population are extremely diverse across different countries.

Emerging Meningococcal B Meningitis in Japan: A Case Report of a 50-Year-Old Japanese Man with Diabetes.

BACKGROUND Meningococcal meningitis is rare in Japan; however, when outbreaks do occur, they predominantly involve domestically infected cases rather than those contracted overseas. CASE REPORT A Japanese man with diabetes in his 50s experienced fever and loss of consciousness, with no history of international travel. In our hospital, gram-negative diplococci were detected in the cerebrospinal fluid (CSF) of the patient by Gram staining, although the rapid agglutination test and cultures of blood and CSF were negative. Multiplex polymerase-chain reaction (PCR) testing returned positive results for meningococcus and parechovirus. Brain MRI revealed a finding of meningitis, but there were no indications of encephalitis. To determine the serotype and genotype, we sent the sample to the National Institute of Infectious Diseases, which identified the serogroup and sequence type (ST) as type B and 2057, respectively. Despite the unknown antimicrobial susceptibility, the patient responded well to empirical treatment with ceftriaxone at 2 g every 12 h, and was discharged with remaining symptoms of dizziness, headache, difficulty hearing in the left ear, and tinnitus in the left ear. CONCLUSIONS In Japan, vaccines covering serogroups A, C, and W/Y are available but not routinely administered. According to epidemiological surveillance reports, serogroup B is the second most common cause of meningococcal meningitis in Japan, yet there is no corresponding vaccine available in the country. This case has prompted a review of the epidemiology of meningococcus in Japan, encompassing strategies for vaccination and hospital infection control to prevent droplet transmission, which includes post-exposure prophylaxis when no prior measures have been implemented.

Genetic characterization and estimated 4CMenB vaccine strain coverage of 284 Neisseria meningitidis isolates causing invasive meningococcal disease in Argentina in 2010-2014.

Meningococcal (Neisseria meningitidis) serogroup B (MenB) strain antigens are diverse and a limited number of strains can be evaluated using the human serum bactericidal antibody (hSBA) assay. The genetic Meningococcal Antigen Typing System (gMATS) was developed to predict the likelihood of coverage for large numbers of isolates by the 4CMenB vaccine, which includes antigens Neisseria adhesin A (NadA), Neisserial Heparin-Binding Antigen (NHBA), factor H-binding protein (fHbp), and Porin A (PorA). In this study, we characterized by whole-genome analyses 284 invasive MenB isolates collected from 2010 to 2014 by the Argentinian National Laboratories Network (52-61 isolates per year). Strain coverage was estimated by gMATS on all isolates and by hSBA assay on 74 randomly selected isolates, representative of the whole panel. The four most common clonal complexes (CCs), accounting for 81.3% of isolates, were CC-865 (75 isolates, 26.4%), CC-32 (59, 20.8%), CC-35 (59, 20.8%), and CC-41/44 (38, 13.4%). Vaccine antigen genotyping showed diversity. The most prevalent variants/peptides were fHbp variant 2, NHBA peptides 24, 21, and 2, and PorA variable region 2 profiles 16-36 and 14. The nadA gene was present in 66 (23.2%) isolates. Estimated strain coverage by hSBA assay showed 78.4% of isolates were killed by pooled adolescent sera, and 51.4% and 64.9% (based on two different thresholds) were killed by pooled infant sera. Estimated coverage by gMATS (61.3%; prediction interval: 55.5%, 66.7%) was consistent with the infant hSBA assay results. Continued genomic surveillance is needed to evaluate the persistence of major MenB CCs in Argentina.

The most common clinical manifestations of invasive meningococcal disease include meningitis and septicemia, which can be deadly, and many survivors suffer long-term serious after-effects. Most cases of invasive meningococcal disease are caused by six meningococcal serogroups (types), including serogroup B. Although vaccines are available against meningococcal serogroup B infection, these vaccines target antigens that are highly diverse. Consequently, the effectiveness of vaccination may vary from country to country because the meningococcal serogroup B strains circulating in particular regions carry different forms of the target vaccine antigens. This means it is important to test serogroup B strains isolated from specific populations to estimate the percentage of strains that a vaccine is likely to be effective against (known as 'vaccine strain coverage'). The genetic Meningococcal Antigen Typing System (gMATS) was developed to predict strain coverage by the four-component meningococcal serogroup B vaccine, 4CMenB, against large numbers of serogroup B strains. In this study, we analyzed 284 invasive meningococcal serogroup B isolates collected between 2010 and 2014 in Argentina. Genetic analyses showed that the vaccine antigens of the isolates were diverse and some genetic characteristics had not been found in isolates from other countries. However, vaccine strain coverage estimated by gMATS was consistent with that reported in other parts of the world and with strain coverage results obtained for a subset via another method, the human serum bactericidal antibody (hSBA) assay. These results highlight the need for continued monitoring of circulating bacterial strains to assess the estimated strain coverage of meningococcal serogroup B vaccines.

Neisserial adhesin A (NadA) binds human Siglec-5 and Siglec-14 with high affinity and promotes bacterial adhesion/invasion.

Neisserial adhesin A (NadA) is a meningococcal surface protein included as recombinant antigen in 4CMenB, a protein-based vaccine able to induce protective immune responses against Neisseria meningitidis serogroup B (MenB). Although NadA is involved in the adhesion/invasion of epithelial cells and human myeloid cells, its function in meningococcal physiology is still poorly understood. To clarify the role played by NadA in the host-pathogen interaction, we sought to identify its cellular receptors. We screened a protein microarray encompassing 2,846 human and 297 mouse surface/secreted recombinant proteins using recombinant NadA as probe. Efficient NadA binding was revealed on the paired sialic acid-binding immunoglobulin-type lectins receptors 5 and 14 (Siglec-5 and Siglec-14), but not on Siglec-9 therein used as control. The interaction was confirmed by biochemical tools with the determination of the KD value in the order of nanomolar and the identification of the NadA binding site by hydrogen-deuterium exchange coupled to mass spectrometry. The N-terminal domain of the Siglec-5 that recognizes the sialic acid was identified as the NadA binding domain. Intriguingly, exogenously added recombinant soluble Siglecs, including Siglec-9, were found to decorate N. meningitidis surface in a NadA-dependent manner. However, Siglec-5 and Siglec-14 transiently expressed in CHO-K1 cells endorsed NadA binding and increased N. meningitidis adhesion/invasion while Siglec-9 did not. Taken together, Siglec-5 and Siglec-14 satisfy all features of NadA receptors suggesting a possible role of NadA in the acute meningococcal infection.IMPORTANCEBacteria have developed several strategies for cell colonization and immune evasion. Knowledge of the host and pathogen factors involved in these mechanisms is crucial to build efficacious countermoves. Neisserial adhesin A (NadA) is a meningococcal surface protein included in the anti-meningococcus B vaccine 4CMenB, which mediates adhesion to and invasion of epithelial cells. Although NadA has been shown to bind to other cell types, like myeloid and endothelial cells, it still remains orphan of a defined host receptor. We have identified two strong NadA interactors, Siglec-5 and Siglec-14, which are mainly expressed on myeloid cells. This showcases that NadA is an additional and key player among the Neisseria meningitidis factors targeting immune cells. We thus provide novel insights on the strategies exploited by N. meningitidis during the infection process, which can progress to a severe illness and death.

Exploring meningococcal serogroup B vaccination conversations under shared clinical decision-making in the US.

OBJECTIVE: In 2019, the United States Advisory Committee on Immunization Practices (ACIP) updated their meningococcal serogroup B (MenB) vaccination recommendation for 16-|23-year-olds from individual to shared clinical decision-making (SCDM). SCDM recommendations are individually based and informed by a decision process between patients and healthcare providers (HCPs). MenB vaccination among 16-23-year-olds remains low. We examined recorded conversations in which MenB vaccine-related discussions between HCPs and patients/caregivers took place, and how these interactions changed following the updated SCDM recommendation. METHODS: An analysis of recordings where MenB vaccination was discussed between HCPs and patients (16-|23 years old)/caregivers was conducted using retrospective anonymized dialogue data (January 2015-October 2022). Shared decision-making strength was measured using a modified OPTION5 framework. RESULTS: Of 97 included recorded conversations, the average duration was 11.3 min. Within these conversations, MenB disease was discussed for 0.25 min (38.9% of words in total vaccine-preventable diseases discussion) and MenB vaccination was discussed for 1.36 min (60.9% of words in total vaccine discussion), on average. HCPs spoke 78.8% of MenB vaccine-related words and most (99.0%) initiated the MenB vaccination discussion. In 40.2% of recordings, HCPs acknowledged the MenB vaccine without providing a clear recommendation. HCP recommendations often favored MenB vaccination (87.0%) and recommendations were 21.4% stronger post-recommendation change to SCDM. As measured by the modified OPTION5 framework, most recordings did not reflect a high degree of shared decision-making between HCPs and patients/caregivers. CONCLUSIONS: MenB vaccination discussions were brief, and the degree of shared decision-making was low. Targeted education of HCPs and patients/caregivers may improve MenB vaccination awareness, SCDM implementation, and vaccine uptake.

Meningitis is a serious and sometimes deadly disease. In the United States (US), the Centers for Disease Control and Prevention (CDC) recommends that 16­23-year-olds get vaccinated against meningococcal serogroup B (MenB), which causes a specific type of meningitis called invasive meningococcal disease. As of 2019, the CDC recommends that healthcare providers and patients or their caregivers have a shared decision-making discussion about deciding to get vaccinated against MenB. Despite these recommendations, vaccination against MenB among 16­23-year-olds is very low. Only about 3 in 10 17-year-olds had received the MenB vaccine in 2022. We studied conversations between healthcare providers and patients or their caregivers that included discussions of MenB vaccination. These discussions were largely brief and led by the healthcare providers. We found that healthcare providers most often made recommendations that were in favor of their patients getting vaccinated against MenB. However, we also found that healthcare providers missed many opportunities to have these shared decision-making discussions about MenB vaccination with patients or their caregivers. Providing education and resources for patients, caregivers, and healthcare providers focused on increasing awareness about MenB vaccination and the role they can play in having shared decision-making discussions may lead to more adolescents and young adults getting vaccinated against MenB. More research is needed to find out how we can improve MenB vaccination coverage in the US.

A Fluorinated Sialic Acid Vaccine Lead Against Meningitis B and C.

Inspired by the specificity of α-(2,9)-sialyl epitopes in bacterial capsular polysaccharides (CPS), a doubly fluorinated disaccharide has been validated as a vaccine lead against Neisseria meningitidis serogroups C and/or B. Emulating the importance of fluorine in drug discovery, this molecular editing approach serves a multitude of purposes, which range from controlling α-selective chemical sialylation to mitigating competing elimination. Conjugation of the disialoside with two carrier proteins (CRM197 and PorA) enabled a semisynthetic vaccine to be generated; this was then investigated in six groups of six mice. The individual levels of antibodies formed were compared and classified as highly glycan-specific and protective. All glycoconjugates induced a stable and long-term IgG response and binding to the native CPS epitope was achieved. The generated antibodies were protective against MenC and/or MenB; this was validated in vitro by SBA and OPKA assays. By merging the fluorinated glycan epitope of MenC with an outer cell membrane protein of MenB, a bivalent vaccine against both serogroups was created. It is envisaged that validation of this synthetic, fluorinated disialoside bioisostere as a potent antigen will open new therapeutic avenues.

Prediction by genetic MATS of 4CMenB vaccine strain coverage of invasive meningococcal serogroup B isolates circulating in Taiwan between 2003 and 2020.

Neisseria meningitidis serogroup B (NmB) strains have diverse antigens, necessitating methods for predicting meningococcal serogroup B (MenB) vaccine strain coverage. The genetic Meningococcal Antigen Typing System (gMATS), a correlate of MATS estimates, predicts strain coverage by the 4-component MenB (4CMenB) vaccine in cultivable and non-cultivable NmB isolates. In Taiwan, 134 invasive, disease-causing NmB isolates were collected in 2003-2020 (23.1%, 4.5%, 5.2%, 29.8%, and 37.3% from individuals aged ≤11 months, 12-23 months, 2-4 years, 5-29 years, and ≥30 years, respectively). NmB isolates were characterized by whole-genome sequencing and vaccine antigen genotyping, and 4CMenB strain coverage was predicted using gMATS. Analysis of phylogenetic relationships with 502 global NmB genomes showed that most isolates belonged to three global hyperinvasive clonal complexes: ST-4821 (27.6%), ST-32 (23.9%), and ST-41/44 (14.9%). Predicted strain coverage by gMATS was 62.7%, with 27.6% isolates covered, 2.2% not covered, and 66.4% unpredictable by gMATS. Age group coverage point estimates ranged from 42.9% (2-4 years) to 66.1% (≤11 months). Antigen coverage estimates and percentages predicted as covered/not covered were highly variable, with higher estimates for isolates with one or more gMATS-positive antigens than for isolates positive for one 4CMenB antigen. In conclusion, this first study on NmB strain coverage by 4CMenB in Taiwan shows 62.7% coverage by gMATS, with predictable coverage for 29.8% of isolates. These could be underestimated since the gMATS calculation does not consider synergistic mechanisms associated with simultaneous antibody binding to multiple targets elicited by multicomponent vaccines or the contributions of minor outer membrane vesicle vaccine components.IMPORTANCEMeningococcal diseases, caused by the bacterium Neisseria meningitidis (meningococcus), include meningitis and septicemia. Although rare, invasive meningococcal disease is often severe and can be fatal. Nearly all cases are caused by six meningococcal serogroups (types), including meningococcal serogroup B. Vaccines are available against meningococcal serogroup B, but the antigens targeted by these vaccines have highly variable genetic features and expression levels, so the effectiveness of vaccination may vary depending on the strains circulating in particular countries. It is therefore important to test meningococcal serogroup B strains isolated from specific populations to estimate the percentage of bacterial strains that a vaccine can protect against (vaccine strain coverage). Meningococcal isolates were collected in Taiwan between 2003 and 2020, of which 134 were identified as serogroup B. We did further investigations on these isolates, including using a method (called gMATS) to predict vaccine strain coverage by the 4-component meningococcal serogroup B vaccine (4CMenB).

Available evidence on the co-administration of the four-component meningococcal B vaccine (4CMenB) with three vaccines at the same visit among pediatric individuals.

Vaccine co-administration is a useful strategy for improving vaccine coverage and adherence. In Italy, an update to the national immunization program (NIP) in 2023 included recommendations for co-administration of pediatric vaccines, including the four-component vaccine for meningococcus B (4CMenB), pneumococcal conjugate vaccine (PCV), hexavalent vaccines, and oral rotavirus vaccines. Safety is a major concern when considering vaccine co-administration; therefore, a literature review of the available evidence on 4CMenB co-administration with PCV, hexavalent/pentavalent, and rotavirus vaccines was performed. Of 763 publications screened, two studies were reviewed that reported safety data on 4CMenB co-administration with PCV, hexavalent/pentavalent, and rotavirus vaccines in infants aged 0-24 months. Overall, these studies supported that there were no significant safety signals when co-administering 4CMenB with PCV, hexavalent/pentavalent, and rotavirus vaccines, compared with individual vaccination. This review provides key insights for healthcare professionals on the tolerability of co-administering 4CMenB with routine vaccines.

Serogroup B Invasive Meningococcal Disease in Older Adults Identified by Genomic Surveillance, England, 2022-2023.

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

Neisseria meningitidis with decreased susceptibility to penicillin G and molecular characterization of the penA gene in strains isolated at University Hospital Centers of Casablanca and Marrakech (Morocco).

Introduction: the laboratory diagnosis of meningococcal meningitis relies on conventional techniques. This study aims to evaluate the correlation between the reduced sensitivity to penicillin G of Neisseria meningitidis (N.m) strains and the expression of the altered PBP 2 gene. Methods: out of 190 strains of N.m isolated between 2010 and 2021 at the bacteriology laboratories of Ibn Rochd University Hospital Centre (IR-UHC) in Casablanca and the UHC Mohammed VI in Marrakech, 23 isolates were part of our study. We first determined their state of sensitivity to penicillin G by E-Test strips and searched for the expression of the penA gene by PCR followed by Sanger sequencing. Results: of all the confirmed cases of N.m, 93.15% (n=177) are of serogroup B, 75.2% (n = 143) are sensitive to penicillin G and 24.73% (n = 47) are of intermediate sensitivity. No resistance to penicillin G was observed. Reduced sensitivity to penicillin G in N.m is characterized by mutations namely F504 L, A510 V, I515 V, G541 N and I566 V located in the C-terminal region of the penA gene encoding the penicillin-binding protein 2 (PBP2) (mosaic gene). Conclusion: our study presents useful data for the phenotypic and genotypic monitoring of resistance to penicillin G in N.m and can contribute to the analysis of genetic exchanges between different Neisseria species.

Use of the Pfizer Pentavalent Meningococcal Vaccine Among Persons Aged ≥10 Years: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Meningococcal disease is a life-threatening invasive infection caused by Neisseria meningitidis. Two quadrivalent (serogroups A, C, W, and Y) meningococcal conjugate vaccines (MenACWY) (MenACWY-CRM [Menveo, GSK] and MenACWY-TT [MenQuadfi, Sanofi Pasteur]) and two serogroup B meningococcal vaccines (MenB) (MenB-4C [Bexsero, GSK] and MenB-FHbp [Trumenba, Pfizer Inc.]), are licensed and available in the United States and have been recommended by CDC's Advisory Committee on Immunization Practices (ACIP). On October 20, 2023, the Food and Drug Administration approved the use of a pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp [Penbraya, Pfizer Inc.]) for prevention of invasive disease caused by N. meningitidis serogroups A, B, C, W, and Y among persons aged 10-25 years. On October 25, 2023, ACIP recommended that MenACWY-TT/MenB-FHbp may be used when both MenACWY and MenB are indicated at the same visit for the following groups: 1) healthy persons aged 16-23 years (routine schedule) when shared clinical decision-making favors administration of MenB vaccine, and 2) persons aged ≥10 years who are at increased risk for meningococcal disease (e.g., because of persistent complement deficiencies, complement inhibitor use, or functional or anatomic asplenia). Different manufacturers' serogroup B-containing vaccines are not interchangeable; therefore, when MenACWY-TT/MenB-FHbp is used, subsequent doses of MenB should be from the same manufacturer (Pfizer Inc.). This report summarizes evidence considered for these recommendations and provides clinical guidance for the use of MenACWY-TT/MenB-FHbp.

Bactericidal killing of meningococcal W strains isolated in Argentina by the sera of adolescents and infants immunized with 4-component meningococcal serogroup B vaccine (4CMenB).

Invasive meningococcal disease (IMD) is a life-threatening disease caused by meningococcal serogroups A, B, C, W, X, and Y, of which B and W are most common in Argentina. The 4-component meningococcal serogroup B (4CMenB) vaccine contains three purified recombinant protein antigens (Neisseria adhesin A [NadA], factor H binding protein [fHbp], and Neisserial Heparin Binding Antigen [NHBA]) and outer membrane vesicles (OMV), which is derived from the New Zealand epidemic strain and contains Porin A 1.4. These antigens are present and conserved in strains that belong to other serogroups. In this study, we show that 10/11 (91%) meningococcal serogroup W (MenW) strains selected to be representative of MenW isolates that caused IMD in Argentina during 2010-2011 were killed in bactericidal assays by the sera of adolescents and infants who had been immunized with the 4CMenB vaccine. We also show that MenW strains that caused IMD in Argentina during 2018-2021 were genetically similar to the earlier strains, indicating that the 4CMenB vaccine would likely still provide protection against current MenW strains. These data highlight the potential of 4CMenB vaccination to protect adolescents and infants against MenW strains that are endemic in Argentina.

Aceptación y desigualdades socioeconómicas en la vacunación frente a meningococo B en la Comunidad de Madrid en el periodo anterior a su inclusión en el calendario / Acceptance and socioeconomic inequalities in meningococcal B vaccination in the community of Madrid prior to its inclusion in the immunization schedule

Introducción: La principal medida de prevención frente a la enfermedad meningocócica invasiva es la vacunación. El objetivo de este estudio es evaluar la aceptabilidad y las desigualdades socioeconómicas en el acceso a la vacuna frente a meningococo B (MenB) en la Comunidad de Madrid en el periodo previo a la introducción de la misma en el calendario. Materiales y métodos: Se realizó un estudio observacional descriptivo en la cohorte de niños/as nacidos entre 2016 y 2019, de tipo ecológico, empleando registros poblacionales electrónicos. Se describieron las coberturas de vacunación, se analizaron los factores asociados al estado vacunal, se describieron las distribuciones espaciales de cobertura de vacunación y de índice de privación (IP) y se analizó la asociación entre ambas mediante regresión espacial. Resultados: Se observó una tendencia creciente de las coberturas de primovacunación, pasando de un 44% en la cohorte de nacidos en el año 2016 a un 68% en la cohorte de 2019. Se encontró asociación estadísticamente significativa entre el estado vacunal y el IP (OR de primovacunación en zonas con IP5 respecto a zonas con IP1: 0,38; IC 95%: 0,39-0,50; p<0,001). El análisis espacial mostró correlación inversa entre el IP y la cobertura de vacunación. Conclusiones: El ascenso de las coberturas de esta vacuna muestra aceptación por parte de la población. La relación entre nivel socioeconómico y cobertura de vacunación confirma la existencia de una desigualdad en salud, y subraya la importancia de su inclusión en el calendario.(AU)

Introduction: The main preventive measure against invasive meningococcal disease is vaccination. The aim of our study was to evaluate the acceptability of the meningococcal B (MenB) vaccine and socioeconomic inequalities in the access to the vaccine in the Community of Madrid in the period prior to its introduction in the immunization schedule. Materials and methods: We conducted an observational and ecological descriptive study in the cohort of children born between 2016 and 2019 using population-based electronic records. We calculated the vaccination coverage and analysed factors associated with vaccination status, determined the spatial distribution of vaccination coverage and the deprivation index (DI) and assessed the association between them by means of spatial regression. Results: We observed an increasing trend in primary vaccination coverage, from 44% in the cohort born in 2016 to 68% in the 2019 cohort. We found a statistically significant association between vaccination status and the DI (OR of primary vaccination in areas with DI5 compared to areas with DP1, 0.38; 95% confidence interval: 0.39-0.50; P<.001). The spatial analysis showed an inverse correlation between the DI and vaccination coverage. Conclusions: The rise in the coverages of the MenB vaccine shows acceptance by the population. The association between socioeconomic level and vaccination coverage confirms the existence of health inequality and underlines the importance including this vaccine in the immunization schedule.(AU)

Bioinformatics Analysis of Global Diversity in Meningococcal Vaccine Antigens over the Past 10 Years: Vaccine Efficacy Prognosis.

Neisseria meningitidis (N. meningitidis) serogroup B (MenB) is the leading cause of invasive meningococcal disease worldwide. The pathogen has a wide range of virulence factors, which are potential vaccine components. Studying the genetic variability of antigens within a population, especially their long-term persistence, is necessary to develop new vaccines and predict the effectiveness of existing ones. The multicomponent 4CMenB vaccine (Bexsero), used since 2014, contains three major genome-derived recombinant proteins: factor H-binding protein (fHbp), Neisserial Heparin-Binding Antigen (NHBA) and Neisserial adhesin A (NadA). Here, we assessed the prevalence and sequence variations of these vaccine antigens in a panel of 5667 meningococcal isolates collected worldwide over the past 10 years and deposited in the PubMLST database. Using multiple amino acid sequence alignments and Random Forest Classifier machine learning methods, we estimated the potential strain coverage of fHbp and NHBA vaccine variants (51 and about 25%, respectively); the NadA antigen sequence was found in only 18% of MenB genomes analyzed, but cross-reactive variants were present in less than 1% of isolates. Based on our findings, we proposed various strategies to improve the 4CMenB vaccine and broaden the coverage of N. meningitidis strains.

Analysis of meningococcal vaccine uptake in patients with invasive meningococcal disease, Czech Republic, 2006-2022.

In 2006-2022, 958 cases of invasive meningococcal disease (IMD) were reported to the surveillance programme in the Czech Republic, of which 21 (2.19%) had a history of vaccination with one of the meningococcal vaccines. Data analysis shows that these vaccines provide a very good protection against IMD. It was found that vaccinated patients with IMD either were not vaccinated against the causative serogroup and/or did not receive a booster dose. The results of this analysis show the benefit of both vaccines available in the Czech Republic: recombinant vaccine containing meningococcal serogroup B antigens (MenB vaccine) and tetravalent conjugate vaccine containing antigens of four meningococcal serogroups A, C, W, Y (A, C, W, Y conjugate vaccine). The results also show the benefit of meningococcal vaccine booster doses and the need for giving MenB vaccine to young children as early as possible.

Evolución de la vacunación frente al meningococo del serogrupo B: ¿qué ha cambiado a lo largo de 5 años? / Evolution of vaccination against serogroup B meningococcus: what has changed over 5 years?

Introducción: la infección por meningococo del serogrupo B puede provocar enfermedad meningocócica invasiva, con un 20-30% de secuelas y hasta un 10% de mortalidad. Material y métodos: estudio observacional, descriptivo y retrospectivo de vacunación frente al meningococo del serogrupo B en la población pediátrica del Sector I de Zaragoza desde octubre de 2015 hasta diciembre de 2019. Se estudió: edad de inicio de la vacunación, edad a la fecha de la primera dosis (≤3 meses, 4-11 meses, 12-23 meses, 2-9 años, 10-16 años), sexo, centro de salud (CS) y número de dosis recibidas. Resultados: se vacunó a 11 776 pacientes, de los cuales un 51,6% fueron varones. Presentaron una edad media de inicio de vacunación a los 5,0 ± 4,4 años y 2,2 ± 0,6 dosis recibidas. La distribución del total de vacunados fue muy variada, con una diferencia del 17,8% entre el CS con más vacunados y el CS con menos vacunados. El 0,7% recibieron primera dosis en 2015, el 23,8% en 2016, el 38% en 2017, el 26,7% en 2018 y el 10,8% en 2019. El 12% tenía ≤3 meses al inicio de la vacunación, el 11,5% tenía 4-11 meses, el 6,7% tenía 12-23 meses, el 50,4% 2-9 años y el 19,5% 10-16 años, existiendo diferencias en relación con la fecha de primera dosis (p = 0,000). El 2017 cuenta con mayor incidencia de vacunación global (12,2%), aunque en lactantes fue superior en 2018 (42,1%) y en los grupos de 2-9 años y adolescentes en 2017: el 15,8 y el 5,4% respectivamente. La incidencia global acumulada fue 32,5%, siendo en lactantes de 133,5%. Conclusiones: a pesar de las prometedoras cifras de incidencia acumulada, encontramos numerosas diferencias de vacunación entre grupos de edad y CS, por lo que resulta interesante la vacunación sistemática y financiada de meningococo B (AU)

Introduction: infection by serogroup B meningococcus can cause invasive meningococcal disease, with development of sequelae in 20-30% of cases and a mortality of up to 10%.Material and methods: observational, descriptive and retrospective study of vaccination against serogroup B meningococcus in the paediatric population of health sector I of Zaragoza between October 2015 and December 2019. We analysed the age at primary vaccination, age group at time of first dose (≤3 months, 4-11 months, 12-23 months, 2-9 years, 10-16 years), sex, primary care centre (PCC) and number of received doses.Results: 11 776 patients were vaccinated, of who 51.6% were male. The mean age at initiation of vaccination was 5.0 ± 4.4 years, and they received a mean of 2.2 ± 0.6 doses. The distribution of vaccinated patients by PCC was heterogeneous, with a difference of 17.8% between the centre with the most vaccinated patients and the centre with the least. Of all patients, 0.7% received the first dose in 2015, 23.8% in 2016, 38% in 2017, 26.7% in 2018 and 10.8% in 2019. Twelve percent were aged 3 months or less when they received the first dose, 11.5% 4-11 months, 6.7% 12-23 months, 50.4% 2-9 years and 19.5% 10-16 years, with differences based on the date of the first dose (p = 0.000). The highest frequency of overall vaccination corresponded to 2017 (12.2%), although in children under 2 years it was higher in 2018 (42.1%) and in children aged 2-9 years and adolescents it was highest in 2017: 15.8% and 5.4%, respectively. The cumulative frequency of vaccination was 32.5% in the overall sample and 133.5% in the group aged less than 2 years.Conclusions: although we found promising cumulative vaccination rates, there were numerous differences in vaccination between age groups and PCCs, which is why publicly funded routine vaccination against meningococcus B is worth contemplating. (AU)

Enfermedad meningocócica invasiva por serogrupo C en la era posvacunal y fallos vacunales / Serogroup C invasive meningococcal disease in the post-vaccine era and vaccine failures

INTRODUCCIÓN: La incidencia de la enfermedad meningocócica invasiva (EMI) por serogrupo C ha disminuido desde la introducción de la vacunación sistemática el año 2000. El objetivo de este estudio es determinar los casos de EMI diagnosticados desde entonces y los fallos vacunales en los casos por serogrupo C. PACIENTES Y MÉTODOS: Análisis retrospectivo de pacientes diagnosticados de EMI confirmada por cultivo o reacción en cadena de la polimerasa, en un hospital infantil de tercer nivel de Barcelona, entre 2001 y 2018. Se analizó el número de dosis de vacuna recibidas y la edad, recogidos de la historia clínica y del carnet de vacunaciones. RESULTADOS: Se confirmaron 128 casos de EMI (7,1 casos/año; 70,3% en < 5 años). Se estudió el serogrupo en 125 casos (97,6%): 103 fueron B (82,4%), 10 fueron C (8%), uno fue 29E (0,8%) y uno fue Y (0,8%); solo 10 (8%) no fueron serogrupables. De los 10 pacientes con serogrupo C, 4 no estaban vacunados y en 3 la pauta fue incompleta en cuanto a número de dosis; 3 de ellos recibieron la pauta completa según la edad y el calendario vacunal vigente, por lo que se consideran fallos vacunales. Fallecieron 6 pacientes (tasa de letalidad: 4,7%): 5 por serogrupo B (letalidad: 4,8%) y uno por serogrupo C (letalidad: 10%). CONCLUSIONES: El serogrupo C representó solo el 8% de los casos de EMI en el periodo de estudio y los fallos vacunales de este serogrupo fueron del 30%

INTRODUCTION: The incidence of serogroup C invasive meningococcal disease (IMD) has decreased since the introduction of systematic vaccination in 2000. The aim of this study is to determine the number of serogroup C IMD cases diagnosed since then and the vaccine failures. PATIENTS AND METHODS: A retrospective analysis was performed on patients diagnosed with IMD by culture or polymerase chain reaction (PCR) in a maternity and childhood hospital in Barcelona between 2001 and 2018. An analysis was made of the number of vaccine doses and the age received, as well as on the medical records and vaccine cards. RESULTS: There were 128 confirmed cases of IMD (7.1 cases/year; 70.3 in < 5 years). The serogroup was studied in 125 (97.6%) cases, in which 103 (82.4%) were B, 10 (8%) were C, one (0.8%) was 29E, and one (0.8%) was Y, and only 10 (8%) were not able to be serogrouped. Of the 10 patients with serogroup C, 4 were not vaccinated, and in 3, the course was not complete as regards the number of doses. The other 3 received the complete course according to age and current calendar, and thus were considered vaccine failures. A total of 6 patients died (mortality rate: 4.7%), 5 due to serogroup B (mortality: 4.8%), and one due to serogroup C (mortality: 10%). CONCLUSIONS: Serogroup C only represented 8% of IMD cases in the period studied, with 30% of cases due to this serogroup being vaccine failures

Evaluación económica de la inclusión en el calendario vacunal de 4CMenB (Bexsero(R)) en España / Economic evaluation of the introduction of 4CMenB (Bexsero(R)) in the national vaccine schedule in Spain

INTRODUCCIÓN: Bexsero® (4CMenB), vacuna contra el meningococo B, fue autorizada en Europa en 2013. En España, a pesar de que el meningococo B es la principal causa de enfermedad meningocócica invasiva (EMI), Bexsero® está recomendada y financiada para pacientes con alto riesgo de EMI pero no de forma sistemática en el calendario vacunal del SNS. OBJETIVO: Evaluar el coste-utilidad, el impacto epidemiológico y los costes totales de la introducción de 4CMenB para una política vacunal informada en España. MÉTODO: Se adaptó para España un análisis de coste-utilidad, árbol de decisión probabilístico. Una cohorte de recién nacidos en 2015 fue modelizada con dos posologías mediante dos estrategias: vacunación sistemática con 4CMenB o no vacunación. Los costes se midieron desde la perspectiva del pagador y los beneficios se calcularon en años de vida ajustados por calidad (AVAC). Se realizó un análisis de Monte Carlo y se consideraron 32 escenarios para valorar la robustez y la incertidumbre de los resultados. RESULTADOS: Con la pauta 3+1, la vacunación sistemática previno el 54% de los casos y de las muertes, y se estimó una razón de coste-utilidad incremental (RCUI) de 351.389 €/AVAC (intervalo de confianza del 95% [IC95%]: 265.193-538.428). La pauta 2+1 previno el 50% de los casos y de las muertes, con una RCUI de 278.556 €/AVAC (IC95%: 210.285-430.122). CONCLUSIONES: Dada la incidencia actual de enfermedad meningocócica invasiva en España y la información disponible sobre 4CMenB, nuestro modelo indica que la vacunación sistemática no es coste-efectiva con el actual precio. Solo con un precio de 1,45 € para la pauta 3+1 o de 3,37 € para la pauta 2+1 podría ser recomendada basándose en su eficiencia

INTRODUCTION: Bexsero® (4CMenB), meningococcal B vaccine, was licensed in Europe in 2013. In Spain, despite MenB being the most frequent cause of invasive meningococcal disease (IMD), Bexsero® is recommended and financed for patients at increased risk of IMD but is not financed by the NHS in the routine vaccination schedule. OBJECTIVE: to evaluate the cost-utility, epidemiological impact, and total costs of the introduction of 4CMenB into the vaccination schedule to help inform vaccine policy in Spain. METHOD: We adapted a cost-utility analysis, a probabilistic decision-tree, to Spain. A cohort of new-born infants in 2015 was modelled with two dosages, using two different strategies: routine vaccination schedule with 4CMenB and non-vaccination. Costs were measured from a payer perspective and benefits were calculated in quality-adjusted life years (QALYs). A Monte Carlo analysis and 32 scenarios were performed to assess the robustness and the uncertainty of our results. RESULTS: With the 3+1 dosage, routine vaccination prevented 54% of cases and deaths and an incremental cost-utility ratio (ICUR) of 351.389 €/QALY (95% confidence interval [95%CI]: 265,193-538,428) was estimated. The 2+1 dosage prevented 50% of cases and deaths, with an ICUR of 278.556 €/QALY (95%CI: 210,285-430,122). CONCLUSIONS: Given the current incidence of invasive meningococcal disease in Spain and the information available from 4CMenB, our model shows that routine vaccination is not cost-effective at the current price. Only with a vaccine price of 1.45 € for the 3+1 schedule or 3.37 € for the 2+1 schedule could it be recommended based on efficiency criteria

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Sobre la evaluación económica de la inclusión en el calendario vacunal de 4CMenB (Bexsero) / No disponible

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