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.

Hybrid response to SARS-CoV-2 and Neisseria meningitidis C after an OMV-adjuvanted immunization in mice and their offspring.

COVID-19, caused by SARS-CoV-2, and meningococcal disease, caused by Neisseria meningitidis, are relevant infectious diseases, preventable through vaccination. Outer membrane vesicles (OMVs), released from Gram-negative bacteria, such as N. meningitidis, present adjuvant characteristics and may confer protection against meningococcal disease. Here, we evaluated in mice the humoral and cellular immune response to different doses of receptor binding domain (RBD) of SARS-CoV-2 adjuvanted by N. meningitidis C:2a:P1.5 OMVs and aluminum hydroxide, as a combined preparation for these pathogens. The immunization induced IgG antibodies of high avidity for RBD and OMVs, besides IgG that recognized the Omicron BA.2 variant of SARS-CoV-2 with intermediary avidity. Cellular immunity showed IFN-γ and IL-4 secretion in response to RBD and OMV stimuli, demonstrating immunologic memory and a mixed Th1/Th2 response. Offspring presented transferred IgG of similar levels and avidity as their mothers. Humoral immunity did not point to the superiority of any RBD dose, but the group immunized with a lower antigenic dose (0.5 µg) had the better cellular response. Overall, OMVs enhanced RBD immunogenicity and conferred an immune response directed to N. meningitidis too.

Derrotar a meningite até 2030 - Um Roteiro Mundial

A meningite é letal e debilitante; ela ataca rapidamente, tem graves consequências sociais, econômicas e de saúde e afeta pessoas de todas as idades em todos os países do mundo. A meningite bacteriana pode causar epidemias, levar à morte em menos de 24 horas e deixar um em cada cinco pacientes com deficiência permanente após a infecção. Muitos casos e mortes por meningite podem ser evitados com vacinas, mas o progresso na luta contra a meningite está atrasado em relação a outras doenças imunopreveníveis. Este primeiro roteiro mundial de meningite define um plano para combater as principais causas de meningite bacteriana aguda (meningococo, pneumococo, Haemophilus influenzae e estreptococo do grupo B). O roteiro da meningite foi designado como uma estratégia global emblemática do Décimo Terceiro Programa Geral de Trabalho da OMS, 2019–2023, e é um componente vital para alcançar a cobertura universal de saúde. O roteiro reforçará e se combinará com iniciativas mais amplas, como as que visam fortalecer a atenção primária à saúde e os sistemas de saúde, aumentar a cobertura de imunização, melhorar a segurança sanitária mundial, combater a resistência aos antimicrobianos e defender os direitos das pessoas com deficiência.

Derrotar a meningite até 2030 - Um Roteiro Mundial

A meningite é letal e debilitante; ela ataca rapidamente, tem graves consequências sociais, econômicas e de saúde e afeta pessoas de todas as idades em todos os países do mundo. A meningite bacteriana pode causar epidemias, levar à morte em menos de 24 horas e deixar um em cada cinco pacientes com deficiência permanente após a infecção. Muitos casos e mortes por meningite podem ser evitados com vacinas, mas o progresso na luta contra a meningite está atrasado em relação a outras doenças imunopreveníveis. Este primeiro roteiro mundial de meningite define um plano para combater as principais causas de meningite bacteriana aguda (meningococo, pneumococo, Haemophilus influenzae e estreptococo do grupo B). O roteiro da meningite foi designado como uma estratégia global emblemática do Décimo Terceiro Programa Geral de Trabalho da OMS, 2019–2023, e é um componente vital para alcançar a cobertura universal de saúde. O roteiro reforçará e se combinará com iniciativas mais amplas, como as que visam fortalecer a atenção primária à saúde e os sistemas de saúde, aumentar a cobertura de imunização, melhorar a segurança sanitária mundial, combater a resistência aos antimicrobianos e defender os direitos das pessoas com deficiência.

Calendario de inmunizaciones 2024 / immunisation schedule 2024

Calendario de Inmunizaciones 2024 de población infantil, escolar y adulta.

Calendario de inmunizaciones infantil 2024 / childhood immunisation schedule 2024

Calendario de inmunización para población infantil.

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.

Association between contextual factors and coverage of the Acwy meningococcal vaccine, after three years of its overdue, in the vaccination calendar of adolescents in the state of Minas Gerais, Brazil: global space regressions.

The objective of the study was to analyze the spatial distribution of vaccination coverage of bacterial meningitis vaccine: A, C, W and Y (menacwy) and identify the association between socioeconomic and social environment factors with menacwy vaccine coverage among adolescents in the state of Minas Gerais (MG), Brazil. This is an ecological, mixed study, conducted with secondary data from the 853 municipalities of the State of MG, Brazil, from 2020 to 2022, provided by the information system of the National Immunization Program. For spatial statistical analysis, spatial dependence and the presence of spatial clusters formed by municipalities with high and low vaccination coverage of Menacwy were evaluated. In the year 2021, MG presented the largest vaccination coverage (60.58%) since the introduction of the Menacwy vaccine by the PNI. Regarding the analysis of global regressions, it is observed that for the year 2020, as the MG Index of Social Responsibility-Health increased and MG Index of Social Responsibility-Public Security increased, increased the vaccination coverage of the municipalities of the Menacwy vaccine. Finally, compared to 2021, similar association was observed in relation to the proportion of the population served by the Family Health Strategy of the municipalities of the state of MG and per capita spending on education activities: as this indicator increased, with increased coverage of the Vaccine of the Menacwy vaccine of the state municipalities. They reinforce the importance of assessing the quality-of-care management and health surveillance system, professional training, and damage reduction to populations, especially adolescents.

Hypervirulent Strains of Neisseria meningitidis and Clinical Manifestations in Children With Invasive Meningococcal Disease.

BACKGROUND: Hypervirulent clonal complex (cc) have been associated with higher incidence and case fatality rate of invasive meningococcal disease (IMD). The aim of this study was to describe the clinical manifestations of the hypervirulent cc of meningococcus in children. METHODS: Retrospective study in patients hospitalized by IMD microbiologically confirmed at three children's tertiary health care centers in Santiago, Chile, between 2010 and 2018. Demographic, clinical information and determination of the cc and factor H binding protein (fHbp) alleles were performed. RESULTS: In total 93 cases were evaluated, sequence typing was available for 91 cases, and 87 (95.6%) had a cc assigned; 63.7% were MenW and 31.8% MenB. The median age was 9 months, 67% were male and 18.7% had any comorbidity. A 26.4% presented neurological deficit, 25.3% petechiae and 20% diarrhea. Sixty-seven percent were admitted to the pediatric intensive care unit (PICU) and the case fatality rate was 9.9%. Regarding cc and fHbp alleles, ST11, ST41/44 and allele 22 were the most frequently identified, with 63.7%, 19.8% and 72.5%, respectively. We found statistically significant differences between the cc and presence of petechiae, diagnosis of meningococcemia plus meningitis, admission and days in PICU and advanced support. Allele 22 for fHbp was associated with the absence of petechiae, low suspicion of IMD, less diagnosis of meningitis+meningococcemia, PICU admission, advanced support and adrenal insufficiency. CONCLUSION: Epidemiological and microbiological surveillance of IMD should integrate clinical and laboratory components, including molecular and genetic characterization, to enrich the dynamic understanding of the clinical evolution of IMD.

Understanding barriers to vaccination against invasive meningococcal disease: a survey of the knowledge gap and potential solutions.

INTRODUCTION: Invasive meningococcal disease (IMD) is a leading cause of life-threatening bacterial meningitis and septicemia. Evidence points to a knowledge gap among parents, teenagers, and healthcare providers (HCPs) regarding IMD and available vaccines, including those against the highly prevalent serogroup B. AREAS COVERED: An online survey was conducted between March 27 and 12 April 2019, to gather insights into the knowledge that parents/guardians have about IMD vaccines. The children were aged 2 months to 10 years in Australia, Brazil, Germany, Greece, Italy, and Spain, 5-20 years in the UK, and 16-23 years in the USA. The findings were discussed in the context of the available literature and solutions were proposed to minimize the knowledge gap and the barriers to vaccination against IMD. EXPERT OPINION: The survey demonstrated that parents have a good understanding of IMD but a limited understanding of the different serogroups and vaccines. The available literature highlighted multiple barriers to IMD vaccine uptake; these may be reduced through education of HCPs, clear recommendations to parents by HCPs, the use of technology, and disease-awareness initiatives that engage parents through physical and digital channels. Further studies are warranted to assess the impact of the COVID-19 pandemic on IMD vaccination.

Quadrivalent meningococcal tetanus toxoid-conjugate booster vaccination in adolescents and adults: phase III randomized study.

BACKGROUND: The immunogenicity and safety of a booster dose of tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT), alone or co-administered with MenB vaccine, were assessed in healthy 13-25-year olds who received MenACYW-TT or a CRM-conjugate vaccine (MCV4-CRM) 3-6 years earlier. METHODS: This phase IIIb open-label trial (NCT04084769) evaluated MenACYW-TT-primed participants, randomized to receive MenACYW-TT alone or with a MenB vaccine, and MCV4-CRM-primed participants who received MenACYW-TT alone. Functional antibodies against serogroups A, C, W and Y were measured using human complement serum bactericidal antibody assay (hSBA). The primary endpoint was vaccine seroresponse (post-vaccination titers ≥1:16 if pre-vaccination titers <1:8; or a ≥4-fold increase if pre-vaccination titers ≥1:8) 30 days post booster. Safety was evaluated throughout the study. RESULTS: The persistence of the immune response following primary vaccination with MenACYW-TT was demonstrated. Seroresponse after MenACYW-TT booster was high regardless of priming vaccine (serogroup A: 94.8% vs 93.2%; C: 97.1% vs 98.9%; W: 97.7% vs 98.9%; and Y; 98.9% vs 100% for MenACWY-TT-primed and MCV4-CRM-primed groups, respectively). Co-administration with MenB vaccines did not affect MenACWY-TT immunogenicity. No vaccine-related serious adverse events were reported. CONCLUSIONS: MenACYW-TT booster induced robust immunogenicity against all serogroups, regardless of the primary vaccine received, and had an acceptable safety profile. IMPACT: A booster dose of MenACYW-TT induces robust immune responses in children and adolescents primed with MenACYW-TT or another MCV4 (MCV4-DT or MCV4-CRM), respectively. Here, we demonstrate that MenACYW-TT booster 3-6 years after primary vaccination induced robust immunogenicity against all serogroups, regardless of the priming vaccine (MenACWY-TT or MCV4-CRM), and was well tolerated. Persistence of the immune response following previous primary vaccination with MenACYW-TT was demonstrated. MenACYW-TT booster with MenB vaccine co-administration did not affect MenACWY-TT immunogenicity and was well tolerated. These findings will facilitate the provision of broader protection against IMD particularly in higher-risk groups such as adolescents.

Surveillance of invasive meningococcal disease in southern Brazil: considerations of an immunization programme.

Invasive meningococcal disease (IMD) is a major cause of meningitis and septicaemia worldwide. Changes in serogroup predominance contribute to the unpredictable nature of the disease, with significant health impact. This study aimed to determine the epidemiological profile of IMD in Rio Grande do Sul, Santa Catarina and Paraná, three states in southern Brazil. We analysed 1024 IMD cases that had been confirmed by clinical and/or laboratory criteria and reported to the national information system for notifiable diseases between 2015 and 2019. Additionally, we calculated the proportions of serogroup and incidence by age. Of 1024 cases, 562 (55 %) were caused by serogroup C. Furthermore, serogroup W was responsible for almost half of the cases among children younger than 5 years between 2017 and 2018, with an overall incidence of 1.5 cases/100 000 infants. IMD remains a significant healthcare issue in southern Brazil despite reduced serogroup C incidence after the introduction of the meningococcal C conjugate vaccine into the childhood immunization programme. Changes in disease epidemiology were observed, and serogroup W was the most common serogroup among children younger than 5 years in 2017 and 2018. Although future cost-effectiveness studies are necessary, our results could have future implications for meningococcal vaccination programmes.

Coste-efectividad de la vacunación sistemática frente a enfermedad meningocócica invasiva por serogrupo B en la infancia / Cost-effectiveness of systematic vaccination against invasive meningococcal disease due to serogroup B in childhood

INTRODUCCIÓN La enfermedad meningocócica invasiva (EMI) es una enfermedad infecciosa aguda causada por Neisseria meningitidis o meningococo, y es una de las causas más comunes de meningitis bacteriana en población infantil y adolescente. En España, la EMI afecta fundamentalmente a niños y niñas menores de 5 años, siendo los serogrupos B (60% del total de los casos en menores de 5 años en la temporada 2017-2018), C, W e Y los más frecuentes. La prevención de la EMI y la meningitis en general se realiza mediante la vacunación. Algunos países, como Andorra, Austria, Francia, Italia, Irlanda, Lituania, Luxemburgo, Malta, Portugal, Reino Unido, República Checa y San Marino han incluido en su calendario de vacunación infantil la vacuna Bexsero® frente a EMI por serogrupo B (MenB) a partir de los 2 meses de edad y algunas regiones de Italia también la vacuna Trumenba® en la adolescencia. En nuestro país, esta vacunación no está incluida en el calendario común de vacunación a lo largo de toda la vida para la población general, pero sí se recomienda para ciertas personas inmunodeprimidas, personas que hayan padecido una enfermedad meningocócica con anterioridad, grupos de población con condiciones de riesgo o en los casos de brotes. OBJETIVOS Evaluar el coste-efectividad, las consideraciones éticas, de pacientes, sociales, legales y organizacionales, así como describir las necesidades de investigación de la vacunación sistemática frente a MenB en niños y niñas menores de 12 meses. METODOLOGÍA Coste-efectividad y análisis de impacto presupuestario En primer lugar, se llevó a cabo una RS de la evidencia científica sobre el coste-efectividad de la vacunación frente a MenB en población infantil y adolescente (hasta 18 años). Se incluyeron evaluaciones económicas completas que compararan una estrategia de vacunación sistemática frente a MenB frente la no vacunación o a otra estrategia. Se valoró la calidad metodológica mediante los criterios de Drummond et al. Se llevó a cabo una evaluación económica completa de novo en la que se evaluaron los costes y los resultados en salud de la vacunación sistemática frente a MenB en población infantil menor de 12 meses (pauta 2+1 y pauta 3+1) desde la perspectiva del SNS frente a no vacunar. El análisis se basó en un modelo de decisión que sintetiza la información obtenida en la literatura sobre la incidencia de la enfermedad, la eficacia de la vacuna frente a MenB, así como sobre las consecuencias y/o secuelas de la EMI asociada a MenB (en términos tanto de costes como en AVAC) que se evitan por la introducción de un programa de vacunación sistemática. Para ello, se realizó un modelo matemático que combina un árbol de decisión y un modelo tipo Markov con ciclos anuales. El horizonte temporal abarca toda la vida del paciente y se aplica un descuento del 3% tanto a costes como a efectos. Además, se realizaron análisis de sensibilidad probabilísticos y determinísticos. Por último, se realizó un análisis de impacto presupuestario a 5 años (de 2022 a 2026), para informar del coste que supondría la implantación de una estrategia de vacunación sistemática infantil (en población infantil menor de 12 meses) frente a MenB en España. Aspectos organizativos, éticos, sociales y/o legales Se realizó una RS de la literatura, partiendo de la misma población, intervención y comparación mencionadas en el apartado de coste efectividad. La revisión se enfocó en dos de los Criterios de Evaluación para Fundamentar Modificaciones en el Programa de Vacunación en España (2011): la carga de la enfermedad y la modificación del calendario vacunal y sus repercusiones. RESULTADOS Coste-efectividad y análisis de impacto presupuestario La RS sobre coste-efectividad permitió identificar 16 evaluaciones económicas, 11 incluidas en una revisión previa y otras 5 publicadas entre 2019 y 2022. Todos los estudios coinciden en que la vacunación frente a MenB reduce el número de casos y de muertes por meningitis. Todos los estudios, excepto uno, concluyen, además, que la vacunación no es coste efectiva al encontrar todos ellos ratios coste-efectividad incremental muy elevadas. Varios autores lo explican debido a la baja incidencia de la enfermedad en sus respectivos países como Canadá, Francia o Países Bajos y/o el alto coste de la vacuna. El precio umbral de la vacuna que se estima en siete estudios que haría que la vacunación fuera coste-efectiva varía entre 1,45€ y 10€ según los autores. Los resultados de la modelización realizada muestran que tanto con la pauta de vacunación 2+1 como con la pauta 3+1 se evitan casos de EMI, tanto leves como graves, así como muertes debidas a la enfermedad. Los resultados del análisis de coste-efectividad muestran que el coste promedio por individuo para la estrategia de no vacunar, vacunar con la pauta 2+1 y vacunar con la pauta 3+1 es de 13.19 €, 229.40 € y 303.23 € respectivamente. Los AVAC promedio son ligeramente más elevados con la estrategia de vacunar con la pauta 3+1 que con el resto de las estrategias comparadas. Sin embargo, esta pequeña diferencia en AVAC entre alternativas hace que las opciones de vacunar (con cualquier pauta) frente a MenB no resulten ser intervenciones coste-efectivas desde la perspectiva del SNS (RCEI > 25.000 €/AVAC) considerando la incidencia actual de la enfermedad en nuestro país. El análisis de sensibilidad por escenarios muestra que variaciones en la incidencia de la enfermedad y en la efectividad de la vacuna tienen un efecto significativo sobre los resultados de coste-efectividad. El análisis de impacto presupuestario muestra que, dada la baja incidencia actual de la enfermedad y el elevado precio de la vacuna, el coste de los casos de MenB evitados por la vacuna, tanto leves como graves, no supera el de la vacunación sistemática a toda la población infantil objeto de vacunación. Por tanto, la implantación de una estrategia de vacunación sistemática frente a MenB con la pauta 2+1 podría suponer un gasto para el SNS que podría alcanzar los 44 millones de euros al quinto año de su introducción en todo el territorio nacional. Esta estimación asume que no se produce un coste extra por la administración de la vacuna infantil dado que se aplicaría dentro de las revisiones de salud pediátricas rutinarias. Aspectos organizativos, éticos, sociales y/o legales Se incluyeron un total de 5 estudios que abordaron estos aspectos. Los estudios incluidos describen las secuelas físicas, neurológicas y psicosociales de la EMI que aumentan la carga sanitaria y socio-familiar asociada a la enfermedad y repercuten negativamente en la calidad de vida a largo plazo de los infectados y sus familias. Solo un estudio que analiza casos de niños y niñas con EMI grave del serogrupo B, identifico otras secuelas adicionales a largo plazo como daño óseo y retraso en el habla. Los resultados muestran que algunos factores estructurales asociados con el incumplimiento del esquema de vacunación frente a MenB, están relacionados con determinantes sociales, como el absentismo escolar, la residencia geográfica, la raza/etnicidad, los ingresos familiares y el género. En conjunto, los hallazgos tienen escasa relevancia, debido a que las medidas de resultado utilizadas son dispersas, el período de seguimiento es muy variable y presentan conflictos de interés. Además, presentan diversos diseños metodológicos. No se identificó ningún estudio con metodología cualitativa que pudiera arrojar mayor claridad acerca del fenómeno estudiado. Las investigaciones provienen de países de ingresos altos, pero ninguna realizada en nuestro contexto. CONCLUSIONES De acuerdo a la literatura científica revisada, la vacunación sistemática infantil frente a MenB no estaría justificada desde el punto de vista del coste-efectividad. • El análisis de coste-efectividad de novo realizado en este informe con datos de España, concluye que la incorporación de una estrategia de vacunación sistemática infantil frente a MenB, no sería una opción coste-efectiva desde la perspectiva del SNS teniendo en cuenta la incidencia de la enfermedad y el precio de la vacuna actuales. • El análisis por escenarios realizado muestra que al considerar una efectividad de la vacuna de al menos el 80%, considerando la incidencia actual, una estrategia de vacunación sistemática frente a MenB con la pauta 2+1 sería una alternativa coste-efectiva desde la perspectiva del SNS siempre y cuando el precio por dosis de la vacuna fuera de 4.5€. • El análisis de impacto presupuestario estima que la incorporación de una estrategia de vacunación sistemática frente a MenB en población menor de 12 meses con una pauta de vacunación 2+1, podría suponer un gasto de hasta 44 240 831 € el quinto año de su introducción en el SNS. El análisis de los aspectos éticos, organizativos, sociales, de pacientes y ambientales relativos a la vacunación frente a MenB en la infancia y en la adolescencia muestra que los estudios son escasos y sus resultados poco concluyentes, particularmente aquellos estudios referidos a la carga de la enfermedad, la calidad de vida y la modificación del calendario vacunal y sus repercusiones. • Se destaca la ausencia de estudios con metodología cualitativa o mixta que permitan contribuir a la profundización del análisis de la carga de la enfermedad, la calidad de vida a largo plazo y las razones que influyen en el incumplimiento del esquema de vacunación frente a MenB.

INTRODUCTION Invasive meningococcal disease (IMD) is an acute infectious disease caused by Neisseria meningitidis, or meningococcus, and is one of the most common cause of bacterial meningitis in children and adolescents. In Spain, IMD mainly affects children under five years of age, with serogroups B (60% of all cases in children under five years of age in the 2017-2018 season), C, W and Y being the most frequent. The prevention of IMD and meningitis in general is through vaccination. Some countries, such as Andorra, Italy, Ireland, Lithuania, Malta, Portugal, the United Kingdom and San Marino have included the Bexsero® vaccine against IMD by serogroup B (MenB) in their childhood vaccination schedule starting at two months of age. Some regions of Italy also use the Trumenba® vaccine in adolescence. In the case of Spain, this vaccination is not included in the common vaccination schedule throughout life for the general population, but it is recommended for certain immunosuppressed people, those who have previously suffered from meningococcal disease, certain risk groups, or in cases of outbreaks. AIMS To assess cost-effectiveness, ethical, patient, social, legal, and organizational considerations, as well as to describe the research needs for routine MenB vaccination of children under twelve months of age. METHODOLOGY Cost-effectiveness and budget impact analysis Firstly, a systematic review (SR) of the scientific evidence on the cost effectiveness of vaccination against MenB in children and adolescents (up to 18 years of age) was carried out. Complete economic evaluations comparing a routine vaccination strategy against MenB versus no vaccination, or another strategy were included. The methodological quality was assessed using the criteria of Drummond et al. A complete de novo economic evaluation was conducted out in which the costs and health outcomes of routine vaccination against MenB in children under twelve months of age (2+1 regimen and 3+1 regimen) were evaluated versus not vaccinating from the perspective of the NHS. The analysis was based on a decision model that synthesizes the information obtained in the literature on the incidence of the disease, the efficacy of the vaccine against MenB, as well as the consequences and/or sequelae of IMD associated with MenB (in terms of both cost and QALY) that are avoided by the introduction of a routine vaccination programme. In order to do this, a mathematical model was built that combines a decision tree and a Markov type model with annual cycles. The time horizon was patient lifetime and a discount of 3% is applied to both costs and effects. In addition, probabilistic and deterministic sensitivity analysis by scenarios were carried out. Finally, a five-year budget impact analysis (from 2022 to 2026) was performed to inform about the cost of implementing a systematic childhood vaccination strategy (in children under 12 months of age) against MenB in Spain. Organizational, ethical, social and/or legal issues An SR of the literature was performed, starting from the same population, intervention, and comparison mentioned in the cost-effectiveness section. The review focused on two of the Evaluation Criteria to Support Modifications in the Vaccination Program in Spain (2011): the burden of the disease and the modification of the vaccination schedule and its repercussions. RESULTS Cost-effectiveness and budgetary impact analysis The SR on cost-effectiveness revealed sixteen economic evaluations, eleven of which were included in a previous review and another five were published between 2019 and 2022. All the studies agree that vaccination against MenB reduces the number of cases and deaths from meningitis. All the studies, except one, also conclude that vaccination is not cost effective, as all of them found very high incremental cost-effectiveness ratios. Several authors explain that this is due to the low incidence of the disease in their respective countries such as Canada, France or the Netherlands and/or the high cost of the vaccine. The threshold price of the vaccine estimated in seven studies that would make the vaccination cost-effective varies between €1.45 and €10 according to the authors. The results of the modeling carried out show that both the 2+1 vaccination schedule and the 3+1 schedule prevent cases of IMD, both mild and severe, as well as deaths caused by the disease. The results of the cost-effectiveness analysis show that the mean average cost per individual for the strategy of not vaccinating, vaccinating with the 2+1 regimen and vaccinating with the 3+1 regimen is €13.19, €229.40, and €303.23, respectively. The mean QALYs are slightly higher with the strategy of vaccinating with the 3+1 regimen than with the other strategies. However, this small difference in QALYs between alternatives means that the options to vaccinate (with any regimen) against MenB do not turn out to be cost-effective interventions from the NHS perspective (ICER > €25,000/QALY) considering the current incidence of the disease in Spain. The sensitivity analysis by scenarios shows that variations in the incidence of the disease and in the effectiveness of the vaccine have a significant effect on the cost-effectiveness results. The budget impact analysis shows that, given the current low incidence of the disease and the high price of the vaccine, the cost of MenB, cases averted by the vaccine, both mild and severe, does not exceed that of routine vaccination throughout Spain for the target child population. Therefore, the implementation of a systematic vaccination strategy against MenB with the 2+1 regimen could mean an expense for the NHS that could reach forty-four million euros in the fifth year of its introduction across Spain. This estimated expense assumes that there is no extra cost for the administration of the childhood vaccine, since it would be applied as part of routine pediatric health check-ups. Organizational, ethical, social and/or legal issues Six studies that addressed these issues were included. The included studies described the physical, neurological and psychosocial sequelae of IMD that increase the health and socio-familial burden associated with the disease and have a negative impact on the long-term quality of life of those infected and their families. Only one study analyzed cases of children with severe serogroup B IMD, and it identified additional long term sequelae such as bone damage and speech delay. The results showed different structural factors associated with non compliance with the MenB vaccination schedule, which are related to social determinants, such as school absenteeism, geographic residence, race/ethnicity, family income and gender. Overall, the findings were of little relevance, since the outcome measures used were disperse, the follow-up period was highly variable, and they presented conflicts of interest. In addition, they had differing methodological designs. No study with qualitative methodology was found that could provide greater clarity about the phenomenon studied and the research came from high-income countries, but none were conducted in the Spanish context. CONCLUSIONS • According to the reviewed scientific literature, routine childhood vaccination against MenB would not be justified from the point of view of cost-effectiveness. • The de novo cost-effectiveness analysis conducted in this report with data from Spain concludes that the incorporation of a systematic childhood vaccination strategy against MenB would not be a cost-effective option from the perspective of the NHS, taking into account the incidence of the disease and the price of the currently available vaccine. • The analysis by scenarios shows that considering a vaccine effectiveness of at least 80% and the current incidence, a systematic vaccination strategy against MenB with the 2+1 regimen would be a cost-effective alternative from the perspective of the NHS as long as the price per dose of the vaccine was €4.5. • The analysis of the budget impact estimates that the incorporation of a systematic vaccination strategy against MenB in the population under twelve months of age with a 2+1 vaccination schedule could mean an expense for the NHS of up to €44,240,831 in the fifth year of its introduction. • The analysis of the ethical, organizational, social, patient and environmental aspects related to vaccination against MenB in childhood and adolescence shows that there are few studies and their results are inconclusive, particularly those studies referring to the burden of the disease, quality of life and the modification of the vaccination schedule and its repercussions. • The absence of studies with qualitative or mixed methodology that could contribute a deeper analysis of the burden of the disease, the long-term quality of life and the reasons influencing non-compliance with the vaccination scheme against MenB is noteworthy.

Economic burden of meningococcal disease in children and adolescents in Tijuana, Mexico.

Invasive meningococcal disease (IMD) is an uncommon but serious and potentially fatal condition mainly affecting children and adolescents. Active surveillance between 2005 and 2016 at Tijuana General Hospital, Mexico, indicated that the incidence of IMD in Tijuana was higher than previously thought, at 2.69 per 100,000 population aged <16 years. The objective of this study was to estimate the economic burden associated with 51 IMD cases in children aged <16 years identified over the 11 years of active surveillance at Tijuana General Hospital, Mexico. Healthcare resource usage for the IMD cases was obtained from the hospital database and combined with unit costs from the hospital purchasing department or national databases to estimate total healthcare costs over a follow-up period of 3 months. Societal costs were represented by the value of lost wages for parents or guardians. All costs were expressed in US$. Over the 11-year study period there were 51 IMD cases, of which 13 (25%) were fatal. The total cost for all 51 cases over the 11-year study period was US$1,054,499 (average per case US$20,676), of which direct healthcare costs comprised US$1,029,948 (average per case US$20,195) and societal costs US$24,551 (average per case US$481). Extrapolated to the population of Tijuana region aged <16 years, the estimated annual economic burden of IMD was US$268,794. The major cost driver was the cost of hospitalization. These data illustrate the significant economic burden associated with IMD in Tijuana, and will be useful in assessing optimal vaccination programs against meningococcal disease in Mexico.

Invasive Meningococcal X Disease during the COVID-19 Pandemic, Brazil.

Invasive meningococcal disease persists as a fulminant disorder worldwide. Although cases caused by Neisseria meningitidis serogroup X (MenX) occur infrequently, outbreaks have been reported in countries in Africa in recent decades. We report 2 cases of MenX invasive meningococcal disease in São Paulo, Brazil, in 2021 and 2022, during the COVID-19 pandemic.

Intranasal and Intramuscular Immunization with Outer Membrane Vesicles from Serogroup C Meningococci Induced Functional Antibodies and Immunologic Memory.

BACKGROUND: Immunization is the key to prevent invasive meningococcal disease (IMD), caused by Neisseria meningitidis. Outer membrane vesicles (OMVs) can be used as meningococcal antigens. METHODS: Isogenic mice A/Sn (H2a) were immunized with low antigenic doses of OMVs of an N. meningitidis C:2a:P1.5 strain, via intranasal/intramuscular route, adjuvanted by cholera toxin subunit B (CTB) or via intramuscular route only, adjuvanted by aluminium hydroxide (AH). Mice were followed until old age and humoral and cellular responses were assessed by ELISA, Immunoblotting, Dot-blot, Serum-bactericidal assay, Immunohistochemistry and ELISpot. RESULTS: OMV+CTB and OMV+AH groups presented statistically higher antibodies titers, which persisted until middle and old ages. IgG isotypes point to a Th2 type of response. Avidity indexes were considered high, regardless of adjuvant use, but only groups immunized with OMVs and adjuvants (OMV+CTB and OMV+AH) presented bactericidal activity. The antibodies recognized antigens of molecular weights attributed to porin and cross-reactivity proteins. Although the spleen of old mice did not present differences in immunohistochemistry marking of CD68+, CD4+, CD79+ and CD25+ cells, splenocytes of immune groups secreted IL-4 and IL-17 when stimulated with OMVs and meningococcal C polysaccharide. CONCLUSION: We concluded that both adjuvants, CTB and AH, improved the immunogenicity of low doses of OMVs and contributed to a persistent immune response. Even though AH is well established in the vaccinology area, CTB seems to be a promising adjuvant candidate for meningococcal vaccines: it is suitable for mucosal delivery and supports a Th2 type of response. Therefore, OMVs are still a relevant vaccine platform.

Preguntas frecuentes sobre la enfermedad meningocócica

El meningococo, o Neisseria meningitidis, es una bacteria que puede alojarse sin causar efectos nocivos en la faringe humana o puede evolucionar hacia la enfermedad meningocócica invasora, manifestándose como septicemia o meningitis. Mientras que los adolescentes y los adultos jóvenes tienen las tasas más altas de estado de portador, los lactantes tienen la tasa más alta de enfermedad meningocócica invasora, lo que ocasiona una importante morbilidad, discapacidad y mortalidad. El meningococo se encuentra en todo el mundo, incluso en la Región de las Américas, y presenta variaciones regionales de las cepas predominantes y en la carga de la enfermedad. La enfermedad meningocócica puede prevenirse mediante la vacunación. La Organización Mundial de la Salud y sus asociados han elaborado una hoja de ruta mundial con el fin de derrotar a la meningitis para el 2030. Mediante estas preguntas frecuentes, la Organización Panamericana de la Salud prevé responder a diversas interrogantes sobre el meningococo, que comprenden los temas de la enfermedad meningocócica, la vacunación, la seguridad de las vacunas, las cuestiones programáticas, así como los mitos y conceptos erróneos en torno a la enfermedad meningocócica y las vacunas. Aunque esta publicación se dirige principalmente a los profesionales de salud, la información que contiene es adecuada para un público más amplio. Su objetivo es sensibilizar y proporcionar una perspectiva general y más clara de la enfermedad meningocócica, incluyendo sus presentaciones, diagnóstico y prevención. Resume la información actual sobre las vacunas utilizadas para controlar la enfermedad meningocócica invasora, sus tipos, su composición y su administración.

Sequelae at Hospital Discharge in 61 Children With Invasive Meningococcal Disease, Chile, 2009-2019.

BACKGROUND: Invasive meningococcal disease (IMD) is an unpredictable and severe infection caused by Neisseria meningitidis . Its case fatality rate could vary from 9.7% to 26% and up to 36% of survivors may experience long-term sequelae, representing a challenge for public health. AIMED: To describe the sequelae at hospital discharge caused by IMD in children between years 2009-2019. METHODS: Cross-sectional study performed in 2 pediatric hospitals. Patients with microbiologically confirmed diagnosis of IMD from 2009 to 2019 were included. Bivariate and logistic regression analysis were performed. RESULTS: The records of 61 patients were reviewed and included. Sixty-seven percent were male, median age 9 months (interquartile range 4-27), 72% were admitted to intensive care unit. Thirty-seven (60.5%) had at least 1 sequela (75% and 37% in patients with or without meningitis, respectively). The most frequents sequelae were neurological 72%, hearing loss 32%, and osteoarticular 24%. Significant differences were found comparing patients with and without sequelae: drowsiness 67.6% versus 41.7% ( P = 0.04), irritability 67.6% versus 25% ( P = 0.01), meningeal signs 62.2% versus 29.2% ( P = 0.01). In logistic regression analysis, postdischarge follow-up had OR 21.25 (95% confidence intervals [CI]: 4.93-91.44), irritability had OR 8.53 (95% CI: 1.64-44.12), meningeal signs had OR 8.21 (95% CI: 0.71-94.05), invasive mechanical ventilation had OR 8.23 (95% CI: 0.78-85.95), meningitis plus meningococcemia OR 1.70 (95% CI: 0.18-15.67) to have sequelae, while children with meningococcemia and vomiting had a OR 0.04 (95% CI: 0.00-0.36) and OR 0.27 (95% CI: 0.03-2.14), respectively. N. meningitidis serogroup W (MenW) was isolated in 54.1% (33/61), and N. meningitidis serogroup B (MenB) in 31.1% (19/61) of cases. A significant difference was found in osteoarticular sequelae ( P = 0.05) between MenB and MenW. There was a decrease in cases after the meningococcal conjugate vaccine against serogroups A, C, W and Y was implemented (2015-2019). CONCLUSIONS: IMD remains as a public health concern. A high rate of sequelae was found in pediatric patients in our series, even in the clinical manifestations other than meningitis. Neurological sequelae were the most prevalent. Multidisciplinary follow-up protocols to reduce long-term impact must be urgently established to assess all children with IMD.