Letter to the Editor

Early evidence of expanding W ST-11 CC meningococcal incidence in Spain

La enfermedad meningocócica invasiva (EMI) supone una causa importante de morbimortalidad en niños y adultos. Objetivo principal: describir las características clínicas y epidemiológicas de los pacientes con EMI. Objetivos secundarios: describir las diferencias entre niños y adultos, factores pronósticos y cambios epidemiológicos en los últimos 14 años.

Estudio retrospectivo realizado en un hospital terciario. Se incluyeron los pacientes diagnosticados de EMI entre 2004 y 2017, recogiéndose datos epidemiológicos, clínicos y microbiológicos.

Fueron diagnosticados 84 pacientes con EMI, 50 (59,5%) niños. Edad mediana en niños 2 años (RIC: 0,7-7,5) y adultos 41,2 años (RIC: 26,4-69,3). Bacteriemia en 47 casos (56%), meningitis en 24 (28,6%) y ambas en 13 (15,5%). Predominio del serogrupo B (MenB), en el 40,5%, seguido del serogrupo C (MenC), en el 15,5%, con mayor proporción de MenC en adultos (26,5 vs. 8%; p = 0,022). Disminución en la incidencia de 2004-2010 a 2011-2017, pasando de 3,14 a 1,33 casos/100.000 urgencias en el centro de estudio (p < 0,001). El 84% de los niños había recibido ≥ 1 dosis de vacuna frente a MenC, ninguno frente a MenB. Mayor proporción de ingreso en UCI en niños (78 vs. 44,1%; p = 0,001). Tendencia a mayor letalidad en adultos (11,8 vs. 2%; p = 0,153). La intubación y la trombocitopenia fueron factores de riesgo independientes de desenlace adverso, y la leucopenia y el exantema purpúrico de gravedad.

Se objetivó un descenso en la incidencia de EMI, siendo MenB el mayoritario. El mayor porcentaje de MenC en adultos probablemente esté relacionado con una menor cobertura vacunal. La trombocitopenia, la leucopenia y el exantema purpúrico fueron factores de riesgo relacionados con peor pronóstico.

Invasive meningococcal disease (IMD) has a high morbidity and mortality in children and adults. The aim of this study was to describe the clinical and epidemiological characteristics of patients with IMD, to compare them among children and adults, and to determine prognostic factors and changes in epidemiology during a 14-year period.

A retrospective study was conducted on patients admitted to a third level hospital with IMD between 2004 and 2017. An analysis was made of the clinical, epidemiological and microbiological data.

A total of 84 patients were diagnosed with IMD, of which 50 (59.5%) were children. Median age was 2 years (IQR 0.7-7.5) for children and 41.2 years (IQR 26.4-69.3) for adults. Diagnosis was bacteraemia in 47 patients (56%), meningitis in 24 (28.6%), and both in 13 (15.5%). Serogroup B (MenB) was the most common cause of IMD (40.5%), followed by serogroup C (MenC) in 15.5%, which was more common among adults (26.5% vs 8%, P = .022). Incidence rate decreased between 2004-2010 and 2011-2017, from 3.14 to 1.33 cases/100.000 emergencies attended in the study hospital (P< .001). Eighty-four percent of children had received ≥ 1 dose of vaccine against MenC, with none against MenB. Children had higher proportion of ICU admissions (78% vs 44.1%, P = .001). Mortality was slightly higher in adults (11.8% vs 2.0%, P = .153). Adverse outcomes (sequelae or mortality) were independently associated with intubation and thrombocytopenia, while disease severity with leukopenia and purpuric rash.

IMD incidence has decreased in our setting, with MenB being the most common serogroup. The higher prevalence of MenC in adults was probably related to lower vaccination coverage. According to this study, thrombocytopenia, leukopenia, and purpuric rash were parameters associated with worse outcome.

We evaluated antibody persistence up to 68 months (M) post-vaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) or a licensed monovalent MenC conjugate vaccine (MenC-CRM₁₉₇) and subsequent booster responses to MenACWY-TT in healthy European children.

In the initial study (NCT00674583), healthy children, 2–10 years of age, were randomized to receive a single dose of either MenACWY-TT or MenC-CRM₁₉₇. In the follow-up study, we present the persistence at 32, 44, 56, and 68 M post-vaccination, overall and stratified by age (2–5 and 6–10 years), and the immunogenicity and safety of MenACWY-TT administered to all study participants at M68 post-primary vaccination.

At M68, 33.3% (age group 2–5 years) and 47.1% (age group 6–10 years) of the children vaccinated with MenACWY-TT, and 50.0% (age group 2–5 years) and 75.9% (age group 6–10 years) vaccinated with MenC-CRM₁₉₇ retained titers ≥1:8 for MenC, as assessed by a serum bactericidal assay using rabbit complement (rSBA). In the MenACWY-TT recipients, the percentages of children retaining rSBA titers ≥1:8 for MenA, MenW, and MenY were 81.7%, 47.3% and 66.7% in age group 2–5 years and 91.8%, 58,8% and 76.5% in age group 6–10 years, respectively. The booster dose induced robust responses (100% for all serogroups) and was well-tolerated.

Antibody persistence (rSBA titers ≥ 1:8) for serogroups A, W and Y was observed in more than 50.0% of the children 68 M after receiving one dose of MenACWY-TT; for MenC, antibody persistence was observed in more than one third of MenACWY-TT and more than half of MenC-CRM₁₉₇ recipients. Vaccination with a booster dose of MenACWY-TT induced robust immune responses for all serogroups.

Neisseria meningitidis group W (NmW) belonging to the clonal complex ST-11 (NmW/cc11) spread in Europe and in France in 2000 and declined thereafter. In France, invasive meningococcal disease (IMD) due to NmW increased again in 2012 and thereafter since 2015. Several sub-lineages of NmW/cc11 are circulating worldwide with successive epidemic waves. We aimed to describe recent epidemiological trends of NmW in France and to explore the microbiological and epidemiological characteristics associated with different NmW/cc11 sub-lineages.

The epidemiology of NmW was described based on data collected through mandatory notification of IMD and strain typing data for culture-confirmed and PCR-confirmed cases for the period 2000–2016. All culture-confirmed cases due to NmW from the period 2010–2016 were characterised by whole genome sequencing (WGS). A detailed epidemiological analysis was performed for culture-confirmed cases on the basis of WGS data.

During the period 2010–2016, genotyping was obtained for 148 cases including all the 132 culture-confirmed cases, among which 127 were matched with epidemiological data, and 16 PCR-confirmed cases (out of a total of 47 PCR-confirmed cases). An increase in IMD was observed in 2012 and was linked to isolates belonging to the “Anglo-French-Hajj” sub-lineage. These isolates have decreased significantly since 2013 and have been replaced by NmW/cc11 isolates related to the “South American – UK” sub-lineage which caused a marked increase in the number of cases of NmW in 2016. In this sub-lineage, the “original UK strain” was first detected in 2012 and increased thereafter, followed by the recently described “UK 2013-strain”. Isolates related to the “South American-UK” sub-lineage represented 45% of all NmW cultured isolates from the whole period 2010–2016 but were the most frequent isolates in 2016, representing 76% of the total NmW typed isolates and 94% of the typed NmW/cc11 isolates. A changing pattern in the epidemiology of NmW has been observed in 2015–2016 in relation to the spread of the “UK 2013-strain” with a sharp increase in the number of cases among persons aged 15 years and over and a high case fatality rate (CFR). Among cases due to the “UK 2013-strain”, 94% of cases were aged 15 years and over and the CFR was 28%.

Our data suggest a recent clonal replacement among NmW/cc11 isolates with the expansion of the “South American-UK” sub-lineage in France and particularly the “UK 2013-strain” which was predominant in 2015 and 2016. A shift in the age-distribution of IMD due to NmW to older ages and the high CFR are consistent with the expansion of a new virulent clone in a naive population. These data may have an impact on tailoring vaccination strategies against NmW.

Since 2009, the incidence of meningococcal serogroup W disease has increased rapidly in the UK because of a single strain (the so-called original UK strain) belonging to the hypervirulent sequence type-11 clonal complex (cc11), with a variant outbreak strain (the so-called 2013 strain) emerging in 2013. Subsequently, the Netherlands has had an increase in the incidence of meningococcal serogroup W disease. We assessed the temporal and phylogenetic associations between the serogroup W outbreaks in the Netherlands and England, and the historical serogroup C outbreaks in both countries.

For this observational cohort study, we used national surveillance data for meningococcal serogroup W and serogroup C disease in the Netherlands and England for the epidemiological years (July to June) 1992–93 to 2015–16. We also did whole genome sequencing and core genome multilocus sequence typing (1546 loci) on serogroup W disease isolates from both countries for surveillance years 2008–09 to 2015–16. We used Poisson regression to compare the annual relative increase in the incidence of serogroup W and serogroup C between both countries.

In the Netherlands, the incidence of meningococcal serogroup W disease increased substantially in 2015–16 compared with 2014–15, with an incidence rate ratio of 5·2 (95% CI 2·0–13·5) and 11% case fatality. In England, the incidence increased substantially in 2012–13 compared with 2011–12, with an incidence rate ratio of 1·8 (1·2–2·8). The relative increase in the Netherlands from 2014–15 to 2015–16 was 418% (95% CI 99–1248), which was significantly higher than the annual relative increase of 79% (61–99) per year in England from 2011–12 to 2014–15 (p=0·03). Cases due to meningococcal serogroup W cc11 (MenW:cc11) emerged in 2012–13 in the Netherlands. Of 29 MenW:cc11 cases found up to 2015–16, 26 (90%) were caused by the 2013 strain. For both the current serogroup W outbreak and the historical serogroup C outbreak, the increase in incidence started several years later in the Netherlands than in England, the rate of increase was higher in the Netherlands, and age distributions were similar in both countries.

Given the historical similarities of meningococcal serogroup W with meningococcal serogroup C emergence, the rapid expansion of the MenW:cc11 2013 strain in the Netherlands, its high case fatality, and the availability of a safe and effective vaccine, urgent consideration is needed for public health interventions in the Netherlands and other affected countries to prevent further serogroup W cases and deaths.

National Institute for Public Health and the Environment (Netherlands), Academic Medical Center (Netherlands), and Public Health England.

El CAV-AEP actualiza anualmente el calendario de vacunaciones sistemáticas que estima idóneo para los niños residentes en España, teniendo en cuenta la evidencia disponible sobre vacunas. Sus recomendaciones se publican en Anales de Pediatría, el órgano de expresión de la AEP. Además, el comité realiza recomendaciones sobre vacunas no incluidas en los calendarios oficiales (no financiadas), como rotavirus, meningococo B y meningococo tetravalente.

En cuanto a las vacunas financiadas, se sigue recomendando emplear esquemas 2 + 1 (2, 4 y 11-12 meses) con las vacunas hexavalentes y con la antineumocócica conjugada 13-valente.

Se aconseja un refuerzo a los 6 años preferentemente con DTPa, junto a una dosis de polio para aquellos que recibieron esquemas 2 + 1, así como vacunación con Tdpa en adolescentes y durante el embarazo entre las semanas 27 y 32.

Se emplearán esquemas de dos dosis para triple vírica (12 meses y 2-4 años) y varicela (15 meses y 2-4 años).

Se deben incrementar las coberturas frente al papilomavirus en niñas de 12 años con dos dosis (0-6 meses), así como informar a los varones de los beneficios potenciales de la vacunación y valorar la recomendación del preparado tetravalente.

En adolescentes, la opción óptima es la vacuna antimeningocócica tetravalente.

Respecto a las vacunas recomendadas no financiadas, dada su disponibilidad en las farmacias comunitarias, se recomienda la vacuna frente al meningococo B, con esquema 3 + 1, solicitando su entrada en el calendario. Es recomendable vacunar a todos los lactantes frente al rotavirus.

The Vaccine Advisory Committee of the Spanish Paediatrics Association (CAV-AEP) annually publishes the immunisation schedule which, in our opinion, is optimal for children resident in Spain, considering the evidence available on current vaccines. Pneumococcal and varicella immunisation in early childhood is already included in all of the funded vaccines present in the regional immunisation programmes. Furthermore, this Committee establishes recommendations about vaccines not included in official calendars (non-funded immunisations) such as like rotavirus, meningococcal B, and meningococcal AC.

As regards funded immunisations, the 2 + 1 strategy (2, 4, 11-12 months) with hexavalent (DTPa-IPV-Hib-HB), and 13-valent pneumococcal vaccines are recommended.

Administration of the 6-year booster dose with DTPa is recommended, and a poliomyelitis dose for children who had received the 2 + 1 scheme, as well as Tdap vaccine for adolescents and pregnant women between 27 and 32 weeks’ gestation.

The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years).

Coverage of human papillomavirus vaccination in girls aged 12 with a two dose scheme (0, 6 months) should be improved. Information and recommendation for male adolescents about potential beneficial effects of this immunisation should also be provided.

Meningococcal ACWY vaccine is the optimal choice in adolescents.

As regards the recommended unfunded immunisations, the CAV-AEP recommends the administration of meningococcal B vaccine, due to the current availability in Spanish community pharmacies, with a 3 + 1 scheme. The CAV-AEP requests the incorporation of this vaccine into the funded unified schedule. Vaccination against rotavirus is recommended in all infants.