Outcomes of invasive meningococcal serogroup B disease in children and adolescents (MOSAIC): a case-control study.
ABSTRACT Serogroup B meningococcal disease is the commonest cause of meningitis and septicaemia in high-income countries. Assessment of new serogroup B meningococcal vaccines is hampered by a scarcity of data on the burden of disease in survivors. We aimed to estimate the disease burden in children having survived serogroup B meningococcal disease.
In this case-control study, we recruited children from the UK National Meningococcal Registry between May, 2008, and September, 2010. Eligible children were survivors who had had serogroup B meningococcal disease confirmed by culture or PCR and were aged 1 month to 13 years at disease. Age-matched and sex-matched controls were recruited through the family doctor of the children who had the meningococcal disease. Physical, psychological, neurocognitive, and educational outcomes were assessed through a standardised interview with validated instruments. We did matched analyses using generalised estimating equations (GEE). Researchers were masked to the children's serogroup B meningococcal status.
Of the 537 children who had serogroup B meningococcal disease and were available for recruitment, 245 were assessed. 328 controls were also recruited; 221 controls were matched with a case and 107 were additional unmatched controls. The mean age was 6·5 (SD 2·8) years in children with serogroup B meningococcal disease and 6·9 (2·9) in controls. In the full sample, children who had serogroup B meningococcal disease were more likely than controls to have bilateral sensorineural hearing loss of 40 dB or more (unmatched 11 [5%] of 232 children with meningococcal disease vs three [<1%] of 318 controls; matched odds ratio [OR] 4·8, 95% CI 1·3 to 17·4, p=0·02), lower full-scale IQ (matched mean 99·5 for children with meningococcal disease and 107·2 for controls; matched coefficient -7·6, 95% CI -9·9 to -5·4, p<0·0001), and psychological disorders (61 [26%] of 235 children with meningococcal disease vs 33 (10%) of 322 controls; matched full sample OR 2·6, 1·6 to 4·2, p<0·0001). Disabling amputations were noted in three (1%) of 239 children who had serogroup B meningococcal disease compared with none of the 322 controls. Children with meningococcal disease were also more likely to have deficits in executive function and multiple aspects of memory. Deficits were identified in 87 (36%) of 244 children with serogroup B meningococcal disease and 49 (15%) of 328 controls (matched OR 2·7, 1·8 to 4·1, p<0·0001). Major disabling deficits were identified in 21 (9%) of 244 children with meningococcal disease compared with six (2%) of 328 controls (matched OR 5·0, 2·0 to 12·6, p=0·001). No significant differences were noted in attentional function or post-traumatic stress disorder between children with serogroup B meningococcal disease and controls.
Most children survive serogroup B meningococcal disease without major sequelae. However, about a tenth have major disabling deficits and more than a third have one or more deficits in physical, cognitive, and psychological functioning, with the additional burden of memory deficits and executive function problems. These findings should help to guide assessments of new vaccines and suggest that all survivors of serogroup B meningococcal disease should be screened for psychological disorders and cognitive deficits in addition to hearing loss.
Meningitis Trust and Big Lottery Fund, UK.
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ABSTRACT: Neisseria meningitidis is a gram-negative diplococcus, for which humans are the only reservoir. While colonization is common, invasive meningococcal disease in the form of meningitis or bacteremia can be devastating and potentially fatal. Certain populations are at higher risk for disease including infants, adolescents, those with asplenia or complement deficiencies, and potentially those with human immunodeficiency virus (HIV) infection. Use of conjugate meningococcal vaccines has impacted disease epidemiology in both high- and low-income countries. Outbreaks of serogroup B disease at university campuses have drawn further attention to the recent development of a novel serogroup B vaccine now approved in many countries. This review covers key aspects of the pathogenesis and management of meningococcal disease, as well as the very recent developments in disease epidemiology, outbreaks, and the evolution of meningococcal immunizations.Current Neurology and Neuroscience Reports 03/2015; 15(3):524. DOI:10.1007/s11910-015-0524-6 · 3.67 Impact Factor
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ABSTRACT: Serogroup B Neisseria meningitidis (MenB) is a major cause of severe sepsis and invasive meningococcal disease, which is associated with 5-15% mortality and devastating long-term sequelae. Neisserial adhesin A (NadA), a trimeric autotransporter adhesin (TAA) that acts in adhesion to and invasion of host epithelial cells, is one of the three antigens discovered by genome mining that are part of the MenB vaccine that recently was approved by the European Medicines Agency. Here we present the crystal structure of NadA variant 5 at 2 Å resolution and transmission electron microscopy data for NadA variant 3 that is present in the vaccine. The two variants show similar overall topology with a novel TAA fold predominantly composed of trimeric coiled-coils with three protruding wing-like structures that create an unusual N-terminal head domain. Detailed mapping of the binding site of a bactericidal antibody by hydrogen/deuterium exchange MS shows that a protective conformational epitope is located in the head of NadA. These results provide information that is important for elucidating the biological function and vaccine efficacy of NadA.Proceedings of the National Academy of Sciences 11/2014; 111(48). DOI:10.1073/pnas.1419686111 · 9.81 Impact Factor
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ABSTRACT: In countries with established programmes for vaccination of infants, toddlers and adolescents with meningococcal conjugate vaccines, serogroup B invasive meningococcal disease remains the major cause of septicaemia and meningitis in the paediatric and adolescent age groups. Novartis has developed a serogroup B meningococcal vaccine, 4CMenB, to meet this need. We reviewed all 4CMenB studies. The studies found 4CMenB to be highly immunogenic when administered in all schedules, with protective antibody levels (serum bactericidal antibody titres ≥4 or ≥5 with human complement, hSBA) against serogroup B strains expressing vaccine antigens in >95% of vaccinated cohorts. When antibody levels waned, all tested groups demonstrated booster responses. Although possibly an underestimation, the Meningococcal Antigen Typing System (MATS) technique predicts that global coverage of 4CMenB against all serogroup B strains is in the range 66% (Canada) to 91% (USA). The vaccine was found to be generally well tolerated, although local and systemic reactions, notably fever in infants, typical of many vaccines, were increased following concomitant administration of 4CMenB with routine vaccines. When tested, prophylactic paracetamol significantly decreased the frequency and severity of reactions in infants, with no clinically significant impact on immunogenicity of 4CMenB or concomitant routine vaccines. The vaccine is approved for use in the following age groups in the European Union (2 months+), Canada (2 months through 17 years), Australia (2 months+) and Chile (2 months+), following clinical evaluation in 4843 infants and toddlers, and 1712 adolescents and adults, in schedules including a three-dose (2, 3, 4 or 2, 4, 6 months) and a two-dose (6-11 months) infant series with a booster in the second year of life, a two-dose series in toddlers (12-23 months) and children (2-10 years) given 2 months apart (with a booster at least in the EU), and a two-dose series in adolescents (11-17 years) given 1-6 months apart. 4CMenB presents a solution to the unmet medical need of offering protection against serogroup B invasive meningococcal disease in all age groups above 2 months.01/2015; 3(1):13-23. DOI:10.1177/2051013614557477