Meningococcal carriage in periods of high and low invasive meningococcal disease incidence in the UK: comparison of UKMenCar1-4 cross-sectional survey results.

BACKGROUND: The incidence of invasive meningococcal disease in the UK decreased by approximately four times from 1999 to 2014, with reductions in serogroup C and serogroup B disease. Lower serogroup C invasive meningococcal disease incidence was attributable to implementation of the meningococcal serogroup C conjugate vaccine in 1999, through direct and indirect protection, but no vaccine was implemented against serogroup B disease. UK Meningococcal Carriage surveys 1-3 (UKMenCar1-3), conducted in 1999, 2000, and 2001, were essential for understanding the impact of vaccination. To investigate the decline in invasive meningococcal disease incidence, we did a large oropharyngeal carriage survey in 2014-15, immediately before the changes to meningococcal vaccines in the UK national immunisation schedule. METHODS: UKMenCar4 was a cross-sectional survey in adolescents aged 15-19 years who were enrolled from schools and colleges geographically local to one of 11 UK sampling centres between Sept 1, 2014, and March 30, 2015. Participants provided an oropharyngeal swab sample and completed a questionnaire on risk factors for carriage, including social behaviours. Samples were cultured for putative Neisseria spp, which were characterised with serogrouping and whole-genome sequencing. Data from this study were compared with the results from the UKMenCar1-3 surveys (1999-2001). FINDINGS: From the 19 641 participants (11 332 female, 8242 male, 67 not stated) in UKMenCar4 with culturable swabs and completed risk-factor questionnaires, 1420 meningococci were isolated, with a carriage prevalence of 7·23% (95% CI 6·88-7·60). Carriage prevalence was substantially lower in UKMenCar4 than in the previous surveys: carriage prevalence was 16·6% (95% CI 15·89-17·22; 2306/13 901) in UKMenCar1 (1999), 17·6% (17·05-18·22; 2873/16 295) in UKMenCar2 (2000), and 18·7% (18·12-19·27; 3283/17 569) in UKMenCar3 (2001). Carriage prevalence was lower for all serogroups in UKMenCar4 than in UKMenCar1-3, except for serogroup Y, which was unchanged. The prevalence of carriage-promoting social behaviours decreased from 1999 to 2014-15, with individuals reporting regular cigarette smoking decreasing from 2932 (21·5%) of 13 650 to 2202 (11·2%) of 19 641, kissing in the past week from 6127 (44·8%) of 13 679 to 7320 (37·3%) of 19 641, and attendance at pubs and nightclubs in the past week from 8436 (62·1%) of 13 594 to 7662 (39·0%) of 19 641 (all p<0·0001). INTERPRETATION: We show that meningococcal carriage prevalence in adolescents sampled nationally during a low incidence period (2014-15) was less than half of that in an equivalent population during a high incidence period (1999-2001). Disease and carriage caused by serogroup C was well controlled by ongoing vaccination. The prevalence of behaviours associated with carriage declined, suggesting that public health policies aimed at influencing behaviour might have further reduced disease. FUNDING: Wellcome Trust, UK Department of Health, and National Institute for Health Research.

Electrophysiological Evidence of Early Cortical Sensitivity to Human Conspecific Mimic Voice as a Distinct Category of Natural Sound.

Purpose From an anthropological perspective of hominin communication, the human auditory system likely evolved to enable special sensitivity to sounds produced by the vocal tracts of human conspecifics whether attended or passively heard. While numerous electrophysiological studies have used stereotypical human-produced verbal (speech voice and singing voice) and nonverbal vocalizations to identify human voice-sensitive responses, controversy remains as to when (and where) processing of acoustic signal attributes characteristic of "human voiceness" per se initiate in the brain. Method To explore this, we used animal vocalizations and human-mimicked versions of those calls ("mimic voice") to examine late auditory evoked potential responses in humans. Results Here, we revealed an N1b component (96-120 ms poststimulus) during a nonattending listening condition showing significantly greater magnitude in response to mimics, beginning as early as primary auditory cortices, preceding the time window reported in previous studies that revealed species-specific vocalization processing initiating in the range of 147-219 ms. During a sound discrimination task, a P600 (500-700 ms poststimulus) component showed specificity for accurate discrimination of human mimic voice. Distinct acoustic signal attributes and features of the stimuli were used in a classifier model, which could distinguish most human from animal voice comparably to behavioral data-though none of these single features could adequately distinguish human voiceness. Conclusions These results provide novel ideas for algorithms used in neuromimetic hearing aids, as well as direct electrophysiological support for a neurocognitive model of natural sound processing that informs both neurodevelopmental and anthropological models regarding the establishment of auditory communication systems in humans. Supplemental Material https://doi.org/10.23641/asha.12903839.

UKMenCar4: A cross-sectional survey of asymptomatic meningococcal carriage amongst UK adolescents at a period of low invasive meningococcal disease incidence.

Carriage of Neisseria meningitidis, the meningococcus, is a prerequisite for invasive meningococcal disease (IMD), a potentially devastating infection that disproportionately afflicts infants and children. Humans are the sole known reservoir for the meningococcus, and it is carried asymptomatically in the nasopharynx of ~10% of the population. Rates of carriage are dependent on age of the host and social and behavioural factors. In the UK, meningococcal carriage has been studied through large, multi-centre carriage surveys of adolescents in 1999, 2000, and 2001, demonstrating carriage can be affected by immunisation with the capsular group C meningococcal conjugate vaccine, inducing population immunity against carriage. Fifteen years after these surveys were carried out, invasive meningococcal disease incidence had declined from a peak in 1999.  The UKMenCar4 study was conducted in 2014/15 to investigate rates of carriage amongst the adolescent population during a period of low disease incidence. The protocols and methodology used to perform UKMenCar4, a large carriage survey, are described here.

Does tDCS over prefrontal cortex improve episodic memory retrieval? Potential importance of time of day.

We report 4 experiments aiming to replicate and extend the finding that anodal transcranial direct current stimulation (tDCS) over dorsolateral prefrontal cortex after encoding and just prior to retrieval improves accuracy on an episodic recollection task. Our first 3 experiments failed to replicate the tDCS effect in planned analyses, but post-hoc analyses uncovered tDCS effects on recollection accuracy during morning sessions. To further investigate, Experiment 4 randomly assigned participants to morning or afternoon sessions. As predicted, tDCS (compared to sham stimulation) improved recollection accuracy in the morning. We hypothesize that tDCS effects are easier to detect during nonoptimal cognitive processing times (e.g., mornings for younger adults). Importantly, we found both significant and null tDCS results across our experiments, indicating that more research is needed to determine the extent that anodal tDCS to left prefrontal cortex reliably improves recollection accuracy at different stimulation times.

Epidemiology, clinical presentation, risk factors, intensive care admission and outcomes of invasive meningococcal disease in England, 2010-2015.

The epidemiology of invasive meningococcal disease (IMD) is constantly changing as new strains are introduced into a population and older strains are removed through vaccination, population immunity or natural trends. Consequently, the clinical disease associated with circulating strains may also change over time. In England, IMD incidence has declined from 1.8/100,000 in 2010/2011 to 1.1/100,000 in 2013/2014, with a small increase in 2014/2015 to 1.3/100,000. Between 01 January 2011 and 30 June 2015, MenB was responsible for 73.0% (n = 2489) of 3411 laboratory-confirmed IMD cases, followed by MenW (n = 371, 10.9%), MenY (n = 373, 10.9%) and MenC (n = 129, 3.8%); other capsular groups were rare (n = 49, 1.4%). Detailed questionnaires were completed for all 3411 laboratory-confirmed cases. Clinical presentation varied by capsular group and age. Atypical presentations were uncommon (244/3411; 7.2%), increasing from 1.2% (41/3411) in children to 3.5% (120/3411) in older adults. Known IMD risk factors were rare (18/3411; 0.5%) and included complement deficiency (n = 11), asplenia (n = 6) or both (n = 1). Nearly a third of cases required intensive care (1069/3411; 31.3%), with rates highest in adults. The 28-day CFR was 6.9% (n = 237), with the lowest rates in 0-14 year-olds (85/1885, 4.5%) and highest among 85+ year-olds (30/94, 31.9%). These observations provide a useful baseline for the current burden of IMD in a European country with enhanced national surveillance.

Meningococcal carriage within households in the African meningitis belt: A longitudinal pilot study.

OBJECTIVES: Carriers of Neisseria meningitidis are a key source of transmission. In the African meningitis belt, where risk of meningococcal disease is highest, a greater understanding of meningococcal carriage dynamics is needed. METHODS: We randomly selected an age-stratified sample of 400 residents from 116 households in Bamako, Mali, and collected pharyngeal swabs in May 2010. A month later, we enrolled all 202 residents of 20 of these households (6 with known carriers) and collected swabs monthly for 6 months prior to MenAfriVac vaccine introduction and returned 10 months later to collect swabs monthly for 3 months. We used standard bacteriological methods to identify N. meningitidis carriers and fit hidden Markov models to assess acquisition and clearance overall and by sex and age. RESULTS: During the cross-sectional study 5.0% of individuals (20/400) were carriers. During the longitudinal study, 73 carriage events were identified from 1422 swabs analyzed, and 16.3% of individuals (33/202) were identified as carriers at least once. The majority of isolates were non-groupable; no serogroup A carriers were identified. CONCLUSIONS: Our results suggest that the duration of carriage with any N. meningitidis averages 2.9 months and that males and children acquire and lose carriage more frequently in an urban setting in Mali. Our study informed the design of a larger study implemented in seven countries of the African meningitis belt.

Temporal associations between national outbreaks of meningococcal serogroup W and C disease in the Netherlands and England: an observational cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Institute for Public Health and the Environment (Netherlands), Academic Medical Center (Netherlands), and Public Health England.

Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.

BACKGROUND: The UK introduced 4CMenB-a multicomponent vaccine against serogroup B meningococcal disease-into the national infant immunisation programme in September, 2015. The Meningococcal Antigen Typing System (MATS) was used to estimate coverage by 4CMenB of invasive meningococcal group B isolates obtained during 2007-08 in England and Wales (MATS coverage). We aimed to repeat the MATS survey for invasive meningococcal group B isolates obtained during 2014-15, before 4CMenB introduction; compare strain coverage between 2007-08 and 2014-15; and investigate associations between MATS coverage, age, region, and disease outcomes. METHODS: Invasive serogroup B meningococcal isolates from cases in England, Wales, and Northern Ireland during 2014-15 were assayed using MATS and compared with 2007-08 data. MATS coverage was assessed by geographical region and age group. Clinical characteristics, risk factors, and outcomes were assessed according to MATS coverage for 2014-15 English cases. FINDINGS: In 2014-15, 165 of 251 (66%; 95% CI 52-80) meningococcal group B isolates were estimated by MATS to be covered by 4CMenB, compared with 391 of 535 (73%; 95% CI 57-87) in 2007-08. The proportion of MATS-positive isolates with one vaccine antigen increased from 23% (122 of 535) in 2007-08 to 31% (78 of 251) in 2014-15, whereas the proportion with more than one antigen fell from 50% (269 of 535) to 35% (87 of 251). This effect reflected changes in circulating strains, particularly ST-269 clonal complex strains. MATS coverage increased with age, varied by geographical region, and was associated with more severe disease. INTERPRETATION: In 2014-15, two-thirds of meningococcal group B isolates were predicted to be covered by 4CMenB. Temporal changes in MATS coverage underscore the need for continued monitoring of antigen expression and diversity, particularly in countries with 4CMenB programmes. FUNDING: Public Health England, GlaxoSmithKline.

Paranormal psychic believers and skeptics: a large-scale test of the cognitive differences hypothesis.

Belief in paranormal psychic phenomena is widespread in the United States, with over a third of the population believing in extrasensory perception (ESP). Why do some people believe, while others are skeptical? According to the cognitive differences hypothesis, individual differences in the way people process information about the world can contribute to the creation of psychic beliefs, such as differences in memory accuracy (e.g., selectively remembering a fortune teller's correct predictions) or analytical thinking (e.g., relying on intuition rather than scrutinizing evidence). While this hypothesis is prevalent in the literature, few have attempted to empirically test it. Here, we provided the most comprehensive test of the cognitive differences hypothesis to date. In 3 studies, we used online screening to recruit groups of strong believers and strong skeptics, matched on key demographics (age, sex, and years of education). These groups were then tested in laboratory and online settings using multiple cognitive tasks and other measures. Our cognitive testing showed that there were no consistent group differences on tasks of episodic memory distortion, autobiographical memory distortion, or working memory capacity, but skeptics consistently outperformed believers on several tasks tapping analytical or logical thinking as well as vocabulary. These findings demonstrate cognitive similarities and differences between these groups and suggest that differences in analytical thinking and conceptual knowledge might contribute to the development of psychic beliefs. We also found that psychic belief was associated with greater life satisfaction, demonstrating benefits associated with psychic beliefs and highlighting the role of both cognitive and noncognitive factors in understanding these individual differences.

Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study.

BACKGROUND: Invasive meningococcal disease (IMD) is a worldwide health issue that is potentially preventable with vaccination. In view of its sporadic nature and the high diversity of Neisseria meningitidis, epidemiological surveillance incorporating detailed isolate characterisation is crucial for effective control and understanding the evolving epidemiology of IMD. The Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL) exploits whole-genome sequencing (WGS) for this purpose and presents data on a comprehensive and coherent IMD isolate collection from England and Wales via the internet. We assessed the contribution of these data to investigating IMD epidemiology. METHODS: WGS data were obtained for all 899 IMD isolates available for England and Wales in epidemiological years 2010-11 and 2011-12. The data had been annotated at 1720 loci, analysed, and disseminated online. Information was also available on meningococcal population structure and vaccine (Bexsero, GlaxoSmithKline, Brentford, Middlesex, UK) antigen variants, which enabled the investigation of IMD-associated genotypes over time and by patients' age groups. Population genomic analyses were done with a hierarchical gene-by-gene approach. FINDINGS: The methods used by MRF-MGL efficiently characterised IMD isolates and information was provided in plain language. At least 20 meningococcal lineages were identified, three of which (hyperinvasive clonal complexes 41/44 [lineage 3], 269 [lineage 2], and 23 [lineage 23]) were responsible for 528 (59%) of IMD isolates. Lineages were highly diverse and showed evidence of extensive recombination. Specific lineages were associated with IMD in particular age groups, with notable diversity in the youngest and oldest individuals. The increased incidence of IMD from 1984 to 2010 in England and Wales was due to successive and concurrent epidemics of different lineages. Genetically, 74% of isolates were characterised as encoding group B capsules: 16% group Y, 6% group W, and 3% group C. Exact peptide matches for individual Bexsero vaccine antigens were present in up to 26% of isolates. INTERPRETATION: The MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis. FUNDING: Meningitis Research Foundation, Wellcome Trust, Public Health England, European Union.

Electrically stimulating prefrontal cortex at retrieval improves recollection accuracy.

Neuroimaging and brain damage studies suggest that dorsolateral prefrontal cortex (dlPFC) is involved in the cognitive control of episodic recollection. If dlPFC is causally involved in retrieval, then transcranial direct current stimulation (tDCS) of this brain region should increase recollection accuracy, especially when recollection is difficult and requires cognitive control. Here, we report the first brain stimulation experiment to directly test this hypothesis. We administered tDCS to dlPFC immediately after studying to-be-learned material but just prior to recollection testing, thereby targeting retrieval processes. We found that stimulation of dlPFC significantly increased recollection accuracy, relative to a no-stimulation sham condition and also relative to active stimulation of a comparison region in left parietal cortex. There was no significant difference in the size of this increase between hemispheres. Moreover, these dlPFC stimulation effects were behaviorally selective, increasing accuracy only when participants needed to recollect difficult information. Electrically stimulating dlPFC allowed people to more accurately recollect specific details of their experiences, demonstrating a causal role of dlPFC in the retrieval of episodic memories.

Disregarding familiarity during recollection attempts: content-specific recapitulation as a retrieval orientation strategy.

People can use a content-specific recapitulation strategy to trigger memories (i.e., mentally reinstating encoding conditions), but how people deploy this strategy is unclear. Is recapitulation naturally used to guide all recollection attempts, or is it only used selectively, after retrieving incomplete information that requires additional monitoring? According to a retrieval orientation model, people use recapitulation whenever they search memory for specific information, regardless of what information might come to mind. In contrast, according to a postretrieval monitoring model, people selectively engage recapitulation only after retrieving ambiguous information in order to evaluate this information and guide additional retrieval attempts. We tested between these models using a criterial recollection task, and by manipulating the strength of ambiguous information associated with to-be-rejected foils (i.e., familiarity or noncriterial information). Replicating prior work, foil rejections were greater when people attempted to recollect targets studied at a semantic level (deep test) compared to an orthographic level (shallow test), implicating more accurate retrieval monitoring. To investigate the role of a recapitulation strategy in this monitoring process, a final test assessed memory for the foils that were earlier processed on these recollection tests. Performance on this foil recognition test suggested that people had engaged in more elaborative content-specific recapitulation when initially tested for deep compared to shallow recollections, and critically, this elaboration effect did not interact with the experimental manipulation of foil strength. These results support the retrieval orientation model, whereby a recapitulation strategy was used to orient retrieval toward specific information during every recollection attempt.

Memory's aging echo: age-related decline in neural reactivation of perceptual details during recollection.

Episodic memory decline is a hallmark of normal cognitive aging. Here, we report the first event-related fMRI study to directly investigate age differences in the neural reactivation of qualitatively rich perceptual details during recollection. Younger and older adults studied pictures of complex scenes at different presentation durations along with descriptive verbal labels, and these labels subsequently were used during fMRI scanning to cue picture recollections of varying perceptual detail. As expected from prior behavioral work, the two age groups subjectively rated their recollections as containing similar amounts of perceptual detail, despite objectively measured recollection impairment in older adults. In both age groups, comparisons of retrieval trials that varied in recollected detail revealed robust activity in brain regions previously linked to recollection, including hippocampus and both medial and lateral regions of the prefrontal and posterior parietal cortex. Critically, this analysis also revealed recollection-related activity in visual processing regions that were active in an independent picture-perception task, and these regions showed age-related reductions in activity during recollection that cannot be attributed to age differences in response criteria. These fMRI findings provide new evidence that aging reduces the absolute quantity of perceptual details that are reactivated from memory, and they help to explain why aging reduces the reliability of subjective memory judgments.

The distribution and 'in vivo' phase variation status of haemoglobin receptors in invasive meningococcal serogroup B disease: genotypic and phenotypic analysis.

Two haemoglobin-binding proteins, HmbR and HpuAB, contribute to iron acquisition by Neisseria meningitidis. These receptors are subject to high frequency, reversible switches in gene expression--phase variation (PV)--due to mutations in homopolymeric (poly-G) repeats present in the open reading frame. The distribution and PV state of these receptors was assessed for a representative collection of isolates from invasive meningococcal disease patients of England, Wales and Northern Ireland. Most of the major clonal complexes had only the HmbR receptor whilst the recently expanding ST-275-centred cluster of the ST-269 clonal complex had both receptors. At least one of the receptors was in an 'ON' configuration in 76.3% of the isolates, a finding that was largely consistent with phenotypic analyses. As PV status may change during isolation and culture of meningococci, a PCR-based protocol was utilised to confirm the expression status of the receptors within contemporaneously acquired clinical specimens (blood/cerebrospinal fluid) from the respective patients. The expression state was confirmed for all isolate/specimen pairs with <15 tract repeats indicating that the PV status of these receptors is stable during isolation. This study therefore establishes a protocol for determining in vivo PV status to aid in determining the contributions of phase variable genes to invasive meningococcal disease. Furthermore, the results of the study support a putative but non-essential role of the meningococcal haemoglobin receptors as virulence factors whilst further highlighting their vaccine candidacy.

Genetic distribution of noncapsular meningococcal group B vaccine antigens in Neisseria lactamica.

The poor immunogenicity of the meningococcal serogroup B (MenB) capsule has led to the development of vaccines targeting subcapsular antigens, in particular the immunodominant and diverse outer membrane porin, PorA. These vaccines are largely strain specific; however, they offer limited protection against the diverse MenB-associated diseases observed in many industrialized nations. To broaden the scope of its protection, the multicomponent vaccine (4CMenB) incorporates a PorA-containing outer membrane vesicle (OMV) alongside relatively conserved recombinant protein components, including factor H-binding protein (fHbp), Neisseria adhesin A (NadA), and neisserial heparin-binding antigen (NHBA). The expression of PorA is unique to meningococci (Neisseria meningitidis); however, many subcapsular antigens are shared with nonpathogenic members of the genus Neisseria that also inhabit the nasopharynx. These organisms may elicit cross-protective immunity against meningococci and/or occupy a niche that might otherwise accommodate pathogens. The potential for 4CMenB responses to impact such species (and vice versa) was investigated by determining the genetic distribution of the primary 4CMenB antigens among diverse members of the common childhood commensal, Neisseria lactamica. All the isolates possessed nhba but were devoid of fhbp and nadA. The nhba alleles were mainly distinct from but closely related to those observed among a representative panel of invasive MenB isolates from the same broad geographic region. We made similar findings for the immunogenic typing antigen, FetA, which constitutes a major part of the 4CMenB OMV. Thus, 4CMenB vaccine responses may impact or be impacted by nasopharyngeal carriage of commensal neisseriae. This highlights an area for further research and surveillance should the vaccine be routinely implemented.

Invasive meningococcal disease in England and Wales: implications for the introduction of new vaccines.

A number of meningococcal vaccines have either been recently licensed or are in late-phase clinical trials. To inform national vaccination policy, it is important to define the burden of disease and the potential impact of any new vaccine. This study describes the epidemiology of invasive meningococcal disease across all age groups in England and Wales for recent epidemiological years between 2006 and 2010. The Health Protection Agency (HPA) conducts enhanced national meningococcal surveillance through a combination of clinical and laboratory reporting. Between 2006/07 and 2010/11, the average annual incidence of invasive meningococcal disease across all age groups was 2.0/100,000. Capsular group B (MenB) accounted for 87% (4777/5471) cases, with an overall incidence of 1.8/100,000. The highest MenB incidence observed among infants (36.2/100,000) where cases increased from birth to 5 months of age then gradually declined. An annual average of 245 MenB cases occurred in infants (135 in those aged ≤ 6 months) representing 26% (and 14%) of all MenB cases, respectively. After infancy, MenB rates declined until the age of 12 years, rising to a second smaller peak at 18 years. MenB case fatality ratio (CFR) was 5.2% (247/4777 cases) overall and was highest among ≥ 65 year-olds (28/161; 17.4%). The largest number of deaths (n=125), however, occurred among <5 year-olds. Clonal complexes cc269 and cc41/44 each accounted for around a third of cases across the age groups. Other capsular groups rarely caused invasive disease, although capsular group Y (MenY) cases more than doubled from 35 in 2006/07 to 86 in 2010/11. Thus, universal meningococcal vaccination with an effective broad-spectrum formulation has potential to prevent most disease, particularly if the vaccine is immunogenic early in infancy, but, there is currently little justification for routine quadrivalent ACWY conjugate vaccination in the UK, although the increase in MenY disease warrants continued surveillance.

Invasive meningococcal capsular group Y disease, England and Wales, 2007-2009.

Enhanced national surveillance for invasive meningococcal disease in England and Wales identified an increase in laboratory-confirmed capsular group Y (MenY) disease from 34 cases in 2007 to 44 in 2008 and 65 in 2009. For cases diagnosed in 2009, patient median age at disease onset was 60 years; 39% of patients had underlying medical conditions, and 19% died. MenY isolates causing invasive disease during 2007-2009 belonged mainly to 1 of 4 clonal complexes (cc), cc23 (56% of isolates), cc174 (21%), cc167 (11%), and cc22 (8%). The 2009 increase resulted primarily from sequence type 1655 (cc23) (22 cases in 2009, compared with 4 cases each in 2007 and 2008). cc23 was associated with lpxL1 mutations and meningitis in younger age groups (<25 years); cc174 was associated with nonmeningitis, particularly pneumonia, in older age groups (>65 years). The increase in MenY disease requires careful epidemiologic and molecular monitoring.

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction.

Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence.

Neisseria meningitidis can utilize haem, haemoglobin and haemoglobin-haptoglobin complexes as sources of iron via two TonB-dependent phase variable haemoglobin receptors, HmbR and HpuAB. HmbR is over-represented in disease isolates, suggesting a link between haemoglobin acquisition and meningococcal disease. This study compared the distribution of HpuAB and phase variation (PV) status of both receptors in disease and carriage isolates. Meningococcal disease (n = 214) and carriage (n = 305) isolates representative of multiple clonal complexes (CCs) were investigated for the distribution, polyG tract lengths and ON/OFF status of both haemoglobin receptors, and for the deletion mechanism for HpuAB. Strains with both receptors or only hmbR were present at similar frequencies among meningococcal disease isolates as compared with carriage isolates. However, >90 % of isolates from the three CCs CC5, CC8 and CC11 with the highest disease to carriage ratios contained both receptors. Strains with an hpuAB-only phenotype were under-represented among disease isolates, suggesting selection against this receptor during systemic disease, possibly due to the receptor having a high level of immunogenicity or being inefficient in acquisition of iron during systemic spread. Absence of hpuAB resulted from either complete deletion or replacement by an insertion element. In an examination of PV status, one or both receptors were found in an ON state in 91 % of disease and 71 % of carriage isolates. We suggest that expression of a haemoglobin receptor, either HmbR or HpuAB, is of major importance for systemic spread of meningococci, and that the presence of both receptors contributes to virulence in some strains.

Molecular targets in meningococci: efficient routine characterization and optimal outbreak investigation in conjunction with routine surveillance of the meningococcal group B vaccine candidate, fHBP.

In 2007, recommendations were proposed for the molecular typing of meningococci. Multilocus sequence typing (MLST) was recommended to guide national and international disease management and facilitate studies of population biology and evolution. Sequencing of porA variable regions (VRs) 1 and 2 and the fetA VR was recommended for monitoring antigenic distribution and investigating potential outbreaks. porB characterization was recommended if further resolution was required. Several investigational "group B" meningococcal vaccines, including two in the advanced stages of development, incorporate factor H-binding protein (fHBP). The requirement for routine surveillance of fhbp places additional pressure on reference laboratories, both financially and in terms of labor. This study investigated the optimal and most efficient molecular typing schemes for (i) routine meningococcal characterization and (ii) the investigation of potential outbreaks, in conjunction with routine surveillance of fhbp. All invasive disease isolates received by the Health Protection Agency Meningococcal Reference Unit between July 2007 and June 2008 (n = 613) were characterized in terms of capsular group, porA, fetA VR, fhbp, and sequence type (ST). Following capsular grouping and porA genosubtyping, several predominant capsular group-porA combinations were identified. The levels of additional resolution afforded by fetA and fhbp were comparable and partially complementary. fhbp constitutes an effective substitute for fetA as a routine marker of antigenic distribution, thereby reducing costs in conjunction with fhbp surveillance. MLST afforded markedly superior resolution overall and is the optimal scheme for investigating outbreaks in which (i) typing data are unavailable for the index case or (ii) the index case possesses a known, predominant capsular group-porA repertoire.