Steve J. Gray

Serogroup W135 meningococcal disease in Hajj pilgrims

An outbreak of W135 meningococcal disease occurred in the spring of 2000 among pilgrims returning from Saudi Arabia and their contacts. Clinical isolates from England and France were examined and compared with reference strains from other countries. Characterisation of isolates by a range of typing methods showed them to be of clonal origin (ET-37) and closely related to other meningococci with an established propensity to cause disease clusters. A reappraisal of vaccination strategies for travellers is required.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

BACKGROUND Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING Novartis Vaccines.

Increase in Endemic Neisseria meningitidis Capsular Group W Sequence Type 11 Complex Associated With Severe Invasive Disease in England and Wales

BACKGROUND In England and Wales, the incidence of invasive meningococcal disease has been declining for more than a decade, but meningococcal group W (MenW) cases have been increasing since 2009. METHODS Public Health England conducts enhanced national surveillance of invasive meningococcal disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed MenW cases diagnosed during 3 epidemiologic years (2010-2011 to 2012-2013), alongside whole-genome sequencing analysis of the clinical isolates. RESULTS The year-on-year increase in invasive MenW disease across all age groups since 2009-2010 was due to rapid endemic expansion of a single clone belonging to the sequence type 11 complex (cc11). In 2013-2014, MenW was responsible for 15% of all invasive meningococcal disease. All but 1 of the recent MenW:cc11 isolates were very closely related, consistent with recent clonal expansion. Clinical follow-up of all 129 MenW cases diagnosed during 2010-2011 to 2012-2013 revealed that most patients were previously healthy (n = 105 [81%]), had not travelled abroad prior to illness and the majority presented with septicemia (n = 63 [49%]), meningitis (n = 16 [12%]) or both (n = 21 [16%]); however, one-quarter had atypical presentations including pneumonia (n = 15 [12%]), septic arthritis (n = 9 [7%]), and epiglottitis/supraglottitis (n = 5 [4%]). Forty-eight (37%) required intensive care and 15 (12%) died. There was no association between infecting strain, clinical disease, or outcome. CONCLUSIONS The recent increase in invasive MenW disease in England and Wales is due to rapid endemic expansion of a single clone belonging to cc11 and is associated with severe disease with unusual clinical presentations. This increase will require careful monitoring in the coming years.

Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.

Summary Objectives Neisseria meningitidis is a leading cause of meningitis and septicaemia. The hyperinvasive ST-11 clonal complex (cc11) caused serogroup C (MenC) outbreaks in the US military in the 1960s and UK universities in the 1990s, a global Hajj-associated serogroup W (MenW) outbreak in 2000–2001, and subsequent MenW epidemics in sub-Saharan Africa. More recently, endemic MenW disease has expanded in South Africa, South America and the UK, and MenC cases have been reported among European and North American men who have sex with men (MSM). Routine typing schemes poorly resolve cc11 so we established the population structure at genomic resolution. Methods Representatives of these episodes and other geo-temporally diverse cc11 meningococci (n = 750) were compared across 1546 core genes and visualised on phylogenetic networks. Results MenW isolates were confined to a distal portion of one of two main lineages with MenB and MenC isolates interspersed elsewhere. An expanding South American/UK MenW strain was distinct from the ‘Hajj outbreak’ strain and a closely related endemic South African strain. Recent MenC isolates from MSM in France and the UK were closely related but distinct. Conclusions High resolution ‘genomic’ multilocus sequence typing is necessary to resolve and monitor the spread of diverse cc11 lineages globally.

W135 meningococcal disease in England and Wales associated with Hajj 2000 and 2001.

An outbreak of W135 meningococcal disease was seen in 2000 and 2001 among pilgrims returning from Saudi Arabia and their contacts. The Public Health Laboratory Service set up enhanced surveillance to monitor spread and virulence of the outbreak strain, and to collect data on case characteristics. The number of cases reported from England and Wales in 2001 was similar to the number reported during 2000, despite a change in the recommendation for pilgrims to receive quadrivalent vaccine (against serogroup A, C, W135, and Y) instead of the A/C vaccine recommended in 2000. Both the recommendation and vaccine were not available until January, 2001, and coverage among pilgrims to the Hajj 2001 was low. The case--fatality ratio was high, and sustained transmission of the virulent outbreak strain was seen. Current control policies, both in primary and secondary prevention, might need better implementation.

A prospective study of etiology of childhood acute bacterial meningitis, Turkey.

Vaccines to prevent bacterial meningitis in this region must provide reliable protection against serogroup W-135.

An international invasive meningococcal disease outbreak due to a novel and rapidly expanding serogroup W strain, Scotland and Sweden, July to August 2015.

The 23rd World Scout Jamboree in 2015 took place in Japan and included over 33,000 scouts from 162 countries. Within nine days of the meeting ending, six cases of laboratory-confirmed invasive serogroup W meningococcal disease occurred among scouts and their close contacts in Scotland and Sweden. The isolates responsible were identical to one-another by routine typing and, where known (4 isolates), belonged to the ST-11 clonal complex (cc11) which is associated with large outbreaks and high case fatality rates. Recent studies have demonstrated the need for high-resolution genomic typing schemes to assign serogroup W cc11 isolates to several distinct strains circulating globally over the past two decades. Here we used such schemes to confirm that the Jamboree-associated cases constituted a genuine outbreak and that this was due to a novel and rapidly expanding strain descended from the strain that has recently expanded in South America and the United Kingdom. We also identify the genetic differences that define the novel strain including four point mutations and three putative recombination events involving the horizontal exchange of 17, six and two genes, respectively. Noteworthy outcomes of these changes were antigenic shifts and the disruption of a transcriptional regulator.

Added value of PCR-testing for confirmation of invasive meningococcal disease in England

OBJECTIVES In England, national guidance recommends that all patients with suspected invasive meningococcal disease (IMD) should be investigated by blood culture and polymerase chain reaction (PCR) testing. The Meningococcal Reference Unit (MRU) provides a national service for meningococcal species confirmation and PCR-testing of clinical samples. We performed a population-level assessment of the added value of PCR-testing for IMD to augment traditional culture confirmation. METHODS We analysed all PCR-samples and invasive meningococcal isolates received by MRU in 2009 and 2010. We assumed that all patients with PCR-samples submitted to MRU also had blood cultures performed and that positive blood cultures were referred to MRU. We confirmed this assertion by case ascertainment. RESULTS In total, 25,379 specimens from 22,039 patients were submitted for PCR-testing and 1492 (6.8%) tested PCR-positive. MRU received 825 invasive meningococcal isolates; 393 confirmed by PCR and culture, 405 without a PCR-specimen submitted and 27 with a PCR-negative result. Thus, of 1924 reported IMD cases, 1099 (57.1%) were confirmed by PCR only, 432 (22.5%) by culture only and 393 (20.4%) by both tests. CONCLUSION More than half of all confirmed IMD cases were confirmed by PCR only, indicating this service ensures high case ascertainment for national surveillance.

An epidemiologically valuable typing method for Neisseria meningitidis by analysis of restriction fragment length polymorphisms

A restriction fragment length polymorphism (RFLP) typing method was developed for Neisseria meningitidis. A cloned EcoRI fragment from a Neisseria meningitidis Group B serotype 15P1.16 sulphonamide-resistant strain was used to probe Southern blots of total chromosomal DNA restriction fragments (enzyme AvaI). A group of 75 apparently unrelated organisms gave rise to 26 different restriction fragment length patterns and two different groups of epidemiologically related strains had RFLP patterns that were distinct for each group. The technique was highly reproducible and discriminatory. The RFLP data were compared with the results of serotyping and subtyping and isoenzyme electrophoretotyping. The RFLP data were consistent with those from the alternative typing methods; clones defined by isoenzyme analysis were subdivided by this technique. The use of RFLP typing by cloned probes should be of considerable epidemiological value.

Four-month outbreak of invasive meningococcal disease caused by a rare serogroup B strain, identified through the use of molecular PorA subtyping, England, 2013

Molecular PorA subtyping provides information that increasingly requires the adaptation of standard public health approaches to outbreak management. We report an outbreak of a rare subtype of meningococcal infection not previously identified in the United Kingdom (UK). The outbreak occurred in the Warwickshire area in England between February and June 2013. Molecular subtyping allowed the identification of additional cases, prompting an enhanced public health response that included efforts to identify potential social networks that might benefit from chemoprophylaxis. It also prompted swabbing to define nasopharyngeal carriage in the focal nursery and helped explain the unusual epidemiological pattern. Without subtyping to identify a link, the additional cases would have been managed as sporadic cases in accordance with current UK guidance.