Invasive Meningococcal Disease In England Research Articles

A re-assessment of 4CMenB vaccine effectiveness against serogroup B invasive meningococcal disease in England based on an incidence model

BackgroundThe four-component serogroup B meningococcal 4CMenB vaccine (Bexsero, GSK) has been routinely given to all infants in the United Kingdom at 2, 4 and 12 months of age since September 2015. After 3 years, Public Health England (PHE) reported a 75% [95% confidence interval 64%; 81%] reduction in the incidence of serogroup B invasive meningococcal disease (IMD) in age groups eligible to be fully vaccinated. In contrast, vaccine effectiveness (VE) evaluated in the same immunization program applying the screening method was not statistically significant. We re-analyzed the data using an incidence model.MethodsAggregate data—stratified by age, year and doses received—were provided by PHE: serogroup B IMD case counts for the entire population of England (years 2011–2018) and 4CMenB vaccine uptake in infants. We combined uptake with national population estimates to obtain counts of vaccinated and unvaccinated person-time by age and time. We re-estimated VE comparing incidence rates in vaccinated and non-vaccinated subjects using a Bayesian Poisson model for case counts with person-time data as an offset. The model was adjusted for age, time and number of doses received.ResultsThe incidence model showed that cases decreased until 2013–2014, followed by an increasing trend that continued in the non-vaccinated population during the immunization program. VE in fully vaccinated subjects (three doses) was 80.1% [95% Bayesian credible interval (BCI): 70.3%; 86.7%]. After a single dose, VE was 33.5% [12.4%; 49.7%]95%BCI and after two doses, 78.7% [71.5%; 84.5%]95%BCI. We estimated that vaccination averted 312 cases [252; 368]95%BCI between 2015 and 2018. VE was in line with the previously reported incidence reduction.ConclusionsOur estimates of VE had higher precision than previous estimates based on the screening method, which were statistically not significant, and in line with the 75% incidence reduction previously reported by PHE. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible for vaccination may not be precise enough and may produce misleading point-estimates. Precise and accurate VE estimates are fundamental to inform public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination.

Evaluating the Impact of Meningococcal Vaccines With Synthetic Controls.

Invasive meningococcal disease (IMD) has a low and unpredictable incidence, presenting challenges for real-world evaluations of meningococcal vaccines. Traditionally, meningococcal vaccine impact is evaluated by predicting counterfactuals from pre-immunization IMD incidences, possibly controlling for IMD in unvaccinated age groups, but the selection of controls can influence results. We retrospectively applied a synthetic control (SC) method, previously used for pneumococcal disease, to data from 2 programs for immunization of infants against serogroups B and C IMD in England and Brazil. Time series of infectious/noninfectious diseases in infants and IMD cases in older unvaccinated age groups were used as candidate controls, automatically combined in a SC through Bayesian variable selection. SC closely predicted IMD in absence of vaccination, adjusting for nontrivial changes in IMD incidence. Vaccine impact estimates were in line with previous assessments. IMD cases in unvaccinated age groups were the most frequent SC-selected controls. Similar results were obtained when excluding IMD from control sets and using other diseases only, particularly respiratory diseases and measles. Using non-IMD controls may be important where there are herd immunity effects. SC is a robust and flexible method that addresses uncertainty introduced when equally plausible controls exhibit different post-immunization behaviors, allowing objective comparisons of IMD programs between countries.

Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: An application to England

Invasive meningococcal disease (IMD), an uncommon but severe disease, affects mainly infants, young children and adolescents. Meningococcal B (4CMenB) and ACWY (MenACWY) vaccines targeting IMD-causing serogroups B and A, C, W and Y, respectively are available for these mostly-affected age-groups. The objective was to assess the impact of 4CMenB and/or MenACWY vaccination strategies on IMD in England, considering MenACWY carriage protection and potential cross-protection of 4CMenB against non-B serogroups.A novel dynamic transmission model was developed, accounting for vaccine characteristics, with separate variables for meningococcal carriage and IMD for three groups: B; ACWY; and ’Other‘ mostly non-pathogenic serogroups. A dynamic force of infection is assumed for each group. The model analysis uses data from England before 2015 (when 4CMenB and MenACWY were introduced), and accounts for existing MenC vaccination impact.Compared with no vaccination, the smallest decrease in IMD cases is observed for MenACWY strategies (toddler and/or adolescent). 4CMenB (infant or infant/adolescent), alone or with MenACWY, always results in the most rapid and steep decline in IMD cases. Combined strategies with adolescent 4CMenB result in the largest decrease in IMD cases, whereas adding MenACWY for toddlers has a minor impact. With potential 4CMenB cross-protection, 4CMenB infant strategy has a notable impact on reduction of MenW and MenY IMD cases in strategies where MenACWY toddler and/or adolescent vaccination is absent.This novel model allows for analysis of combined 4CMenB and MenACWY strategies including potential 4CMenB cross-protection. In settings comparable to England, a comprehensive meningococcal vaccination programme should include infant 4CMenB as essential building block. Decisions to include MenACWY toddler programmes should consider herd effects of MenACWY adolescent programmes and 4CMenB potential cross-protection effects. Extending 4CMenB infant and MenACWY adolescent programmes with a 4CMenB adolescent programme allows for the largest overall reduction in IMD cases.

Vaccination of Infants with Meningococcal Group B Vaccine (4CMenB) in England

BackgroundIn September 2015, the United Kingdom introduced the multicomponent meningococcal group B vaccine (4CMenB, Bexsero) into its publicly funded national immunization program at a reduced two-dose priming schedule for infants, with a 12-month booster.MethodsUsing data from enhanced national surveillance of invasive meningococcal disease in England, we evaluated the effect of vaccination on the incidence of meningococcal group B disease during the first 3 years of the program. The effect of vaccination was assessed by comparing the observed incidence of disease with the expected incidence based on the incidence during the 4-year prevaccination period in equivalent cohorts and with the use of disease trends in cohorts of children younger than 5 years of age who were not eligible to receive the vaccine. Vaccine effectiveness was estimated with the use of the indirect screening method.Results4CMenB uptake in England remained consistently high; data from the first 3 months of 2018 showed that 92.5% of children had completed the primary immunizations by their first birthday and 87.9% had received all three doses by 2 years. From September 2015 through August 2018, the incidence of meningococcal group B disease in England (average annual birth cohort, approximately 650,000 infants) was significantly lower in vaccine-eligible cohorts than the expected incidence (63 observed cases as compared with 253 expected cases; incidence rate ratio, 0.25; 95% confidence interval [CI], 0.19 to 0.36), with a 75% reduction in age groups that were fully eligible for vaccination. The adjusted vaccine effectiveness against meningococcal group B disease was 52.7% (95% CI, −33.5 to 83.2) with a two-dose priming schedule for infants and 59.1% (95% CI, −31.1 to 87.2) with a two-dose priming schedule plus a booster at 1 year). Over the 3-year period, there were 169 cases of meningococcal group B disease in the vaccine-eligible cohorts, and an estimated 277 cases (95% CI, 236 to 323) were prevented.ConclusionsThe 4CMenB program was associated with continued positive effect against meningococcal group B disease in children in England, and protection after three doses of the vaccine was sustained for at least 2 years. (Funded by Public Health England.)

Variable clinical presentation by the main capsular groups causing invasive meningococcal disease in England

Invasive meningococcal disease (IMD) typically presents as meningitis, septicaemia or both. Atypical clinical presentations are rare but well-described. We aimed to assess the relationship between meningococcal capsular group, age, clinical presentation, diagnosis and outcome among IMD cases diagnosed in England during 2014. Public Health England conducts enhanced national surveillance of IMD in England. Clinical data for laboratory-confirmed MenB, MenW and MenY cases in ≥5 year-olds were used to classify presenting symptoms, diagnosis and outcomes. Multivariable logistic regression was used to assess independent associations between meningococcal capsular group, clinical presentation, gender, age and death. In 2014, there were 340 laboratory-confirmed IMD cases caused by MenB (n = 179), MenW (n = 95) and MenY (n = 66). Clinical presentation with meningitis alone was more prevalent among MenB cases (28%) and among 15-24 year-olds (20%), whilst bacteraemic pneumonia was most prevalent among MenY cases (26%) and among ≥65 year-olds (24%). Gastrointestinal symptoms were recorded preceding or during presentation in 15% (40/269) cases with available information, including 5% (7/140) MenB, 17% (8/47) MenY and 30% (25/82) MenW cases. Upper respiratory tract symptoms were reported in 16% (22/141) MenB, 23% (11/47) MenY and 31% (26/84) MenW cases. Increasing age was also independently associated with bacteraemic meningococcal pneumonia, with no cases among 5-14 year-olds compared to 24% in ≥65 year-olds. Case fatality rates increased with age but no significant associations with death were identified. Healthcare professionals should be aware of the atypical clinical presentations associated with the less prevalent meningococcal capsular groups in different age-groups.

Invasive meningococcal disease in patients with complement deficiencies: a case series (2008\u20132017)

BackgroundTo describe patients with inherited and acquired complement deficiency who developed invasive meningococcal disease (IMD) in England over the last decade.MethodsPublic Health England conducts enhanced surveillance of IMD in England. We retrospectively identified patients with complement deficiency who developed IMD in England during 2008–2017 and retrieved information on their clinical presentation, vaccination status, medication history, recurrence of infection and outcomes, as well as characteristics of the infecting meningococcal strain.ResultsA total of 16 patients with 20 IMD episodes were identified, including four with two episodes. Six patients had inherited complement deficiencies, two had immune-mediated conditions associated with complement deficiency (glomerulonephritis and vasculitis), and eight others were on Eculizumab therapy, five for paroxysmal nocturnal haemoglobinuria and three for atypical haemolytic uraemic syndrome. Cultures were available for 7 of 11 episodes among those with inherited complement deficiencies/immune-mediated conditions and the predominant capsular group was Y (7/11), followed by B (3/11) and non-groupable (1/11) strains. Among patients receiving Eculizumab therapy, 3 of the 9 episodes were due to group B (3/9), three others were NG but genotypically group B, and one case each of groups E, W and Y.ConclusionsIn England, complement deficiency is rare among IMD cases and includes inherited disorders of the late complement pathway, immune-mediated disorders associated with low complement levels and patients on Eculizumab therapy. IMD due to capsular group Y predominates in patient with inherited complement deficiency, whilst those on Eculizumab therapy develop IMD due to more diverse capsular groups including non-encapsulated strains.

Lower risk of invasive meningococcal disease during pregnancy: national prospective surveillance in England, 2011-2014.

To describe cases of invasive meningococcal disease (IMD) in women of childbearing age and to estimate the disease incidence and relative risk of IMD in pregnant compared with non-pregnant women. Prospective enhanced national surveillance for IMD. England. Women of reproductive age (15-44years) with laboratory-confirmed IMD. Public Health England conducts enhanced national surveillance for IMD in England. Laboratory-confirmed cases are followed up with postal questionnaires to general practitioners. All cases confirmed in women of reproductive age from 1 January 2011 to 31 December 2014 were included. Annual IMD incidence and relative risk of IMD in pregnant compared with non-pregnant women of reproductive age. During the 4-year surveillance period, there were 1502 cases of IMD in females across England; of these, 310 (20.6%) cases were in women of reproductive age, including four women who were pregnant at the time of IMD confirmation (1.3%). Serogroup distribution of IMD cases in women of childbearing age was similar to the overall distribution. The four cases in otherwise healthy pregnant women were confirmed across all trimesters and all survived; one case in the first trimester had a septic miscarriage. The incidence of IMD was lower in pregnant than in non-pregnant women (0.16 compared with 0.76 per 100000 pregnant and non-pregnant years, respectively), giving a lower risk of IMD in pregnant women (incidence rate ratio, IRR, 0.21; 95% confidence interval, 0.06-0.54). Pregnant women are nearly five times less likely to develop IMD compared with non-pregnant women, but the infection can be severe. The risk of meningococcal disease is lower in pregnant women compared with non-pregnant women; the infection can occur across all trimesters and can be severe.

The epidemiology and management of clusters of invasive meningococcal disease in England, 2010–15

Guidance for public health management of invasive meningococcal disease (IMD) in in England recommends the use of antibiotic chemoprophylaxis and vaccination. We summarized clinical and epidemiological data collected during routine management of IMD clusters in England. Data on epidemiology and operational decisions for public health management were reviewed for clusters between April 2010 and December 2015. Clusters were generally 2-3 cases (53/58; 91%) within a single age band <18-years. Nurseries (n = 20, 34%), households/social networks (n = 14, 24%) and schools (n = 10, 17%) were the commonest settings. Chemoprophylaxis alone was used in 36 (58%) clusters, including most serogroup B clusters (31/41; 76%). Chemoprophylaxis and vaccination was used in a further 20 (32%) clusters. Vaccine was delivered promptly (<7 days). Four clusters had cases with onset post-chemoprophylaxis; no clusters recorded cases with onset post-vaccination. No pattern was observed between interventions and setting/population at risk, and interventions were consistent with national guidance. Challenges to management included logistical issues related to intervention delivery. Public health management of IMD clusters presents challenges in decision-making and implementation of interventions. Nonetheless, few cases were observed following intervention. Responses were consistent with national guidance. A systematic data collection tool should be developed to support future evaluation.

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.

Clinical diagnoses and outcomes of 4619 hospitalised cases of laboratory-confirmed invasive meningococcal disease in England: Linkage analysis of multiple national databases

Invasive meningococcal disease (IMD) is rare but remains one of the most feared infectious diseases worldwide. We linked multiple national datasets to describe disease characteristics and outcomes of IMD in England over a five-year period. IMD cases confirmed by Public Health England (2007-11) were linked with national hospitalisation records and death registrations. Cases were analysed by age, gender, capsular group, clinical presentation, diagnostic test and outcome. Risk factors for death were assessed using multivariable logistic regression. Overall, 4619 of 5115 (90.30%) laboratory-confirmed IMD cases were successfully linked to a hospitalisation record. Group B meningococci were responsible for 87.33% (n=4034) of hospitalised IMD cases, ranging from 93.56% (2294/2452) in <15 year-oldto 53.52% (152/284) among ≥65 year-old. Most cases presented with meningitis only (n=2057, 44.53%), septicaemia only (n=1725, 37.35%) or both meningitis and septicaemia (n=389, 8.42%). Over half the cases (2526/4619, 54.69%) were confirmed by PCR only, 22.91% (1058/4619) by culture only and 22.41% (1035/4619) by both. The case fatality rate was 4.46% (206/4619; 95% CI, 3.88-5.10%) and varied by age, clinical presentation and capsular group. Children under 15 years who died within 30 days of diagnosis were significantly more likely to have been diagnosed by culture than by PCR alone (OR, 1.56; 95% CI, 1.02-2.39; P=0.040). We identified complex interactions between age, meningococcal capsular group, clinical presentation, diagnostic method and death. The recent introduction of two new meningococcal immunisation programmes in the UK should significantly reduce IMD cases and deaths in the coming years.

Invasive meningococcal disease in England: assessing disease burden through linkage of multiple national data sources.

BackgroundIn England, Public Health England conducts enhanced surveillance of invasive meningococcal disease (IMD). The continuing decline in reported IMD cases has raised concerns that the MRU may be underestimating true IMD incidence.MethodsWe linked five national datasets to estimate disease burden over five years, including PHE Meningococcal Reference Unit (MRU) confirmations, hospital episode statistics (HES), electronic reports of significant infections by National Health Service (NHS) Hospitals, death registrations and private laboratory reports.ResultsDuring 2007–11, MRU confirmed 5115 IMD cases and 4275 (84 %) matched to HES, including 3935 (92 %) with A39* (meningococcal disease) and 340 (8 %) with G00* (bacterial meningo-encephalitis) ICD-10 codes. An additional 2792 hospitalised cases with an A39* code were identified in HES. Of these, 1465 (52 %) matched to one of 53,806 samples tested PCR-negative for IMD by MRU and only 73 of the remaining 1327 hospitalised A39* cases were confirmed locally or by a private laboratory. The characteristics of hospitalised cases without laboratory confirmation were similar to PCR-negative than PCR-positive IMD cases.ConclusionsInterrogation of multiple national data sources identified very few laboratory confirmations in addition to the MRU-confirmed cases. The large number of unconfirmed and PCR-negative cases in HES suggests increased awareness among clinicians with low thresholds for hospitalising patients with suspected IMD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1247-7) contains supplementary material, which is available to authorized users.

Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.

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. 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. 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. 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.

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

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. 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. 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. More than half of all confirmed IMD cases were confirmed by PCR only, indicating this service ensures high case ascertainment for national surveillance.

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 5months of age then gradually declined. An annual average of 245 MenB cases occurred in infants (135 in those aged ≤6months) representing 26% (and 14%) of all MenB cases, respectively. After infancy, MenB rates declined until the age of 12years, rising to a second smaller peak at 18years. MenB case fatality ratio (CFR) was 5.2% (247/4777 cases) overall and was highest among ≥65year-olds (28/161; 17.4%). The largest number of deaths (n=125), however, occurred among <5year-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.