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

BACKGROUND: In 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. METHODS: Using 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. RESULTS: 4CMenB 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. CONCLUSIONS: The 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.).

Immunogenicity of a Meningococcal B Vaccine during a University Outbreak.

BACKROUND: In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak. METHODS: We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher. RESULTS: Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson's correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearson's correlation,-0.06; P=0.43). CONCLUSIONS: Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.).

Invasive meningococcal disease in patients with complement deficiencies: a case series (2008-2017).

BACKGROUND: To describe patients with inherited and acquired complement deficiency who developed invasive meningococcal disease (IMD) in England over the last decade. METHODS: Public 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. RESULTS: A 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. CONCLUSIONS: In 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.

Antibody responses after primary immunization in infants born to women receiving a pertussis-containing vaccine during pregnancy: single arm observational study with a historical comparator.

INTRODUCTION: In England, antenatal pertussis immunization using a tetanus/low-dose diphtheria/5-component acellular-pertussis/inactivated-polio (TdaP5/IPV) vaccine was introduced in October 2012. We assessed infant responses to antigens in the maternal vaccine and to those conjugated to tetanus (TT) or the diphtheria toxin variant, CRM. METHODS: Infants of 141 TdaP5/IPV-vaccinated mothers in Southern England immunized with DTaP5/IPV/Haemophilus influenzae b (Hib-TT) vaccine at 2-3-4 months, 13-valent pneumococcal vaccine (PCV13, CRM-conjugated) at 2-4 months and 1 or 2 meningococcal C vaccine (MCC-CRM- or MCC-TT) doses at 3-4 months had blood samples taken at 2 and/or 5 months of age. RESULTS: Antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae 2 + 3 (FIMs), diphtheria, tetanus, Hib, MCC and PCV13 serotypes were compared to responses in a historical cohort of 246 infants born to mothers not vaccinated in pregnancy. Infants had high pertussis antibody concentrations pre-immunization but only PT antibodies increased post-immunization (fold-change, 2.64; 95% confidence interval [CI], 2.12-3.30; P < .001), whereas FHA antibodies fell (fold-change, 0.56; 95% CI, .48-.65; P < .001). Compared with infants of unvaccinated mothers, PT, FHA, and FIMs antibodies were lower post-vaccination, with fold-differences of 0.67 (0.58-0.77; P < .001), 0.62 (0.54-0.71; P < .001) and 0.51 (0.42-0.62; P < .001), respectively. Antibodies to diphtheria and some CRM-conjugated antigens were also lower, although most infants achieved protective thresholds; antibodies to tetanus and Hib were higher. CONCLUSIONS: Antenatal pertussis immunization results in high infant pre-immunization antibody concentrations, but blunts subsequent responses to pertussis vaccine and some CRM-conjugated antigens. In countries with no pertussis booster until school age, continued monitoring of protection against pertussis is essential.

Population-Level Persistence of Immunity 2 Years After the PsA-TT Mass-Vaccination Campaign in Mali.

BACKGROUND: In 2010, Africa's first preventive meningococcal mass vaccination campaign was launched using a newly developed Neisseria meningitidis group A (NmA) polysaccharide-tetanus toxoid conjugate vaccine, PsA-TT (MenAfriVac), designed specifically for the meningitis belt. Given PsA-TT's recent introduction, the duration of protection against meningococcal group A is unknown. METHODS: We conducted a household-based, age-stratified seroprevalence survey in Bamako, Mali, in 2012, 2 years after the vaccination campaign targeted all 1- to 29-year-olds. Randomly selected participants who had been eligible for PsA-TT provided a blood sample and responded to a questionnaire. Sera were analyzed to assess NmA-specific serum bactericidal antibody titers using rabbit complement (rSBA) and NmA-specific immunoglobulin G (IgG) by enzyme-linked immunosorbent assay. The proportion of participants putatively protected and the age group- and sex-specific rSBA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) were determined. RESULTS: Two years postvaccination, nearly all of the 800 participants (99.0%; 95% confidence interval [CI], 98.3%-99.7%) maintained NmA-specific rSBA titers ≥8, the accepted threshold for protection; 98.6% (95% CI, 97.8%-99.4%) had titers ≥128, and 89.5% (95% CI, 87.4%-91.6%) had titers ≥1024. The rSBA GMTs were significantly higher in females than in males aged <18 years at vaccination (P < .0001). NmA-specific IgG levels ≥2 µg/mL were found in 88.5% (95% CI, 86.3%-90.7%) of participants. CONCLUSIONS: Two years after PsA-TT introduction, a very high proportion of the population targeted for vaccination maintains high antibody titers against NmA. Assessing the duration of protection provided by PsA-TT is a priority for implementing evidence-based vaccination strategies. Representative, population-based seroprevalence studies complement clinical trials and provide this key evidence.

Meningococcal Seroepidemiology 1 Year After the PsA-TT Mass Immunization Campaign in Burkina Faso.

BACKGROUND: A group A meningococcal (MenA) conjugate vaccine, PsA-TT (MenAfriVac), was introduced in Burkina Faso via mass campaigns between September and December 2010, targeting the 1- to 29-year-old population. This study describes specific antibody titers in the general population 11 months later and compares them to preintroduction data obtained during 2008 using the same protocol. METHODS: During October-November 2011, we recruited a representative sample of the population of urban Bobo-Dioulasso aged 6 months to 29 years, who underwent standardized interviews and blood draws. We assessed anti-MenA immunoglobulin G (IgG) concentrations (n = 200) and, using rabbit complement, serum bactericidal antibody (SBA) titers against 2 group A strains: reference strain F8238 (SBAref) (n = 562) and strain 3125 (SBA3125) (n = 200). RESULTS: Among the 562 participants, 481 (86%) were aged ≥23 months and had been eligible for the PsA-TT campaign. Among them, vaccine coverage was 86.3% (95% confidence interval [CI], 82.7%-89.9%). Prevalence of putatively protective antibodies among vaccine-eligible age groups was 97.3% (95% CI, 95.9%-98.7%) for SBAref titers ≥128, 83.6% (95% CI, 77.6%-89.7%) for SBA3125 ≥128, and 84.2% (95% CI, 78.7%-89.7%) for anti-MenA IgG ≥2 µg/mL. Compared to the population aged 23 months to 29 years during 2008, geometric mean titers of SBAref were 7.59-fold higher during 2011, 51.88-fold for SBA3125, and 10.56-fold for IgG. CONCLUSIONS: This study shows high seroprevalence against group A meningococci in Burkina Faso following MenAfriVac introduction. Follow-up surveys will provide evidence on the persistence of population-level immunity and the optimal vaccination strategy for long-term control of MenA meningitis in the African meningitis belt.

Phase variation mediates reductions in expression of surface proteins during persistent meningococcal carriage.

Asymptomatic and persistent colonization of the upper respiratory tract by Neisseria meningitidis occurs despite elicitation of adaptive immune responses against surface antigens. A putative mechanism for facilitating host persistence of this bacterial commensal and pathogen is alterations in expression of surface antigens by simple sequence repeat (SSR)-mediated phase variation. We investigated how often phase variation occurs during persistent carriage by analyzing the SSRs of eight loci in multiple isolates from 21 carriers representative of 1 to 6 months carriage. Alterations in repeat number were detected by a GeneScan analysis and occurred at 0.06 mutations/gene/month of carriage. The expression states were determined by Western blotting and two genes, fetA and nadA, exhibited trends toward low expression states. A critical finding from our unique examination of combinatorial expression states, "phasotypes," was for significant reductions in expression of multiple phase-variable surface proteins during persistent carriage of some strains. The immune responses in these carriers were examined by measuring variant-specific PorA IgG antibodies, capsular group Y IgG antibodies and serum bactericidal activity in concomitant serum samples. Persistent carriage was associated with high levels of specific IgG antibodies and serum bactericidal activity while recent strain acquisition correlated with a significant induction of antibodies. We conclude that phase-variable genes are driven into lower expression states during long-term persistent meningococcal carriage, in part due to continuous exposure to antibody-mediated selection, suggesting localized hypermutation has evolved to facilitate host persistence.

Design and evaluation of meningococcal vaccines through structure-based modification of host and pathogen molecules.

Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps.

Meningococcal disease in the Middle East: A report from the Global Meningococcal Initiative.

This review details recent findings from the Global Meningococcal Initiative's (GMI) recent meeting on the surveillance and control strategies for invasive meningococcal disease in the Middle East. The nature of case reporting and notification varies across the region, with many countries using bacterial meningitis as an IMD case definition in lieu of meningitis and septicaemia. This may overlook a significant burden associated with IMD leading to underreporting or misreporting of the disease. Based on these current definitions, IMD reported incidence remains low across the region, with historical outbreaks mainly occurring due to the Hajj and Umrah mass gatherings. The use of case confirmation techniques also varies in Middle Eastern countries. While typical microbiological techniques, such as culture and Gram staining, are widely used for characterisation, polymerase chain reaction (PCR) testing is utilised in a small number of countries. PCR testing may be inaccessible for several reasons including sample transportation, cost, or a lack of laboratory expertise. These barriers, not exclusive to PCR use, may impact surveillance systems more broadly. Another concern throughout the region is potentially widespread ciprofloxacin resistance since its use for chemoprophylaxis remains high in many countries.

Outcomes of meningococcal serogroup B disease in children after implementation of routine infant 4CMenB vaccination in England: an active, prospective, national surveillance study.

BACKGROUND: In 2015, the UK included 4CMenB, a multi-component, recombinant protein-based vaccine against meningococcal serogroup B (MenB) disease, in the national infant immunisation programme. We aimed to assess the effect of 4CMenB vaccination on the severity of MenB disease presentation and outcomes. METHODS: In this active, prospective, national surveillance study, we used data from the UK Health Security Agency national surveillance of meningococcal disease. We included data from follow-up of children younger than 5 years with laboratory-confirmed MenB disease who were eligible for 4CMenB vaccination with general practice 3-6 months after disease onset. All invasive MenB isolates were tested using the Meningococcal Antigen Typing System to determine whether the isolate was potentially preventable by 4CMenB. Admission to intensive care, death, and, when possible, reported sequelae in survivors were reviewed alongside vaccine status. For the epidemiological analysis, we compared laboratory-confirmed MenB disease cases before 4CMenB implementation (Sept 1, 2010, to March 31, 2015) with those after implementation (Sept 1, 2015, to March 31, 2020). For clinical follow-up and outcomes, we included all children younger than 5 years with laboratory-confirmed MenB disease between Sept 1, 2015, and March 31, 2021. FINDINGS: Between Sept 1, 2015, and March 31, 2021, there were 371 cases of MenB disease in children younger than 5 years, including 256 (69%) in those younger than 1 year and 128 (35%) in those younger than 3 months. After the introduction of 4CMenB, the peak age of patients with MenB disease shifted from 5-6 months to 1-3 months. Overall, 108 (29%) of 371 children were too young for vaccination, unvaccinated, or developed MenB disease within 14 days of the first dose. Of 110 meningococcal strains characterised, 11 (92%) of 12 were potentially preventable by 4CMenB in unvaccinated children compared with 53 (66%) of 80 in partly vaccinated and 11 (69%) of 16 in fully vaccinated children. 78 (21%) of 371 children required intensive care, and the case fatality ratio was 5% (17 of 371), with 11 of 17 deaths occurring before 1 year of age, including seven in infants who were too young (<8 weeks) for vaccination. Of 354 survivors, 57 (16%) had 74 sequelae reported; 45 (61%) of 74 were neurological, 17 (23%) were physical, two (3%) were behavioural or psychological, and ten (14%) were other complications. Prevalence of sequelae was similar in unvaccinated (15 [15%] of 98) and vaccinated (42 [16%] 256) children, as were composite outcomes of death or sequelae, and intensive care or death or sequelae. INTERPRETATION: Cases of MenB disease in vaccine-eligible children declined after 4CMenB implementation, but morbidity in vaccinated and unvaccinated children remained unchanged, highlighting the importance of vaccination to prevent MenB disease. The lower peak age of infants with MenB disease after 4CMenB implementation, with a higher case fatality ratio in young infants, highlights the importance of timely vaccination. FUNDING: UK Health Security Agency.

Epidemiological and strain characteristics of invasive meningococcal disease prior to, during and after COVID-19 pandemic restrictions in England.

OBJECTIVES: In 2020, COVID-19 pandemic restrictions led to a major suppression of meningococcal disease in England. Here we describe the epidemiology of invasive meningococcal disease in the three years prior to the COVID-19 pandemic, and the three years immediately after the introduction of restrictions. METHODS: The UK Health Security Agency conducts national meningococcal disease surveillance in England consisting of laboratory-based case confirmation with strain characterisation by culture and/or molecular detection, as well as clinical follow-up of all cases. RESULTS: In the pre-pandemic period, 554-742 IMD cases were laboratory-confirmed per year. MenB caused 57.2% of cases, followed by MenW (22.7%), MenY (10.6%) and MenC (7.7%). The introduction of restrictions in late March 2020 led to a 73% reduction in IMD. After the removal of restrictions in 2021, a resurgence in MenB was observed, primarily in teenagers and young adults. During the following winter period (2022/23), MenB disease increased to the highest level since 2012 with cases rising across multiple age groups, however, cases in young children eligible for MenB vaccination remained lower than prior to the pandemic. MenACWY cases remained very low throughout the pandemic period. CONCLUSIONS: Once pandemic restrictions in England were removed, MenB quickly rebounded- initially driven by a resurgence in teenagers/young adults, but later among other age groups. MenACWY cases remain very low due to the protection afforded by the adolescent MenACWY conjugate vaccine programme.

Impact of an adolescent meningococcal ACWY immunisation programme to control a national outbreak of group W meningococcal disease in England: a national surveillance and modelling study.

BACKGROUND: In August, 2015, the UK implemented an emergency adolescent immunisation programme with the meningococcal ACWY conjugate vaccine to combat a national outbreak of meningococcal group W (MenW) disease due to a hypervirulent ST-11 complex strain, which is currently causing regional and national outbreaks worldwide. This immunisation programme specifically targeted adolescents aged 13-18 years, an age group with low disease incidence but high nasopharyngeal carriage, with the aim of interrupting transmission and providing indirect (herd) protection across the population. Here, we report the impact of the first 4 years of the programme in England. METHODS: Public Health England conducts meningococcal disease surveillance in England. Laboratory-confirmed cases of invasive meningococcal disease during the academic years 2010-11 to 2014-15 (Sept 1 to Aug 31) were used to predict post-vaccination trends, based on the assumption that cases would plateau 1 year after vaccine implementation (conservative scenario) or that cases would continue to rise for 4 years after vaccine implementation (extreme scenario). Vaccine uptake evaluated in August, 2019, was 37-41% in adolescents aged 18 years immunised in primary care and 71-86% in younger teenagers routinely vaccinated in school. Vaccine effectiveness was estimated with the indirect screening method. FINDINGS: MenW and MenY cases plateaued within 12 months and then declined, while MenC cases remained low throughout. Significant reductions were observed among adolescents aged 14-18 years for MenW (incidence rate ratio [IRR] 0·35 [95% CI 0·17-0·76]) and MenY (0·21 [0·07-0·59]) cases, with a non-significant reduction in MenC cases (0·11 [0·01-1·01]). Based on conservative and extreme scenarios, 205-1193 MenW cases were prevented through the indirect effects of the programme and 25 through direct protection. For MenY, an estimated 60-106 cases were prevented through the indirect effects of the programme and 19 through direct protection. Ignoring any residual effect from an earlier MenC-containing vaccine, the overall vaccine effectiveness against MenCWY disease combined was 94% (95% CI 80-99). INTERPRETATION: A meningococcal immunisation programme specifically targeting adolescent carriers succeeded in rapidly controlling a national MenW outbreak, even with moderate initial vaccine uptake. FUNDING: Public Health England.

An analysis of Neisseria meningitidis strains causing meningococcal septic arthritis in England and Wales: 2010-2020.

OBJECTIVES: To analyze clinical meningococcal strains associated with meningococcal septic arthritis cases in England and Wales, and to identify associations between patient age, the synovial joint affected and strain characteristics. METHODS: IMD cases confirmed by the Meningococcal Reference Unit (UK Health Security Agency) between January 2010 and December 2020 were included in the analysis. Septic arthritis cases were defined as those featuring detection and/or isolation of N. meningitidis from an articular site. Capsular grouping was performed by serology on clinical isolates and/or real-time PCR on clinical samples. RESULTS: We identified 162 cases of meningococcal septic arthritis, representing 2% of all invasive meningococcal disease cases during the study period. The knee and the hip were the most commonly affected joints, with the former significantly more frequent in adults and the latter seen more commonly in children and adolescents. Group B strains were between 2 and 6 times less likely to cause septic arthritis in relation to groups W, C and Y strains. CONCLUSIONS: Meningococcal septic arthritis remains a rare manifestation of invasive meningococcal disease. Strain and age associations identified in this study remain unexplained. Future analyzes including clinical case information may help to explain these findings.

Invasive serogroup B meningococci in England following three years of 4CMenB vaccination - First real-world data.

OBJECTIVES: In 2015 the UK became the first country to implement the meningococcal B (MenB) vaccine, 4CMenB, into the national infant program. 4CMenB is expected to cover meningococci expressing sufficient levels of cross-reactive proteins. This study presents clonal complex, 4CMenB antigen genotyping, and 4CMenB coverage data for all English invasive MenB isolates from 2014/15 (1 year pre-vaccine) through 2017/18 and compares data from vaccinated and unvaccinated ≤3 year olds. METHODS: Vaccine coverage of all invasive MenB isolates from 2014/15 to 2017/18 (n = 784) was analysed using the Meningococcal Antigen Typing System. Genotyping utilised the Meningococcus Genome Library. RESULTS: Among ≤3 year olds, proportionally fewer cases in vaccinees (1, 2 or 3 doses) were associated with well-covered strains e.g. cc41/44 (20.5% versus 36.4%; P<0.01) and antigens e.g. PorA P1.4 (7.2% versus 17.3%; P = 0.02) or fHbp variant 1 peptides (44.6% vs 69.1%; P<0.01). Conversely, proportionally more cases in vaccinees were associated with poorly-covered strains e.g. cc213 (22.9% versus 9.6%; P<0.01) and antigens e.g. variant 2 or 3 fHbp peptides (54.2% versus 30.9%; P<0.01). CONCLUSIONS: 4CMenB reduces disease due to strains with cross-reactive antigen variants. No increase in absolute numbers of cases due to poorly covered strains was observed in the study period.

Surveillance and control of meningococcal disease in the COVID-19 era: A Global Meningococcal Initiative review.

This review article incorporates information from the 4th Global Meningococcal Initiative summit meeting. Since the introduction of stringent COVID-19 infection control and lockdown measures globally in 2020, there has been an impact on IMD prevalence, surveillance, and vaccination compliance. Incidence rates and associated mortality fell across various regions during 2020. A reduction in vaccine uptake during 2020 remains a concern globally. In addition, several Neisseria meningitidis clonal complexes, particularly CC4821 and CC11, continue to exhibit resistance to antibiotics, with resistance to ciprofloxacin or beta-lactams mainly linked to modifications of gyrA or penA alleles, respectively. Beta-lactamase acquisition was also reported through horizontal gene transfer (blaROB-1) involving other bacterial species. Despite the challenges over the past year, progress has also been made on meningococcal vaccine development, with several pentavalent (serogroups ABCWY and ACWYX) vaccines currently being studied in late-stage clinical trial programmes.

Meningococcal disease in North America: Updates from the Global Meningococcal Initiative.

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of ß-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

Antibiotic resistance among invasive Neisseria meningitidis isolates in England, Wales and Northern Ireland (2010/11 to 2018/19).

Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, can have a fatality rate as high as 10%, even with appropriate treatment. In the UK, penicillin is administered to patients in primary care whilst third generation cephalosporins, cefotaxime and ceftriaxone, are administered in secondary care. The first-choice antibiotic for chemoprophylaxis of close contacts is ciprofloxacin, followed by rifampicin. Immunocompromised individuals are often recommended antibiotic chemoprophylaxis and vaccination due to a greater risk of IMD. Resistance to antibiotics among meningococci is relatively rare, however reduced susceptibility and resistance to penicillin are increasing globally. Resistance to third generation cephalosporins is seldom reported, however reduced susceptibility to both cefotaxime and ceftriaxone has been observed. Rifampicin resistance has been reported among meningococci, mainly following prophylaxis, and ciprofloxacin resistance, whilst uncommon, has also been reported across the globe. The Public Health England Meningococcal Reference Unit receives and characterises the majority of isolates from IMD cases in England, Wales and Northern Ireland. This study assessed the distribution of antibiotic resistance to penicillin, rifampicin, ciprofloxacin and cefotaxime among IMD isolates received at the MRU from 2010/11 to 2018/19 (n = 4,122). Out of the 4,122 IMD isolates, 113 were penicillin-resistant, five were ciprofloxacin-resistant, two were rifampicin-resistant, and one was cefotaxime-resistant. Penicillin resistance was due to altered penA alleles whilst rifampicin and ciprofloxacin resistance was due to altered rpoB and gyrA alleles, respectively. Cefotaxime resistance was observed in one isolate which had an altered penA allele containing additional mutations to those harboured by the penicillin-resistant isolates. This study identified several isolates with resistance to antibiotics used for current treatment and prophylaxis of IMD and highlights the need for continued surveillance of resistance among meningococci to ensure continued effective use.

Comparative genomic analyses of Chinese serogroup W ST-11 complex Neisseria meningitidis isolates.

Although serogroup W ST-11 complex (cc11) (W:cc11) Neisseria meningitidis has been widespread in China over the past ten years, its origin and genetic relatedness has not yet been described. In this study, we described the genetic relatedness and discuss the possible origin of Chinese W:cc11 isolates by comparing their genome sequences with those of other cc11 strains globally. Comparative genomic analysis with geo-temporally diverse cc11 isolates showed that the Chinese W:cc11 isolates exclusively formed two closely related subclusters within a distinct sublineage (proposed as the Chinese-strain sublineage) of lineage 11.1 close to the interface between the Hajj-strain sublineage and the South American-strain sublineage. Several isolates from Africa and Europe were closely related to the Chinese subclusters which were largely segregated from one another among distinct provinces of China. No alleles were identified that were unique to the Chinese isolates as a whole, though each subcluster possessed unique alleles differentiating itself from the other subcluster as well as closely related isolates within the extended sublineage. Three genes differentiated the two subclusters with allele combinations that were each present among the non-Chinese isolates within the wider sublineage. These results indicate that the Chinese W:cc11 isolates formed part of a previously undescribed W:cc11 sublineage that is closely related to, but distinct from, the Hajj-strain sublineage and South American-strain sublineage. The geographical source of the Chinese subclusters was indeterminate based on available data.

Does vaccination with 4CMenB convey protection against meningococcal serogroup B strains not predicted to be covered by MATS? A study of the UK clonal complex cc269.

The Meningococcal Antigen Typing System (MATS) has been developed as an hSBA surrogate to evaluate potential coverage afforded by the 4-component meningococcal serogroup B vaccine (4CMenB: Bexsero, GSK). We investigated whether the lower value of MATS coverage among invasive Meningococcus serogroup B clonal complex 269 strains from the United Kingdom (53% in 2014-2015 versus 73% in 2007-2008) reflected the lower bactericidal activity of the vaccine against these isolates. A total of 34 MATS-negative strains (31 were cc269 or closely related) were tested against pooled sera from 32 or 72 4CMenB-vaccinated infants in a serum bactericidal antibody assay in presence of human complement (hSBA). All infants had received four 4CMenB doses in the first 2 y of life. Baseline sera comprised 180 pooled samples from healthy-unvaccinated 2-month-old infants. Twenty of the 34 (59%) MATS-negative strains were killed in hSBA with titers ≥4 by pooled sera from vaccinated infants. There were 13/34 strains with hSBA titers ≥4 and at least a 4-fold rise in titer with respect to pooled baseline sera, and 10/34 with hSBA titers ≥8 and at least a 4-fold rise in titer with respect to baseline. These data confirm MATS as a conservative estimate for predicting strain coverage by 4CMenB.

Genomic analysis of the meningococcal ST-4821 complex-Western clade, potential sexual transmission and predicted antibiotic susceptibility and vaccine coverage.

INTRODUCTION: The ST-4821 complex (cc4821) is a leading cause of serogroup C and serogroup B invasive meningococcal disease in China where diverse strains in two phylogenetic groups (groups 1 and 2) have acquired fluoroquinolone resistance. cc4821 was recently prevalent among carriage isolates in men who have sex with men in New York City (USA). Genome-level population studies have thus far been limited to Chinese isolates. The aim of the present study was to build upon these with an extended panel of international cc4821 isolates. METHODS: Genomes of isolates from Asia (1972 to 2017), Europe (2011 to 2018), North America (2007), and South America (2014) were sequenced or obtained from the PubMLST Neisseria database. Core genome comparisons were performed in PubMLST. RESULTS: Four lineages were identified. Western isolates formed a distinct, mainly serogroup B sublineage with alleles associated with fluoroquinolone susceptibility (MIC <0.03 mg/L) and reduced penicillin susceptibility (MIC 0.094 to 1 mg/L). A third of these were from anogenital sites in men who have sex with men and had unique denitrification gene alleles. Generally 4CMenB vaccine strain coverage was reliant on strain-specific NHBA peptides. DISCUSSION: The previously identified cc4821 group 2 was resolved into three separate lineages. Clustering of western isolates was surprising given the overall diversity of cc4821. Possible association of this cluster with the anogenital niche is worthy of monitoring given concerns surrounding antibiotic resistance and potential subcapsular vaccine escape.