Publications by authors named "Martin C J Maiden"

250 Publications

Factor H binding protein (fHbp)-mediated differential complement resistance of a serogroup C isolate from cerebrospinal fluid of a patient with invasive meningococcal disease.

Access Microbiol 2021 9;3(9):000255. Epub 2021 Sep 9.

Division of Bacteriology, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK.

During an outbreak of invasive meningococcal disease (IMD) at the University of Southampton, UK, in 1997, two serogroup C isolates were retrieved from a student ('Case'), who died of IMD, and a close contact ('Carrier') who, after mouth-to-mouth resuscitation on the deceased, did not contract the disease. Genomic comparison of the isolates demonstrated extensive nucleotide sequence identity, with differences identified in eight genes. Here, comparative proteomics was used to measure differential protein expression between the isolates and investigate whether the differences contributed to the clinical outcomes. A total of six proteins were differentially expressed: four proteins (methylcitrate synthase, PrpC; hypothetical integral membrane protein, Imp; fructose-1,6-bisphosphate aldolase, Fba; aldehyde dehydrogenase A, AldA) were upregulated in the Case isolate, while one protein (Type IV pilus-associated protein, PilC2) was downregulated. Peptides for factor H binding protein (fHbp), a major virulence factor and antigenic protein, were only detected in the Case, with a single base deletion (ΔT366) in the Carrier fHbp causing lack of its expression. Expression of fHbp resulted in an increased resistance of the Case isolate to complement-mediated killing in serum. Complementation of fHbp expression in the Carrier increased its serum resistance by approximately 8-fold. Moreover, a higher serum bactericidal antibody titre was seen for the Case isolate when using sera from mice immunized with Bexsero (GlaxoSmithKline), a vaccine containing fHbp as an antigenic component. This study highlights the role of fHbp in the differential complement resistance of the Case and the Carrier isolates. Expression of fHbp in the Case resulted in its increased survival in serum, possibly leading to active proliferation of the bacteria in blood and death of the student through IMD. Moreover, enhanced killing of the Case isolate by sera raised against an fHbp-containing vaccine, Bexsero, underlines the role and importance of fHbp in infection and immunity.
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http://dx.doi.org/10.1099/acmi.0.000255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549389PMC
September 2021

Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis.

PLoS Pathog 2021 10 18;17(10):e1009992. Epub 2021 Oct 18.

Department of Zoology, University of Oxford, Oxford, United Kingdom.

Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract that is nevertheless a leading cause of meningitis and sepsis. An initial GWAS discovered bacterial genetic variants, including single nucleotide polymorphisms (SNPs), associated with invasive meningococcal disease (IMD) versus carriage in several loci across the meningococcal genome, encoding antigens and other extracellular components, confirming the polygenic nature of the invasive phenotype. In particular, there was a significant peak of association around the fHbp locus, encoding factor H binding protein (fHbp), which promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. The association around fHbp with IMD was confirmed by a validation GWAS, and we found that the SNPs identified in the validation affected the 5' region of fHbp mRNA, altering secondary RNA structures, thereby increasing fHbp expression and enhancing bacterial escape from complement-mediated killing. This finding is consistent with the known link between complement deficiencies and CFH variation with human susceptibility to IMD. These observations demonstrate the importance of human and bacterial genetic variation across the fHbp:CFH interface in determining IMD susceptibility, the transition from carriage to disease.
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http://dx.doi.org/10.1371/journal.ppat.1009992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553145PMC
October 2021

'B Part of It' School Leaver study: a repeat cross-sectional study to assess the impact of increasing coverage with meningococcal B (4CMenB) vaccine on carriage of Neisseria meningitidis.

J Infect Dis 2021 Sep 6. Epub 2021 Sep 6.

Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia.

Background: Recombinant protein-based vaccines targeting serogroup B meningococci protect against invasive disease, but impacts on carriage are uncertain. This study assessed carriage prevalence of disease-associated meningococci from 2018-2020, as the proportion of vaccinated adolescents increased following introduction of a school-based 4CMenB immunisation program.

Methods: Eligible participants who completed high school (age 17-25) in South Australia in the previous year had an oropharyngeal swab taken and completed a risk factor questionnaire. Disease-associated meningococci (genogroups A, B, C, W, X, Y) were detected by meningococcal and genogroup-specific polymerase chain reaction.

Results: The final analysis included 4104 participants in 2018, 2690 in 2019, and 1338 in 2020. The proportion vaccinated with 4CMenB increased from 43% in 2018, to 78% in 2019, and 76% in 2020. Carriage prevalence of disease-associated meningococci in 2018 was 225/4104 (5.5%). There was little difference between the carriage prevalence in 2019 (134/2690, 5.0%, adjusted odds ratio [aOR] 0.82, 95% CI 0.64-1.05) and 2020 (68/1338, 5.1% aOR 0.82, 95% CI 0.57-1.17) compared to 2018.

Conclusions: Increased 4CMenB uptake in adolescents was not associated with a decline in carriage of disease-associated meningococci. 4CMenB immunisation programs should focus on direct (individual) protection for groups at greatest risk of disease.
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http://dx.doi.org/10.1093/infdis/jiab444DOI Listing
September 2021

An evaluation of the species and subspecies of the genus Salmonella with whole genome sequence data: Proposal of type strains and epithets for novel S. enterica subspecies VII, VIII, IX, X and XI.

Genomics 2021 Sep 7;113(5):3152-3162. Epub 2021 Jul 7.

Public Health England, Gastrointestinal Bacteria Reference Unit, 61 Colindale Avenue, London NW9 5EQ, United Kingdom. Electronic address:

Species and subspecies within the Salmonella genus have been defined for public health purposes by biochemical properties; however, reference laboratories have increasingly adopted sequence-based, and especially whole genome sequence (WGS), methods for surveillance and routine identification. This leads to potential disparities in subspecies definitions, routine typing, and the ability to detect novel subspecies. A large-scale analysis of WGS data from the routine sequencing of clinical isolates was employed to define and characterise Salmonella subspecies population structure, demonstrating that the Salmonella species and subspecies were genetically distinct, including those previously identified through phylogenetic approaches, namely: S. enterica subspecies londinensis (VII), subspecies brasiliensis (VIII), subspecies hibernicus (IX) and subspecies essexiensis (X). The analysis also identified an additional novel subspecies, reptilium (XI). Further, these analyses indicated that S. enterica subspecies arizonae (IIIa) isolates were divergent from the other S. enterica subspecies, which clustered together and, on the basis of ANI analysis, subspecies IIIa was sufficiently distinct to be classified as a separate species, S. arizonae. Multiple phylogenetic and statistical approaches generated congruent results, suggesting that the proposed species and subspecies structure was sufficiently biologically robust for routine application. Biochemical analyses demonstrated that not all subspecies were distinguishable by these means and that biochemical approaches did not capture the genomic diversity of the genus. We recommend the adoption of standardised genomic definitions of species and subspecies and a genome sequence-based approach to routine typing for the identification and definition of novel subspecies.
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http://dx.doi.org/10.1016/j.ygeno.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426187PMC
September 2021

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.

Lancet Digit Health 2021 06;3(6):e360-e370

Irish Meningitis and Sepsis Reference Laboratory, Children's Health Ireland at Temple Street, Dublin, Ireland; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Background: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic.

Methods: In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed.

Findings: 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded.

Interpretation: The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide.

Funding: Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).
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http://dx.doi.org/10.1016/S2589-7500(21)00077-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166576PMC
June 2021

Genomic epidemiology of group B streptococci spanning 10 years in an Irish maternity hospital, 2008-2017.

J Infect 2021 07 20;83(1):37-45. Epub 2021 Apr 20.

Irish Meningitis and Sepsis Reference Laboratory, Children's Health Ireland at Temple Street, Dublin, Ireland; Clinical Innovation Unit, Rotunda Hospital, Dublin, Ireland; Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland.

Objectives: The genomic epidemiology of group b streptococcal (GBS) isolates from the Rotunda maternity hospital, Dublin, 2008-2017, was investigated.

Methods: Whole genome sequences of isolates (invasive, n = 114; non-invasive, n = 76) from infants and women were analysed using the PubMLST database (https://pubmlst.org/sagalactiae/).

Results: Serotypes III (36%), Ia (18%), V (17%), II (11%) and Ib, (9%) and sequence types (ST) 17 (23%), ST-23 (14%), ST-1 (12%) and ST-19 (7%) were most common. Core genome MLST (cgMLST) differentiated isolates of the same ST, grouped STs into five lineages congruent with known clonal complexes and identified known mother-baby pairs and suspected linked infant cases. Clonal complex (CC) 17 accounted for 40% and 22% of infant and maternal invasive cases, respectively and 21% of non-invasive isolates. CC23 and CC19 were associated with maternal disease (30%) and carriage (24%), respectively. Erythromycin (26%) and clindamycin (18%) resistance increased over the study period and was associated with presence of the erm(B) gene (55%), CC1 (33%) and CC19 (24%). A multi-resistant integrative conjugative element incorporated in the PI-1 locus was detected in CC17, an ST-12 and ST-23 isolate confirming the global dissemination of this element. All isolates possessed one or more pilus islands. Genes encoding other potential protective proteins including Sip, C5a peptidase and Srr1 were present in 100%, 99.5% and 65.8% of isolates, respectively. The srr2 gene was unique to CC17.

Conclusions: The PubMLST.org website provides a valuable framework for genomic GBS surveillance to inform on local and global GBS epidemiology, preventive and control measures.
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http://dx.doi.org/10.1016/j.jinf.2021.04.003DOI Listing
July 2021

Emergence and evolution of antimicrobial resistance genes and mutations in Neisseria gonorrhoeae.

Genome Med 2021 03 30;13(1):51. Epub 2021 Mar 30.

Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.

Background: Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; however, the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown.

Methods: We studied the evolution of penA alleles by obtaining the complete genomes from three Japanese ST-1901 clinical isolates harboring mosaic penA allele 34 (penA-34) dating from 2005 and generating a phylogenetic representation of 1075 strains sampled from 35 countries. We also sequenced the genomes of 103 Japanese ST-7363 N. gonorrhoeae isolates from 1996 to 2005 and reconstructed a phylogeny including 88 previously sequenced genomes.

Results: Based on an estimate of the time-of-emergence of ST-1901 (harboring mosaic penA-34) and ST-7363 (harboring mosaic penA-10), and > 300 additional genome sequences of Japanese strains representing multiple STs isolated in 1996-2015, we suggest that penA-34 in ST-1901 was generated from penA-10 via recombination with another Neisseria species, followed by recombination with a gonococcal strain harboring wildtype penA-1. Following the acquisition of penA-10 in ST-7363, a dominant sub-lineage rapidly acquired fluoroquinolone resistance mutations at GyrA 95 and ParC 87-88, by independent mutations rather than horizontal gene transfer. Data in the literature suggest that the emergence of these resistance determinants may reflect selection from the standard treatment regimens in Japan at that time.

Conclusions: Our findings highlight how antibiotic use and recombination across and within Neisseria species intersect in driving the emergence and spread of drug-resistant gonorrhea.
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http://dx.doi.org/10.1186/s13073-021-00860-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008663PMC
March 2021

Evolution of Sequence Type 4821 Clonal Complex Hyperinvasive and Quinolone-Resistant Meningococci.

Emerg Infect Dis 2021 04;27(4):1110-1122

Expansion of quinolone-resistant Neisseria meningitidis clone China from sequence type (ST) 4821 clonal complex (CC4821) caused a serogroup shift from serogroup A to serogroup C invasive meningococcal disease (IMD) in China. To determine the relationship among globally distributed CC4821 meningococci, we analyzed whole-genome sequence data from 173 CC4821 meningococci isolated from 4 continents during 1972-2019. These meningococci clustered into 4 sublineages (1-4); sublineage 1 primarily comprised of IMD isolates (41/50, 82%). Most isolates from outside China (40/49, 81.6%) formed a distinct sublineage, the Europe-USA cluster, with the typical strain designation B:P1.17-6,23:F3-36:ST-3200(CC4821), harboring mutations in penicillin-binding protein 2. These data show that the quinolone-resistant clone China has expanded to other countries. The increasing distribution worldwide of serogroup B CC4821 raises the concern that CC4821 has the potential to cause a pandemic that would be challenging to control, despite indirect evidence that the Trumenba vaccine might afford some protection.
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http://dx.doi.org/10.3201/eid2704.203612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007298PMC
April 2021

Molecular diagnostic assays for the detection of common bacterial meningitis pathogens: A narrative review.

EBioMedicine 2021 Mar 12;65:103274. Epub 2021 Mar 12.

Department of Zoology, University of Oxford, South Parks Rd, Oxford OX1 3SY, United Kingdom. Electronic address:

Bacterial meningitis is a major global cause of morbidity and mortality. Rapid identification of the aetiological agent of meningitis is essential for clinical and public health management and disease prevention given the wide range of pathogens that cause the clinical syndrome and the availability of vaccines that protect against some, but not all, of these. Since microbiological culture is complex, slow, and often impacted by prior antimicrobial treatment of the patient, molecular diagnostic assays have been developed for bacterial detection. Distinguishing between meningitis caused by Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and Streptococcus agalactiae and identifying their polysaccharide capsules is especially important. Here, we review methods used in the identification of these bacteria, providing an up-to-date account of available assays, allowing clinicians and diagnostic laboratories to make informed decisions about which assays to use.
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http://dx.doi.org/10.1016/j.ebiom.2021.103274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957090PMC
March 2021

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

Lancet Infect Dis 2021 05 19;21(5):677-687. Epub 2021 Jan 19.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.

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.
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http://dx.doi.org/10.1016/S1473-3099(20)30842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064914PMC
May 2021

A Mathematical Modeling Approach to Uncover Factors Influencing the Spread of in a Flock of Broiler-Breeder Chickens.

Front Microbiol 2020 28;11:576646. Epub 2020 Oct 28.

Mathematical Ecology Research Group, Department of Zoology, University of Oxford, Oxford, United Kingdom.

Despite continued efforts to improve biosecurity protocols, continues to be detected in the majority of commercial chicken flocks across Europe. Using an extensive data set of prevalence within a chicken breeder flock for over a year, multiple Bayesian models are presented to explore the dynamics of the spread of in response to seasonal variation, species-specificity, bird health, and total colonization prevalence. These models indicated that birds within the flock varied greatly in their response to bacterial challenge, and that this phenomenon had a large impact on the overall prevalence of different species of . appeared more frequently in the summer, while persisted for a longer duration, amplified by the most susceptible birds in the flock. Our study suggests that strains of that appear most frequently likely possess no demographic advantage, but are instead amplified due to the health of the birds that ingest it.
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http://dx.doi.org/10.3389/fmicb.2020.576646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655537PMC
October 2020

'Be on the TEAM' Study (Teenagers Against Meningitis): protocol for a controlled clinical trial evaluating the impact of 4CMenB or MenB-fHbp vaccination on the pharyngeal carriage of meningococci in adolescents.

BMJ Open 2020 10 22;10(10):e037358. Epub 2020 Oct 22.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Introduction: Capsular group B (MenB) is the most common cause of invasive meningococcal disease (IMD) in many parts of the world. A MenB vaccine directed against the polysaccharide capsule remains elusive due to poor immunogenicity and safety concerns. The vaccines licensed for the prevention of MenB disease, 4CMenB (Bexsero) and MenB-fHbp (Trumenba), are serogroup B 'substitute' vaccines, comprised of subcapsular proteins and are designed to provide protection against most MenB disease-causing strains. In many high-income countries, such as the UK, adolescents are at increased risk of IMD and have the highest rates of meningococcal carriage. Beginning in the late 1990s, immunisation of this age group with the meningococcal group C conjugate vaccine reduced asymptomatic carriage and disrupted transmission of this organism, resulting in lower group C IMD incidence across all age groups. Whether vaccinating teenagers with the novel 'MenB' protein-based vaccines will prevent acquisition or reduce duration of carriage and generate herd protection was unknown at the time of vaccine introduction and could not be inferred from the effects of the conjugate vaccines. 4CMenB and MenB-fHbp may also impact on non-MenB disease-causing capsular groups as well as commensal spp. This study will evaluate the impact of vaccination with 4CMenB or MenB-fHbp on oropharyngeal carriage of pathogenic meningococci in teenagers, and consequently the potential for these vaccines to provide broad community protection against MenB disease.

Methods And Analysis: The 'Be on the TEAM' (Teenagers Against Meningitis) Study is a pragmatic, partially randomised controlled trial of 24 000 students aged 16-19 years in their penultimate year of secondary school across the UK with regional allocation to a 0+6 month schedule of 4CMenB or MenB-fHbp or to a control group. Culture-confirmed oropharyngeal carriage will be assessed at baseline and at 12 months, following which the control group will be eligible for 4CMenB vaccination. The primary outcome is the carriage prevalence of potentially pathogenic meningococci (defined as those with genogroups B, C, W, Y or X), in each vaccine group compared separately to the control group at 12 months post-enrolment, that is, 12 months after the first vaccine dose and 6 months after the second vaccine dose. Secondary outcomes include impact on carriage of: genogroup B meningococci; hyperinvasive meningococci; all meningococci; those meningococci expressing vaccine antigens and; other spp. A sample size of 8000 in each arm will provide 80% power to detect a 30% reduction in meningococcal carriage, assuming genogroup B, C, W, Y or X meningococci carriage of 3.43%, a design effect of 1.5, a retention rate of 80% and a significance level of 0.05. Study results will be available in 2021 and will inform the UK and international immunisation policy and future vaccine development.

Ethics And Dissemination: This study is approved by the National Health Service South Central Research Ethics Committee (18/SC/0055); the UK Health Research Authority (IRAS ID 239091) and the UK Medicines and Healthcare products Regulatory Agency. Publications arising from this study will be submitted to peer-reviewed journals. Study results will be disseminated in public forums, online, presented at local and international conferences and made available to the participating schools.

Trial Registration Numbers: ISRCTN75858406; Pre-results, EudraCT 2017-004609-42.
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http://dx.doi.org/10.1136/bmjopen-2020-037358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583083PMC
October 2020

Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) Index: a Rapid and Accessible Tool That Exploits Genomic Data in Public Health and Clinical Microbiology Applications.

J Clin Microbiol 2020 12 17;59(1). Epub 2020 Dec 17.

Department of Zoology, University of Oxford, Oxford, United Kingdom

As microbial genomics makes increasingly important contributions to clinical and public health microbiology, the interpretation of whole-genome sequence data by nonspecialists becomes essential. In the absence of capsule-based vaccines, two protein-based vaccines have been used for the prevention of invasive serogroup B meningococcal disease (IMD) since their licensure in 2013 and 2014. These vaccines have different components and different levels of coverage of meningococcal variants. Hence, decisions regarding which vaccine to use in managing serogroup B IMD outbreaks require information about the index case isolate, including (i) the presence of particular vaccine antigen variants, (ii) the expression of vaccine antigens, and (iii) the likely susceptibility of its antigen variants to antibody-dependent bactericidal killing. To obtain this information requires a multitude of laboratory assays, impractical in real-time clinical settings, where the information is most urgently needed. To facilitate assessment for public health and clinical purposes, we synthesized genomic and experimental data from published sources to develop and implement the Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) Index, which is publicly available on PubMLST (https://pubmlst.org). Using whole-genome sequences or individual gene sequences obtained from IMD isolates or clinical specimens, the MenDeVAR Index provides rapid evidence-based information on the presence and possible immunological cross-reactivity of different meningococcal vaccine antigen variants. The MenDeVAR Index enables practitioners who are not genomics specialists to assess the likely reactivity of vaccines for individual cases, outbreak management, or the assessment of public health vaccine programs. The MenDeVAR Index has been developed in consultation with, but independently of, both the 4CMenB (Bexsero; GSK) and rLP2086 (Trumenba; Pfizer, Inc.) vaccine manufacturers.
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http://dx.doi.org/10.1128/JCM.02161-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771438PMC
December 2020

Impact of a Meningococcal Protein-based Serogroup B Vaccine on Serogroup W Invasive Disease in Children.

Clin Infect Dis 2021 10;73(7):e1669-e1672

Department of Zoology, University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1093/cid/ciaa1253DOI Listing
October 2021

The global meningitis genome partnership.

J Infect 2020 10 29;81(4):510-520. Epub 2020 Jun 29.

Meningitis Research Foundation, Newminster House, 27-29 Newminster House, Baldwin Street, Bristol BS1 1LT, UK.

Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1935), Sa (9026); The Wellcome Sanger Institute: Nm (13,711), Sp (> 24,000), Sa (6200), Hi (1738); and BMGAP: Nm (8785), Hi (2030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data.
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http://dx.doi.org/10.1016/j.jinf.2020.06.064DOI Listing
October 2020

Microevolution of Campylobacter jejuni during long-term infection in an immunocompromised host.

Sci Rep 2020 06 22;10(1):10109. Epub 2020 Jun 22.

Gastrointestinal Bacteria Reference Unit, Public Health England, Colindale, London, UK.

Campylobacteriosis typically manifests as a short-lived, self-limiting gastrointestinal infection in humans, however prolonged infection can be seen in cases with underlying immunodeficiency. Public Health England received 25 isolates of Campylobacter jejuni from an individual with combined variable immunodeficiency over a period of 15 years. All isolates were typed and archived at the time of receipt. Whole genome sequencing (WGS) and antimicrobial susceptibility testing were performed to examine the relatedness of the isolates and to investigate the changes in the genome that had taken place over the course of the infection. Genomic typing methods were compared to conventional phenotypic methods, and revealed that the infection was caused by a single, persistent strain of C. jejuni belonging to clonal complex ST-45, with evidence of adaptation and selection in the genome over the course of the infection. Genomic analysis of sequence variants associated with antimicrobial resistance identified the genetic background behind rRNA gene mutations causing variable levels of resistance to erythromycin. This application of WGS to examine a persistent case of campylobacteriosis provides insight into the mutations and selective pressures occurring over the course of an infection, some of which have important clinical relevance.
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http://dx.doi.org/10.1038/s41598-020-66771-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308304PMC
June 2020

Pan-GWAS of Streptococcus agalactiae Highlights Lineage-Specific Genes Associated with Virulence and Niche Adaptation.

mBio 2020 06 9;11(3). Epub 2020 Jun 9.

NIHR Mucosal Pathogens Research Unit, Division of Infection and Immunity, University College London, London, United Kingdom.

(group B streptococcus; GBS) is a colonizer of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterized by clonal complexes (CCs) with different invasive potentials. CC17, for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with comorbidities. The genetic basis of GBS virulence and the extent to which different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome-wide association study (GWAS) approach to 1,988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism, and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23, for example, we have identified genes encoding pilus, quorum-sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence. GBS is a leading cause of mortality in newborn babies in high- and low-income countries worldwide. Different strains of GBS are characterized by different degrees of virulence, where some are harmlessly carried by humans or animals and others are much more likely to cause disease.The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host.These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted.
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http://dx.doi.org/10.1128/mBio.00728-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373188PMC
June 2020

Distribution of class 1 integrons in historic and contemporary collections of human pathogenic Escherichia coli.

PLoS One 2020 2;15(6):e0233315. Epub 2020 Jun 2.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Integrons play a major role in the evolution and spread of antimicrobial resistance in human pathogens, including Escherichia coli. This study describes the occurrence of class 1 integrons in human pathogenic E. coli, in three isolate collections involving three periods from the last 100 years (i) the Murray collection (n = 58 bacteria isolated from the 1910s to 1940s); (ii) the E. coli reference (ECOR) collection (n = 37 isolates mainly from the 1980s); and (iii) a recently assembled collection (n = 88 isolates obtained in 2016). High-quality whole genome sequences (WGSs) were available for all isolates. Integrons were detected in the WGSs with the program IntegronFinder and the results compared with three established methods: (i) polymerase chain reaction detection of the integrase gene; (ii) BLAST searching using draft genomes; and (iii) mapping of short reads. No integrons were found in any of the Murray Collection isolates; however, integrons were present in 3% of the isolates from ECOR collection, assembled in the 1980s, and 26% of the isolates from the 2010s. Similarly, antimicrobial resistance determinants were not present in the Murray Collection isolates, whereas they were present in 19% of the ECOR Collection isolates and in 55% of the isolates obtained in during the 2010s.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233315PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266292PMC
August 2020

Relationships among streptococci from the mitis group, misidentified as Streptococcus pneumoniae.

Eur J Clin Microbiol Infect Dis 2020 Oct 14;39(10):1865-1878. Epub 2020 May 14.

Department of Epidemiology and Clinical Microbiology, National Medicines Institute, Chełmska 30/34, 00-725, Warsaw, Poland.

The aim of our study was to investigate phenotypic and genotypic features of streptococci misidentified (misID) as Streptococcus pneumoniae, obtained over 20 years from hospital patients in Poland. Sixty-three isolates demonstrating microbiological features typical for pneumococci (optochin susceptibility and/or bile solubility) were investigated by phenotypic tests, lytA and 16S rRNA gene polymorphism and whole-genome sequencing (WGS). All isolates had a 6-bp deletion in the lytA 3' terminus, characteristic for Mitis streptococc and all but two isolates lacked the pneumococcal signature cytosine at nucleotide position 203 in the 16S rRNA genes. The counterparts of psaA and ply were present in 100% and 81.0% of isolates, respectively; the spn9802 and spn9828 loci were characteristic for 49.2% and 38.1% of isolates, respectively. Phylogenetic trees and networks, based on the multilocus sequence analysis (MLSA) scheme, ribosomal multilocus sequence typing (rMLST) scheme and core-genome analysis, clearly separated investigated isolates from S. pneumoniae and demonstrated the polyclonal character of misID streptococci, associated with the Streptococcus pseudopneumoniae and Streptococcus mitis groups. While the S. pseudopneumoniae clade was relatively well defined in all three analyses, only the core-genome analysis revealed the presence of another cluster comprising a fraction of misID streptococci and a strain proposed elsewhere as a representative of a novel species in the Mitis group. Our findings point to complex phylogenetic and taxonomic relationships among S. mitis-like bacteria and support the notion that this group may in fact consist of several distinct species.
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http://dx.doi.org/10.1007/s10096-020-03916-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497345PMC
October 2020

Agricultural intensification and the evolution of host specialism in the enteric pathogen .

Proc Natl Acad Sci U S A 2020 05 4;117(20):11018-11028. Epub 2020 May 4.

The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, BA2 7AY Bath, United Kingdom;

Modern agriculture has dramatically changed the distribution of animal species on Earth. Changes to host ecology have a major impact on the microbiota, potentially increasing the risk of zoonotic pathogens being transmitted to humans, but the impact of intensive livestock production on host-associated bacteria has rarely been studied. Here, we use large isolate collections and comparative genomics techniques, linked to phenotype studies, to understand the timescale and genomic adaptations associated with the proliferation of the most common food-born bacterial pathogen () in the most prolific agricultural mammal (cattle). Our findings reveal the emergence of cattle specialist lineages from a background of host generalist strains that coincided with the dramatic rise in cattle numbers in the 20th century. Cattle adaptation was associated with horizontal gene transfer and significant gene gain and loss. This may be related to differences in host diet, anatomy, and physiology, leading to the proliferation of globally disseminated cattle specialists of major public health importance. This work highlights how genomic plasticity can allow important zoonotic pathogens to exploit altered niches in the face of anthropogenic change and provides information for mitigating some of the risks posed by modern agricultural systems.
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http://dx.doi.org/10.1073/pnas.1917168117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245135PMC
May 2020

Localized Hypermutation is the Major Driver of Meningococcal Genetic Variability during Persistent Asymptomatic Carriage.

mBio 2020 03 24;11(2). Epub 2020 Mar 24.

Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom

Host persistence of bacteria is facilitated by mutational and recombinatorial processes that counteract loss of genetic variation during transmission and selection from evolving host responses. Genetic variation was investigated during persistent asymptomatic carriage of Interrogation of whole-genome sequences for paired isolates from 25 carriers showed that mutations were infrequent, while horizontal gene transfer occurred in 16% of carriers. Examination of multiple isolates per time point enabled separation of sporadic and transient allelic variation from directional variation. A comprehensive comparative analysis of directional allelic variation with hypermutation of simple sequence repeats and hyperrecombination of class 1 type IV pilus genes detected an average of seven events per carrier and 2:1 bias for changes due to localized hypermutation. Directional genetic variation was focused on the outer membrane with 69% of events occurring in genes encoding enzymatic modifiers of surface structures or outer membrane proteins. Multiple carriers exhibited directional and opposed switching of allelic variants of the surface-located Opa proteins that enables continuous expression of these adhesins alongside antigenic variation. A trend for switching from PilC1 to PilC2 expression was detected, indicating selection for specific alterations in the activities of the type IV pilus, whereas phase variation of restriction modification (RM) systems, as well as associated phasevarions, was infrequent. We conclude that asymptomatic meningococcal carriage on mucosal surfaces is facilitated by frequent localized hypermutation and horizontal gene transfer affecting genes encoding surface modifiers such that optimization of adhesive functions occurs alongside escape of immune responses by antigenic variation. Many bacterial pathogens coexist with host organisms, rarely causing disease while adapting to host responses. , a major cause of meningitis and septicemia, is a frequent persistent colonizer of asymptomatic teenagers/young adults. To assess how genetic variation contributes to host persistence, whole-genome sequencing and hypermutable sequence analyses were performed on multiple isolates obtained from students naturally colonized with meningococci. High frequencies of gene transfer were observed, occurring in 16% of carriers and affecting 51% of all nonhypermutable variable genes. Comparative analyses showed that hypermutable sequences were the major mechanism of variation, causing 2-fold more changes in gene function than other mechanisms. Genetic variation was focused on genes affecting the outer membrane, with directional changes in proteins responsible for bacterial adhesion to host surfaces. This comprehensive examination of genetic plasticity in individual hosts provides a significant new platform for rationale design of approaches to prevent the spread of this pathogen.
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http://dx.doi.org/10.1128/mBio.03068-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157529PMC
March 2020

Neisseria gonorrhoeae Population Genomics: Use of the Gonococcal Core Genome to Improve Surveillance of Antimicrobial Resistance.

J Infect Dis 2020 11;222(11):1816-1825

Department of Zoology, The Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford, United Kingdom.

Background: Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, is a globally prevalent sexually transmitted infection. The dynamics of gonococcal population biology have been poorly defined due to a lack of resolution in strain typing methods.

Methods: In this study, we assess how the core genome can be used to improve our understanding of gonococcal population structure compared with current typing schemes.

Results: A total of 1668 loci were identified as core to the gonococcal genome. These were organized into a core genome multilocus sequence typing scheme (N gonorrhoeae cgMLST v1.0). A clustering algorithm using a threshold of 400 allelic differences between isolates resolved gonococci into discrete and stable core genome groups, some of which persisted for multiple decades. These groups were associated with antimicrobial genotypes and non-overlapping NG-STAR and NG-MAST sequence types. The MLST-STs were more widely distributed among core genome groups.

Conclusions: Clustering with cgMLST identified globally distributed, persistent, gonococcal lineages improving understanding of the population biology of gonococci and revealing its population structure. These findings have implications for the emergence of antimicrobial resistance in gonococci and how this is associated with lineages, some of which are more predisposed to developing antimicrobial resistance than others.
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http://dx.doi.org/10.1093/infdis/jiaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653085PMC
November 2020

Association of Neisseria gonorrhoeae Plasmids With Distinct Lineages and The Economic Status of Their Country of Origin.

J Infect Dis 2020 11;222(11):1826-1836

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.

Plasmids are vehicles for horizontal gene transfer between bacteria, and in Neisseria gonorrhoeae plasmids can mediate high-level antimicrobial resistance (AMR). Using genomic and phylogenetic analyses, we show that plasmids are widespread in a collection of 3724 gonococcal isolates from 56 countries, and characterized the conjugative, β-lactamase and cryptic plasmids. We found that variants of the conjugative plasmid (which can mediate tetracycline resistance) and the β-lactamase plasmid expressing TEM-135 are associated with distinct gonococcal lineages. Furthermore, AMR plasmids are significantly more prevalent in gonococci from less wealthy countries, highlighting the need for further studies. More than 94% of gonococci possess the cryptic plasmid, with its absence correlated with the presence of a novel chromosomal type IV secretion system. Our results reveal the extent of plasmid-mediated AMR in the gonococcus, particularly in less wealthy countries, where diagnostic and therapeutic options can be limited, and highlight the risk of their global spread.
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http://dx.doi.org/10.1093/infdis/jiaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653084PMC
November 2020

Complete genome and methylome analysis of Neisseria meningitidis associated with increased serogroup Y disease.

Sci Rep 2020 02 27;10(1):3644. Epub 2020 Feb 27.

Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

Invasive meningococcal disease (IMD) due to serogroup Y Neisseria meningitidis emerged in Europe during the 2000s. Draft genomes of serogroup Y isolates in Sweden revealed that although the population structure of these isolates was similar to other serogroup Y isolates internationally, a distinct strain (YI) and more specifically a sublineage (1) of this strain was responsible for the increase of serogroup Y IMD in Sweden. We performed single molecule real-time (SMRT) sequencing on eight serogroup Y isolates from different sublineages to unravel the genetic and epigenetic factors delineating them, in order to understand the serogroup Y emergence. Extensive comparisons between the serogroup Y sublineages of all coding sequences, complex genomic regions, intergenic regions, and methylation motifs revealed small point mutations in genes mainly encoding hypothetical and metabolic proteins, and non-synonymous variants in genes involved in adhesion, iron acquisition, and endotoxin production. The methylation motif CACNNNNNTAC was only found in isolates of sublineage 2. Only seven genes were putatively differentially expressed, and another two genes encoding hypothetical proteins were only present in sublineage 2. These data suggest that the serogroup Y IMD increase in Sweden was most probably due to small changes in genes important for colonization and transmission.
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http://dx.doi.org/10.1038/s41598-020-59509-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046676PMC
February 2020

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

N Engl J Med 2020 01;382(4):318-327

From the Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network (H.S.M.), the Robinson Research Institute and Adelaide Medical School (H.S.M., M.M.), and the School of Public Health (T.R.S.), University of Adelaide, the Communicable Disease Control Branch, SA Health (A.P.K.), and SA Pathology (A.L.), Adelaide, and the Marshall Centre for Infectious Disease Research and Training, School of Biomedical Science (C.M.K.), and the School of Medicine (P.R.), University of Western Australia, the Departments of General Paediatrics and Immunology, Perth Children's Hospital (P.R.), and Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kid's Institute (P.R.), Perth - all in Australia; the Department of Zoology, University of Oxford, Oxford (J.M.M., M.C.J.M.), the Immunization Department, Public Health England, London (S.N.L., M.E.R., C.T.), the Departments of Pathology and Veterinary Medicine, University of Cambridge, Cambridge (C.T.), the Meningococcal Reference Unit, Public Health England, Manchester (R.B.), and Bristol Children's Vaccine Centre, Schools of Cellular and Molecular Medicine and of Population Health Sciences, University of Bristol, Bristol (A.F.) - all in the United Kingdom; GlaxoSmithKline Vaccines, Amsterdam (J.W.); and GlaxoSmithKline Vaccines, Rockville, MD (K.V.).

Background: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain.

Methods: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for (encoding porin protein A) and genogroups. Secondary outcomes included carriage prevalence and acquisition of all and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline.

Results: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified.

Conclusions: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).
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http://dx.doi.org/10.1056/NEJMoa1900236DOI Listing
January 2020

Genetic determinants of genus-level glycan diversity in a bacterial protein glycosylation system.

PLoS Genet 2019 12 23;15(12):e1008532. Epub 2019 Dec 23.

Department of Biosciences, Center for Integrative Microbial Evolution, University of Oslo, Oslo, Norway.

The human pathogens N. gonorrhoeae and N. meningitidis display robust intra- and interstrain glycan diversity associated with their O-linked protein glycosylation (pgl) systems. In an effort to better understand the evolution and function of protein glycosylation operating there, we aimed to determine if other human-restricted, Neisseria species similarly glycosylate proteins and if so, to assess the levels of glycoform diversity. Comparative genomics revealed the conservation of a subset of genes minimally required for O-linked protein glycosylation glycan and established those pgl genes as core genome constituents of the genus. In conjunction with mass spectrometric-based glycan phenotyping, we found that extant glycoform repertoires in N. gonorrhoeae, N. meningitidis and the closely related species N. polysaccharea and N. lactamica reflect the functional replacement of a progenitor glycan biosynthetic pathway. This replacement involved loss of pgl gene components of the primordial pathway coincident with the acquisition of two exogenous glycosyltransferase genes. Critical to this discovery was the identification of a ubiquitous but previously unrecognized glycosyltransferase gene (pglP) that has uniquely undergone parallel but independent pseudogenization in N. gonorrhoeae and N. meningitidis. We suggest that the pseudogenization events are driven by processes of compositional epistasis leading to gene decay. Additionally, we documented instances where inter-species recombination influences pgl gene status and creates discordant genetic interactions due ostensibly to the multi-locus nature of pgl gene networks. In summary, these findings provide a novel perspective on the evolution of protein glycosylation systems and identify phylogenetically informative, genetic differences associated with Neisseria species.
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http://dx.doi.org/10.1371/journal.pgen.1008532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959607PMC
December 2019

Toward a Global Genomic Epidemiology of Meningococcal Disease.

J Infect Dis 2019 10;220(220 Suppl 4):S266-S273

Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Whole-genome sequencing (WGS) is invaluable for studying the epidemiology of meningococcal disease. Here we provide a perspective on the use of WGS for meningococcal molecular surveillance and outbreak investigation, where it helps to characterize pathogens, predict pathogen traits, identify emerging pathogens, and investigate pathogen transmission during outbreaks. Standardization of WGS workflows has facilitated their implementation by clinical and public health laboratories (PHLs), but further development is required for metagenomic shotgun sequencing and targeted sequencing to be widely available for culture-free characterization of bacterial meningitis pathogens. Internet-accessible servers are being established to support bioinformatics analysis, data management, and data sharing among PHLs. However, establishing WGS capacity requires investments in laboratory infrastructure and technical knowledge, which is particularly challenging in resource-limited regions, including the African meningitis belt. Strategic WGS implementation is necessary to monitor the molecular epidemiology of meningococcal disease in these regions and construct a global view of meningococcal disease epidemiology.
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http://dx.doi.org/10.1093/infdis/jiz279DOI Listing
October 2019

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

Wellcome Open Res 2019 28;4:118. Epub 2019 Oct 28.

Peter Medawar Building for Pathogen Research, Department of Zoology, University of Oxford, Oxford, OX1 3SY, UK.

Carriage of , 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.
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http://dx.doi.org/10.12688/wellcomeopenres.15362.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749934PMC
October 2019

Genomic characterization of novel Neisseria species.

Sci Rep 2019 09 24;9(1):13742. Epub 2019 Sep 24.

Department of Zoology, University of Oxford, Oxford, UK.

Of the ten human-restricted Neisseria species two, Neisseria meningitidis, and Neisseria gonorrhoeae, cause invasive disease: the other eight are carried asymptomatically in the pharynx, possibly modulating meningococcal and gonococcal infections. Consequently, characterizing their diversity is important for understanding the microbiome in health and disease. Whole genome sequences from 181 Neisseria isolates were examined, including those of three well-defined species (N. meningitidis; N. gonorrhoeae; and Neisseria polysaccharea) and genomes of isolates unassigned to any species (Nspp). Sequence analysis of ribosomal genes, and a set of core (cgMLST) genes were used to infer phylogenetic relationships. Average Nucleotide Identity (ANI) and phenotypic data were used to define species clusters, and morphological and metabolic differences among them. Phylogenetic analyses identified two polyphyletic clusters (N. polysaccharea and Nspp.), while, cgMLST data grouped Nspp isolates into nine clusters and identified at least three N. polysaccharea clusters. ANI results classified Nspp into seven putative species, and also indicated at least three putative N. polysaccharea species. Electron microscopy identified morphological differences among these species. This genomic approach provided a consistent methodology for species characterization using distinct phylogenetic clusters. Seven putative novel Neisseria species were identified, confirming the importance of genomic studies in the characterization of the genus Neisseria.
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http://dx.doi.org/10.1038/s41598-019-50203-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760525PMC
September 2019

has acquired sequences within the capsule locus by horizontal genetic transfer.

Wellcome Open Res 2019 2;4:99. Epub 2019 Aug 2.

Department of Zoology, University of Oxford, Oxford, OX1 3SY, UK.

Expression of a capsule from one of serogroups A, B, C, W, X or Y is usually required for ( ) to cause invasive meningococcal disease. The capsule is encoded by the capsule locus, , which is proposed to have been acquired by a formerly capsule null organism by horizontal genetic transfer (HGT) from another species. Following identification of putative capsule genes in non-pathogenic species, this hypothesis is re-examined. Whole genome sequence data from species, including genomes from a diverse range of clonal complexes and capsule genogroups, and non- species, were obtained from PubMLST and GenBank. Sequence alignments of genes from the meningococcal , and predicted orthologues in other species, were analysed using Neighbor-nets, BOOTSCANing and maximum likelihood phylogenies. The meningococcal was highly mosaic within regions B, C and D. A subset of sequences within regions B and C were phylogenetically nested within homologous sequences belonging to , consistent with HGT event in which was the donor. In the of 23/39 isolates, the two copies of region D were highly divergent, with sequences being more closely related to predicted orthologues in the proposed species (GenBank accession number CP023429.1) than the same genes in isolates lacking a capsule. There was also evidence of mosaicism in the sequences of the remaining 16 isolates, as well as from many isolates. Data are consistent with the acquisition of in meningococci from , followed by further recombination events with other species. Nevertheless, the data cannot refute an alternative model, in which native meningococcal capsule existed prior to undergoing HGT with and other species. Within-genus recombination events may have given rise to the diversity of meningococcal capsule serogroups.
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http://dx.doi.org/10.12688/wellcomeopenres.15333.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619384PMC
August 2019
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