Invasive Group B Streptococcus Disease With Recurrence and in Multiples: Towards a Better Understanding of GBS Late-Onset Sepsis.

Group B Streptococcus (GBS) is a common intestinal colonizer during the neonatal period, but also may cause late-onset sepsis or meningitis in up to 0.5% of otherwise healthy colonized infants after day 3 of life. Transmission routes and risk factors of this late-onset form of invasive GBS disease (iGBS) are not fully understood. Cases of iGBS with recurrence (n=25) and those occurring in parallel in twins/triplets (n=32) from the UK and Ireland (national surveillance study 2014/15) and from Germany and Switzerland (retrospective case collection) were analyzed to unravel shared (in affected multiples) or fixed (in recurrent disease) risk factors for GBS disease. The risk of iGBS among infants from multiple births was high (17%), if one infant had already developed GBS disease. The interval of onset of iGBS between siblings was 4.5 days and in recurrent cases 12.5 days. Disturbances of the individual microbiome, including persistence of infectious foci are suggested e.g. by high usage of perinatal antibiotics in mothers of affected multiples, and by the association of an increased risk of recurrence with a short term of antibiotics [aOR 4.2 (1.3-14.2), P=0.02]. Identical GBS serotypes in both recurrent infections and concurrently infected multiples might indicate a failed microbiome integration of GBS strains that are generally regarded as commensals in healthy infants. The dynamics of recurrent GBS infections or concurrent infections in multiples suggest individual patterns of exposure and fluctuations in host immunity, causing failure of natural niche occupation

Genomic surveillance and meningococcal group B vaccine coverage estimates after introduction of the vaccine into the national immunisation programme in the UK

In September, 2015, the meningococcal group B vaccine (Bexsero, GlaxoSmithKline) was introduced into the UK childhood immunisation schedule. Prelicensure coverage estimates used Meningococcal Antigen Typing System (MATS) to determine phenotype and function of circulating meningococci. Using whole-genome sequencing, we aimed to perform rapid, scalable, high-resolutio

Genomic surveillance and meningococcal group B vaccine coverage estimates after introduction of the vaccine into the national immunisation programme in the UK

In September, 2015, the meningococcal group B vaccine (Bexsero, GlaxoSmithKline) was introduced into the UK childhood immunisation schedule. Prelicensure coverage estimates used Meningococcal Antigen Typing System (MATS) to determine phenotype and function of circulating meningococci. Using whole-genome sequencing, we aimed to perform rapid, scalable, high-resolutio

Enterovirus and parechovirus meningitis in infants younger than 90 days old in the UK and Republic of Ireland: a British Paediatric Surveillance Unit study.

OBJECTIVES: This study aimed to prospectively collect detailed clinical information for all enterovirus (EV) and human parechovirus (HPeV) meningitis cases in infants aged <90 days in the UK and Ireland. PARTICIPANTS, DESIGN AND SETTING: Prospective, active national surveillance during July 2014 to July 2015 through the British Paediatric Surveillance Unit. Reporting paediatricians completed questionnaires requesting information on clinical presentation, investigations, management and outcomes at hospital discharge and after 12 months. MAIN OUTCOME MEASURES: To describe the clinical burden of EV and HPeV meningitis in infants aged <90 days. RESULTS: During the 13-month surveillance period, 703 cases (668 EV, incidence0.79/1,000 live- births; 35 HPeV, 0.04/1,000 live-births) were identified. The most common clinical presentations were fever (EV: 570/668(85%); HPeV: 28/35(80%)), irritability (EV: 441/668(66%); HPeV: 23/35(66%)) and reduced feeding (EV: 363/668(54%); HPeV 23/35(66%)). Features of circulatory shock were present in 27% (182/668) of EV and 43% (15/35) of HPeV cases. Overall, 11% (76/668) of EV and 23% (8/35) of HPeV cases required intensive care support. Nearly all cases (678/703, 96%) were confirmed by cerebrospinal fluid (CSF) PCR, with 52% (309/600) having normal CSF white cell count for age. Two infants with EV meningitis died (2/668, 0.3%) and four survivors (4/666, 0.6%) had long-term complications at 12 months' follow-up. Infants with HPeV meningitis survived without sequelae. Overall 189 infants had a formal hearing test and none had sensorineural hearing loss. CONCLUSION: The incidence of laboratory-confirmed EV/HPeV meningitis in young infants is more than twice that for bacterial meningitis. Less than 1% will develop severe neurological complications or die of their infection. Further studies are required to formally assess long-term neurodevelopmental sequelae

Resolution of a protracted serogroup B meningococcal outbreak with whole genome sequencing shows inter species genetic transfer.

A carriage study was undertaken (n=112) to ascertain the prevalence Neisseria spp. following the eighth case of invasive meningococcal disease in young children (5-46 months) and members of a large extended indigenous ethnic minority Traveller family (n=123), typically associated with high occupancy living conditions.Nested Multi Locus Sequence Typing (MLST) was employed for case specimen extracts. Isolates were genome sequenced, then assembled de novo and deposited into the Bacterial Isolate Genome Sequencing database (BIGSdb). This facilitated an expanded MLST approach utilising large numbers of loci for isolate characterisation and discrimination.A rare sequence type 6697 predominated in disease specimens and carried isolates (n=8/14), persisting for at least 44 months, likely driven by the high population density of houses (n=67/112) and trailers (n=45/112). Carriage was more likely in the smaller, more densely populated trailers for N. meningitidis (p&lt;0.05) and N. lactamica (p&lt;0.002) (2-sided Fishers exact test). Meningococcal carriage was highest in 24-39 year olds (45%, n=9/20). Evidence of horizontal gene transfer (HGT) was observed in four individuals co-colonized by Nersseria lactamica and Neisseria meningitidis One HGT event resulted in the acquisition of 26 consecutive N. lactamica alleles.This study demonstrates how housing density can drive meningococcal transmission and carriage, which likely facilitated the persistence of ST6697 and prolonging the outbreak. Whole genome MLST can effectively distinguish between highly similar outbreak strain isolates, including those isolated from person-to-person transmission, and also highlighted how a few HGT events can distort the true phylogenetic relationship between highly similar clonal isolates

Genomic epidemiology of group B streptococci spanning 10 years in an Irish Maternity Hospital, 2008-2017

Objectives: The genomic epidemiology of group b streptococcus (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.</p

Potential coverage of the 4CMenB vaccine against invasive serogroup B Neisseria meningitidis isolated from 2009 to 2013 in the Republic of Ireland

Neisseria meningitidis is a common cause of bacterial meningitis in children and young adults worldwide. The 4CMenB vaccine (Bexsero), developed to combat meningococcal serogroup B (MenB) disease, contains subcapsular antigens that may induce immunity against strains of N. meningitidis, regardless of serogroup. Owing to differential levels of expression and peptide diversity in vaccine antigens across meningococcal strains, the meningococcal antigen typing system (MATS) was developed to estimate the potential MenB strain coverage of 4CMenB. Prior to introducing the 4CMenB vaccine into routine use, we sought to estimate the potential 4CMenB coverage against invasive MenB strains isolated in the Republic of Ireland (RoI) over four consecutive epidemiological years. MATS was applied to a panel of 105 invasive MenB strains isolated during July 2009 to June 2013. Sequence data characterizing the multilocus sequence typing (MLST) alleles and the major 4CMenB target peptides were extracted from isolate genome sequence data, hosted in the Bacterial Isolate Sequencing database (BIGSdb). MATS data indicated that 4CMenB may induce protective immunity against 69.5% (95% confidence interval [CI95%], 64.8% to 84.8%) of circulating MenB strains. Estimated coverage was highest against the most prevalent disease-causing lineage, cc41/44, where the most frequently observed sequence types, ST-154 and ST-41 (21% of isolates, collectively), were typically covered by three antigens. No significant temporal trends were observed. Overall, these data provide a baseline of strain coverage prior to the introduction of 4CMenB and indicate that a decrease in invasive meningococcal disease (IMD) is predicted following the introduction of 4CMenB into the routine infant immunization schedule in the RoI