Invasive pneumococcal disease 3 years after introduction of a reduced 1 + 1 infant 13-valent pneumococcal conjugate vaccine immunisation schedule in England: a prospective national observational surveillance study.

BACKGROUND: The UK transition from a 2 + 1 to a 1 + 1 infant immunisation schedule with the 13-valent pneumococcal conjugate vaccine (PCV13) on Jan 1, 2020, coincided with the start of the COVID-19 pandemic. We describe the epidemiology of invasive pneumococcal disease (IPD) in England over 6 financial years (April 1 to March 31) between 2017-18 and 2022-23. METHODS: We used prospective national surveillance data, including serotyping and whole-genome sequencing of invasive isolates, to analyse IPD trends in England by age and financial year. We compared breakthrough infections and vaccine failure rates in 2022-23 among children eligible for the 1 + 1 schedule with rates in cohorts of children eligible for the 2 + 1 schedule between 2017-18 and 2019-20. We assessed genomic changes over time by comparing Global Pneumococcal Sequencing Clusters and multilocus sequence types among PCV13 serotypes causing IPD. FINDINGS: There were 4598 laboratory-confirmed IPD cases in 2022-23, 3025 in 2021-22, 1240 in 2020-21, and 5316 in 2019-20. IPD incidence in 2022-23 was 14% lower than in 2019-20 (incidence rate ratio [IRR] 0·86, 95% CI 0·81-0·91; p<0·001). IPD incidence in 2022-23 compared with 2019-20 was 34% higher in children (aged <15 years) (378 cases vs 292 cases; IRR 1·34, 95% CI 1·08-1·68; p=0·009) and 17% lower in adults (aged 15 years and older; 4220 vs 5024; 0·83, 0·78-0·88; p<0·001). The proportion of PCV13-type IPD increased from 19·4% (95% CI 18·2-20·4; 957 of 4947) in 2019-20 to 29·7% (28·3-31·0; 1283 of 4326) in 2022-23, mainly due to serotype 3, but also serotypes 19F, 19A, and 4, alongside a decrease in non-PCV13 serotypes 8, 12F, and 9N. The increase in IPD incidence due to serotypes 3, 19A, and 19F was driven by clonal expansion of previously circulating strains, whereas serotype 4 expansion was driven by newer strains (ie, sequence types 801 and 15603). Breakthrough infections and vaccine failure rates were similar in children eligible for the 1 + 1 (1·08 per 100 000 person-years) and 2 + 1 (0·76 per 100 000 person-years; IRR 1·42, 95% CI 0·78-2·49; p=0·20) PCV13 schedules. INTERPRETATION: Overall, IPD incidence in England was lower in 2022-23, 2 years after removal of pandemic restrictions, than in 2019-20. Breakthrough and vaccine failure rates were not significantly different between children who received the 1 + 1 compared with the 2 + 1 PCV13 immunisation schedule. The post-pandemic increase in childhood IPD incidence and especially PCV13-type IPD will require close monitoring. FUNDING: None.

National public health response to an outbreak of toxigenic Corynebacterium diphtheriae among asylum seekers in England, 2022: a descriptive epidemiological study.

BACKGROUND: In July, 2022, an increase in diphtheria cases caused by toxigenic Corynebacterium diphtheriae (C diphtheriae) was reported among asylum seekers arriving by small boats to England. Rising case numbers presented challenges for case and contact management in initial reception centres, prompting changes to national guidance and implementation of population-based control measures. This study aimed to describe the outbreak of toxigenic C diphtheriae among asylum seekers arriving by small boats to England during 2022 by use of national surveillance data. METHODS: We undertook a descriptive epidemiological analysis of cases of toxigenic C diphtheriae among asylum seekers arriving by small boats to England during 2022, incorporating genomic sequencing data, antibiotic susceptibility testing results, and epidemiological data obtained through the UK Health Security Agency's national enhanced surveillance programme. Health Protection Teams conducted risk assessments, and operational data (including details regarding offer and uptake of antibiotics and vaccinations) were obtained from National Health Service partners supporting the intervention programme. FINDINGS: In 2022, C diphtheriae isolates from 86 asylum seekers arriving by small boats were submitted to the National Reference Laboratory for confirmation and testing. Toxigenic C diphtheriae was confirmed for 72 (84%) cases and one individual with typical diphtheritic lesions but from whom no C diphtheriae was isolated from clinical swabs was also included as a probable case, resulting in 73 cases of diphtheria. 71 (97%) were male, 39 (53%) were younger than 18 years, and 36 (49%) presented with cutaneous diphtheria. The prevalence of diphtheria was highest among Afghans (1·3%) compared with all other nationalities (<0·1%). Local antibiotic susceptibility testing identified six cases with a macrolide resistant strain. INTERPRETATION: The increase in diphtheria coincided with a high volume of asylum seekers arriving by small boats to England during 2022, and subsequently increased clinical awareness of the disease among this population. Long-term disruption to vaccination programmes in origin countries along with barriers to accessing health care along migrant routes puts asylum seekers arriving by small boats at risk of disease. With arrivals expected to continue in 2023, the UK Health Security Agency has recommended continuation of population-based control measures in England until October, 2023, subject to ongoing review. FUNDING: The UK Health Security Agency.

Household transmission of non-toxigenic diphtheria toxin gene-bearing Corynebacterium diphtheriae following a cluster of cutaneous cases in a specialist outpatient setting.

Introduction. Combination of PCR and Elek testing to identify toxigenic corynebacteria has revealed organisms described as non-toxigenic toxin-gene bearing (NTTB) Corynebacterium diphtheriae or C. ulcerans (i.e. PCR tox positive; Elek negative). These organisms carry part or all of tox, but are unable to express diphtheria toxin (DT) and present a challenge to clinical and public health case management.Gap analysis/Hypothesis. There are few data on the theoretical risk of NTTB reversion to toxigenicity. This unique cluster and subsequent epidemiologically linked isolates allowed the opportunity to determine any change in DT expression status.Aim. To characterize a cluster of infections due to NTTB in a skin clinic and subsequent cases in two household contacts.Methodology. Epidemiological and microbiological investigations were carried out according to existing national guidance at the time. Susceptibility testing used gradient strips. The tox operon analysis and multi-locus sequence typing (MLST) was derived from whole-genome sequencing. Alignment of the tox operon and phylogenetic analyses were performed using clustalW, mega, the public core-genome MLST (cgMLST) scheme and an in-house bioinformatic single nucleotide polymorphism (SNP) typing pipeline.Results. Isolates of NTTB C. diphtheriae were recovered from four cases (cases 1 to 4) with epidermolysis bullosa attending the clinic. Two further isolates were subsequently recovered from case 4, >18 months later, and from two household contacts (cases 5 and 6) after a further 18 months and 3.5 years, respectively. All eight strains were NTTB C. diphtheriae biovar mitis, belonged to the same sequence type (ST-336) with the same deletion in tox. Phylogenetic analysis showed relatively high diversity between the eight strains with 7-199 SNP and 3-109 cgMLST loci differences between them. The number of SNPs between the three isolates from case 4 and two household contacts (cases 5 and 6) was 44-70 with 28-38 cgMLST loci differences.Conclusions. We report a cluster of NTTB C. diphtheriae cases in a skin clinic and evidence of onward household transmission. We conclude the deletion in the tox was responsible for the non-expression of DT. There was no evidence of reversion to DT expression over the 6.5 year period studied. These data informed revision to guidance in the management of NTTB cases and their contacts in the UK.

Trends in invasive Haemophilus influenzae serotype a disease in England from 2008-09 to 2021-22: a prospective national surveillance study.

BACKGROUND: Invasive Haemophilus influenzae serotype a (Hia) disease is rare, with most cases reported among Indigenous populations in North America. In England, national surveillance was enhanced following an increase in laboratory-confirmed invasive Hia disease since the 2016-17 epidemiological year. This study aimed to describe the epidemiological trends, clinical characteristics of cases, and assess potential genomic drivers. METHODS: Hospital laboratories in England routinely submit invasive H influenzae isolates to the UK Health Security Agency for confirmation and serotyping. In this prospective national surveillance study we contacted the general practitioners and clinicians of all patients with laboratory-confirmed invasive Hia from the 2008-09 to the 2021-22 epidemiological year to complete a clinical questionnaire on demographics, underlying conditions, clinical presentation, complications, outcomes, and travel history of the patient. All Hia invasive isolates from residents in England were included in the study; non-invasive isolates were excluded. Multilocus sequence typing (MLST), whole genome single-nucleotide polymorphism, and k-mer-based analysis of bacterial isolates were performed following Illumina whole-genome sequencing (WGS). Outcomes included epidemiological trends, clinical characteristics of confirmed Hia cases, and genomic analyses. FINDINGS: From the 2008-09 to the 2021-22 epidemiological years, there were 52 cases of invasive infection with H influenzae serotype a in England (25 [48%] in female patients and 27 [52%] in male patients). There were zero to two annual Hia cases (accounting for <0·5% of serotyped H influenzae isolates) until 2015-16, after which cases increased across England to 19 cases in 2021-22 (incidence 0·03 cases per 100 000), when Hia accounted for 19 (4%) of 484 serotyped H influenzae isolates, 19 (19%) of 100 capsulated cases, and 37% (19 of 52) of all H influenzae cases between 2008-09 and 2021-22. Most of the recent increase in cases occurred among individuals aged 65 years and older (17 [33%] of 52), who typically presented with bacteraemic pneumonia (13 [76%] of 17), and infants younger than 1 year, who had the highest incidence and were more likely to present with meningitis (five [50%] of ten). Overall case fatality rate was 7·7% (95% CI 2·1-19·7; four of 52 patients). WGS found that closely related MLST sequence types ST1511 (20 [39%] of 51), ST23 (13 [25%] of 51), and ST56 (seven [14%] of 51) accounted for most cases, with no evidence of serotype b strains switching capsule to Hia. Duplication of the capsule operon, associated with more severe disease, was present in 32 (80%) of 40 of these sequence types. Analysis of the core and accessory genome content grouped most isolates into a single strain. INTERPRETATION: The persistent increase in invasive Hia cases across England and across all age groups suggests widespread transmission, consistent with reports from other European countries, and will require close monitoring. FUNDING: UK Health Security Agency.

Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA.

BACKGROUND: The respiratory pathogen Streptococcus pneumoniae (the pneumococcus) is a genetically diverse bacterium associated with over 101 immunologically distinct polysaccharide capsules (serotypes). Polysaccharide conjugate vaccines (PCVs) have successfully eliminated multiple targeted serotypes, yet the mucoid serotype 3 has persisted despite its inclusion in PCV13. This capsule type is predominantly associated with a single globally disseminated strain, GPSC12 (clonal complex 180). METHODS: A genomic epidemiology study combined previous surveillance datasets of serotype 3 pneumococci to analyse the population structure, dynamics, and differences in rates of diversification within GPSC12 during the period of PCV introductions. Transcriptomic analyses, whole genome sequencing, mutagenesis, and electron microscopy were used to characterise the phenotypic impact of loci hypothesised to affect this strain's evolution. RESULTS: GPSC12 was split into clades by a genomic analysis. Clade I, the most common, rarely underwent transformation, but was typically infected with the prophage ϕOXC141. Prior to the introduction of PCV13, this clade's composition shifted towards a ϕOXC141-negative subpopulation in a systematically sampled UK collection. In the post-PCV13 era, more rapidly recombining non-Clade I isolates, also ϕOXC141-negative, have risen in prevalence. The low in vitro transformation efficiency of a Clade I isolate could not be fully explained by the ~100-fold reduction attributable to the serotype 3 capsule. Accordingly, prophage ϕOXC141 was found to modify csRNA3, a non-coding RNA that inhibits the induction of transformation. This alteration was identified in ~30% of all pneumococci and was particularly common in the unusually clonal serotype 1 GPSC2 strain. RNA-seq and quantitative reverse transcriptase PCR experiments using a genetically tractable pneumococcus demonstrated the altered csRNA3 was more effective at inhibiting production of the competence-stimulating peptide pheromone. This resulted in a reduction in the induction of competence for transformation. CONCLUSION: This interference with the quorum sensing needed to induce competence reduces the risk of the prophage being deleted by homologous recombination. Hence the selfish prophage-driven alteration of a regulatory RNA limits cell-cell communication and horizontal gene transfer, complicating the interpretation of post-vaccine population dynamics.

The role of interspecies recombination in the evolution of antibiotic-resistant pneumococci.

Multidrug-resistant Streptococcus pneumoniae emerge through the modification of core genome loci by interspecies homologous recombinations, and acquisition of gene cassettes. Both occurred in the otherwise contrasting histories of the antibiotic-resistant S. pneumoniae lineages PMEN3 and PMEN9. A single PMEN3 clade spread globally, evading vaccine-induced immunity through frequent serotype switching, whereas locally circulating PMEN9 clades independently gained resistance. Both lineages repeatedly integrated Tn916-type and Tn1207.1-type elements, conferring tetracycline and macrolide resistance, respectively, through homologous recombination importing sequences originating in other species. A species-wide dataset found over 100 instances of such interspecific acquisitions of resistance cassettes and flanking homologous arms. Phylodynamic analysis of the most commonly sampled Tn1207.1-type insertion in PMEN9, originating from a commensal and disrupting a competence gene, suggested its expansion across Germany was driven by a high ratio of macrolide-to-ß-lactam consumption. Hence, selection from antibiotic consumption was sufficient for these atypically large recombinations to overcome species boundaries across the pneumococcal chromosome.

Genomic epidemiology of penicillin-non-susceptible Streptococcus pneumoniae.

Penicillin-non-susceptible Streptococcus pneumoniae (PNSP) were first detected in the 1960s, and are now common worldwide, predominantly through the international spread of a limited number of strains. Extant PNSP are characterized by mosaic pbp2x, pbp2b and pbp1a genes generated by interspecies recombinations, with the extent of these alterations determining the range and concentrations of ß-lactams to which the genotype is non-susceptible. The complexity of the genetics underlying these phenotypes has been the subject of both molecular microbiology and genome-wide association and epistasis analyses. Such studies can aid our understanding of PNSP evolution and help improve the already highly-performing bioinformatic methods capable of identifying PNSP from genomic surveillance data.