Evolution of Streptococcus pneumoniae Serotype 3 in England and Wales: A Major Vaccine Evader.

Despite its inclusion in pneumococcal conjugate vaccine 13 (PCV13), Streptococcus pneumoniae serotype 3 remains a major cause of invasive pneumococcal disease in England and Wales. Previous studies have indicated that there are distinct lineages within serotype 3 clonal complex 180 and the clade distributions have shifted in recent years with the emergence of clade II. We undertook whole genome sequencing and genomic analysis of 616 serotype 3 isolates from England and Wales between 2003 and 2018, including invasive and carriage isolates. Our investigations showed that clade II has expanded since 2014 and now represents 50% of serotype 3 invasive pneumococcal disease (IPD) isolates in England and Wales. Genomic analysis of antibiotic resistance and protein antigen genes showed that distinct profiles are present within the clades which could account for the recent emergence of this clade. This investigation highlights the importance and utility of routine whole genome sequencing and its ability to identify new and emerging variation at the single nucleotide level which informs surveillance and will impact future vaccine development

Long COVID and the mental and physical health of children and young people: National matched cohort study protocol (the CLoCk study)

Introduction There is uncertainty surrounding the diagnosis, prevalence, phenotype, duration and treatment of Long COVID. This study aims to (A) describe the clinical phenotype of post-COVID symptomatology in children and young people (CYP) with laboratory-confirmed SARS-CoV-2 infection compared with test-negative controls, (B) produce an operational definition of Long COVID in CYP, and (C) establish its prevalence in CYP. Methods and analysis A cohort study of SARS-CoV-2-positive CYP aged 11-17 years compared with age, sex and geographically matched SARS-CoV-2 test-negative CYP. CYP aged 11-17 testing positive and negative for SARS-CoV-2 infection will be identified and contacted 3, 6, 12 and 24 months after the test date. Consenting CYP will complete an online questionnaire. We initially planned to recruit 3000 test positives and 3000 test negatives but have since extended our target. Data visualisation techniques will be used to examine trajectories over time for symptoms and variables measured repeatedly, separately by original test status. Summary measures of fatigue and mental health dimensions will be generated using dimension reduction methods such as latent variables/latent class/principal component analysis methods. Cross-tabulation of collected and derived variables against test status and discriminant analysis will help operationalise preliminary definitions of Long COVID. Ethics and dissemination Research Ethics Committee approval granted. Data will be stored in secure Public Health England servers or University College London's Data Safe Haven. Risks of harm will be minimised by providing information on where to seek support. Results will be published on a preprint server followed by journal publication, with reuse of articles under a CC BY licence. Data will be published with protection against identification when there are small frequencies involved. Trial registration number ISRCTN34804192; Pre-results

Characteristics of Invasive Pneumococcal Disease Caused by Emerging Serotypes After the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in England: A Prospective Observational Cohort Study, 2014-2018.

BACKGROUND: England is experiencing a rapid increase in invasive pneumococcal disease (IPD) caused by serotypes 8, 12F, and 9N; their clinical characteristics and outcomes have not been described. METHODS: Public Health England conducts national IPD surveillance. Cases due to emerging serotypes were compared with those included in the 13-valent pneumococcal conjugate vaccine (PCV13) and the remaining non-PCV13 serotypes. RESULTS: There were 21 592 IPD cases during 2014-15 to 2017-18, including 20 108 (93.1%) with serotyped isolates and 17 450 (86.8%) with completed questionnaires. PCV13 serotypes were responsible for 20.1% (n = 4033), while serotype 8 (3881/20 108 [19.3%]), 12F (2365/20 108 [11.8%]), and 9N (1 296/20 108 [6.4%]) were together responsible for 37.5% of cases. Invasive pneumonia was the most common presentation (11 424/16 346 [69.9%]) and, overall, 67.0% (n = 11 033) had an underlying comorbidity. The median age (interquartile range) at IPD due to serotypes 8 (59 [45-72] years) and 12F (56 [41-70] years) was lower than serotype 9N (67 [53-80] years), PCV13 serotypes (68 [52-81] years), and remaining non-PCV13 serotypes (70 [53-82] years). Serotype 9N IPD cases also had higher comorbidity prevalence (748/1087 [68.8%]) compared to serotype 8 (1901/3228 [58.9%]) or 12F (1042/1994 [52.3%]), and higher case fatality (212/1128 [18.8%]) compared to 8.6% (291/3365) or 10.0% (209/2086), respectively. CONCLUSIONS: Serotypes 8 and 12F were more likely to cause IPD in younger, healthier individuals and less likely to be fatal, while serotype 9N affected older adults with comorbidities and had higher case fatality

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

Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Invasive Pneumococcal Disease and Risk of Pneumococcal Coinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Prospective National Cohort Study, England.

BACKGROUND: Streptococcus pneumoniae coinfection with influenza results in synergistic lethality, but there are limited data on pneumococcal coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Public Health England conducts invasive pneumococcal disease (IPD) and SARS-CoV-2 surveillance in England. IPD trends during 2000/2001-2019/2020 epidemiological years were analyzed and cases during February-June 2020 linked with laboratory-confirmed SARS-CoV-2 infections. Multivariable logistic regression was used to assess risk factors for death. RESULTS: IPD incidence in 2019/2020 (7.6/100 000; n = 3964) was 30% (IRR, .70; 95% CI, .18-2.67) lower compared with 2018/2019 (10.9/100 000; n = 5666), with large reductions observed across all age groups during March-June 2020. There were 160 886 SARS-CoV-2 and 1137 IPD cases during February-June 2020, including 40 IPD/coronavirus disease 2019 (COVID-19) co-infections (.025% [95% CI, .018-.034] of SARS-CoV-2 infections; 3.5% [2.5-4.8] of IPD cases), 21 with COVID-19 diagnosed 3-27 days after IPD, and 27 who developed COVID-19 ≥28 days after IPD. Case-fatality rates (CFRs) were 62.5 (25/40), 47.6% (10/21), and 33.3% (9/27), respectively (P < .001). In addition to an independent association with increasing age and serotype group, CFR was 7.8-fold (95% CI, 3.8-15.8) higher in those with IPD/COVID-19 coinfection and 3.9-fold (95% CI, 1.4-10.7) higher in patients who developed COVID-19 3-27 days after IPD compared with patients with IPD only. CONCLUSIONS: Large declines in IPD were observed following COVID-19 lockdown. IPD/COVID-19 coinfections were rare but associated with high CFR, mainly in older adults. The rarity, age and serotype distribution of IPD/COVID-19 coinfections do not support wider extension of pneumococcal vaccination

Feasibility and acceptability of SARS-CoV-2 testing and surveillance in primary school children in England: Prospective, cross-sectional study.

BACKGROUND: The reopening of schools during the COVID-19 pandemic has raised concerns about widespread infection and transmission of SARS-CoV-2 in educational settings. In June 2020, Public Health England (PHE) initiated prospective national surveillance of SARS-CoV-2 in primary schools across England (sKIDs). We used this opportunity to assess the feasibility and agreeability of large-scale surveillance and testing for SARS-CoV-2 infections in school among staff, parents and students. METHODS: Staff and students in 131 primary schools were asked to complete a questionnaire at recruitment and provide weekly nasal swabs for SARS-CoV-2 RT-PCR testing (n = 86) or swabs with blood samples for antibody testing (n = 45) at the beginning and end the summer half-term. In six blood sampling schools, students were asked to complete a pictorial questionnaire before and after their investigations. RESULTS: In total, 135 children aged 4-7 years (n = 40) or 8-11 years (n = 95) completed the pictorial questionnaire fully or partially. Prior to sampling, oral fluid sampling was the most acceptable test (107/132, 81%) followed by throat swabs (80/134, 59%), nose swabs (77/132, 58%), and blood tests (48/130, 37%). Younger students were more nervous about all tests than older students but, after completing their tests, most children reported a "better than expected" experience with all the investigations. Students were more likely to agree to additional testing for nose swabs (93/113, 82%) and oral fluid (93/114, 82%), followed by throat swabs (85/113, 75%) and blood tests (72/108, 67%). Parents (n = 3,994) and staff (n = 2,580) selected a preference for weekly testing with nose swabs, throat swabs or oral fluid sampling, although staff were more flexible about testing frequency. CONCLUSIONS: Primary school staff and parents were supportive of regular tests for SARS-CoV-2 and selected a preference for weekly testing. Children preferred nose swabs and oral fluids over throat swabs or blood sampling

Evaluation of immunogenicity and reactogenicity of COVID-19 vaccines in pregnant women.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with increased risk of adverse maternal and perinatal outcomes. Vaccines are highly effective at preventing severe coronavirus disease 2019 (COVID-19), but there are limited data on COVID-19 vaccines in pregnancy. This study aimed to investigate the reactogenicity and immunogenicity of COVID-19 vaccines in pregnant women when administered according to the 12-week-interval dosing schedule recommended in the UK. METHODS: This was a cohort study of pregnant women receiving COVID-19 vaccination between April and September 2021. The outcomes were immunogenicity and reactogenicity after COVID-19 vaccination. Pregnant women were recruited by phone, e-mail and/or text and were vaccinated according to vaccine availability at their local vaccination center. For immunogenicity assessment, blood samples were taken at specific timepoints after each dose to evaluate nucleocapsid protein (N) and spike protein (S) antibody titers. The comparator group comprised non-pregnant female healthcare workers in the same age group who were vaccinated as part of the national immunization program in a contemporaneous longitudinal cohort study. Longitudinal changes in serum antibody titers and association with pregnancy status were assessed using a two-step regression approach. Reactogenicity assessment in pregnant women was undertaken using an online questionnaire. The comparator group comprised non-pregnant women aged 18-49 years who had received two vaccine doses in primary care. The association of pregnancy status with reactogenicity was assessed using logistic regression analysis. RESULTS: Overall, 67 pregnant women, of whom 66 had received a mRNA vaccine, and 79 non-pregnant women, of whom 50 had received a mRNA vaccine, were included in the immunogenicity study. Most (61.2%) pregnant women received their first vaccine dose in the third trimester, while 3.0% received it in the first trimester and 35.8% in the second trimester. SARS-CoV-2 S-antibody geometric mean concentrations after mRNA vaccination were not significantly different at 2-6 weeks after the first dose but were significantly lower at 2-6 weeks after the second dose in infection-naïve pregnant compared with non-pregnant women. In pregnant women, prior infection was associated with higher antibody levels at 2-6 weeks after the second vaccine dose. Reactogenicity analysis included 108 pregnant women and 116 non-pregnant women. After the first dose, tiredness and chills were reported less commonly in pregnant compared with non-pregnant women (P = 0.043 and P = 0.029, respectively). After the second dose, feeling generally unwell was reported less commonly (P = 0.046) in pregnant compared with non-pregnant women. CONCLUSIONS: Using an extended 12-week interval between vaccine doses, antibody responses after two doses of mRNA COVID-19 vaccine were found to be lower in pregnant compared with non-pregnant women. Strong antibody responses were achieved after one dose in previously infected women, regardless of pregnancy status. Pregnant women reported fewer adverse events after both the first and second dose of vaccine. These findings should now be addressed in larger controlled studies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

COVID-19 deaths in children and young people in England, March 2020 to December 2021: An active prospective national surveillance study.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) deaths are rare in children and young people (CYP). The high rates of asymptomatic and mild infections complicate assessment of cause of death in CYP. We assessed the cause of death in all CYP with a positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test since the start of the pandemic in England. METHODS AND FINDINGS: CYP aged <20 years who died within 100 days of laboratory-confirmed SARS-CoV-2 infection between 01 March 2020 and 31 December 2021 in England were followed up in detail, using national databases, surveillance questionnaires, post-mortem reports, and clinician interviews. There were 185 deaths during the 22-month follow-up and 81 (43.8%) were due to COVID-19. Compared to non-COVID-19 deaths in CYP with a positive SARS-CoV-2 test, death due to COVID-19 was independently associated with older age (aOR 1.06 95% confidence interval (CI) 1.01 to 1.11, p = 0.02) and underlying comorbidities (aOR 2.52 95% CI 1.27 to 5.01, p = 0.008), after adjusting for age, sex, ethnicity group, and underlying conditions, with a shorter interval between SARS-CoV-2 testing and death. Half the COVID-19 deaths (41/81, 50.6%) occurred within 7 days of confirmation of SARS-CoV-2 infection and 91% (74/81) within 30 days. Of the COVID-19 deaths, 61 (75.3%) had an underlying condition, especially severe neurodisability (n = 27) and immunocompromising conditions (n = 12). Over the 22-month surveillance period, SARS-CoV-2 was responsible for 1.2% (81/6,790) of all deaths in CYP aged <20 years, with an infection fatality rate of 0.70/100,000 SARS-CoV-2 infections in this age group estimated through real-time, nowcasting modelling, and a mortality rate of 0.61/100,000. Limitations include possible under-ascertainment of deaths in CYP who were not tested for SARS-CoV-2 and lack of direct access to clinical data for hospitalised CYP. CONCLUSIONS: COVID-19 deaths remain extremely rare in CYP, with most fatalities occurring within 30 days of infection and in children with specific underlying conditions

Implementation of preventive measures to prevent COVID-19: a national study of English primary schools in summer 2020.

We examined the feasibility of implementing preventive measures to prevent SARS-CoV-2 transmission across 105 English primary schools in summer 2020 via a survey and interviews with headteachers. High rates of implementation of most recommended measures were noted with the exception of requiring 2 m distance for students, fitting hand sanitizers in classrooms and introducing one-way systems in school corridors. Measures such as regular handwashing and stopping assemblies were considered easy to implement. Majorly challenging measures included distancing between individuals (for students: 51%, N = 99; for staff: 34%; N = 98; for parents: 26%, N = 100), spacing out desks (34%, N = 99), keeping same staff assigned to each student group (33%, N = 97) and staggering break times (25%, N = 99). Rapid implementation was facilitated by staff commitment and communication among stakeholders, but hampered by limitations with guidance received, physical environments, resources, parental adherence and balancing preventive measures with learning. Difficulties with distancing for younger children suggest that smaller bubbles with fewer distancing requirements within these may be a policy option. Schools require further financial, human resource and other support for effective implementation of preventive measures