A Mechanogenetic Toolkit for Interrogating Cell Signaling in Space and Time.

Tools capable of imaging and perturbing mechanical signaling pathways with fine spatiotemporal resolution have been elusive, despite their importance in diverse cellular processes. The challenge in developing a mechanogenetic toolkit (i.e., selective and quantitative activation of genetically encoded mechanoreceptors) stems from the fact that many mechanically activated processes are localized in space and time yet additionally require mechanical loading to become activated. To address this challenge, we synthesized magnetoplasmonic nanoparticles that can image, localize, and mechanically load targeted proteins with high spatiotemporal resolution. We demonstrate their utility by investigating the cell-surface activation of two mechanoreceptors: Notch and E-cadherin. By measuring cellular responses to a spectrum of spatial, chemical, temporal, and mechanical inputs at the single-molecule and single-cell levels, we reveal how spatial segregation and mechanical force cooperate to direct receptor activation dynamics. This generalizable technique can be used to control and understand diverse mechanosensitive processes in cell signaling. VIDEO ABSTRACT.

Optimization of Timing of Maternal Pertussis Immunization From 6 Years of Postimplementation Surveillance Data in England.

BACKGROUND: England's third-trimester maternal pertussis vaccination, introduced in October 2012, was extended to the second trimester in 2016. Maternal vaccination provides high protection against infant disease, but routine second-trimester vaccination has not previously been assessed. METHODS: National laboratory-confirmed pertussis case surveillance determined vaccination history, maternal vaccination history and hospitalization. Pertussis hospital admissions between 2012 and 2019 were extracted from the Hospital Episode Statistics data set. Vaccine effectiveness (VE) was calculated for pertussis case patients born between October 2012 and September 2018 using the screening method and matching with a nationally representative data set. RESULTS: Higher coverage was observed after earlier maternal vaccination with approximately 40% of pregnant women vaccinated ≥13 weeks before delivery. Cases and hospitalizations stabilized at low levels in younger infants but remained elevated in older infants, children, and adults. No deaths occurred in infants with vaccinated mothers after 2016. Of 1162 laboratory-confirmed pertussis cases in the study, 599 (52%) were in infants aged <93 days: 463 (77%) with unvaccinated and 136 (23%) with vaccinated mothers. The VE was equivalent in infants with mothers vaccinated at different gestational periods except in those with mothers vaccinated between 7 days before and 41 days after delivery. Children whose mothers were unvaccinated but with vaccination in a previous pregnancy had a VE against disease of 44% (95% confidence interval, 19%-75%). There was no increased disease risk after primary vaccination in children with mothers vaccinated at least 7 days before delivery. CONCLUSIONS: National policy recommending vaccination in the second trimester increased earlier maternal vaccine uptake with sustained high VE and impact against early infant disease.

Increased Incidence of Invasive Pneumococcal Disease among Children after COVID-19 Pandemic, England.

During July-December 2021, after COVID-19 restrictions were removed in England, invasive pneumococcal disease incidence in children <15 years of age was higher (1.96/100,000 children) than during the same period in 2020 (0.7/100,000 children) and in prepandemic years 2017-2019 (1.43/100,000 children). Childhood vaccine coverage should be maintained to protect the population.

Impact of the COVID-19 pandemic on Bordetella pertussis infections in England.

BACKGROUND: In March 2020, England went into its first lockdown in response to the COVID-19 pandemic. Restrictions eased temporarily, followed by second and third waves in October 2020 and January 2021. Recent data showed that the COVID-19 pandemic resulted in reduced transmission of some invasive diseases. We assess the impact of the COVID-19 pandemic on pertussis incidence and on the immunisation programme in England. METHODS: We assessed trends in pertussis cases from 2012 to 2020 by age group and month. Incidence from the time that England eased its initial lockdown measures in July 2020 through to summer 2021 was calculated and the incidence rate ratios of pertussis cases from five years prior to the pandemic (July 2014 - June 2019) compared to the same time period during the pandemic (July 2020 - June 2021). Vaccine coverage estimates for pertussis containing vaccines were reviewed for the maternal and childhood programmes. RESULTS: A substantial decline in pertussis cases was observed from April 2020 onwards, marking the lowest number of cases in the last decade. Pertussis incidence dropped in all age groups, particularly among infants less than one year old (0.50 / 100,000 during July 2020 to June 2021 compared to 24.49/ 100,000 from July 2014 to June 2019). The incidence rate ratio was 0.02 (95% CI 0.01 to 0.02) for July 2014 to June 2019 (pre-pandemic) compared to the pandemic period of July 2020 to June 2021. None of the cases had a co-infection with SARS-CoV-2. Vaccine coverage for infants born between January to March 2020 with three doses of pertussis vaccine by 12 months of age decreased by 1.1% points compared to infants born between January to March 2019 (91.6% and 92.7%, respectively). Prenatal pertussis coverage for the 2020 to 2021 financial year was 2.7% points lower than the year prior to the pandemic (70.5% and 76.8%, respectively). CONCLUSIONS: Lockdown measures due to the COVID-19 pandemic have had a significant impact on pertussis transmission. With the easing of restrictions it is important to continue monitoring pertussis cases in England alongside coverage of the maternal and childhood immunisation programmes.

The Global Landscape of Pediatric Bacterial Meningitis Data Reported to the World Health Organization-Coordinated Invasive Bacterial Vaccine-Preventable Disease Surveillance Network, 2014-2019.

BACKGROUND: The World Health Organization (WHO) coordinates the Global Invasive Bacterial Vaccine-Preventable Diseases (IB-VPD) Surveillance Network to support vaccine introduction decisions and use. The network was established to strengthen surveillance and laboratory confirmation of meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. METHODS: Sentinel hospitals report cases of children <5 years of age hospitalized for suspected meningitis. Laboratories report confirmatory testing results and strain characterization tested by polymerase chain reaction. In 2019, the network included 123 laboratories that follow validated, standardized testing and reporting strategies. RESULTS: From 2014 through 2019, >137 000 suspected meningitis cases were reported by 58 participating countries, with 44.6% (n = 61 386) reported from countries in the WHO African Region. More than half (56.6%, n = 77 873) were among children <1 year of age, and 4.0% (n = 4010) died among those with reported disease outcome. Among suspected meningitis cases, 8.6% (n = 11 798) were classified as probable bacterial meningitis. One of 3 bacterial pathogens was identified in 30.3% (n = 3576) of these cases, namely S. pneumoniae (n = 2177 [60.9%]), H. influenzae (n = 633 [17.7%]), and N. meningitidis (n = 766 [21.4%]). Among confirmed bacterial meningitis cases with outcome reported, 11.0% died; case fatality ratio varied by pathogen (S. pneumoniae, 12.2%; H. influenzae, 6.1%; N. meningitidis, 11.0%). Among the 277 children who died with confirmed bacterial meningitis, 189 (68.2%) had confirmed S. pneumoniae. The proportion of pneumococcal cases with pneumococcal conjugate vaccine (PCV) serotypes decreased as the number of countries implementing PCV increased, from 77.8% (n = 273) to 47.5% (n = 248). Of 397 H. influenzae specimens serotyped, 49.1% (n = 195) were type b. Predominant N. meningitidis serogroups varied by region. CONCLUSIONS: This multitier, global surveillance network has supported countries in detecting and serotyping the 3 principal invasive bacterial pathogens that cause pediatric meningitis. Streptococcus pneumoniae was the most common bacterial pathogen detected globally despite the growing number of countries that have nationally introduced PCV. The large proportions of deaths due to S. pneumoniae reflect the high proportion of meningitis cases caused by this pathogen. This global network demonstrated a strong correlation between PCV introduction status and reduction in the proportion of pneumococcal meningitis infections caused by vaccine serotypes. Maintaining case-based, active surveillance with laboratory confirmation for prioritized vaccine-preventable diseases remains a critical component of the global agenda in public health.The World Health Organization (WHO)-coordinated Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network reported data from 2014 to 2019, contributing to the estimates of the disease burden and serotypes of pediatric meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.

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.

Investigation of a pertussis outbreak and comparison of two acellular booster pertussis vaccines in a junior school in South East England, 2019.

In March 2019, a pertussis outbreak occurred in children in a junior school (7-11 years) in England who had been offered pertussis-containing booster vaccine at 40 months of age. In a case-control investigation, we assessed the extent of transmission and any difference in protection afforded to those who had previously received a booster 3- or 5-component acellular pertussis vaccine (aP). We took oral fluid specimens from the students to determine IgG antibodies against pertussis toxin (anti-PT). Parents of students attending the school were sent a questionnaire on pertussis symptoms and vaccination status was retrieved from general practitioner records for all students. Of 381 students, 134 (35.2%) were classified as pertussis cases, 133 by demonstration of significant anti-PT IgG titres and one clinically. There was no significant difference in the risk of pertussis between students receiving 3-component (33.7%) or 5-component (32.3%) aP boosters. However, pertussis infection differed significantly in school year 4, with 22.9%, 50.0%, 23.7% and 38.1% pertussis cases in years 3, 4, 5 and 6, respectively. The proportion of students with incomplete vaccinations recorded was higher than the proportion of those not covered according to the national reported coverage, possibly contributing to sustained transmission within the school.

Retrospective cohort study investigating extent of pertussis transmission during a boarding school outbreak, England, December 2017 to June 2018.

On 1 May 2018, a pertussis outbreak was declared and widespread vaccination recommended at an all-female secondary boarding school in southern England. We conducted a retrospective cohort study to determine the extent of pertussis transmission and identify risk factors in this semi-closed population. Of 504 students and staff assessed before post-exposure vaccination, 48% (n = 240) had evidence of pertussis. A sub-analysis of 409 students found that both residential dormitory (p = 0.05) and school year (p = 0.03) were associated with pertussis, with odds decreasing by 11% for each increase in school year (95% confidence interval: 0.7-20.2). Odds of pertussis were 1.7 times higher in those assumed to have received acellular vaccines for their primary course compared with those assumed to have received whole-cell vaccines (based on date of birth), although this difference was not significant (p = 0.12). Our findings support the need for timely, widespread vaccination following identification of cases among adolescents in a semi-closed United Kingdom (UK) setting and to review the evidence for the introduction of an adolescent pertussis booster to the UK routine vaccination programme.

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.

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: A case-control test-negative design study.

BACKGROUND: Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP). METHODS AND FINDINGS: Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 - odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%-40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%-40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI -5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI -37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%-46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups. CONCLUSIONS: In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults.

Pneumococcal serotype trends, surveillance and risk factors in UK adult pneumonia, 2013-18.

BACKGROUND: Changes over the last 5 years (2013-18) in the serotypes implicated in adult pneumococcal pneumonia and the patient groups associated with vaccine-type disease are largely unknown. METHODS: We conducted a population-based prospective cohort study of adults admitted to two large university hospitals with community-acquired pneumonia (CAP) between September 2013 and August 2018. Pneumococcal serotypes were identified using a novel 24-valent urinary monoclonal antibody assay and from blood cultures. Trends in incidence rates were compared against national invasive pneumococcal disease (IPD) data. Persons at risk of vaccine-type pneumonia (pneumococcal conjugate vaccine (PCV)13 and pneumococcal polysaccharide vaccine (PPV)23) were determined from multivariate analyses. FINDINGS: Of 2934 adults hospitalised with CAP, 1075 (36.6%) had pneumococcal pneumonia. The annual incidence of pneumococcal pneumonia increased from 32.2 to 48.2 per 100 000 population (2013-18), predominantly due to increases in PCV13non7-serotype and non-vaccine type (NVT)-serotype pneumonia (annual incidence rate ratio 1.12, 95% CI 1.04 to 1.21 and 1.19, 95% CI 1.10 to 1.28, respectively). Incidence trends were broadly similar to IPD data. PCV13non7 (56.9% serotype 3) and PPV23non13 (44.1% serotype 8) serotypes were identified in 349 (32.5%) and 431 (40.1%) patients with pneumococcal pneumonia, respectively. PCV13-serotype pneumonia (dominated by serotype 3) was more likely in patients in the UK pneumococcal vaccination clinical risk group (adjusted OR (aOR) 1.73, 95% CI 1.31 to 2.28) while PPV23-serotype pneumonia was more likely in patients outside the clinical risk group (aOR 1.54, 95% CI 1.13 to 2.10). INTERPRETATION: The incidence of pneumococcal CAP is increasing, predominantly due to NVT serotypes and serotype 3. PPV23-serotype pneumonia is more likely in adults outside currently identified clinical risk groups.

The changing epidemiology of diphtheria in the United Kingdom, 2009 to 2017.

BackgroundDiphtheria is a potentially fatal disease caused by toxigenic strains of Corynebacterium diphtheriae, C. ulcerans or C. pseudotuberculosis.AimOur objective was to review the epidemiology of diphtheria in the United Kingdom (UK) and the impact of recent changes in public health management and surveillance.MethodsPutative human toxigenic diphtheria isolates in the UK are sent for species confirmation and toxigenicity testing to the National Reference Laboratory. Clinical, epidemiological and microbiological information for toxigenic cases between 2009 and 2017 are described in this population-based prospective surveillance study.ResultsThere were 33 toxigenic cases of diphtheria aged 4 to 82 years. Causative species were C. diphtheriae (n = 18) and C. ulcerans (n = 15). Most C. diphtheriae cases were cutaneous (14/18) while more than half of C. ulcerans cases had respiratory presentations (8/15). Two thirds (23/33) of cases were inadequately immunised. Two cases with C. ulcerans infections died, both inadequately immunised. The major risk factor for C. diphtheriae aquisition was travel to an endemic area and for C. ulcerans, contact with a companion animal. Most confirmed C. diphtheriae or C. ulcerans isolates (441/507; 87%) submitted for toxigenicity testing were non-toxigenic, however, toxin positivity rates were higher (15/23) for C. ulcerans than C. diphtheriae (18/469). Ten non-toxigenic toxin gene-bearing (NTTB) C. diphtheriae were also detected.ConclusionDiphtheria is a rare disease in the UK. In the last decade, milder cutaneous C. diphtheriae cases have become more frequent. Incomplete vaccination status was strongly associated with the risk of hospitalisation and death.

Hybrid Lithographic and DNA-Directed Assembly of a Configurable Plasmonic Metamaterial That Exhibits Electromagnetically Induced Transparency.

Metamaterials are architectures that interact with light in novel ways by virtue of symmetry manipulation, and have opened a window into studying unprecedented light-matter interactions. However, they are commonly fabricated via lithographic methods, are usually static structures, and are limited in how they can react to external stimuli. Here we show that by combining lithographic techniques with DNA-based self-assembly methods, we can construct responsive plasmonic metamaterials that exhibit the plasmonic analog of an effect known as electromagnetically induced transparency (EIT), which can dramatically change their spectra upon motion of their constituent parts. Correlative scanning electron microscopy measurements, scattering dark-field microscopy, and computational simulations are performed on single assemblies to determine the relationship between their structures and spectral responses to a variety of external stimuli. The strength of the EIT-like effect in these assemblies can be tuned by precisely controlling the positioning of the plasmonic nanoparticles in these structures. For example, changing the ionic environment or dehydrating the sample will change the conformation of the DNA linkers and therefore the distance between the nanoparticles. Dark-field spectra of individual assemblies show peak shifts of up to many tens of nanometers upon DNA perturbations. This dynamic metamaterial represents a stepping stone toward state-of-the-art plasmonic sensing platforms and next-generation dynamic metamaterials.

Transmission of toxigenic Corynebacterium diphtheriae by a fully immunised resident returning from a visit to West Africa, United Kingdom, 2017.

In early 2017, a United Kingdom (UK)-born person in their 20s presented with a skin ulcer on the foot 3 weeks after returning from Ghana. The patient had last received a diphtheria-containing vaccine in 2013, completing the recommended course. MALDI-TOF of a cutaneous swab identified Corynebacterium diphtheriae. Real-time PCR ascertained the species and presence of the diphtheria toxin gene. An Elek test confirmed toxigenicity. The isolate was macrolide sensitive and penicillin resistant. The local Public Health England (PHE) Health Protection Team obtained the patient's clinical history and traced contacts to inform appropriate public health action. One close contact (in their early 80s with uncertain immunisation status who had not recently travelled) had a positive throat swab for toxigenic C. diphtheriae and reported a history of mild coryzal symptoms. Multilocus sequence typing revealed that strains from the index case and contact had Sequence Type 463. Diphtheria is extremely rare in the UK due to high vaccine coverage and this is the first documented transmission in 30 years. Clinicians and laboratory staff should remain highly suspicious of lesions in overseas travellers, even when patients are fully vaccinated. Older individuals who might not have completed a full immunisation course may have higher diphtheria susceptibility.

Neonatal invasive Haemophilus influenzae disease in England and Wales: epidemiology, clinical characteristics, and outcome.

BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) frequently causes noninvasive upper respiratory tract infections in children but can cause invasive disease, mainly in older adults. An increased burden of invasive NTHi disease in the perinatal period has been reported by a number of studies. Here we describe the epidemiology, clinical characteristics, and outcome of neonatal invasive H. influenzae disease in England and Wales over a 5-year period. METHODS: Public Health England conducts enhanced national surveillance of invasive H. influenzae disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed cases in infants aged ≤31 days during 2009-2013. RESULTS: Overall, 118 live-born neonates had laboratory-confirmed invasive H. influenzae disease: 115 (97%) were NTHi, 2 were serotype f, and 1 was serotype b. NTHi was isolated within 48 hours of birth (early-onset) in 110 of 115 (96%) cases, and 70 of 110 (64%) presented with septicemia. Only 17 mothers (15%) had suspected bacterial infection requiring antibiotics during labor. Few (8/110 [7%]) neonates had comorbidities. The incidence of early-onset NTHi increased exponentially with prematurity, from 0.9 per 100 000 (95% confidence interval [CI], .6-1.4) in term neonates to 342 per 100 000 (95% CI, 233.9-482.7) in neonates born at <28 weeks' gestation (incidence rate ratio, 365 [95% CI, 205-659]; P < .001). Case fatality for early-onset NTHi was 19% (21/110); each additional gestational week reduced the odds of dying by 21% (odds ratio, 0.79 [95% CI, .69-.90]; P < .01). A quarter of neonates who survived experienced long-term complications. CONCLUSIONS: Early-onset neonatal NTHi disease is strongly associated with premature birth and causes significant morbidity and mortality.

Colonisation with toxigenic Corynebacterium diphtheriae in a Scottish burns patient, June 2015.

On 12 June 2015, Corynebacterium diphtheriae was identified in a skin swab from a burns patient in Scotland. The isolate was confirmed to be genotypically and phenotypically toxigenic. Multilocus sequence typing of three patient isolates yielded sequence type ST 125. The patient was clinically well. We summarise findings of this case, and results of close contact identification and screening: 12 family and close contacts and 32 hospital staff have been found negative for C. diphtheriae.

Oral fluid testing for pertussis, England and wales, june 2007-august 2009.

Existing pertussis surveillance systems tend to underidentify less severe cases among older children and adults. For routine follow-up of notified, nonconfirmed, clinically diagnosed pertussis cases, use of an oral fluid test was pilot tested in England and Wales during June 2007-August 2009. During that period, 1,852 cases of pertussis were confirmed by established laboratory methods and another 591 by oral fluid testing only. Although introduction of serologic testing in 2002 led to the greatest increase in ascertainment of pertussis, oral fluid testing increased laboratory ascertainment by 32% overall; maximal increase (124%) occurred among children 5-9 years of age. Patients whose pertussis was confirmed by oral fluid testing were least likely to be hospitalized, suggesting that milder community cases were being confirmed by this method. Oral fluid testing is an easily administered, noninvasive surveillance tool that could further our understanding of pertussis epidemiology and thereby contribute to decisions on vaccination strategies.

Risk of invasive Haemophilus influenzae infection during pregnancy and association with adverse fetal outcomes.

IMPORTANCE: Unencapsulated Haemophilus influenzae frequently causes noninvasive upper respiratory tract infections in children but can also cause invasive disease, especially in older adults. A number of studies have reported an increased incidence in neonates and suggested that pregnant women may have an increased susceptibility to invasive unencapsulated H. influenzae disease. OBJECTIVE: To describe the epidemiology, clinical characteristics, and outcomes of invasive H. influenzae disease in women of reproductive age during a 4-year period. DESIGN, SETTING, AND PARTICIPANTS: Public Health England conducts enhanced national surveillance of invasive H. influenzae disease in England and Wales. Clinical questionnaires were sent prospectively to general practitioners caring for all women aged 15 to 44 years with laboratory-confirmed invasive H. influenzae disease during 2009-2012, encompassing 45,215,800 woman-years of follow-up. The final outcome was assessed in June 2013. EXPOSURES: Invasive H. influenzae disease confirmed by positive culture from a normally sterile site. MAIN OUTCOMES AND MEASURES: The primary outcome was H. influenzae infection and the secondary outcomes were pregnancy-related outcomes. RESULTS: In total, 171 women had laboratory-confirmed invasive H. influenzae infection, which included 144 (84.2%; 95% CI, 77.9%-89.3%) with unencapsulated, 11 (6.4%; 95% CI, 3.3%-11.2%) with serotype b, and 16 (9.4%; 95% CI, 5.4%-14.7%) with other encapsulated serotypes. Questionnaire response rate was 100%. Overall, 75 of 171 women (43.9%; 95% CI, 36.3%-51.6%) were pregnant at the time of infection, most of whom were previously healthy and presented with unencapsulated H. influenzae bacteremia. The incidence rate of invasive unencapsulated H. influenzae disease was 17.2 (95% CI, 12.2-24.1; P < .001) times greater among pregnant women (2.98/100,000 woman-years) compared with nonpregnant women (0.17/100,000 woman-years). Unencapsulated H. influenzae infection during the first 24 weeks of pregnancy was associated with fetal loss (44/47; 93.6% [95% CI, 82.5%-98.7%]) and extremely premature birth (3/47; 6.4% [95% CI, 1.3%-17.5%]). Unencapsulated H. influenzae infection during the second half of pregnancy was associated with premature birth in 8 of 28 cases (28.6%; 95% CI, 13.2%-48.7%) and stillbirth in 2 of 28 cases (7.1%; 95% CI, 0.9%-23.5%). The incidence rate ratio for pregnancy loss was 2.91 (95% CI, 2.13-3.88) for all serotypes of H. influenzae and 2.90 (95% CI, 2.11-3.89) for unencapsulated H. influenzae compared with the background rate for pregnant women. CONCLUSIONS AND RELEVANCE: Among women in England and Wales, pregnancy was associated with a greater risk of invasive H. influenzae infection. These infections were associated with poor pregnancy outcomes.

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.