National and regional prevalence of SARS-CoV-2 antibodies in primary and secondary school children in England: the School Infection Survey, a national open cohort study, November 2021

BackgroundRisk factors for infection and, therefore, antibody positivity rates will be different in children compared to adults. We aim to estimate national and regional prevalence of SARS-CoV-2 antibodies in primary (4-11-year-olds) and secondary (11-15-year-olds) school children between 10 November and 10 December 2021. MethodsCross-sectional surveillance in England using two stage sampling, firstly stratifying into regions and selecting local authorities, then selecting schools according to a stratified sample within selected local authorities. Participants were sampled using a novel oral fluid validated assay for SARS-CoV-2 spike and nucleocapsid IgG antibodies. Results4,980 students from 117 state-funded schools (2,706 from 83 primary schools, 2,274 from 34 secondary schools) provided a valid sample. After weighting for age, sex and ethnicity, and adjusting for assay accuracy, the national prevalence of SARS-CoV-2 antibodies in primary school students, who were all unvaccinated, was 40.1% (95%CI; 37.3-43.0). Antibody prevalence increased with age (p<0.001) and were higher in urban than rural schools (p=0.01). In secondary school students, the adjusted, weighted national prevalence of SARS-CoV-2 antibodies was 82.4% (95%CI; 79.5-85.1); including 57.5% (95%CI; 53.9-61.1) in unvaccinated and 97.5% (95%CI; 96.1-98.5) in vaccinated students. Antibody prevalence increased with age (p<0.001), and was not significantly different in urban versus rural students (p=0.1). ConclusionsUsing a validated oral fluid assay, we estimated national and regional seroprevalence of SARS-CoV-2 antibodies in primary and secondary school students. In November 2021, 40% of primary school students and nearly all secondary school students in England had SARS-CoV2 antibodies through a combination of natural infection and vaccination.

Primary Omicron infection elicits weak antibody response but robust cellularimmunity in children

The Omicron variant of SARS-CoV-2 is now globally dominant but despite high prevalence little is known regarding the immune response in children. We determined the antibody and cellular immune response following Omicron infection in children aged 6-14 years and related this to prior SARS-CoV-2 infection and vaccination status. Primary Omicron infection elicited a weak antibody response and only 53% of children developed detectable neutralising antibodies. In contrast, children with secondary Omicron infection following prior infection with a pre-Omicron variant developed 24-fold higher antibody titres and neutralisation of Omicron. Vaccination elicited the highest levels of antibody response and was also strongly immunogenic following prior natural infection with Omicron. Cellular responses against Omicron were robust and broadly equivalent in all study groups. These data reveal that primary Omicron infection elicits a weak humoral immune response in children and may presage a clinical profile of recurrent infection as seen with antecedent seasonal coronaviruses. Vaccination may represent the most effective approach to control infection whilst cellular immunity should offer strong clinical protection.

Asymptomatic SARS-CoV-2 infection by age: A systematic review and meta-analysis

ObjectivesThis systematic review and meta-analysis aimed to estimate the age-specific proportion of asymptomatic SARS-CoV-2 infected persons by year of age. MethodsWe searched PubMed, Embase, medRxiv and Google Scholar on 10 September 2020 and 1 March 2021. We included studies conducted during January to October 2020, prior to routine vaccination against COVID-19. Since we expected the relationship between the asymptomatic proportion and age to be non-linear, multilevel mixed-effects logistic regression (QR decomposition) with a restricted cubic spline was used to model asymptomatic proportions as a function of age. ResultsA total of 38 studies were included in the meta-analysis. In total, 6556 out of 14850 cases were reported as asymptomatic. The overall estimate of the proportion of people who became infected with SARS-CoV-2 and remained asymptomatic throughout infection was 44.1% (6556/14850, 95%CI 43.3%-45.0%). The asymptomatic proportion peaked in adolescents (36.2%, 95%CI 26.0%-46.5%) at 13.5 years, gradually decreased by age and was lowest at 90.5 years of age (8.1%, 95%CI 3.4%-12.7%). ConclusionsGiven the high rates of asymptomatic carriage in adolescents and young adults and their active role in virus transmission in the community, heightened vigilance and public health strategies are needed among these individuals to prevent disease transmission.

Developing a model for predicting impairing physical symptoms in children 3 months after a SARS-CoV-2 PCR-test: The CLoCk Study

ImportancePredictive models can help identify SARS-CoV-2 patients at greatest risk of post-COVID sequelae and direct them towards appropriate care. ObjectiveTo develop and internally validate a model to predict children and young people most likely to experience at least one impairing physical symptom 3 months after a SARS-CoV-2 PCR-test and to determine whether the impact of these predictors differed by SARS-CoV-2 infection status. DesignPotential pre-specified predictors included: SARS-CoV-2 status, sex, age, ethnicity, deprivation, quality of life/functioning (5 EQ-5D-Y items), physical and mental health, and loneliness (all prior to SARS-CoV-2 testing), and number of physical symptoms at testing. Logistic regression was used to develop the model. Model performance was assessed using calibration and discrimination measures; internal validation was performed via bootstrapping; the final model was adjusted for overfitting. SettingNational cohort study of SARS-CoV-2 PCR-positive and PCR-negative participants matched according to age, sex, and geographical area. ParticipantsChildren and young people aged 11-17 years who were tested for SARS-CoV-2 infection in England, January to March 2021. Main outcome measureone or more physical symptom 3 months after initial PCR-testing which affected physical, mental or social well-being and interfered with daily living. ResultsA total of 50,836 children and young people were approached; 7,096 (3,227 test-positives, 3,869 test-negatives) who completed a questionnaire 3 months after their PCR-test were included. 39.6% (1,279/3,227) of SAR-CoV-2 PCR-positives and 30.6% (1,184/3,869) of SAR-CoV-2 PCR-negatives had at least one impairing physical symptom 3 months post-test. The final model contained predictors: SARS-COV-2 status, number of symptoms at testing, sex, age, ethnicity, self-rated physical and mental health, feelings of loneliness and four EQ-5D-Y items before testing. Internal validation showed minimal overfitting with excellent calibration and discrimination measures (optimism adjusted calibration slope:0.97527; C-statistic:0.83640). Conclusions and relevanceWe developed a risk prediction equation to identify those most at risk of experiencing at least one impairing physical symptom 3 months after a SARS-CoV-2 PCR-test which could serve as a useful triage and management tool for children and young people during the ongoing pandemic. External validation is required before large-scale implementation. Key PointsO_ST_ABSQuestionC_ST_ABSWhich children have impairing physical symptoms during the COVID-19 pandemic? FindingsUsing data from a large national matched cohort study in children and young people (CYP) aged 11-17 years (N=7,096), we developed a prediction model for experiencing at least one impairing physical symptom 3 months after testing for SARS-COV-2. Our model had excellent predictive ability, calibration and discrimination; we used it to produce a risk estimation calculator. MeaningOur developed risk calculator could serve as a useful tool in the early identification and management of CYP at risk of persisting physical symptoms in the context of the COVID-19 pandemic.

Lower Risk of Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) with the Delta variant of SARS-CoV-2

Little is known about the MIS-C risk with different SARS-CoV-2 variants. In Southeast England, MIS-C rates per confirmed SARS-CoV-2 infections in 0-16 years-olds were 56% lower (rate ratio, 0.34; 95%CI, 0.23-0.50) during pre-vaccine Delta, 66% lower (0.44; 0.28-0.69) during post-vaccine Delta and 95% lower (0.05; 0.02-0.10) during the Omicron period.

Serological responses and six-month trajectories to COVID-19 Comirnaty and Spikevax booster vaccine, September 2021 to January 2022, London, United Kingdom

In contrast to the increasing levels of high avidity S antibody measured by the Roche assay in the first 6 months following natural infection, marked waning is seen post 2 or 3 doses of vaccine. Although the kinetics differ between those with vaccine-induced immunity compared to those infected prior to vaccination (hybrid immunity), waning rates appear to be similar following 2 or 3 doses of vaccine. These data should allow countries to optimise the timing of future doses of vaccine.

Cross-Sectional Study of University students attitudes to on campus delivery of COVID-19 vaccines and future-proofing MenACWY and MMR vaccination rates by adopting COVID-19 vaccine roll-out strategies

BackgroundUniversity students are a critical group for vaccination programmes against COVID-19, meningococcal disease (MenACWY), and measles, mumps and rubella (MMR). We aimed to evaluate risk factors for vaccine hesitancy (refusal or intention to refuse a vaccine) and views of university students about on-campus vaccine delivery. MethodsCross-sectional anonymous online questionnaire study of undergraduate students at a British university in June 2021. Chi-squared, Fishers exact, univariate and multivariate tests were applied to detect associations. ResultsComplete data were obtained from 827 participants (7.6% response-rate). Two-thirds (64%; 527/827) reported having been vaccinated against COVID-19 and a further 23% (194/827) agreed to be vaccinated. Other responses were either unclear (66) or indicated an intention to refuse vaccination (40). Hesitancy for COVID-19 vaccines was 5% (40/761). COVID-19 vaccine hesitancy was associated with black ethnicity (aOR, 7.01, 95% CI, 1.8-27.3) and concerns about vaccine side-effects (aOR, 1.72; 95% CI, 1.23-2.39). Lower levels of vaccine hesitancy were detected amongst students living in private accommodation (aOR, 0.13; 95% CI, 0.04-0.38) compared to those living at home. Uncertainty about their personal vaccine status was frequently observed for MMR (11%) and MenACWY (26%) vaccines. Campus-associated COVID-19 vaccine campaigns were definitely (45%) or somewhat (16%) favoured by UK-based students and more so among UK-based international students (62% and 12%, respectively). ConclusionsVaccine hesitancy among students of black ethnicity and those living at home requires further exploration because attitudes in these groups may affect COVID-19 vaccine uptake. High levels of uncertainty among students about their MMR and MenACWY vaccine status are also a concern for the effectiveness of these vaccine programmes. This issue could be tackled by extending the capabilities of digital platforms for accessing vaccine information, such as the NHSapp in the UK. Sector-wide implementation of on-campus vaccine delivery may also improve vaccine uptake, especially for international students.

Transmission of SARS-CoV-2 by children and young people in households and schools: a meta-analysis of population-based and contact-tracing studies

BackgroundThe role of children and young people (CYP) in transmission of SARS-CoV-2 in household and educational settings remains unclear. We undertook a systematic review and meta-analysis of contact-tracing and population-based studies at low risk of bias. MethodsWe searched 4 electronic databases on 28 July 2021 for contact-tracing studies and population-based studies informative about transmission of SARS-CoV-2 from 0-19 year olds in household or educational settings. We excluded studies at high risk of bias, including from under-ascertainment of asymptomatic infections. We undertook multilevel random effects meta-analyses of secondary attack rates (SAR: contact-tracing studies) and school infection prevalence, and used meta-regression to examine the impact of community SARS-CoV-2 incidence on school infection prevalence. Findings4529 abstracts were reviewed, resulting in 37 included studies (16 contact-tracing; 19 population studies; 2 mixed studies). The pooled relative transmissibility of CYP compared with adults was 0.92 (0.68, 1.26) in adjusted household studies. The pooled SAR from CYP was lower (p=0.002) in school studies 0.7% (0.2, 2.7) than household studies (7.6% (3.6, 15.9). There was no difference in SAR from CYP to child or adult contacts. School population studies showed some evidence of clustering in classes within schools. School infection prevalence was associated with contemporary community 14-day incidence (OR 1.003 (1.001, 1.004), p<0.001). InterpretationWe found no difference in transmission of SARS-CoV-2 from CYP compared with adults within household settings. SAR were markedly lower in school compared with household settings, suggesting that household transmission is more important than school transmission in this pandemic. School infection prevalence was associated with community infection incidence, supporting hypotheses that school infections broadly reflect community infections. These findings are important for guiding policy decisions on shielding, vaccination school and operations during the pandemic. FundingNo funding obtained.

Risk of SARS-CoV-2 reinfections in children: prospective national surveillance, January 2020 to July 2021, England

BackgroundReinfection after primary SARS-CoV-2 infection is uncommon in adults, but little is known about the risks, characteristics, severity or outcomes of reinfection in children. MethodsWe used national SARS-CoV-2 testing data in England to estimate the risk of reinfection [≥]90 days after primary infection from 01 January 2020 to 31 July 2021, which encompassed both the Alpha and Delta waves in England. Disease severity was assessed by linking reinfection cases to national hospitalisation, intensive care admission and death registrations datasets. FindingsReinfection rates closely followed community infection rates, with a small peak during the Alpha wave and a larger peak during the Delta wave. In children aged [≤]16 years, there were 688,418 primary infections and 2,343 reinfections. The overall reinfection rate was 66{middle dot}88/100,000 population, being higher in adults (72.53/100,000) than in children (21{middle dot}53/100,000). Reinfection rates after primary infection were 0{middle dot}68% overall, 0{middle dot}73% in adults and 0{middle dot}34% in children. Of the 109 reinfections in children admitted to hospital, 78 (72%) had underlying comorbidities. Hospitalisation rates were similar for the first (64/2343, 2{middle dot}73%) and second episode (57/2343, 2{middle dot}43%). Intensive care admission was rare after primary infection (n=7) or reinfection (n=4), mainly in children with comorbidities. 44 deaths occurred after primary infection within 28 days of diagnosis (44/688,418, 0{middle dot}01%), none after possible reinfections. InterpretationThe risk of SARS-CoV-2 reinfection is strongly related to exposure due to community infection rates, especially during the Delta variant wave. Children had a lower risk of reinfection than adults, but reinfections were not associated with more severe disease or fatal outcomes. FundingPHE/UKHSA Research in ContextO_ST_ABSEvidence Before this studyC_ST_ABSWe searched PubMed with the terms "COVID-19" or "SARS-CoV-2" with "reinfection" to identify publications relating to SARS-CoV-2 reinfections from 01 January until 15 November 2021. There were few publications relating to SARS-CoV-2 reinfections, and these primarily related to adults. Published studies reported very low rates of reinfection during the first few months after primary infection in adults. COVID-19 vaccines provide effective immune protection against SARS-CoV-2 infection, but recent studies have reported increasing risk of breakthrough infection with time since primary vaccination due to waning immunity. Several SARS-CoV-2 variants, including the beta, gamma and delta variants have been shown to partially evade immunity after natural infection and vaccination, potentially increasing the risk of reinfections and breakthrough infections, respectively. Data on reinfections in children are lacking and restricted mainly to case reports in immunocompromised children. Added Value of This StudyWe used national SARS-CoV-2 testing data during the first 19 months of the pandemic to estimate the risk of reinfection in children compared to adults during a period that encompassed both the Alpha and the Delta variant waves in England. We found that the risk of reinfection correlated with the risk of SARS-CoV-2 exposure and therefore, closely reflected community infection rates, with most reinfections occurring during the Delta variant wave. Whilst acknowledging the limitation of using national testing data, we found that children had a lower risk of reinfection compared to adults and that the risk of reinfection in children increased with age. Reinfections were not associated with severe disease in terms of hospitalization or intensive care admission and there were no fatalities within 28 days of the reinfection episode in children. Implications of all the Available EvidenceSARS-CoV-2 reinfections are rare in children, especially younger children, and occurred mainly during the Delta wave in England. Reinfections were not associated with more severe disease or fatal outcomes in children. COVID-19 vaccination will provide further protection against primary infections and reinfections in children.

Nucleocapsid antibody positivity as a marker of past SARS-CoV-2 infection in population serosurveillance studies: impact of variant, vaccination, and choice of assay cut-off

Serological surveillance studies sometimes use presence of anti-nucleocapsid antibody as a marker of natural SARS-CoV-2 infection. We explore seroconversion rates and antibody levels following Alpha and Delta variant infections, and vaccine breakthrough infections. We find lower seroconversion rates particularly following Alpha-variant vaccine breakthrough infections. We re-evaluate assay performance with a mix of past waned infections and recent breakthrough infections, that is relevant to current serological surveillance.

Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK

BackgroundCOVID-19 vaccines have been used for 9 months in the UK. Real world data have demonstrated the vaccines to be highly effective against COVID-19, severe disease and death. Here, we estimate vaccine effectiveness over time since the second dose of Comirnaty, Vaxzevria and Spikevax in England. MethodsWe used a test-negative case-control design to estimate vaccine effectiveness against symptomatic disease, hospitalisation and mortality by age, comorbidity status and over time after the second dose to investigate waning separately for Alpha and Delta variants. ResultsVaccine effectiveness against symptomatic disease peaked in the early weeks after the second dose and then fell to 47.3 (95% CI 45 to 49.6) and 69.7 (95% CI 68.7 to 70.5) by 20+ weeks against the Delta variant for Vaxzevria and Comirnaty, respectively. Waning of vaccine effectiveness was greater for 65+ year-olds compared to 40-64 year-olds. Vaccine effectiveness fell less against hospitalisations to 77.0 (70.3 to 82.3) and 92.7 (90.3 to 94.6) beyond 20 weeks post-vaccination and 78.7 (95% CI 52.7 to 90.4) and 90.4 (95% CI 85.1 to 93.8) against death for Vaxzevria and Comirnaty, respectively. Greater waning was observed among 65+ year-olds in a clinically extremely vulnerable group and 40-64-year olds with underlying medical conditions compared to healthy adults. ConclusionsWe observed limited waning in vaccine effectiveness against hospitalisation and death more than 20 weeks post-vaccination with Vaxzevria or Comirnaty. Waning was greater in older adults and those in a clinical risk group, suggesting that these individuals should be prioritised for booster doses.

Comparison of children and young people admitted with SARS-CoV-2 across the UK in the first and second pandemic waves: prospective multicentre observational cohort study

BackgroundChildren and young people (CYP) were less affected than adults in the first wave of SARS-CoV-2 in the UK. We test the hypothesis that clinical characteristics of hospitalized CYP with SARS-CoV-2 in the UK second wave would differ from the first due to the combined impact of the alpha variant, school reopening and relaxation of shielding. MethodsPatients <19 years hospitalised in the UK with clinician-reported SARS-CoV-2 were enrolled in a prospective multicentre observational cohort study between 17th January 2020 and 31st January 2021. Minimum follow up time was two weeks. Clinical characteristics were compared between the first (W1) and second wave (W2) of infections. Findings2044 CYP aged <19 years were reported from 187 hospitals. 427/2044 (20.6%) had asymptomatic/incidental SARS-CoV-2 infection and were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). Patients in W2 were significantly older (median age 6.5 years, IQR 0.3-14.9) than W1 (4.0 (0.4-13.6, p 0.015). Fever was more common in W1, otherwise presenting symptoms and comorbidities were similar across waves. After excluding CYP with MIS-C, patients in W2 had lower PEWS at presentation, lower antibiotic use and less respiratory and cardiovascular support compared to W1. There was no change in the proportion of CYP admitted to critical care between W1 and W2. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year old), had lower Paediatric Early Warning Scores (PEWS) at presentation, shorter length of hospital stay and received less respiratory support. MIS-C was responsible for a large proportion of critical care admissions, invasive and non-invasive ventilatory support, inotrope and intravenous corticosteroid use in CYP without comorbidities. InterpretationSevere disease in CYP admitted with symptomatic SARS-CoV-2 in the UK remains rare. One in five CYP in this cohort had asymptomatic/incidental SARS-CoV-2 infection. We found no evidence of increased disease severity in W2 compared with W1. FundingShort form: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation. Long form: This work is supported by grants from the National Institute for Health Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135). Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). JSN-V-T is seconded to the Department of Health and Social Care, England (DHSC). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust, or PHE.

Children develop strong and sustained cross-reactive immune responses against spike protein following SARS-CoV-2 infection

SARS-CoV-2 infection is generally mild or asymptomatic in children but the biological basis for this is unclear. We studied the profile of antibody and cellular immunity in children aged 3-11 years in comparison with adults. Antibody responses against spike and receptor binding domain (RBD) were high in children and seroconversion boosted antibody responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Seroneutralisation assays against alpha, beta and delta SARS-CoV-2 variants demonstrated comparable neutralising activity between children and adults. T cell responses against spike were >2-fold higher in children compared to adults and displayed a TH1 cytokine profile. SARS-CoV-2 spike-specific T cells were also detected in many seronegative children, revealing pre-existing responses that were cross-reactive with seasonal Alpha and Beta-coronaviruses. Importantly, all children retained high antibody titres and cellular responses at 6 months after infection whilst relative antibody waning was seen in adults. Spike-specific responses in children also remained broadly stable beyond 12 months. Children thus distinctly generate robust, cross-reactive and sustained immune responses after SARS-CoV-2 infection with focussed specificity against spike protein. These observations demonstrate novel features of SARS-CoV-2-specific immune responses in children and may provide insight into their relative clinical protection. Furthermore, this information will help to guide the introduction of vaccination regimens in the paediatric population.

Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT and/or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a setpoint for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

Serological surveillance of SARS-CoV-2: trends and humoral response in a cohort of public health workers

BackgroundAntibody waning after SARS-CoV-2 infection may result in reduction in long-term immunity following natural infection and vaccination, and is therefore a major public health issue. We undertook prospective serosurveillance in a large cohort of healthy adults from the start of the epidemic in England. MethodsClinical and non-clinical healthcare workers were recruited across three English regions and tested monthly from March to November 2020 for SARS-CoV-2 spike (S) protein and nucleoprotein (N) antibodies using five different immunoassays. In positive individuals, antibody responses and long-term trends were modelled using mixed effects regression. FindingsIn total, 2246 individuals attended 12,247 visits and 264 were seropositive in [≥]2 assays. Most seroconversions occurred between March and April 2020. The assays showed >85% agreement for ever-positivity, although this changed markedly over time. Antibodies were detected earlier with Abbott (N) but declined rapidly thereafter. With the EuroImmun (S) and receptor-binding domain (RBD) assays, responses increased for 4 weeks then fell until week 12-16 before stabilising. For Roche (N), responses increased until 8 weeks, stabilised, then declined, but most remained above the positive threshold. For Roche (S), responses continued to climb over the full 24 weeks, with no sero-reversions. Predicted proportions sero-reverting after 52 weeks were 100% for Abbott, 59% (95% credible interval 50-68%) Euroimmun, 41% (30-52%) RBD, 10% (8-14%) Roche (N) <2% Roche (S). InterpretationTrends in SARS-CoV-2 antibodies following infection are highly dependent on the assay used. Ongoing serosurveillance using multiple assays is critical for monitoring the course and long-term progression of SARS-CoV-2 antibodies.

Seroprevalence of SARS-CoV-2 antibodies in children - A prospective multicentre cohort study.

BackgroundStudies based on molecular testing of oral/nasal swabs underestimate SARS-CoV-2 infection due to issues with test sensitivity and timing of testing. The objective of this study was to report the presence of SARS-CoV-2 antibodies, consistent with previous infection, and to report the symptomatology of infection in children. DesignThis multicentre observational cohort study, conducted between 16th April - 3rd July 2020 at 5 UK sites, aimed to recruit 900 children aged 2 to 15 years of age. Participants provided blood samples for SARS-CoV-2 antibody testing and data were gathered regarding unwell contacts and symptoms. Results1007 participants were enrolled, and 992 were included in the final analysis. The median age of participants was 10{middle dot}1 years. There were 68 (6.9%) participants with positive SARS-CoV-2 antibody tests indicative of previous SARS-CoV-2 infection. Of these, 34/68 (50%) reported no symptoms. The presence of antibodies and the mean antibody titre was not influenced by age. Following multivariate analysis 4 independent variables were identified as significantly associated with SARS-CoV-2 infection. These were: known infected household contact; fatigue; gastrointestinal symptoms; and changes in sense of smell or taste. DiscussionIn this study children demonstrated similar antibody titres in response to SARS-CoV-2 irrespective of age. The symptoms of SARS-CoV-2 infection in children were subtle but of those reported, fatigue, gastrointestinal symptoms and changes in sense of smell or taste were most strongly associated with antibody positivity. RegistrationThis study was registered at https://www.clinicaltrials.gov (trial registration: NCT04347408) on the 15/04/2020.

Clinical characteristics of children and young people hospitalised with covid-19 in the United Kingdom: prospective multicentre observational cohort study

ObjectiveTo characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C). DesignProspective observational cohort study with rapid data gathering and near real time analysis. Setting260 acute care hospitals in England, Wales, and Scotland between 17th January and 5th June 2020, with a minimal follow-up time of two weeks (to 19th June 2020). Participants451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2. Main Outcome MeasuresAdmission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C. ResultsMedian age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria. 17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity. Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p<0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p<0.001), myalgia (39% (11/28) vs 7% (12/170), p<0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 x109/L (30% (10/33) vs 10% (24/232), p=0.004). ConclusionsOur data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease. Study registrationISRCTN66726260

SARS-CoV-2 infection, clinical features and outcome of COVID-19 in United Kingdom nursing homes

ObjectivesTo understand SARS-Co-V-2 infection and transmission in UK nursing homes in order to develop preventive strategies for protecting the frail elderly residents. DesignAn outbreak investigation. Setting4 nursing homes affected by COVID-19 outbreaks in central London. Participants394 residents and 70 staff in nursing homes. InterventionsTwo point-prevalence surveys one week apart where residents underwent SARS-CoV-2 testing and had relevant symptoms documented. Asymptomatic staff from three of the four homes were also offered SARS-CoV-2 testing. Main outcome measuresAll-cause mortality, and mortality attributed to COVID-19 on death certificates. Prevalence of SARS-CoV-2 infection and symptoms in residents and staff. ResultsOverall, 26% (95% confidence interval 22 to 31) of residents died over the two-month period. All-cause mortality increased by 203% (95% CI 70 to 336). Systematic testing identified 40% (95% CI 35 to 46) of residents, of whom 43% (95% CI 34 to 52) were asymptomatic and 18% (95% CI 11 to 24) had atypical symptoms, as well as 4% (95% CI -1 to 9) of asymptomatic staff who tested positive for SARS-CoV-2. ConclusionsThe SARS-CoV-2 outbreak was associated with a very high mortality rate in residents of nursing homes. Systematic testing of all residents and a representative sample of staff identified high rates of SARS-CoV-2 positivity across the four nursing homes, highlighting a potential for regular screening to prevent future outbreaks.

Susceptibility to and transmission of COVID-19 amongst children and adolescents compared with adults: a systematic review and meta-analysis

ImportanceThe degree to which children and young people are infected by and transmit the SARS-CoV-2 virus is unclear. The role of children and young people in transmission of SARS-CoV-2 is dependent on susceptibility, symptoms, viral load, social contact patterns and behaviour. ObjectiveWe undertook a rapid systematic review to address the question "What is the susceptibility to and transmission of SARS-CoV-2 by children and adolescents compared with adults?" Data sourcesWe searched PubMed and medRxiv up to 28 July 2020 and identified 13,926 studies, with additional studies identified through handsearching of cited references and professional contacts. Study SelectionWe included studies which provided data on the prevalence of SARS-CoV-2 in children and young people (<20 years) compared with adults derived from contact-tracing or population-screening. We excluded single household studies. Data extraction and SynthesisWe followed PRISMA guidelines for abstracting data, independently by 2 reviewers. Quality was assessed using a critical appraisal checklist for prevalence studies. Random effects meta-analysis was undertaken. Main OutcomesSecondary infection rate (contact-tracing studies) or prevalence or seroprevalence (population-screening studies) amongst children and young people compared with adults. Results32 studies met inclusion criteria; 18 contact-tracing and 14 population-screening. The pooled odds ratio of being an infected contact in children compared with adults was 0.56 (0.37, 0.85) with substantial heterogeneity (95%). Three school contact tracing studies found minimal transmission by child or teacher index cases. Findings from population-screening studies were heterogenous and were not suitable for meta-analysis. The majority of studies were consistent with lower seroprevalence in children compared with adults, although seroprevalence in adolescents appeared similar to adults. ConclusionsThere is preliminary evidence that children and young people have lower susceptibility to SARS-CoV-2, with a 43% lower odds of being an infected contact. There is weak evidence that children and young people play a lesser role in transmission of SARS-CoV-2 at a population level. Our study provides no information on the infectivity of children. Key pointsO_ST_ABSQuestionC_ST_ABSWhat is the evidence on the susceptibility and transmission of children and young people to SARS-CoV-2 in comparison with adults? FindingsIn this systematic review and meta-analysis, children and young people under 18-20 years had an 435 lower odds of secondary infection of with SARS-CoV-2 compared to adults 20 years plus, a significant difference. This finding was most marked in children under 12-14 years. Data were insufficient to conclude whether transmission of SARS-CoV-2 by children is lower than by adults. MeaningWe found preliminary evidence that children have a lower susceptibility for SARS-CoV-2 infection compared with adults, although data for adolescents is less clear. The role that children and young people play in transmission of this pandemic remains unclear.