Mask mandates and COVID-19: A Re-analysis of the Boston school mask study (preprint)

Background: A recent epidemiological analysis of staggered policy implementation reported a 29.4% reduction in COVID-19 cases by maintaining school mask mandates in the greater Boston area during the first half of 2022. The robustness of their results and the appropriateness of methodology are explored. Methods: Using data from the Massachusetts Department of Elementary and Secondary Education and the Centers for Disease Control and Prevention, we re-analyze differences in COVID-19 incidence in school districts that did and did not lift mask mandates using the same districts as the original study and expanded the analysis to the entire state of Massachusetts. We present changes in case rates and differences in prior immunity in areas with different mask lifting policies. Results: The Boston and Chelsea districts, which maintained mask mandates, were outliers in terms of size, demographics, and testing. We failed to find a notable change in student cases in mask mandate districts compared with the 70 districts in the original study (-0.08/1000; p=0.98) and found a slight increase compared with a statewide control group +3.63/1000 (p=0.291). Results were similar for students and staff combined. Districts that dropped mask mandates first experienced the largest decreases in cases (22% drop vs 12% in the masked districts). There was a moderate to strong relationship (R2 = 0.35-0.66; p-values <0.001) between prior community infection burden and district case rates in Spring 2022, with prior immunity alone explaining as much as two-thirds of the variation in case rates in Spring of 2022. Conclusions: We fail to find any consistent notable negative relationship between school mask mandates and infection rates in the Greater Boston Area or state of Massachusetts during the 2021-2022 academic year.

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

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.

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 (preprint)

Background Risk 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. Methods Cross-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. Results 4,980 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). Conclusions Using 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.

A cross-sectional national investigation of COVID-19 outbreaks in nurseries during rapid spread of the Alpha (B.1.1.7) variant of SARS- CoV-2 in England (preprint)

Background: In England, the emergence the more transmissible SARS-CoV-2 variant Alpha (B.1.1.7) led to a third national lockdown from December 2020, including restricted attendance at schools. Nurseries, however, remained fully open. COVID-19 outbreaks (≥ 2 laboratory-confirmed cases within 14 days) in nurseries and assess the risk of SARS-CoV-2 infection and incidence rates in staff and children over a three-month period when community SARS-CoV-2 infections rates were high and the Alpha variant was spreading rapidly across England. Methods This was a cross-sectional national investigation of COVID-19 outbreaks in nurseries across England Nurseries reporting a COVID-19 outbreak to PHE between November 2020 and January 2021 were requested to complete a questionnaire about their outbreak. Results 324 nurseries, comprising 1% (324/32,852) of nurseries in England, reported a COVID-19 outbreak. Of the 315 (97%) nurseries contacted, 173 (55%) reported 1,657 SARS-CoV-2 cases, including 510 (31%) children and 1,147 (69%) staff. A child was the index case in 45 outbreaks (26%) and staff in 125 (72%) outbreaks. Overall, children had an incidence rate of 3.50% (95%CI, 3.21–3.81%) and was similar irrespective of whether the index case was a child (3.55%; 95%CI, 3.01–4.19%) or staff (3.44%; 95%CI, 3.10–3.82%). Among staff, incidence rates were lower if the index case was a child (26.28%; 95%CI, 23.54–29.21%%) compared to a staff member (32.98%; 95%CI, 31.19–34.82%), with the highest incidence rate when the index case was also a staff member (37.52%; 95%CI, 35.39–39.70%). Compared to November 2020, outbreak sizes and incidence rates were higher in January 2021, when the Alpha variant predominated. Nationally, SARS-CoV-2 infection rates in

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

Abstract: Objectives: This systematic review and meta-analysis aimed to estimate the age-specific proportion of asymptomatic SARS-CoV-2 infected persons by year of age. Methods: We 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. Results: A 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%). Conclusions: Given 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 (preprint)

Abstract Importance: Predictive models can help identify SARS-CoV-2 patients at greatest risk of post-COVID sequelae and direct them towards appropriate care. Objective: To 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. Design: Potential 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. Setting: National cohort study of SARS-CoV-2 PCR-positive and PCR-negative participants matched according to age, sex, and geographical area. Participants: Children and young people aged 11-17 years who were tested for SARS-CoV-2 infection in England, January to March 2021. Main outcome measure: one or more physical symptom 3 months after initial PCR-testing which affected physical, mental or social well-being and interfered with daily living. Results: A 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 relevance: We 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.

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

Paediatric Inflammatory Multisystem Syndrome (PIMS-TS, also known as MIS-C) typically occurs 2-6 weeks after exposure to SARS-CoV-2. Early estimates suggested a risk of PIMS-TS of 1 in 3-4000 infected children. Whether this risk is sustained with new SARS-CoV-2 variants remains unknown. We utilised prospective data from the NHS South Thames Paediatric Network (STPN), which manages all cases of PIMS-TS amongst 1.5 million children in South-East England, to assess trends over time. We compared PIMS-TS cases with two independent SARS-CoV-2 infection datasets. We used publicly available UK Health Security Agency case numbers weighted to child population distributions according to area population estimates from the Office for National Statistics (ONS). To avoid bias due to evolving testing behaviour, we also compared PIMS-TS cases to community infection rates, obtained from the ONS COVID-19 Infection Survey, which randomly selects individuals for fortnightly PCR tests. All three datasets were normalised to the peak of the Alpha wave, and plotted against time. PIMS-TS cases were plotted 40 days prior to hospitalisation, corresponding to the best fit of rising SARS-CoV-2 infection and PIMS-TS cases during the Alpha wave. Compared with the Alpha wave, we found fewer cases of PIMS-TS relative to SARS-CoV-2 infections during both initial and subsequent Delta waves. This relative reduction continued into the Omicron wave. Re-infection rates with the Alpha or Delta variants and vaccination rates were very low during the Delta wave. As a result, lower PIMS-TS rate relative to SARS-CoV-2 infections during the Delta wave is unlikely to be explained by population level immunity from prior infection or vaccination. It is most likely due to viral mutations in key antigenic epitopes responsible for triggering the hyperinflammatory response observed with PIMS-TS.

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

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 (preprint)

Background University 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. Methods Cross-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. Results Complete 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). Conclusions Vaccine 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 (preprint)

Background The 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. Methods We 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. Findings 4529 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). Interpretation We 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.

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

Background Reinfection 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. Methods We 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. Findings Reinfection 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 66.88/100,000 population, being higher in adults (72.53/100,000) than in children (21.53/100,000). Reinfection rates after primary infection were 0.68% overall, 0.73% in adults and 0.34% 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, 2.73%) and second episode (57/2343, 2.43%). 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, 0.01%), none after possible reinfections. Interpretation The 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. Funding PHE/UKHSA

mRNA COVID-19 vaccines induce enhanced antibody and cellular responses compared to ChAdOx1 or natural infection in children (preprint)

We present a comprehensive analysis of antibody and cellular responses in children aged 12-16 years who received COVID-19 vaccination with ChAdOx1 (n=6) or mRNA vaccine (mRNA-1273 or BNT162b2, n=9) using a 12-week extended-interval schedule. mRNA vaccination of seropositive children induces high antibody levels, with one dose, but a second dose is required in infection-naïve children. Following a second ChAdOx1 dose, antibody titres were higher than natural infection, but lower than mRNA vaccination. Vaccination induced live virus neutralising antibodies against Alpha, Beta and Delta variants, however, a second dose is required in infection-naïve children. We found higher T-cell responses following mRNA vaccination than ChAdOx1. Phenotyping of responses showed predominantly early effector-memory CD4 T cell populations, with a type-1 cytotoxic cytokine signature, with IL-10. These data demonstrate mRNA vaccination induces a co-ordinated superior antibody and robust cellular responses in children. Seronegative children require a prime-boost regime for optimal protection.

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 (preprint)

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 titres 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.

Persistent Symptoms Following SARS-CoV-2 Infection Among Children and Young People: A Meta-Analysis of Controlled and Uncontrolled Studies (preprint)

Background: Data on the long-term impact of SARS-CoV-2 infection in children and young people (CYP) is conflicting. We assessed evidence on long-term post-COVID symptoms in CYP examining prevalence, risk factors, type and duration.Methods: Systematic search of published and unpublished literature using 13 online databases between 01/12/2019 – 31/07/2021. Eligible studies reported CYP ≤19 years with confirmed or probable SARS-CoV-2 with any symptoms persisting beyond acute illness. Random effects meta-analyses examined pooled risk difference in symptom prevalence (controlled studies only) and pooled prevalence (uncontrolled studies also included). Meta-regression examined study characteristics hypothesised to be associated with symptom prevalence. Prospectively registered: CRD42021233153. Findings: Twenty two of 3357 unique studies were eligible, including 23,141 CYP. Median duration of follow-up was 125 days (IQR 99-231).Pooled risk difference in post-COVID cases compared to controls (5 studies) were significantly higher for cognitive difficulties (3% (95% CI 1, 4)), headache (5% (1, 8)), loss of smell (8%, (2, 15)), sore throat (2% (1, 2)) and sore eyes (2% (1, 3)) but not abdominal pain, cough, fatigue, myalgia, insomnia, diarrhoea, fever, dizziness or dyspnoea.Pooled prevalence of symptoms in post-COVID participants in 17 studies ranged from 15% (diarrhoea) to 47% (fatigue). Age was associated with higher prevalence of all symptoms except cough. Higher study quality was associated with lower prevalence of all symptoms, except loss of smell and cognitive symptoms.Interpretation: The frequency of the majority of reported persistent symptoms was similar in SARS-CoV-2 positive cases and controls. This systematic review and meta-analysis highlights the critical importance of a control group in studies on CYP post SARS-CoV-2 infection.Funding: None to declare. Declaration of Interest: SAB, RS, SDB, AXDZ, LLO, SNL, BLDS, RMV and OVS have no conflicts of interest. TJS is the Chair of the Health Research Authority for England who reimburse his university for his time. He is not paid personally. He has recused himself from research studies in which he is personally involved and which require ethical approval from the HRA.

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

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 (preprint)

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.

Estimating the Risk of Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) Following SARS-CoV-2 Infection in Children (preprint)

Background: Paediatric Multisystem Inflammatory Syndrome (PIMS-TS) is a rare life-threatening complication that occurs in some children two to four weeks after SARS-CoV-2 infection. Although the precise causal mechanisms underpinning the relationship between SARS-CoV-2 and PIMS-TS are unclear, several recent studies have confirmed a strong temporal association. This study provides further evidence in support of a causal and temporal link. A novel methodology is presented whereby PIMS-TS incidence parameters estimated from data published on SARS-CoV-2 in the first wave of the COVID-19 pandemic in England were used to make accurate projections of PIMS-TS cases in the second wave. Methods: Case classifications and data on PIMS-TS cases were obtained from the British Paediatric Surveillance Unit (BPSU) in an endeavour initiated by Public Heath England (PHE). The dataset contained all PIMS-TS cases presenting as symptomatic in England in the first wave of the pandemic. PIMS-TS incidence rates in children aged <15 years were estimated for the first wave and expressed as a fraction of SARS-CoV-2 cases. Data on SARS-CoV-2 cases were extracted from the PHE-Cambridge real-time model. Temporal analysis was performed to estimate the lag-time between peak SARS-CoV-2 incidence and peak PIMS-TS. The incidence and lag-time parameters estimated during the first wave were used to produce weekly projections of PIMS-TS cases in the second wave. These projections were then employed operationally in a clinical setting. Statistical analyses were performed to assess the accuracy of the forecasts once data on PIMS-TS cases were published by the BPSU approximately three months after the PIMS-TS forecasts were generated. Findings: Statistical analyses show that the PIMS-TS parameters estimated from the first wave produced accurate projections of PIMS-TS incidence in the second wave. Results at the aggregated national level showed there were no statistically significant differences observed between the PIMS-TS admission data and forecasts in England. Forecasts generated at the disaggregated regional level were also accurate, with no statistically significant differences observed between the PIMS-TS admissions data and forecasts in five of the nine Public Health England Centres (PHECs). However, a statistically significant divergence was observed between the PIMS-TS admissions data and the second wave forecasts in the regions of London and in the East, North West, and South West of England.Interpretation: This study provides further evidence in support of a causal and temporal association between SARS-CoV-2 and PIMS-TS, since data on SARS-CoV-2 incidence in the first wave of the COVID-19 pandemic in England have been shown to be a good baseline from which to generate forecasts of PIMS-TS incidence in the second wave, at both aggregated national and disaggregated regional levels.Funding Information: : Department of Health and Social Care (DHSC) Grant-in-aid funding to Public Health England (PHE).Declaration of Interests: None; this study did not receive any specific grant funding from external agencies in the public, commercial or not-for-profit sectors.Ethics Approval Statement: : PHE has legal permission under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002, to conduct national surveillance of communicable diseases in England and, as such, individual patient consent is not required. Public Health Wales, through the established order legislation, is required to conduct surveillance of communicable diseases in Wales and, as such, individual patient consent is not required. The surveillance protocol was approved by the Public Benefit and Privacy Panel for Health and Social Care in Scotland (Ref: 20210041, 19 May 2020).

Secondary Attack Rates in Primary and Secondary School Bubbles Following a Confirmed Case: Active, Prospective National Surveillance, November to December 2020, England (preprint)

Background: Following the full re-opening of schools in England and emergence of the SARS-CoV-2 Alpha variant, we investigated the risk of SARS-CoV-2 infection in students and staff who were contacts of a confirmed case in a school bubble (school groupings with limited interactions), along with their household members. Methods: Primary and secondary school bubbles were recruited into sKIDsBUBBLE after being sent home to self-isolate following a confirmed case of COVID-19 in the bubble. Bubble participants and their household members were sent home-testing kits comprising nasal swabs for RT-PCR testing and whole genome sequencing, and oral fluid swabs for SARS-CoV-2 antibodies. Results: During November-December 2020, 14 bubbles were recruited from 7 schools, including 269 bubble contacts (248 students, 21 staff) and 823 household contacts (524 adults, 299 children). The secondary attack rate was 10.0% (6/60) in primary and 3.9% (4/102) in secondary school students, compared to 6.3% (1/16) and 0% (0/1) among staff, respectively. The incidence rate for household contacts of primary school students was 6.6% (12/183) and 3.7% (1/27) for household contacts of primary school staff. In secondary schools, this was 3.5% (11/317) and 0% (0/1), respectively. Household contacts were more likely to test positive if their bubble contact tested positive although there were new infections among household contacts of uninfected bubble contacts. Interpretation: Compared to other institutional settings, the overall risk of secondary infection in school bubbles and their household contacts was low. Our findings are important for developing evidence-based infection prevention guidelines for educational settings.

Perceptions of Adolescents on the COVID-19 Pandemic and Returning to School: Qualitative Questionnaire Survey, England 2020 (preprint)

Background : Little is known about the views of adolescents returning to secondary school during the current COVID-19 pandemic. Methods: In September 2020, Public Health England (PHE) recruited staff and students in secondary schools to provide nasal swabs, oral fluid and blood samples for SARS-CoV-2 infection and antibody testing. Students aged 11-18 years in five London schools completed a short questionnaire about their perception of the pandemic, returning to school, risk to themselves and to others and infection control measures, and participating in school testing. Results: A questionnaire was completed by 64% (297/462) participants. Students were generally not anxious at all (19.7%; 58/294) or not really anxious (40.0%, 114/295) about returning to school, although 5.4% (n=16/295) were extremely nervous. Most students were very worried about transmitting the virus to their family (60.2%; 177/294) rather than other students (22.0%; 65/296) or school staff (19.3%; 57/296), or catching the infection themselves (12.5%; 37/296). Students better maintained physical distancing in the presence of school staff (84.6%; 247/292) and in public places (79.5%; 233/293) but not when with other students (46.8%; 137/293) or friends (40.8%; 120/294). A greater proportion of younger students (school years 7-9) reported not being anxious at all than 16-18 year olds (47/174 [27.0%] vs 3/63 [4.8%]; p=0.001). They were also less likely to adhere to physical distancing and wearing face masks. Most students reported positive experiences with testing in schools, with 92.3% (262/284) agreeing to have another blood test in future visits.Conclusions: Younger students were less concerned about catching and transmitting SARS-CoV-2 and were less likely to adhere to protective measures. Greater awareness of the potential risks of COVID-19 transmission between secondary school students potentially leading to increased risk of infection in their teachers and their household members may increase adherence to infection control measures within and outside schools.