Association of Spike-Specific T Cells With Relative Protection From Subsequent SARS-CoV-2 Omicron Infection in Young Children.

This cohort study investigates the risk of SARS-CoV-2 reinfection among young children with and without spike-specific T-cell responses.

A cross-sectional study of the health of emerging young adults in England following a COVID-19 infection

Purpose This study describes long COVID symptomatology in a national sample of 18–20-year-olds with PCR-confirmed SARS-CoV-2 and matched test-negative controls in England. Symptoms in 18-20-year-olds were compared to younger adolescents (aged 11-17 years) and all adults (18+). Methods A national database was used to identify SARS-CoV-2 PCR-positive 18–20-year-olds and test-negative controls matched by time of test, age, gender and geographical region. Participants were invited to complete a questionnaire about their health retrospectively at time of test and also when completing the questionnaire. Comparison cohorts included Children and Young People with Long COVID and Real-time Assessment of Community Transmission studies. Results Of 14,986 people invited, 1,001 were included in the analysis (562 test-positive;440 test-negative). At testing, 46.5% of test-positives and 16.4% of test-negatives reported at least one symptom. At the time of questionnaire completion (median 7 months post-testing), 61.5% of test-positives and 47.5% of test-negatives reported one or more symptoms. The most common symptoms were similar amongst test-positives and test-negatives and included tiredness (44.0%;35.7%), shortness of breath (28.8%;16.3%) and headaches (13.7%;12.0%). Prevalence rates were similar to those reported by 11-17-year-olds (66.5%) and higher than those reported in all adults (37.7%). For 18-20-year-olds, there was no significant difference in health-related quality of life and wellbeing (p>0.05). However, test-positives reported being significantly more tired than test-negatives (p=0.04). Conclusions Seven months after PCR test, a high proportion of test-positive and test-negative 18-20-year-olds reported similar symptoms to each other and to those experienced by younger and older counterparts.

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 2021SARS-CoV-2 antibody prevalence in school children.

BACKGROUND: SARS-CoV-2 infection rates are likely to be underestimated in children because of asymptomatic or mild infections. We aim to estimate national and regional prevalence of SARS-CoV-2 antibodies in primary (4-11 years old) and secondary (11-18 years old) 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: 4980 students from 117 state-funded schools (2706 from 83 primary schools, 2274 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 was 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 71.5% (95% CI 65.7-76.8) 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: In November 2021, using a validated oral fluid assay, national SARS-CoV-2 seroprevalence was estimated to be 40.1% in primary school students and 82.4% in secondary school students. In unvaccinated children, this was approximately threefold higher than confirmed infections highlighting the importance of seroprevalence studies to estimate prior exposure. DATA AVAILABILITY: Deidentified study data are available for access by accredited researchers in the ONS Secure Research Service (SRS) for accredited research purposes under part 5, chapter 5 of the Digital Economy Act 2017. For further information about accreditation, contact Research.support@ons.gov.uk or visit the SRS website.

Comparison of UK paediatric SARS-CoV-2 admissions across the first and second pandemic waves.

BACKGROUND: We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the first wave (W1) due to the alpha variant (B.1.1.7), school reopening and relaxation of shielding. METHODS: Prospective multicentre observational cohort study of patients <19 years hospitalised in the UK with SARS-CoV-2 between 17/01/20 and 31/01/21. Clinical characteristics were compared between W1 and W2 (W1 = 17/01/20-31/07/20,W2 = 01/08/20-31/01/21). RESULTS: 2044 CYP < 19 years from 187 hospitals. 427/2044 (20.6%) with asymptomatic/incidental SARS-CoV-2 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). After excluding CYP with MIS-C, patients in W2 had lower Paediatric Early Warning Scores (PEWS, composite vital sign score), lower antibiotic use and less respiratory and cardiovascular support than W1. The proportion of CYP admitted to critical care was unchanged. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year), had lower PEWS, shorter length of stay and less respiratory support. CONCLUSIONS: We found no evidence of increased disease severity in W2 vs W1. A large proportion of hospitalised CYP had no comorbidity. IMPACT: No evidence of increased severity of COVID-19 admissions amongst children and young people (CYP) in the second vs first wave in the UK, despite changes in variant, relaxation of shielding and return to face-to-face schooling. CYP with no comorbidities made up a significant proportion of those admitted. However, they had shorter length of stays and lower treatment requirements than CYP with comorbidities once those with MIS-C were excluded. At least 20% of CYP admitted in this cohort had asymptomatic/incidental SARS-CoV-2 infection. This paper was presented to SAGE to inform CYP vaccination policy in the UK.

Lower Risk of Multisystem Inflammatory Syndrome in Children (MIS-C) with the Delta and Omicron variants 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.

Asymptomatic SARS-CoV-2 Infection by Age: A Global Systematic Review and Meta-analysis.

BACKGROUND: Asymptomatic SARS-CoV-2 infections have raised concerns for public health policies to manage epidemics. This systematic review and meta-analysis aimed to estimate the age-specific proportion of asymptomatic SARS-CoV-2 infected persons globally by year of age. METHODS: We searched PubMed, Embase, medRxiv and Google Scholar on September 10, 2020, and March 1, 2021. We included studies conducted during January to December 2020, before routine vaccination against COVID-19. Because we expected the relationship between the asymptomatic proportion and age to be nonlinear, 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 of 14,850 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% (6556/14,850, 95% CI: 43.3%-45.0%). The predicted asymptomatic proportion peaked in children (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.

Post-COVID-19 condition at 6 months and COVID-19 vaccination in non-hospitalised children and young people.

OBJECTIVES: To describe the physical and mental health of children and young people (CYP) 6 months after infection with SARS-CoV-2 and explore whether this varies by COVID-19 vaccination. DESIGN: A non-hospitalised, national cohort of people aged 11-17 years old with PCR-confirmed SARS-CoV-2 infection and PCR negatives matched at study invitation, by age, sex, region and date of testing who completed questionnaires 6 months after PCR testing. The questionnaire included 21 symptoms and standardised scales (eg, EQ-5D-Y and Chalder Fatigue Scale). RESULTS: 6407 test-positive and 6542 test-negative CYP completed the 6-month questionnaire: 60.9% of test-positive vs 43.2% of test-negative CYP reported at least one symptom 6 months post-test; 27.6% of test-positive vs 15.9% of test-negative CYP reported 3+ symptoms. Common symptoms at 6 months were tiredness and shortness of breath among both test-positive and test-negative CYP; however, the prevalence of both was higher in test-positive (38.4% and 22.8%, respectively) compared with test-negative CYP (26.7% and 10.9%, respectively). 24.5% test-positive vs 17.8% test-negative CYP met the Delphi research definition of long COVID. Mental health, well-being, fatigue and health-related quality of life scores were similar among test-positive and test-negative CYP 6 months post-test. Similarly, symptomatology was similar among COVID-19-vaccinated and COVID-19-unvaccinated test-positive and test-negative CYP. CONCLUSIONS: Six-months post-PCR testing, CYP who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but test-positive CYP had higher symptom prevalence. Mental health, well-being, fatigue and health-related quality of life were similar among test-positive and test-negative CYP, and symptoms at 6 months were similar in COVID-19 vaccinated and unvaccinated. TRIAL REGISTRATION NUMBER: ISRCTN 34804192.

Predictive model for long COVID in children 3 months after a SARS-CoV-2 PCR test.

BACKGROUND: To update and internally validate a model to predict children and young people (CYP) most likely to experience long COVID (i.e. at least one impairing symptom) 3 months after SARS-CoV-2 PCR testing and to determine whether the impact of predictors differed by SARS-CoV-2 status. METHODS: Data from a nationally matched cohort of SARS-CoV-2 test-positive and test-negative CYP aged 11-17 years was used. The main outcome measure, long COVID, was defined as one or more impairing symptoms 3 months after PCR testing. Potential pre-specified predictors included SARS-CoV-2 status, sex, age, ethnicity, deprivation, quality of life/functioning (five EQ-5D-Y items), physical and mental health and loneliness (prior to testing) and number of symptoms at testing. The model was developed using logistic regression; performance was assessed using calibration and discrimination measures; internal validation was performed via bootstrapping and the final model was adjusted for overfitting. RESULTS: A total of 7139 (3246 test-positives, 3893 test-negatives) completing a questionnaire 3 months post-test were included. 25.2% (817/3246) of SARS-CoV-2 PCR-positives and 18.5% (719/3893) of SARS-CoV-2 PCR-negatives had one or more impairing symptoms 3 months post-test. The final model contained SARS-CoV-2 status, number of symptoms at testing, sex, age, ethnicity, physical and mental health, loneliness and four EQ-5D-Y items before testing. Internal validation showed minimal overfitting with excellent calibration and discrimination measures (optimism-adjusted calibration slope: 0.96575; C-statistic: 0.83130). CONCLUSIONS: We updated a risk prediction equation to identify those most at risk of long COVID 3 months after a SARS-CoV-2 PCR test which could serve as a useful triage and management tool for CYP during the ongoing pandemic. External validation is required before large-scale implementation.

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

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

Association of Spike-Specific T Cells With Relative Protection From Subsequent SARS-CoV-2 Omicron Infection in Young Children.

This cohort study investigates the risk of SARS-CoV-2 reinfection among young children with and without spike-specific T-cell responses.

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.

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 were investigated to assess the risk of SARS-CoV-2 infection and cumulative incidence 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: Three hundred and twenty-four 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, cumulative incidence was 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 cumulative incidence when the index case was also a staff member (37.52%; 95%CI, 35.39-39.70%). Compared to November 2020, outbreak sizes and cumulative incidence was higher in January 2021, when the Alpha variant predominated. Nationally, SARS-CoV-2 infection rates in < 5 year-olds remained low and followed trends in older age-groups, increasing during December 2020 and declining thereafter. CONCLUSIONS: In this cross-sectional study of COVID-19 outbreaks in nurseries, one in three staff were affected compared to one in thirty children. There was some evidence of increased transmissibility and higher cumulative incidence associated with the Alpha variant, highlighting the importance of maintaining a low level of community infections.

Parents' and teachers' attitudes to and experiences of the implementation of COVID-19 preventive measures in primary and secondary schools following reopening of schools in autumn 2020: a descriptive cross-sectional survey.

OBJECTIVE: To assess implementation and ease of implementation of control measures in schools as reported by staff and parents. DESIGN: A descriptive cross-sectional survey. SETTING: Staff and parents/guardians of the 132 primary schools and 19 secondary schools participating in COVID-19 surveillance in school kids (sKIDs and sKIDsPLUS Studies). MAIN OUTCOME MEASURE: Prevalence of control measures implemented in schools in autumn 2020, parental and staff perception of ease of implementation. RESULTS: In total, 56 of 151 (37%) schools participated in this study, with 1953 parents and 986 staff members completing the questionnaire. Most common measures implemented by schools included regular hand cleaning for students (52 of 56, 93%) and staff (70 of 73, 96%), as reported by parents and staff, respectively, and was among the easiest to implement at all times for students (57%) and even more so, for staff (78%). Maintaining 2-metre distancing was less commonly reported for students (24%-51%) as it was for staff (81%-84%), but was one of the most difficult to follow at all times for students (25%) and staff (16%) alike. Some measures were more commonly reported by primary school compared to secondary school parents, including keeping students within the same small groups (28 of 41, 68% vs 8 of 15, 53%), ensuring the same teacher for classes (29 of 41, 71% vs 6 of 15, 40%). On the other hand, wearing a face covering while at school was reported by three-quarters of secondary school parents compared with only parents of 4 of 41 (10%) primary schools. Other measures such as student temperature checks (5%-13%) and advising staff work from home if otherwise healthy (7%-15%) were rarely reported. CONCLUSIONS: Variable implementation of infection control measures was reported, with some easier to implement (hand hygiene) than others (physical distancing).

Long COVID in children and adolescents.

PURPOSE OF REVIEW: Although acute COVID-19 has been milder in children and young people compared with adults, there is a concern that they may suffer persistent symptoms. There is a need to define the clinical phenotype, determine those most at risk, the natural course of the condition and evaluate preventive and therapeutic strategies for both mental health and physical symptoms. RECENT FINDINGS: More recent studies with control groups reported a lower prevalence of persistent symptoms in children and young people exposed to SARS-CoV-2. A systematic review and meta-analysis found that the frequency of the majority of reported persistent symptoms is similar in SARS-CoV-2 positive cases and controls. Children and young people infected with SARS-COV-2 had small but significant increases in persisting cognitive difficulties, headache and loss of smell. Factors associated with persisting, impairing symptoms include increased number of symptoms at the time of testing, female sex, older age, worse self-rated physical and mental health, and feelings of loneliness preinfection. SUMMARY: This review highlights the importance of a control group in studies following SARS-CoV-2 infection, the need for case definitions and research to understand the outcomes of long COVID in children and young people.

Acute and Persistent Symptoms in Children With Polymerase Chain Reaction (PCR)-Confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Compared With Test-Negative Children in England: Active, Prospective, National Surveillance.

BACKGROUND: Most children recover quickly after coronavirus disease 2019 (COVID-19), but some may have ongoing symptoms. Follow-up studies have been limited by small sample sizes and lack of appropriate controls. METHODS: We used national testing data to identify children aged 2-16 years with a SARS-CoV-2 PCR test during 1-7 January 2021 and randomly selected 1500 PCR-positive cases and 1500 matched PCR-negative controls. Parents were asked to complete a questionnaire about the acute illness and prespecified neurological, dermatological, sensory, respiratory, cardiovascular, gastrointestinal, mental health (including emotional and behavioral well-being), and other symptoms experienced ≥5 times at 1 month after the PCR test. RESULTS: Overall, 35.0% (859/2456) completed the questionnaire, including 38.0% (472/1242) of cases and 32% (387/1214) of controls, of whom 68% (320/472) and 40% (154/387) were symptomatic, respectively. The most prevalent acute symptoms were cough (249/859, 29.0%), fever (236/859, 27.5%), headache (236/859, 27.4%), and fatigue (231/859, 26.9%). One month later, 21/320 (6.7%) of symptomatic cases and 6/154 (4.2%) of symptomatic controls (P = .24) experienced ongoing symptoms. Of the 65 ongoing symptoms solicited, 3 clusters were significantly (P < .05) more common, albeit at low prevalence, among symptomatic cases (3-7%) than symptomatic controls (0-3%): neurological, sensory, and emotional and behavioral well-being. Mental health symptoms were reported by all groups but more frequently among symptomatic cases than symptomatic controls or asymptomatic children. CONCLUSIONS: Children with symptomatic COVID-19 had a slightly higher prevalence of ongoing symptoms than symptomatic controls, and not as high as previously reported. Healthcare resources should be prioritized to support the mental health of children.

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.

mRNA or ChAd0x1 COVID-19 Vaccination of Adolescents Induces Robust Antibody and Cellular Responses With Continued Recognition of Omicron Following mRNA-1273.

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.

The COVID-19 Schools Infection Survey in England: Protocol and Participation Profile for a Prospective Observational Cohort Study.

BACKGROUND: One of the most debated questions in the COVID-19 pandemic has been the role of schools in SARS-CoV-2 transmission. The COVID-19 Schools Infection Survey (SIS) aims to provide much-needed evidence addressing this issue. OBJECTIVE: We present the study protocol and participation profile for the SIS study, aimed at assessing the role of schools in SARS-CoV-2 infection and transmission within school settings, and investigating how transmission within and from schools could be mitigated through the implementation of school COVID-19 control measures. METHODS: SIS was a multisite, prospective, observational cohort study conducted in a stratified random sample of primary and secondary schools in selected local authorities in England. A total of 6 biobehavioral surveys were planned among participating students and staff during the 2020-2021 academic year, between November 2020 and July 2021. Key measurements were SARS-CoV-2 virus prevalence, assessed by nasal swab polymerase chain reaction; anti-SARS-CoV-2 (nucleocapsid protein) antibody prevalence and conversion, assessed in finger-prick blood for staff and oral fluid for students; student and staff school attendance rates; feasibility and acceptability of school-level implementation of SARS-CoV-2 control measures; and investigation of selected school outbreaks. The study was approved by the United Kingdom Health Security Agency Research Support and Governance Office (NR0237) and London School of Hygiene & Tropical Medicine Ethics Review Committee (reference 22657). RESULTS: Data collection and laboratory analyses were completed by September 2021. A total of 22,585 individuals-1891 staff and 4654 students from 59 primary schools and 5852 staff and 10,188 students from 97 secondary schools-participated in at least one survey. Across all survey rounds, staff and student participation rates were 45.2% and 16.4%, respectively, in primary schools and 30% and 15.2%, respectively, in secondary schools. Although primary student participation increased over time, and secondary student participation remained reasonably consistent, staff participation declined across rounds, especially for secondary school staff (3165/7583, 41.7% in round 1 and 2290/10,374, 22.1% in round 6). Although staff participation overall was generally reflective of the eligible staff population, student participation was higher in schools with low absenteeism, a lower proportion of students eligible for free school meals, and from schools in the least deprived locations (in primary schools, 446/4654, 9.6% of participating students were from schools in the least deprived quintile compared with 1262/22,225, 5.7% of eligible students). CONCLUSIONS: We outline the study design, methods, and participation, and reflect on the strengths of the SIS study as well as the practical challenges encountered and the strategies implemented to address these challenges. The SIS study, by measuring current and incident infection over time, alongside the implementation of control measures in schools across a range of settings in England, aims to inform national guidance and public health policy for educational settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/34075.