key: cord-0259894-mmenuwgo
authors: Ladhani, S. N.; Ireland, G.; Baawuah, F.; Beckmann, J.; Okike, I. O.; Ahmad, S.; Garstang, J.; Brent, A. J.; Brent, B.; Aiano, F.; Amin-Chowdhury, Z.; Kall, M.; Borrow, R.; Linley, E.; Zambon, M.; Poh, J.; Warrener, L.; Lackenby, A.; Ellis, J.; Amirthalingam, G.; Brown, K. E.; Ramsay, M. E.
title: Emergence of SARS-CoV-2 Alpha (B.1.1.7) variant, infection rates, antibody seroconversion and seroprevalence rates in secondary school students and staff: active prospective surveillance, December 2020 to March 2021, England
date: 2021-07-16
journal: nan
DOI: 10.1101/2021.07.14.21260496
sha: 66d2519d19c364f251e60897741c11f657d3435b
doc_id: 259894
cord_uid: mmenuwgo

Background In England, the rapid spread of the SARS-Cov-2 Alpha (B.1.1.7) variant from November 2020 led to national lockdown, including school closures in January 2021. We assessed SARS-CoV-2 infection, seroprevalence and seroconversion in students and staff when secondary schools reopened in March 2021. Methods Public Health England initiated SARS-CoV-2 surveillance in 18 secondary schools across six regions in September 2020. Participants provided nasal swabs for RT-PCR and blood samples for SARS-CoV-2 antibodies at the beginning (September 2020) and end (December 2020) of the autumn term and at the start of the spring term (March 2021). Findings In March 2021, 1895 participants (1100 students, 795 staff) were tested; 5.6% (61/1094) students and 4.4% (35/792) staff had laboratory-confirmed SARS-CoV-2 infection between December 2020 and March 2021. Nucleoprotein antibody seroprevalence was 36.3% (370/1018) in students and 31.9% (245/769) in staff, while spike protein antibody prevalence was 39.5% (402/1018) and 59.8% (459/769), respectively, similar to regional community seroprevalence. Between December 2020 and March 2021 (median 15.9 weeks), 14.8% (97/656; 95% CI: 12.2-17.7) students and 10.0% (59/590; 95% CI: 7.7-12.7) staff seroconverted. Weekly seroconversion rates were similar from September to December 2020 (8.0/1000) and from December 2020 to March 2021 (7.9/1000; students: 9.3/1,000; staff: 6.3/1,000). Interpretation By March 2021, a third of secondary school students and staff had serological evidence of prior infection based on N-antibody seropositivity, and an additional third of staff had evidence of vaccine-induced immunity based on S-antibody seropositivity. Further studies are needed to assess the impact of the Delta variant.

The Alpha variant is 30-70% more transmissible than previously circulating SARS-CoV-2 strains in adults and children. One outbreak investigation in childcare settings estimated similar secondary attack rates with the Alpha variant in children and adults. There are limited data on the impact of the Alpha variant in educational settings. In England, cases in primary and secondary school aged children increased rapidly from late November 2020 and peaked at the end of December 2020, leading to national lockdown including school closures.

Seroconversion rates in staff and students during December 2020 to March 2021, when the Alpha variant was the primary circulating strain in England, were similar to the period between September 2020 and December 2020 when schools were fully open for in-person teaching. By March 2021, a third of students overall and more than half the students in some regions were seropositive for SARS-CoV-2 antibodies. Among staff, too, around a third had evidence of prior infection on serological testing and a further third had vaccine-induced immunity.

SARS-CoV-2 antibody seroprevalence was high among secondary school students in March 2021 and is likely to be higher following the emergence of an even more transmissible Delta variant in May 2021. Education staff are increasingly being protected by the national COVID-19 immunisation programme. These findings have important implications for countries that are considering vaccination of children to control the pandemic . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. To better understand infection and transmission of SARS-CoV-2 in secondary schools, Public Health England (PHE) initiated active, prospective surveillance in 18 schools across six English regions to assess the risk of SARS-CoV-2 infection in students and staff in September 2020. (11) In addition to nasal swabbing to identify acute SARS-CoV-2 infection, we also took blood samples from staff and students to measure SARS-CoV-2 antibody positivity, because it captures both symptomatic and asymptomatic prior infections, which are especially common in children. (11) (12) (13) In December 2020, we found similar antibody seroprevalence and seroconversion rates in staff and students, which were comparable to local community rates at the time.(11) However, towards the end of November 2020, rapid increases in SARS-CoV-2 infection rates were observed across all age groups because of rapid increases in the more transmissible Alpha variant, leading to local tier restriction in areas of high community infections from 19 December 2020 and another national lockdown from 06 January 2021, including school closures from the end of the end of the autumn term in late December 2020 until 08 March 2021. Between 05 January and 08 March 2021 schools were closed for all students except vulnerable children or children of key workers and an estimated 5% of secondary school students and 25% of primary school students attended school during the lockdown period. (14) To assess the impact of the Alpha variant in students and staff, we undertook another round of nasal swabbing and blood sampling when participating schools reopened after . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint prolonged national lockdown in March 2021, with the aim of assessing SARS-CoV-2 infection, antibody seroprevalence and seroconversion rates during a period of rapid spread of the Alpha variant in England.

The COVID-19 Surveillance in Secondary School KIDs (sKIDsPLUS) protocol is available online (https://www.gov.uk/guidance/covid-19-paediatric-surveillance), (15) and results for the first two rounds of testing have been published. (11) The protocol was approved by PHE Research Ethics Governance Group (reference Nr0228; 24 August 2020). The study involved testing secondary school Local anaesthetic cream was offered to all students before blood sampling. A member of the school staff was present with each student. Participating students and staff had a nasal swab and a blood sample taken by the investigation team.

The swabs were tested by a triplex reverse transcription PCR (RT-PCR) assay for the detection of is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint additional measures, including identification and isolation of the participant's contacts inside and outside school premises.

Serology was performed on the Abbott Architect using a chemiluminescent microparticle immunoglobulin G (IgG) immunoassay targeting the nucleoprotein (N) (SARS-CoV-2 IgG, Abbott Commerce Chicago, USA) with a seropositivity threshold of 0.8 (henceforth referred to as Abbott N assay). (18) This assay was shown to detect SARS-CoV-2 N-antibodies as early as 7 days post symptom onset and is, therefore, particularly useful for assessing SARS-CoV-2 antibody seroconversion (negative to positive antibodies) between testing rounds. (19) Where sufficient serum was available, samples from Rounds 2 and 3 were additionally tested for nucleoprotein and spike (S) protein antibodies on the Roche Elecsys Anti-SARS-CoV-2 assay and Elecsys Anti-SARS-CoV-2 S assay respectively (henceforth referred to as Roche N and Roche S assays respectively).

Data were managed in R-Studio and Microsoft Access and analysed in Stata SE (version 15.1). Data that did not follow a normal distribution are described as median with interquartile ranges.

Categorical data are described as proportions and compared with the Chi 2 -test or Fisher's exact.

Participants were linked to routine laboratory report of SARS-CoV-2 to identify diagnoses between testing rounds. Firstly, NHS number was ascertained through linkage of participants to the Personal Demographics Service. A combination of NHS number, full name, sex, date of birth and postcode of residence was used to link participants to the routine laboratory reports of SARS-CoV-2 at PHE. SARS-CoV-2 infection rate and antibody seroprevalence, with 95% confidence intervals (CI), were compared between secondary school students and staff. For comparisons with regional seroprevalence, three-week (round 3: 15 March-11 April) average prevalence data from PHE and NHS Blood and Transplant (NHS BT) serosurveillance of blood donors was provided. A sample of donors are tested for both N and S-antibodies on the Roche assays and for students data was compared to the seroprevalence in 18-30 year olds and staff were compared to 18-64 year old donors. Non-overlapping 95% CIs were used to assess statistical significance between student or staff rates and regional estimates. Antibody seroconversion rates with 95% confidence intervals were calculated for participants who were tested in two sequential rounds and were negative in their first round of testing.

Reported SARs-CoV-2 cases were used in conjunction with questionnaire data to ascertain likely time of infection. Reported SARS-CoV-2 diagnosis date was preferentially taken over reported date of symptom onset and reported date of diagnosis, as provided in the questionnaire.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint Participants were classified as included in each round if they provided a blood or swab sample in that round. For SARS-CoV-2 antibody seroconversion, a multivariable regression model was built using age, sex, ethnicity, school area and school attendance during January to March 2021 lockdown. Variation between schools was allowed for via a school-level random effect.

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Applications for relevant anonymised data should be submitted to the Public Health England Office for Data Release.

Eighteen secondary schools in six school areas enrolled and participated in three rounds of sKIDsPLUS testing. Overall, 1895 participants were tested in Round 3, 1100 students and 795 staff ( Table 1) . Of those who completed the online surveillance questionnaire for Round 3 (students:

78.4%; n=862, staff: 88.4%; n=703), most (82.8%; 707/854) students had not attended school during the third lockdown, with 5.7% (n=49) attending part-time and 11.5% (n=98) attending full-time. In comparison, the staff had all attended school, either part-time (70.3%; 352/501) or full-time (29.7%; n=149). Two-fifths (42.9%; 300/700) of staff were vaccinated, and 1.3% (11/852) students reported being vaccinated).

In 

Serum samples were tested on the Abbott N-antibody platform for all three rounds and seroprevalence increased from 11.0% (193/1754) in Round 1, 13.3% (234/1766) in Round 2 to 20.9%

(377/1800) in Round 3 (p<0.001 for both rounds vs. Round 3) (Figure 1) . Because of an assay-related high antibody waning rate over time with the Abbott N-antibody assay, sera from Round 3 were also . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint tested on the Roche N and S assay. Using the Roche assay, the N-antibody seroprevalence was 36.3%

(370/1018) in students and 31.9% (245/769) in staff, while S-antibody prevalence was 39.5%

(402/1018) and 59.8% (459/767), respectively (Figure 2) . In S-antibody positive staff, 63.0% (259/411) reporting being vaccinated.

When compared to regional seroprevalence data using the NHS BT samples, N-antibody seroprevalence was higher in students from East London and Hertfordshire, and higher in staff from Derbyshire, East London and West Midlands. For S-antibody, seroprevalence was higher in students from West London and West Midlands, and higher in staff from Hertfordshire (Figure 2) .

Overall, 758 students and 688 staff had Abbott N-antibody results from both Rounds 2 and 3, including 656 (86.5%) and 590 (85.8%), respectively, who were negative in Round 2. Between Table 2) . Seroconversion rate was 9.3 per 1,000 weeks (95% CI: 7.5-11.3) between Rounds 2 and 3 in students, compared to 6.8 per 1,000 weeks (95% CI: 4.8-9.4) between Rounds 1 and 2. Among staff, the seroconversion rate was 6.3 per 1,000 weeks (95% CI: 4.8-8.1) between Rounds 2 and 3 and 8.9 per 1,000 weeks (95% CI: 6.7-11.5) between Rounds 1 and 2

Where known, more student seroconverters were asymptomatic than staff (66.7%; 44/66 vs. 30 Using a logistic regression, seroconversion in students between Rounds 2 and 3 was associated with school area (p=0.0060), with higher rates in East London (adjusted Odds Ratio [OR]: 3.60; 95% CI:

1.59-8.14 compared to Derbyshire) and full-time school attendance during the third lockdown (OR: 2.27; 95% CI: 1.06-4.86) when compared to students studying at home ( Table 3 ). In staff, seroconversion was associated with Asian ethnicity (OR: 2.95; 95% CI: 1.11-7.84) when compared to White participants. Clustering was not significant at a school level for students (p=1.0) or staff (p=0.068).

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The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint Between December 2020 and March 2021, 5.7% of secondary school students and 4.4% of staff had laboratory-confirmed COVID-19, mainly during December 2020, when schools were open and case rates of the SARS-CoV-2 Alpha variant were increasing rapidly across England. When assessed using serum antibodies, however, the estimated proportions exposed to the virus over the same period were 14.8% and 10.0%, respectively, likely because of asymptomatic and pauci-symptomatic infections that did not warrant testing for the virus. The weekly seroconversion rate in staff and students was similar between December 2020 and March 2021 when compared with September to December 2020, even though the majority students did not attend school and more than two-thirds of staff attended school part-time during the latter period. By March 2021, 36.3% in students and 31.9% in staff had evidence of SARS-CoV-2 infection based on N-antibody seropositivity. This was supported by similar S-antibody seropositivity of 39.5% in students who were unvaccinated at the time, but 59.8% of staff had detectable spike antibodies because two-thirds of the school staff had been vaccinated as part of the national COVID-19 vaccine rollout.

Serum antibody testing is the most robust investigation for assessing prior exposure to SARS-CoV-2 because it captures both symptomatic and asymptomatic infections, the latter contributing to a significant proportion of total cases among both students (67%) and staff (31%) in our cohort. This is consistent with the published literature, but due to testing and isolation guidance, PCR-testing only provides a point estimate of asymptomatic infection prevalence in participants who were in school on the day of testing.(20) At the same time, testing of symptomatic individuals only will miss more than half the infections, as evidenced through linkage of our cohort with the national SARS-CoV-2 testing database, which estimated an infection prevalence of around 5% compared to more than twice this estimate through seroconversion.

We initially used the Abbott N-antibody testing platform because our early validation studies indicated that seropositivity was detected quicker after acute infection compared to other commercial platforms. (19, 21, 22) Using this assay, we found that the weekly seroconversion rates were similar between September-December 2020 and from December 2020 to March 2021, despite most students not attending school and staff attending part-time only during the latter period. The date of PCR-testing among symptomatic participants indicated that most infections occurred during the peak of the Alpha variant outbreak nationally in December 2020, although cases also occurred at lower rates during January and February 2021. Notably, attending school was associated with an increased risk of seroconversion in students, and marginally non-significant in staff, although we were not able to ascertain whether the infection was acquired inside or outside school. Data from the Schools Infection Survey (SIS) also showed similar N-antibody seroconversion rates in among primary and secondary school staff for the autumn term and lockdown period, although data on . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint students and more detailed estimates by attendance are yet to be published.(23) A number of epidemiological studies have reported that most confirmed SARS-CoV-2 infections in school-aged children are acquired outside school, usually from a household member, with very low rates of inperson transmission of SARS-CoV-2 within school premises, even with active case finding. (24) (25) (26) This is consistent with seroprevalence studies in both primary and secondary schools when all students were attending in-person teaching. (11, 12, 27) That seroconversion rates were lower in students who did not attend in-person teaching is not surprising since their risk of coming into contact with an infected person would be significantly reduced.

An as-yet unexplained phenomenon of the Abbott nucleoprotein assay is a very high antibody seroreversion rate over time. (21) This appears to be specific to this particular platform because such a high seroreversion rates is not observed when the same sera are tested on other commercial nucleoprotein or spike protein antibody platforms. (21) Consequently, we re-tested all samples in round 3 in the Roche N assay, which reported seroprevalence rates around 65% higher than the Abbott nucleoprotein assay (Figure 1 ).

London to almost 50% in East London. In students, the antibodies were most likely through natural infection, since vaccination was not recommended for this age-group. Observational data from England indicates that secondary attack rates followed an inverted U relationship with age, such that the risk of transmission increased from 9% in 0-9 year-olds to 12% among 10-19 year-olds and 16% among 20-29 year-olds and remaining at 20-24% thereafter. (28) Additionally, secondary attack rates were higher across all age-groups for the Alpha variant compared to previously circulating strains. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 16, 2021. ; https://doi.org/10.1101/2021.07.14.21260496 doi: medRxiv preprint hospitalisation and deaths because of the national rollout of the COVID-19 immunisation programme since the end of December 2020. (32) The programme prioritised vaccination for older adults, followed by health and social care workers, those with underlying co-morbidities and the progressively in younger adults in 10-year age-bands.(33) School staff were not prioritised for vaccination in the UK because their risk of COVID-19 was similar to other professions.(34) Instead, they were vaccinated according to their age and comorbidity status. Since we also measured spike antibodies using the Roche S assay in Round 3, we were able to estimate that around 60% of school staff were protected by March 2021, either through natural infection or vaccination. Since 17 May, however, cases and outbreaks have been increasing in school-aged children, with the Delta variant now accounting for >90% of SARS-CoV-2 infections in England. (32, 35) It is likely that SARS-CoV-2 antibody prevalence in students will now be higher than in March 2021.

The high seroprevalence rate in secondary school-aged children has implications for vaccinating secondary school students following approval of the Pfizer-BioNTech mRNA vaccine from adults down to 12 year-olds.(36) Some countries including the United States, Canada and Israel have already started vaccinating adolescents but others, including the UK, are yet to make a recommendation. The decision to recommend COVID-19 vaccination for teenagers should consider the added value of vaccinating a group with a high prevalence of natural immunity or, alternatively, whether a single dose, or a lower dose, might be sufficient to confer immunity whilst limiting the risk of potential adverse events, including myocarditis in teenagers and young adults. 

The strength of this surveillance lies in the rapid recruitment and longitudinal assessment of secondary schools as soon as they reopened after national lockdown in September 2020. There are, however, some limitations. We only recruited schools in regions where we had paediatric investigation teams to take blood samples from large numbers of staff and students. Our schools are, therefore, not intended to be representative of all secondary schools in England. We avoided recruiting some secondary school years with end-of-year national examinations to minimise disruption of their education. Additionally, as already discussed, we were unable to assess whether the confirmed infections occurred within or outside the school premises. We are currently conducting a larger national School Infection Survey (SIS) involving 150 schools across England during the 2020/21 academic year.(42)

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MR reports that The Immunisation and Countermeasures Division has provided vaccine manufacturers with post-marketing surveillance reports on pneumococcal and meningococcal infection which the companies are required to submit to the UK Licensing authority in compliance with their Risk . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 16, 2021. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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