A collaborative approach to improving representation in viral genomic surveillance (preprint)

The lack of routine viral genomic surveillance delayed the initial detection of SARS-CoV-2, allowing the virus to spread unfettered at the outset of the U.S. epidemic. Over subsequent months, poor surveillance enabled variants to emerge unnoticed. Against this backdrop, long-standing social and racial inequities have contributed to a greater burden of cases and deaths among minority groups. To begin to address these problems, we developed a new variant surveillance model geared toward building microbial genome sequencing capacity at universities in or near rural areas and engaging the participation of their local communities. The resulting genomic surveillance network has generated more than 1,000 SARS-CoV-2 genomes to date, including the first confirmed case in northeast Louisiana of Omicron, and the first and sixth confirmed cases in Georgia of the emergent BA.2.75 and BQ.1.1 variants, respectively. In agreement with other studies, significantly higher viral gene copy numbers were observed in Delta variant samples compared to those from Omicron BA.1 variant infections, and lower copy numbers were seen in asymptomatic infections relative to symptomatic ones. Collectively, the results and outcomes from our collaborative work demonstrate that establishing genomic surveillance capacity at smaller academic institutions in rural areas and fostering relationships between academic teams and local health clinics represent a robust pathway to improve pandemic readiness. Author summaryGenomic surveillance involves decoding a pathogens genetic code to track its spread and evolution. During the pandemic, genomic surveillance programs around the world provided valuable data to scientists, doctors, and public health officials. Knowing the complete SARS-CoV-2 genome has helped detect the emergence of new variants, including ones that are more transmissible or cause more severe disease, and has supported the development of diagnostics, vaccines, and therapeutics. The impact of genomic surveillance on public health depends on representative sampling that accurately reflects the diversity and distribution of populations, as well as rapid turnaround time from sampling to data sharing. After a slow start, SARS-CoV-2 genomic surveillance in the United States grew exponentially. Despite this, many rural regions and ethnic minorities remain poorly represented, leaving significant gaps in the data that informs public health responses. To address this problem, we formed a network of universities and clinics in Louisiana, Georgia, and Mississippi with the goal of increasing SARS-CoV-2 sequencing volume, representation, and equity. Our results demonstrate the advantages of rapidly sequencing pathogens in the same communities where the cases occur and present a model that leverages existing academic and clinical infrastructure for a powerful decentralized genomic surveillance system.

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

Broad-spectrum extracellular antiviral properties of Cucurbit[n]urils (preprint)

Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortality and morbidity worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a macrocycle chemical compound existing as a range of homologues; due to their structure they can bind to biological materials, acting as supramolecular “hosts” to “guests”, such as amino acids. Due to the increasing need for a non-toxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including RSV and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n] mixtures, having an antiviral effect against enveloped and non-enveloped species. High levels of efficacy were observed with five-minute contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalisation or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals) demonstrating the potential of supramolecular interactions for future antiviral disinfectants.

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

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 profiles in children were strong with high titres against spike protein and receptor binding domain (RBD). SARS-CoV-2 seroconversion in children strongly boosted antibody responses against seasonal beta-coronaviruses, partly through cross-recognition of the S2 domain, indicating a broad humoral response that was not seen in adults. T cell responses against spike were also >2-fold higher in children compared to adults and displayed a strong Th1 cytokine profile. SARS-CoV-2 spike-reactive cellular responses were present in more than half the seronegative children, indicating pre-existing cross-reactive responses or sensitization against SARS-CoV-2. Importantly, all children retained high antibody titres and cellular responses for more than 6 months after infection whilst relative antibody waning was seen in adults. 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 several novel features of SARS-CoV-2-specific immune responses in children and may provide insights into relative clinical protection in this group. Such information on the profile of natural infection will help to guide the introduction of vaccination regimens into the paediatric population.

COVID-19 Outbreaks in Nurseries During Rapid Spread of the B.1.1.7 Variant of SARS-CoV-2 in England: Cross-Sectional National Surveillance, November 2020 – January 2021 (preprint)

Background: The reopening of schools during the COVID-19 pandemic has raised concerns about widespread infection and transmission of SARS-CoV-2 in educational settings. In June 2020, Public Health England (PHE) initiated prospective national surveillance of SARS-CoV-2 in primary schools across England (sKIDs). We used this opportunity to assess the feasibility and agreeability of large-scale surveillance and testing for SARS-CoV-2 infections in school among staff, parents and students.Methods: Staff and students in 131 primary schools were asked to complete a questionnaire at recruitment and provide weekly nasal swabs for SARS-CoV-2 RT-PCR testing (n=86) or swabs with blood samples for antibody testing (n=45) at the beginning and end the summer half-term. In six blood sampling schools, students were asked to complete a pictorial questionnaire before and after their investigations.Results: In total, 134 children aged 4-7 years (n=40) or 8-11 years (n=95) completed the pictorial questionnaire fully or partially. Prior to sampling, oral fluid sampling was the most acceptable test (107/132, 81%) followed by throat swabs (80/134, 59%), nose swabs (77/132, 58%), and blood tests (48/130, 37%). Younger students were more nervous about all tests than older students but, after completing their tests, most children reported a “better than expected” experience with all the investigations. Students were more likely to agree to additional testing for nose swabs (93/113, 82%) and oral fluid (93/114, 82%), followed by throat swabs (85/113, 75%) and blood tests (72/108, 67%). Parents (n=3,994) and staff (n=2,580) selected a preference for weekly testing with nose swabs, throat swabs or oral fluid sampling, although staff were more flexible about testing frequency. Conclusions: Primary school staff and parents were supportive of regular tests for SARS-CoV-2 and selected a preference for weekly testing. Children preferred nose swabs and oral fluids over throat swabs or blood sampling.Funding Statement: This surveillance was internally funded by PHE and did not receive any specific grant funding from agencies in the public, commercial or not-for-profit sectors.Declaration of Interests: None.Ethics Approval Statement: PHE has legal permission, provided by Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002, to process patient confidential information for national surveillance of communicable diseases and as such, individual patient consent is not required.

Feasibility and Acceptability of SARS-CoV-2 Testing and Surveillance in Primary School Children in England (preprint)

Background: The reopening of schools during the COVID-19 pandemic has raised concerns about widespread infection and transmission of SARS-CoV-2 in educational settings. In June 2020, Public Health England (PHE) initiated prospective national surveillance of SARS-CoV-2 in primary schools across England (sKIDs). We used this opportunity to assess the feasibility and agreeability of large-scale surveillance and testing for SARS-CoV-2 infections in school among staff, parents and students.Methods: Staff and students in 131 primary schools were asked to complete a questionnaire at recruitment and provide weekly nasal swabs for SARS-CoV-2 RT-PCR testing (n=86) or swabs with blood samples for antibody testing (n=45) at the beginning and end the summer half-term. In six blood sampling schools, students were asked to complete a pictorial questionnaire before and after their investigations.Results: In total, 134 children aged 4-7 years (n=40) or 8-11 years (n=95) completed the pictorial questionnaire fully or partially. Prior to sampling, oral fluid sampling was the most acceptable test (107/132, 81%) followed by throat swabs (80/134, 59%), nose swabs (77/132, 58%), and blood tests (48/130, 37%). Younger students were more nervous about all tests than older students but, after completing their tests, most children reported a “better than expected” experience with all the investigations. Students were more likely to agree to additional testing for nose swabs (93/113, 82%) and oral fluid (93/114, 82%), followed by throat swabs (85/113, 75%) and blood tests (72/108, 67%). Parents (n=3,994) and staff (n=2,580) selected a preference for weekly testing with nose swabs, throat swabs or oral fluid sampling, although staff were more flexible about testing frequency. Conclusions: Primary school staff and parents were supportive of regular tests for SARS-CoV-2 and selected a preference for weekly testing. Children preferred nose swabs and oral fluids over throat swabs or blood sampling.

Seroprevalence of SARS-CoV-2 Antibodies in University Students: Cross-sectional Study, December 2020, England (preprint)

Background: In England, the reopening of universities in September 2020 coincided with a rapid increase in SARS-CoV-2 infection rates in university aged young adults. This study aimed to estimate SARS-CoV-2 antibody prevalence in students attending universities that had experienced a COVID-19 outbreak after reopening for the autumn term in September 2020.Methods: A cross-sectional serosurvey was conducted during 02-11 December 2020 in students aged ≤ 25 years across five universities in England. Blood samples for SARS-CoV-2 antibody testing were obtained using a self-sampling kit and analysed using the Abbott SARS-CoV-2 N antibody and/or an in-house receptor binding domain (RBD) assay. Findings: SARS-CoV-2 seroprevalence in 2,905 university students was 17.8% (95%CI, 16.5-19.3), ranging between 7.6%-29.7% across the five universities. Seropositivity was associated with being younger likely to represent first year undergraduates (aOR 3.2, 95% CI 2.0-4.9), living in halls of residence (aOR 2.1, 95% CI 1.7-2.7) and sharing a kitchen with an increasing number of students (shared with 4-7 individuals, aOR 1.43, 95%CI 1.12-1.82; shared with 8 or more individuals, aOR 1.53, 95% CI 1.04-2.24). Seropositivity was 49% in students living in halls of residence that reported high SARS-CoV-2 infection rates (>8%) during the autumn term.Interpretation: Despite large numbers of cases and outbreaks in universities, less than one in five students (17.8%) overall had SARS-CoV-2 antibodies at the end of the autumn term in England. In university halls of residence affected by a COVID-19 outbreak, however, nearly half the resident students became infected and developed SARS-CoV-2 antibodies.

COVID-19 Outbreaks Following Full Reopening of Primary and Secondary Schools in England: Retrospective, Cross-Sectional National Surveillance (preprint)

Background: The full reopening of schools in September 2020 was associated with an increase in COVID-19 cases and outbreaks in educational settings across England. Methods: Primary and secondary schools reporting an outbreak (≥2 laboratory-confirmed cases within 14 days) to Public Health England (PHE) between 31 August and 18 October 2020 were contacted to complete an online questionnaire. Interpretation: There were 969 primary (n=450) and secondary school outbreaks (n=519) reported to PHE, representing 3% of primary schools and 15% of secondary schools in England. Of the 369 schools contacted, 190 geographically-representative schools completed the questionnaire; 2,425 cases were reported. Secondary school students (1.20%; 95%CI, 1.13-1.28%) had higher attack rates than primary school students (0.84%; 95%CI, 0.75-0.94%). Outbreaks were larger and across more year groups in secondary schools than in primary schools. When an outbreak occurred, attack rates were higher in staff (926/19,083; 4.85%; 95%CI, 4.55-5.17%) than students, especially among primary school teaching staff (9.81%; 95%CI, 8.90-10.82%) compared to secondary school teaching staff (3.97%; 95%CI, 3.79-5.69%). Staff represented 59% (471/799) of cases in primary school outbreaks and 27% (410/1515) in secondary schools (P<0.001). Teaching staff were more likely to be the index case in primary (48/100, 48%) than in secondary (25/79, 32%) schools (P=0.027).Conclusions: Secondary schools were more likely to be affected by a COVID-19 outbreak than primary schools and to experience larger outbreaks across multiple school years. The higher attack rate among teaching staff during an outbreak suggests that additional protective measures may be needed. Funding: PHE

Prospective Active National Surveillance of Preschools and Primary Schools for SARS-CoV-2 Infection and Transmission in England, June 2020: (sKIDs: COVID-19 Surveillance in School KIDs) (preprint)

Background: Many countries re-opened schools after national lockdown but little is known about the risk of SARS-CoV-2 infection and transmission in educational settings. Public Health England conducted six-month prospective surveillance in primary schools across England. Methods: The COVID-19 Surveillance in School KIDs (sKIDs) study included two arms: weekly nasal swabs for ≥4 weeks following partial reopening during the summer half-term (June to mid-July 2020) and blood sampling with nasal and throat swabs at the beginning and end of the summer half-term, and, following full reopening in September 2020, at the end of the autumn term (end-November 2020). Results: In round 1, 12,026 participants (59.1% students, 40.9% staff) in 131 schools had 43,091 swabs taken. Weekly SARS-CoV-2 infection rates were 3.9 (1/25,537; 95% CI, 0.10-21.8) and 11.3 (2/17,554; 95% CI, 1.4-41.2) per 100,000 students and staff. At recruitment, N-antibody positivity in 45 schools was 11.1% (91/817; 95%CI, 9.2-13.5%) in students and 15.1% (209/1381; 95%CI, 13.3-17.1%) in staff, similar to local community seroprevalence. Seropositivity was not associated with school attendance during lockdown or staff contact with students. Round 2 participation was 73.7% (1,619/2,198) and only five (4 students, 1 staff) seroconverted. In round 3, when 61.9% (1,361/2,198) of round 1 participants were re-tested, seroconversion rates were 3.4% (19/562; 95%CI, 2.0-5.2) in students and 3.9% (36/930; 95%CI, 2.7-5.3) in staff. Conclusions: SARS-CoV-2 infection rates, assessed using nasal swabs for acute infection and serum antibodies for prior infection, were low following partial and full reopening of primary schools in England.Funding Statement: This surveillance was funded by the Department of Health and Social Care (DHSC).Declaration of Interests: None to declare.Ethics Approval Statement: The surveillance protocol was approved by the Public Health England Research Ethics Governance Group (R&D REGG Ref: NR0209, 16 May 2020).

COVID-19 Outbreaks Following Full Reopening of Primary and Secondary Schools in England: Retrospective, Cross-Sectional National Surveillance (preprint)

Background: The full reopening of schools in September 2020 was associated with an increase in COVID-19 cases and outbreaks in educational settings across England.Methods: Primary and secondary schools reporting an outbreak (≥2 laboratory-confirmed cases within 14 days) to Public Health England (PHE) between 31 August and 18 October 2020 were contacted to complete an online questionnaire.Interpretation: There were 969 primary (n=450) and secondary school outbreaks (n=519) reported to PHE, representing 3% of primary schools and 15% of secondary schools in England. Of the 369 schools contacted, 190 geographically-representative schools completed the questionnaire; 2,425 cases were reported. Secondary school students (1.20%; 95%CI, 1.13-1.28%) had higher attack rates than primary school students (0.84%; 95%CI, 0.75-0.94%). Outbreaks were larger and across more year groups in secondary schools than in primary schools. When an outbreak occurred, attack rates were higher in staff (926/19,083; 4.85%; 95%CI, 4.55-5.17%) than students, especially among primary school teaching staff (378/3852; 9.81%; 95%CI, 8.90-10.82%) compared to secondary school teaching staff (284/7146; 3.97%; 95%CI, 3.79-5.69%). Staff represented 59% (471/799) of cases in primary school outbreaks and 27% (410/1515) in secondary schools (P<0.001). Teaching staff were more likely to be the index case in primary (48/100, 48%) than in secondary (25/79, 32%) schools (P=0.027). Conclusions: Secondary schools were more likely to be affected by a COVID-19 outbreak than primary schools and to experience larger outbreaks across multiple school years. The higher attack rate among teaching staff during an outbreak suggests that additional protective measures may be needed.Funding Statement: This surveillance was internally funded by PHE and did not receive any specific grant funding from agencies in the public, commercial or not-for-profit sectors.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: PHE has legal permission, provided by Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002, to process patient confidential information for national surveillance of communicable diseases and as such, individual patient consent is not required.