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.

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.

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 (preprint)

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. Research in Context Evidence Before this study 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. Added Value of This Study 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. Implications of all the Available Evidence 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

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.

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.