Children develop robust and sustained cross-reactive spike-specific immune responses following SARS-CoV-2 infection

Abstract

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.

Immunological imprinting of humoral immunity to SARS-CoV-2 in children

“…This indicates that, whilst infection with a pre-Omicron virus deviates the humoral immune response away from Omicron, the reverse pattern is not observed. In addition, although spike-specific antibody responses after Omicron were weaker than those seen after a pre-Omicron variant infection, the magnitude of the nucleocapsid-specific response was comparable and may indicate a more equivalent recognition of the whole viral proteome, although waning of nucleocapsid-specific antibody responses in the pre-Omicron variant samples make interpretation of this difficult [9].…”

“…Quantitative IgG antibody titres were measured using Mesoscale Diagnostics multiplex assays; Coronavirus Panel 22 and 24, as previously describe [9] following the manufacturer instructions. Briefly, samples were diluted 1:5000 and added wells of the 96 well plate alongside reference standards and controls.…”

“…Data are presented as arbitrary units (AU)/ml determined relative to the standard curve generated. Cut-offs were previously defined against pre-pandemic adult and paediatric samples [9].…”

“…Constructs and 293-ACE2 cells were previously described [9,30]. The assay was performed as previously described [9,30], briefly neutralising activity in each sample was measured against pseudo-virus displaying SARS-CoV-2 spike, either Wuhan sequence or B.1.1.529:BA.2 sequence, by a serial dilution approach. Each sample was serially diluted in triplicate from…”

“…Infections are generally mild or asymptomatic in children and potential determinants of this may include increased expression of IFN-response genes within the mucosal epithelium and enhanced innate immune responses [7, 8]. Despite this, children have been observed to develop robust systemic adaptive immune responses against pre-Omicron variants [9] with increased clonality compared to adults [8], although it is not known if similar findings will be seen following infection with Omicron and related variants. Furthermore, COVID-19 vaccination is now offered to children in many countries but most vaccines utilize a Wuhan spike immunogen which provides lower protection against Omicron compared to previous SARS-CoV-2 variants.…”