Defining the pediatric response to SARS-CoV-2 variants

Abstract

The global population has been severely affected by the coronavirus disease 2019 (COVID-19) pandemic, however, with older age identified as a risk factor, children have been underprioritized. This article discusses the factors contributing to the less severe response observed in children following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including, differing viral entry receptor expression and immune responses. It also discusses how emerging and future variants could present a higher risk to children, including those with underlying comorbidities, in developing severe disease. Furthermore, this perspective discusses the differential inflammatory markers between critical and non-critical cases, as well as discussing the types of variants that may be more pathogenic to children. Importantly, this article highlights where more research is urgently required, in order to protect the most vulnerable of our children.

Keywords: COVID-19; SARS-CoV-2; age-specific response; cellular biology; children; emerging variants; molecular biology; pediatric.

Figure 1

Clinical progression of SARS-CoV-2 infection in children (left) and adults (right). In children, higher proportion of fever, vomiting, and diarrhea were reported compared to adults and severe disease can manifest as severe respiratory symptoms or multisystem inflammatory syndrome (MIS-C), Adults typically present with common respiratory illness symptoms, which can lead to severe complications such as acute respiratory distress syndrome (ARDS) and as well as cardiac, neurological, and renal complications. Created with BioRender.com.

Figure 2

The age-specific innate and adaptive immune responses of children. (A) Baseline variances found in children compared to adults prior viral infection. (i) Greater number and diversity of immune cells with a neutrophil predominance. (ii) Higher levels of genes coding for SARS-CoV-2 pattern recognition receptors (PRRs) and viral RNA sensing enhancers. (iii) Stronger immune-epithelial cell cross-talk. (iv) Presence of a subpopulation of cytotoxic T-cells that allows preservation of virus-specific CD8⁺ T cell response without apoptosis. (B) Differences found in the nasal epithelium/mucosa immune response of children compared to adults following infection of SARS-CoV-2. Children are suggested to mount a stronger anti-viral response with: (i) increased gene expression levels involved with an activated neutrophil phenotype, epithelial repair, and innate immune responses such as response to TNF, leukocyte activation, and IFNG and CCL5 expression, and (ii) presence of a distinct CD8⁺ T cell population with a memory phenotype. (iii) Stable maintenance of the proportion of immune and epithelial cells in nasal epithelium of children. (C) Systemic immune differences found in the blood of children compared to adults. (i) Higher levels of serum IL-17A and IFNγ and circulating CD63⁺ neutrophils. (ii) Reduced proportions of circulating monocytes subsets (classical, intermediate, non-classical), dendritic cells, and natural killer cells. (iii) Antibody response in children primarily consists of anti-S protein IgG antibodies with an overall lower neutralizing activity, but children maintain higher antibody titers against the S protein and RBD six months after seroconversion. Created with BioRender.com. IFN, interferon; IL, interleukin; N, nucleocapsid; RBD, receptor-binding domain; S, spike; TNF, tumor necrosis factor.