SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children

Abstract

Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility, combined with fluctuating mask mandates and school reopenings, has led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remain unclear. Here, we aimed to deeply profile the vaccine-induced humoral immune response in 6- to 11-year-old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children who experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100-μg dose but more variable immunity at a 50-μg dose. Irrespective of titer, children generated antibodies with enhanced Fc receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain, but robustly preserved omicron spike protein binding. Fc receptor binding capabilities were also preserved in a dose-dependent manner. These data indicate that both the 50- and 100-μg doses of mRNA vaccination in children elicit robust cross-VOC antibody responses and that 100-μg doses in children result in highly preserved omicron-specific functional humoral immunity.

Fig. 1.. mRNA-1273 vaccination induces robust binding and neutralizing titers in children.

(A) Relative SARS-CoV-2 spike protein (Wuhan)-specific IgM, IgA1 and IgG1 binding was determined by Luminex in children (6 to 11 years) receiving 50 μg or 100 μg mRNA1273 before (V0_{50 μg}: n=12; V0_{100 μg}: n=12), after the first (V1_{50 μg}: n=9; V1_{100 μg}: n=12) or after the second (V1_{50 μg}: n=11; V2_{100 μg:} n=12) dose or in adults receiving two 100 μg doses (V1: n=19; V2: n=33) as well as in samples from individuals after pediatric COVID (n=9) or MIS-C (n=6). MFI, median fluorescence intensity. (B) The dot plots show the inverse 50% pseudovirus neutralizing titers (pNT₅₀) in children (6-11 years) receiving 50 μg or 100 μg mRNA1273 before (V0_{50 μg}: n=12; V0_{100 μg}: n=12), after the first (V1_{50 μg}: n=9; V1_{100 μg}: n=12) or after the second (V1_{50 μg}: n=9; V2_{100 μg:} n=11) dose or in adults receiving two 100 μg doses (V2: n=14) as well as in convalescent pediatric COVID (n=9) or MIS-C (n=6) samples. Horizontal bars in (A) and (B) indicate mean. (C) Heatmap strips summarize univariate comparison at the V2 timepoint of 100 μg dose vaccinated children to adults (left panel) or to 50 μg dose vaccinated children (right panel). pVNT, pseudovirus-neutralizing titer. The color of the tiles indicate whether antibody binding titer were up-regulated in the respective group: 100 μg vaccinated children (blue shades), adults (red shades), or 50 μg vaccinated children (yellow shades). A Wilcoxon-signed rank test was used to test for statistical significance and asterisks indicate statistically significant differences of the respective feature after Benjamini-Hochberg correction for multiple testing (**p<0.01;***p<0.001; ****p<0.0001).

Fig. 2.. mRNA-1273 vaccination induces higher FcγR binding and phagocytic activity in children.

(A) Binding of SARS-CoV-2-specific antibodies to FcγR2a, 2b, 3a, and 3b was determined by Luminex in children (6 to 11 years) receiving 50 μg or 100 μg mRNA1273 before (V0_{50 μg}: n=12; V0_{100 μg}: n=12), after the first (V1_{50 μg}: n=9; V1₁₀₀: n=12) or after the second (V2_{50 μg}: n=11; V2_{100 μg:} n=12) dose or in adults receiving two 100 μg doses (V1: n=19; V2: n=33) as well as in convalescent pediatric COVID (n=9) or MIS-C (n=6) samples. (B) Heatmap strips summarize univariate comparison of Fc-receptor binding at the V2 timepoint of 100 μg dose vaccinated children to adults (left panel) or to 50 μg dose vaccinated children (right panel). Color of the tiles indicate whether antibody binding titer were up-regulated in the respective group: 100 μg vaccinated children (blue shades), adults (red shades), or 50 μg vaccinated children (yellow shades). (C) The ability of SARS-CoV-2 spike protein-specific antibody Fc to induce ADCD, ADNP, cellular THP-1 monocyte phagocytosis (ADCP), or activation of NK cells marked by expression of MIP-1β was analyzed in the same samples as in (A). (D) Heatmap strips summarize univariate comparison of Fc effector functions at the V2 timepoint of 100 μg dose vaccinated children to adults (left panel) or to 50 μg dose vaccinated children (right panel) as in (B). A Wilcoxon-signed rank test was used to test for statistical significance in (C) and (D) and asterisks indicate statistically significant differences of the respective feature after Benjamini-Hochberg correction for multiple testing (*p<0.05; **p<0.01;***p<0.001; ****p<0.0001).

Fig. 3.. Distinct humoral profiles distinguish adult and pediatric vaccine responses.

(A) A machine learning model was built using a minimal set of LASSO-selected SARS-CoV-2 spike protein-specific features at V2 (left panel) to discriminate between vaccine responses in adult (red) and 100 μg vaccinated children (purple) in a PLS-DA analysis (right panel, VIP indicates the Variable Importance Projection Score). (B) A co-correlation network illustrates all LASSO-selected features. Nodes of selected features are colored whether they were enriched in children (purple) or adults (red). Lines indicate significant (p<0.05) spearman correlations with |r|>0.7 of connected features (only positive correlations with r>0 were observed). (C) PLS-DA model of LASSO selected features at V2 (left panel) to discriminate between vaccine responses in 100 μg (purple) and 50 μg (yellow) vaccinated children. (D) A co-correlation network as in (B) illustrates all LASSO-selected features. A single node of a selected features is colored in purple to indicate enrichment in samples from 100 μg vaccinated children.

Fig. 4.. mRNA-1273 vaccination elicits humoral responses to SARS-CoV-2 VOCs.

(A and B) The line graphs show the vaccine-induced IgM, IgA1 and IgG1 recognition to D614G (wild-type; blue), alpha (B.1.1.7; yellow), beta (B.1.351; purple), delta (B.1.617.2; orange), and omicron (B.1.1.529; red) variants of concern RBDs (A) or full spike protein (B). (C) neutralizing titers are shown as pNT₅₀ values. All plots in (A to C) show results for samples from children (n_{50 μg}=6, n_{100 μg}=9) and adults (n=14) at V2, where each individual’s response is linked across VOC antigens. (D) The line graphs show the FcγR (FcγR2a, FcγR2b, FcγR3a, FcγR3b) binding profiles of vaccine-induced antibodies to RBD or spike protein VOC antigens across children (n_50μg=6, n_100μg=9) or adults (n=14) at V2, where each individual’s response is linked across VOC antigens. (E) Breadth score was calculated by summing up the number of VOC RBD- or spike protein-specific features above the median value for each individual (n_{50 μg}=6, n_{100 μg}=9) or adults (n=14) at V2. Horizontal bars in (E) indicate median. Background corrected data are shown and negative values were set to 100 for graphing purposes in (A to D). A Kruskal-Wallis test with a Benjamini-Hochberg post-test correction for multiple comparisons was used to test for statistical differences between wild-type and VOC titers within groups in (A to D) or between the groups in (E). P-values for significantly different features are shown above and fold change reductions of omicron titers compared to wild-type are shown below each dataset. Data for adult samples has been partly published previously ( 55 )).