Binding and neutralizing antibody responses to SARS-CoV-2 in very young children exceed those in adults

Abstract

BackgroundSARS-CoV-2 infections are frequently milder in children than adults, suggesting that immune responses may vary with age. However, information is limited regarding SARS-CoV-2 immune responses in young children.MethodsWe compared receptor binding domain-binding antibody (RBDAb) titers and SARS-CoV-2-neutralizing antibody titers, measured by pseudovirus-neutralizing antibody assay in serum specimens obtained from children aged 0-4 years and 5-17 years and in adults aged 18-62 years at the time of enrollment in a prospective longitudinal household study of SARS-CoV-2 infection.ResultsAmong 56 seropositive participants at enrollment, children aged 0-4 years had more than 10-fold higher RBDAb titers than adults (416 vs. 31, P < 0.0001) and the highest RBDAb titers in 11 of 12 households with seropositive children and adults. Children aged 0-4 years had only 2-fold higher neutralizing antibody than adults, resulting in higher binding-to-neutralizing antibody ratios compared with adults (2.36 vs. 0.35 for ID50, P = 0.0004).ConclusionThese findings suggest that young children mount robust antibody responses to SARS-CoV-2 following community infections. Additionally, these results support using neutralizing antibody to measure the immunogenicity of COVID-19 vaccines in children aged 0-4 years.FundingCDC (award 75D30120C08737).

Keywords: Adaptive immunity; COVID-19; Infectious disease.

Figure 1. Households contacted, screened, and enrolled in SEARCh, and numbers of participants who were SARS-CoV-2 seropositive at the time of enrollment.

Figure 2. SARS-CoV-2 serum antibody titers at enrollment in SEARCh.

(A) Box-and-whiskers plot of SARS-CoV-2 RBDAb titers (BAU/mL) by age (orange, children 0–4 years; yellow, children 5–17 years; blue, adults). Bars indicate median values, box bounds represent IQRs, whiskers illustrate variability in relation to the IQR, and outliers are depicted beyond the whiskers. (B) RBDAb titers by household. Color scheme is the same as for A; filled circles represent RBDAb titers in seropositive individuals, and open circles represent RBD-seronegative household members not included in the analysis. The horizontal line distinguishes between the 2 groups. (C) WT SARS-CoV-2–neutralizing antibody ID₅₀ titers measured by pseudotyped lentivirus reporter neutralization assay (PsVNA), shown and summarized by age group, as in Figure 1A. Samples with titers below the level of detection were assigned a value of 10. (D) PsVNA ID₅₀ titers by household, using the sequence and color scheme shown for B. Statistical differences in antibody titers were compared using the 2-sided Mann-Whitney-Wilcoxon test. To adjust for 3 age group comparisons for each analysis in A and C, Bonferroni’s correction was applied, and the P value was multiplied by 2. One specimen from a child in the 0–4 year age group was not tested for neutralizing antibodies owing to insufficient sample volume.

Figure 3. Box-and-whiskers plot of SARS-CoV-2 WT PsVNA ID₅₀ titers for all children ages 0–17 versus adults.

Statistical differences in antibody titers for children ages 0–17 (light orange) and adults (blue) were compared using the 2-sided Mann-Whitney-Wilcoxon test. Bars indicate median values, box bounds represent the IQRs, whiskers illustrate variability in relation to the IQR, and outliers are depicted beyond the whiskers. PsVNA, pseudotyped lentivirus reporter neutralization assay.

Figure 4. Ratios of SARS-CoV-2 RBDAb to SARS-CoV-2 PsVNA.

(A) ID₅₀ titers. (B) ID₈₀ titers. Statistical differences in ratios of SARS-CoV-2 RBDAb to SARS-CoV-2 PsVNA (orange, children 0–4 years; yellow, children 5–17 years; blue, adults 18–62 years) were compared using the 2-sided Mann-Whitney-Wilcoxon test. To adjust for 3 age group comparisons for each analysis, Bonferroni’s correction was applied, and the P value was multiplied by 2. Bars indicate median values. RBDAb, receptor binding domain antibody; PsVNA, pseudotyped lentivirus reporter neutralization assay.