Infants and young children generate more durable antibody responses to SARS-CoV-2 infection than adults

Abstract

As SARS-CoV-2 becomes endemic, it is critical to understand immunity following early-life infection. We evaluated humoral responses to SARS-CoV-2 in 23 infants/young children. Antibody responses to SARS-CoV-2 spike antigens peaked approximately 30 days after infection and were maintained up to 500 days with little apparent decay. While the magnitude of humoral responses was similar to an adult cohort recovered from mild/moderate COVID-19, both binding and neutralization titers to WT SARS-CoV-2 were more durable in infants/young children, with spike and RBD IgG antibody half-life nearly 4X as long as in adults. IgG subtype analysis revealed that while IgG1 formed the majority of the response in both groups, IgG3 was more common in adults and IgG2 in infants/young children. These findings raise important questions regarding differential regulation of humoral immunity in infants/young children and adults and could have broad implications for the timing of vaccination and booster strategies in this age group.

Keywords: Clinical finding.

Graphical abstract

Figure 1

Infants/young children generate durable antibody responses to SARS-CoV-2 antigens following infection IgG (A–C) and IgA (D–F) antibodies reactive to SARS-CoV-2 spike (A and D), spike receptor-binding domain (RBD) (B and E), and the spike N-terminal domain (NTD) (C and F) were measured in duplicate by an electrochemiluminescent multiplex immunoassay and reported as arbitrary units per mL (AU/mL) as normalized by a standard curve. Longitudinal antibody titers of SARS-Co-2-infected infants/young children (n = 23) are plotted over days post positive PCR result. The dotted line represents the limit of detection, defined as the mean value pre-infection + 3SD.

Figure 2

Longitudinal antibody responses against other coronavirus spike proteins in infants and their correlation to SARS-CoV-2 spike binding antibody response (A and B) IgG antibodies reactive to the (A) previous epidemic coronaviruses, MERS-CoV and SARS-CoV spike protein, and (B) common human beta-coronaviruses, HKU1 and OC43 spike protein were measured in duplicate by an electrochemiluminescent multiplex immunoassay and reported as arbitrary units per mL (AU/mL) as normalized by a standard curve. Longitudinal antibody titers of SARS-CoV-2-infected infants/young children (n = 23) are plotted over days since the positive PCR result. (C) Pre-SARS-CoV-2 infection IgG binding antibody titers against the spike proteins of currently circulating human beta-coronaviruses, HKU1 and OC43, showed no correlation with the convalescent titers against SARS-CoV-2 spike in infants/young children. Coefficient of determination (R²) and significance were determined by linear regression analysis.

Figure 3

Durability of SARS-CoV-2 spike- and nucleocapsid-binding antibody responses in infants/young children and adults IgG antibodies reactive to SARS-CoV-2 spike (A and E), spike RBD (B and F), spike NTD (C and G), and nucleocapsid (D and H) were measured in duplicate by an electrochemiluminescent multiplex immunoassay in infants/young children (A–D) and adult (E–H) donors and reported as arbitrary units per mL (AU/mL) as normalized by a standard curve. The half-lives and decay curves of the IgG antibodies estimated by the exponential model are shown in red; and the half-lives and decay curves of IgG antibodies estimated by the power law model (at day 150) are shown in blue.

Figure 4

Anti-spike IgG subclass distribution in infants/young children and adults The concentration of anti-spike IgG subclasses was measured at an early (30–140 days post infection, red) and late (250–375 days post infection, blue) time points. (A) Early and late time point samples from the infant and adult donors chosen to assess the antibody subclass distribution. (B) Concentration (ug/mL) of anti-spike IgG1, IgG2, IgG3, and IgG4 antibodies at early and late time points in infants and adults. Statistics were calculated using two-tailed Mann-Whitney test. ns – not significant, ∗p < 0.05, ∗∗p < 0.01.

Figure 5

Neutralizing antibody responses against WT SARS-CoV-2 spike in infants/young children and adults (A) Neutralizing antibody titers against WT SARS-CoV-2 at early and late time points in infants and adult donors. (B) SARS-CoV-2 spike and RBD-reactive IgG (AU/mL) levels correlated with the neutralization titers at matched time points for infant and adult donors. The dotted line (A) represents the limit of detection at 1/20. The comparison between groups was performed using unpaired two-tailed t test (A). The correlation analyses were performed using simple linear regression and coefficient of determination (R²) and significance were determined (B). ns – not significant, ∗p < 0.05.

Figure 6

IgG binding and neutralizing antibody titers against WT, Beta, Delta, and Omicron (BA.1) SARS-CoV-2 RBD in infant and adult donors Infants exhibit similar breadth against VOCs as adults. (A) IgG binding to RBD and (B) neutralizing antibody titers (FRNT50) were analyzed against a panel of VOCs including WT, Beta, Delta, and Omicron (BA.1). The dotted line represents the limit of detection at 1/20 (B). Both infants’ and adults’ plasma samples were compared at early and late time points and fold change was calculated as variant binding (A) or neutralization (B) compared to WT. See also Figure S1.