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. 2023 Oct;94(4):1327-1334.
doi: 10.1038/s41390-023-02627-w. Epub 2023 May 12.

Long-term humoral signatures following acute pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children

Madeleine D Burns #  1   2 , Yannic C Bartsch #  3   4 , Jameson P Davis  1   2 , Brittany P Boribong  1   2   3 , Maggie Loiselle  1   2 , Jaewon Kang  4 , Abigail S Kane  1   2 , Andrea G Edlow  3   5   6 , Alessio Fasano  1   2   3 , Galit Alter  3   4 , Lael M Yonker  7   8   9
Affiliations

Long-term humoral signatures following acute pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children

Madeleine D Burns et al. Pediatr Res. 2023 Oct.

Abstract

Background: Although most children experience mild symptoms during acute SARS-CoV-2 infection, some develop the severe post-COVID-19 complication, Multisystem Inflammatory Syndrome in Children (MIS-C). While acute presentations of COVID-19 and MIS-C have been well immunophenotyped, little is known about the lasting immune profile in children after acute illness.

Methods: Children 2 months-20 years of age presenting with either acute COVID-19 (n = 9) or MIS-C (n = 12) were enrolled in a Pediatric COVID-19 Biorepository at a single medical center. We deeply profiled humoral immune responses and circulating cytokines following pediatric COVID-19 and MIS-C.

Results: Twenty-one children and young adults provided blood samples at both acute presentation and 6-month follow-up (mean: 6.5 months; standard deviation: 1.77 months). Pro-inflammatory cytokine elevations resolved after both acute COVID-19 and MIS-C. Humoral profiles continue to mature after acute COVID-19, displaying decreasing IgM and increasing IgG over time, as well as stronger effector functions, including antibody-dependent monocyte activation. In contrast, MIS-C immune signatures, especially anti-Spike IgG1, diminished over time.

Conclusions: Here, we show the mature immune signature after pediatric COVID-19 and MIS-C, displaying resolving inflammation with recalibration of the humoral responses. These humoral profiles highlight immune activation and vulnerabilities over time in these pediatric post-infectious cohorts.

Impact: The pediatric immune profile matures after both COVID-19 and MIS-C, suggesting a diversified anti-SARS-CoV-2 antibody response after resolution of acute illness. While pro-inflammatory cytokine responses resolve in the months following acute infection in both conditions, antibody-activated responses remain relatively heightened in convalescent COVID-19. These data may inform long-term immunoprotection from reinfection in children with past SARS-CoV-2 infections or MIS-C.

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Conflict of interest statement

G.A. is a V.P. at Moderna, a founder and equity holder of Seromyx Systems, and an employee and equity holder of Leyden Labs. G.A.’s interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict-of-interest policies. A.G.E. reported serving as a medical advisor for Mirvie, Inc. and receiving research funding from Merck & Co. outside of the scope of the submitted work. No other disclosures were reported. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Fig. 1
Fig. 1. Separation between acute and convalescent illness for COVID-19 and MIS-C.
Trajectories of key cytokine profiles are shown using a principal component analysis (PCA) (a, b). IL-6 (c) and IL-10 (d) in pediatric COVID-19 and MIS-C are compared during acute illness and at follow-up, analyzed by t test.
Fig. 2
Fig. 2. Anti-Spike immunoglobulin responses over time following pediatric COVID-19 and MIS-C.
Anti-Spike IgM, IgA1, and IgG1 were profiled during acute COVID-19 and MIS-C and at follow-up (a–c). Effector function of antibody responses were also characterized at acute disease and convalescence were also analyzed (d–f). ADCD antibody-dependent complement deposition, ADNP antibody-dependent neutrophil phagocytosis, ADCP antibody-dependent cellular (monocyte) phagocytosis.
Fig. 3
Fig. 3. Humoral profiles following pediatric COVID-19 and MIS-C.
Changes in anti-SARS-CoV-2-S antibody responses were visualized to show the expansion and/or contraction of anti-SARS-CoV-2 specific immunoglobulin titers (a), functional Fc-binding capacity (b), and effector responses (c) in acute presentation of pediatric COVID-19 or MIS-C and six-month follow-up.
Fig. 4
Fig. 4. Distinctions in humoral profiles following COVID-19 in children and MIS-C during acute illness and convalescence.
A Partial Least-Squares Discriminant Analysis (PLS-DA) model with minimal set of Least Absolute Shrinkage and Selection Operator (LASSO) was used to select features that are highly correlated to nonselected features in pediatric COVID-19 and MIS-C during acute illness (a) and convalescence (b).
Fig. 5
Fig. 5. Coordination of humoral immune response in pediatric COVID-19 and MIS-C.
Pediatric COVID-19 (a) and MIS-C (b) are explored both at the acute and follow-up timepoints, analyzing correlations of antibody titer and FcγR recruitment.
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