Longitudinal serum proteomic signatures associated with rapid SARS-CoV-2 IgG waning after breakthrough infection in elderly adults: a nested case-control study

Abstract

In previously vaccinated older adults, SARS-CoV-2 breakthrough infection induces hybrid immunity, but SARS-CoV-2-specific IgG antibodies may still decline rapidly. Longitudinal serum proteomic correlates of rapid IgG waning in older adults remain insufficiently characterized. In a nested case-control study within the Yichang COVID-19 Antibody Longitudinal Survey (YC-CALS) cohort, 67 previously vaccinated elderly participants with monotonic SARS-CoV-2-specific IgG decline after breakthrough infection were included: slow decliners ( n  = 33) and rapid decliners ( n  = 34). None received additional COVID-19 vaccination during serological follow-up. Serum proteomics was performed on March and October 2023 samples. Linear mixed-effects models, adjusted for age, sex, BMI, and comorbidities, were used to identify candidate dynamic and endpoint proteins. Baseline proteomic profiles and clinical characteristics were then used for exploratory Lasso-based feature selection and internally cross-validated classification modelling. Rapid decliners were older and showed distinct longitudinal proteomic trajectories. Thirteen candidate dynamic proteins, including IGHA1, AZGP1, SERPINA1, and C9, showed significant group-by-time interaction signals and were enriched in complement activation, coagulation cascades, humoral immunity, and serine protease inhibitor activity. Baseline modelling identified 14 Lasso-selected protein features. In exploratory internal cross-validation, the neural network model showed the highest discrimination among the algorithms evaluated (AUC = 0.872), and SHAP analysis highlighted C1QB, GRN, AZGP1, and CFHR4 as major contributors. Longitudinal serum proteomics suggests that rapid hybrid immunity-associated IgG waning after breakthrough infection in elderly adults is associated with complement-coagulation activity and sustained innate immune activation. Baseline proteomic signatures may provide hypothesis-generating candidate biomarkers for future externally validated risk-stratification studies. Clinical trial number: not applicable.