Proteomic signatures linked to rapid antibody waning in older vaccinated adults

Distinct serum protein patterns were associated with rapid declines in SARS-CoV-2-specific IgG after breakthrough infection among previously vaccinated older adults, according to a nested case-control study embedded in the Yichang COVID-19 Antibody Longitudinal Survey. The exploratory findings link faster antibody waning with longitudinal changes involving complement activation, coagulation cascades, humoral immunity and serine protease inhibitor activity, but they do not establish that these molecular changes cause antibody loss or can predict outcomes in other populations. The study included 67 elderly participants whose SARS-CoV-2-specific IgG concentrations declined monotonically following breakthrough infection.

Researchers classified 34 as rapid decliners and 33 as slow decliners according to their antibody trajectories. None received an additional COVID-19 vaccination during serological follow-up. Rapid decliners were older than slow decliners, while the longitudinal models adjusted for age, sex, body-mass index and comorbidities.

Linear mixed-effects models identified 13 candidate dynamic proteins that showed significant group-by-time interaction signals, meaning their measured changes differed between rapid and slow decliners over the proteomic observation period. The candidates included IGHA1, AZGP1, SERPINA1 and C9. Their association with complement, coagulation, humoral immune and serine protease inhibitor pathways suggests that faster IgG waning coincided with a broader pattern of molecular change rather than a single isolated protein response.

The investigators interpreted the results as evidence of an association between rapid, hybrid immunity-associated IgG waning and complement-coagulation activity with sustained innate immune activation, not as proof of a causal pathway. The researchers then combined baseline clinical characteristics and baseline proteomic profiles with exploratory LASSO-based feature selection and internally cross-validated classification modelling. LASSO selected 14 protein features.

Among the algorithms evaluated, a neural network achieved the highest discrimination between rapid and slow decliners, with an area under the receiver operating characteristic curve of 0.872. A SHAP analysis highlighted C1QB, GRN, AZGP1 and CFHR4 as major contributors to the model’s classifications. These analyses were conducted within the study sample and do not demonstrate that the selected proteins can identify antibody-waning trajectories in an independent population.

Several limitations constrain the findings. The sample was small and selected from one longitudinal cohort, consisted entirely of elderly participants, and compared groups with different baseline characteristics, including age. Classification performance was assessed through internal rather than external cross-validation, and the analysis was exploratory.

The authors described the baseline proteomic signatures as hypothesis-generating candidate biomarkers for future externally validated risk-stratification studies. Whether these markers remain associated with rapid IgG waning outside the original cohort, or whether complement-coagulation activity contributes causally to the decline, remains to be determined.

Subject of Research: Serum proteomic correlates of rapid SARS-CoV-2 IgG waning in older vaccinated adults

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

Article References: Yang, C., Wang, H., Zhang, X., Lei, Z., Liu, J., Yan, X., & Wei, S. (2026). Longitudinal serum proteomic signatures associated with rapid SARS-CoV-2 IgG waning after breakthrough infection in elderly adults: a nested case-control study. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14205-6

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14205-6

Keywords: SARS-CoV-2, breakthrough infection, IgG waning, serum proteomics, older adults, hybrid immunity, complement activation, coagulation, innate immunity, biomarker discovery, nested case-control study, Longitudinal