Age-dependent immune profiles and variant-driven humoral alterations across two SARS-CoV-2 epidemic phases

This study investigates age-related immune differences during two SARS-CoV-2 epidemic phases and evaluates the neutralizing responses to the wild-type (WT) strain and XBB.1.5 following natural infection and vaccination.

Throat swab and serum samples were collected from confirmed COVID-19 patients and contemporaneous healthy controls across different age groups during the B.1.1 and XBB epidemic peaks in Hebei Province, China. Serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies, viral load, key cytokines and variant-specific neutralizing capacity against WT and XBB.1.5 pseudoviruses were quantified using magnetic particle chemiluminescence, polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and neutralization assays.

Humoral responses exhibited clear age dependence during both epidemic phases. Following B.1.1 infection, IgM levels peaked around week 3 and were lower in individuals under 18 years of age than in adults. IgG antibody levels increased over 5 weeks, reaching relatively higher concentrations in both infants (0-3 years) and older adults (≥60 years). Cytokine levels were lowest in the 3-18 years group and highest in those aged ≥60 years, consistent with their differential risks for severe disease. Both infection and vaccination induced neutralizing antibodies against the WT virus, but neutralization of XBB.1.5 was markedly reduced across all ages, indicating enhanced immune evasion. Vaccination elicited stronger neutralizing activity than natural infection alone, particularly in older adults, and provided the greatest relative improvement in cross-neutralization against XBB.1.5 in the ≥60 years group. Conversely, vaccinated individuals aged 3-18 years developed high antibody titers that did not translate into superior neutralization of XBB.1.5. Among unvaccinated infants, natural infection generated measurable neutralization of XBB.1.5, though efficacy remained limited.

Immunological responses to SARS-CoV-2 and its variants differ substantially with age and immune history. Vaccination, especially in older adults, partially compensates for age-related immune decline and enhances cross-protection against immune-evasive variants such as XBB.1.5, supporting age-tailored vaccination and booster strategies.