Age-associated impairment of humoral and cellular immune responses to SARS-CoV-2 in a large community cohort with hybrid immunity

Objectives To characterize SARS-CoV-2-specific humoral and cellular immunity in a large community cohort, focusing on age-related differences following hybrid immunity from prior infection and vaccination. Methods In this cross-sectional study, 1,186 adults (median age: 62 years, IQR 43–73) were enrolled from six districts in Jiangsu province, eastern China. Spike-specific immune responses including serum total antibodies (Abs), nasal secretory IgA (sIgA), memory B cells, circulating follicular helper T (cTfh) cells, and CD4⁺/CD8⁺ memory T cell subsets were evaluated. Multivariable logistic regression identified factors associated with immune responses. Results Compared with younger adults, individuals aged ≥65 years exhibited significantly lower levels of spike-specific serum total Abs, spike-specific memory B cells, spike-specific cTfh cells, and spike-specific CD4 + terminally differentiated effector memory T (T EMRA ) cells, but significantly higher levels of spike-specific CD8 + T EMRA cells (all P < 0.05). Spike-specific nasal sIgA, CD4⁺/CD8⁺ T CM and T EM subsets were comparable between age groups. After adjustment for sex, infection history, vaccination status, body mass index (BMI), diabetes, and lifestyle factors, age ≥65 years was associated with reduced spike-specific total Abs (OR 0.653, 95% CI 0.512–0.839), memory B cells (OR 0.780, 95% CI 0.613–0.992), and cTfh cells (OR 0.706, 95% CI 0.554–0.899). In contrast, older age was associated with elevated spike-specific CD8⁺ T EMRA cells (OR 1.396, 95% CI 1.096–1.778). Conclusions Despite widespread hybrid immunity, older adults displayed impaired humoral and T-B helper responses alongside selective expansion of spike-specific CD8⁺ T EMRA cells. These findings define an age-associated immune phenotype in the endemic phase and support age-tailored vaccination and immune monitoring strategies.