Abstract
BACKGROUND: While host immune responses to SARS-CoV-2 vaccination are routinely assessed through IgG measurements, less is known about the temporal dynamics of vaccine-induced cellular immunity, particularly in individuals who fail to develop detectable IgG antibodies after COVID-19 vaccination. OBJECTIVE: To investigate the development and timing of T-cell immunity following SARS-CoV-2 vaccination in antibody-non-responders to COVID-19 vaccination. METHODS: A cross-sectional analysis was conducted on COVID-19-naive individuals who had received full SARS-CoV-2 vaccination, categorized by SARS-CoV-2 IgG serostatus. T-cell response was evaluated using the IGRA methodology T-SPOT(®).COVID (Oxford Immunotec, Abingdon, Oxfordshire, UK). T-cell response rates and levels were compared between SARS-CoV-2 seropositive and seronegative groups, and a temporal cutoff analysis was applied to examine trends in T-cell response over time. RESULTS: Within the seronegative group, IgG levels showed a strong negative correlation with time since vaccination (Spearman ρ = -0.65, p < 0.001), while T-cell response levels exhibited a weak positive time-dependent trend (ρ = 0.15, p = 0.019). Temporal cutoff analysis identified a critical time-point beginning at 80 days post-vaccination, after which both T-cell response rates and levels were significantly higher. Specifically, individuals tested after 80 days showed increased median T-cell response levels (U = 4205, p < 0.001) and higher positive T-cell response rate (67% vs. 38%, Χ(2) = 17.06, p < 0.001). CONCLUSIONS: Cellular immunity response against SARS-CoV-2 may emerge later than expected in antibody-non-responders to COVID-19 vaccination, with the 80-day post-vaccination mark emerging as a critical time point. Our results support the inclusion of cellular assays in post-vaccination monitoring and emphasize the need to reconsider the timing and criteria for evaluating vaccine response.