Delayed Cellular Immunity in SARS-CoV-2 Antibody-Non-responders to COVID-19 Vaccination: Rethinking Post-Vaccine Immune Assessment

Background: While host immunity 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 COVID-19 vaccinated individuals with sub-protective antibody levels. 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 did not exhibit a significant time-dependent trend (ρ=0.1, p>0.05). A modest positive correlation was observed between IgG and T-cell response levels (ρ=0.15, p< 0.05). Temporal cutoff analysis identified a critical window 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=3793, p=0.0139) and higher positive T-cell response (68% vs. 44%, χ²=10.39, p=0.0012). Conclusion: 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.