SARS-CoV-2 Breakthrough Infection Reveals Platform-Associated Long-Term Immune Remodeling in a Central Asian Cohort

This study aimed to evaluate platform-specific immune memory trajectories in patients with breakthrough COVID-19 over a 12-month period. This prospective longitudinal study enrolled adults hospitalized with PCR-confirmed COVID-19. Participants were stratified according to prior COVID-19 vaccination status into three groups: unvaccinated, adenoviral-vector-vaccinated, and inactivated-virus-vaccinated. Comprehensive immune profiling included quantification of humoral responses and flow cytometric analysis of T- and B-cell memory subsets. Group differences were assessed using Kruskal–Wallis tests; longitudinal naïve CD8+ T-cell dynamics were modeled using linear mixed-effects models; multivariate immune signatures were identified using random forest classification with SHAP analysis. The most distinct cellular finding was a sustained reduction in naïve CD8+ T cells in the adenoviral-vector-vaccine group, which persisted for 12 months in patients without pneumonia. Machine learning models demonstrated high discriminative performance for patients without pneumonia (AUC = 0.89–0.92), identifying a specific triad of markers in the adenoviral-vector-vaccine group: decreased naïve CD8+ T cells, decreased double-negative effector memory T cells, and increased naïve CD19+ B cells. Linear mixed-effects modeling confirmed that contraction of the naïve CD8+ T-cell compartment over time was significant exclusively in AdV recipients, whereas pneumonia was the dominant predictor in unvaccinated individuals. No significant temporal or disease-related dynamics were observed in the inactivated vaccine group, whose immune profiles largely overlapped with those of unvaccinated individuals. COVID-19 vaccine platforms induce distinct, durable immune imprints that modulate responses to subsequent breakthrough infections. The adenoviral-vector platform was associated with unique phenotypic remodeling of the T-cell compartment, specifically persistent contraction of the naïve CD8+ pool. These findings suggest that the vaccine platform itself, beyond the target antigen, shapes the trajectory of immune competence and long-term memory.