Revisiting of the Role of CD8+ T-Cells in Vaccine-Induced Protection Against SARS-CoV-2 in Macaques via Mathematical Modeling

Experimental studies have demonstrated that CD8+ T-cells play an important role in vaccine-induced protection against SARS-CoV-2; however, a quantitative understanding of how CD8+ T-cell activity dynamically regulates viral load following vaccination remains limited. In particular, the mechanisms by which CD8+ T-cell–mediated immune responses influence viral clearance across different anatomical compartments have not been systematically quantified. In this study, we developed a mathematical model of SARS-CoV-2 viral dynamics incorporating CD8+ T-cell–mediated immune effects and validated it using experimental viral load data from vaccinated and CD8+ T-cell–depleted rhesus macaques. The model captures interactions between target cells, infected cells, viral replication, and immune effector activity, enabling quantitative comparison of infection dynamics under distinct immunological conditions. Viral load data from nasal swabs and bronchoalveolar lavage (BAL) samples were used to assess how variations in immune effector strength influence viral kinetics. Our results show that CD8+ T-cell activity substantially accelerates viral clearance and reduces infection duration, with vaccination-induced CD8+ T-cell responses leading to markedly lower viral loads compared to CD8+ T-cell–depleted scenarios. Analysis of viral load area under the curve (AUC) reveals threshold such as behavior, whereby increases in immune effector strength beyond critical levels result in disproportionately large reductions in total viral burden. Sensitivity analysis further identifies CD8+ T-cell–associated parameters as key determinants of viral load dynamics. Overall, this study provides a quantitative framework demonstrating that robust CD8+ T-cell responses are critical for effective vaccine-induced control of SARS-CoV-2 infection, offering mechanistic insights into immune thresholds required for optimal viral suppression.