ABSTRACT
Background: SARS-CoV-2 produces variable immune responses leading to different levels of immune protection. The relationship between neutralizing antibody level (NAb) and protective immunity has been well characterized after infection and vaccination. While comparatively specific T cell responses tend to be more variable, the impacts of these responses have broad implications on long-term immunity and their role in protective immunity has not been as clearly defined. Using data from our prospective cohort study and studies of clinical protective immunity/efficacy (from vaccines), we predicted protective immunity over time in relation to SARS-CoV-2-specific T cell dynamics. Methods: With linear mixed-effects models from our published immune data from people recovering from COVID-19, we simulated the Spike (S)-specific interferon-γ (IFNγ)+ CD4+, S-specific IFNγ+ CD8+, and nucleocapsid (N)-specific IFNγ+ CD8+ T cells over time (n=500 individuals). We then predicted NAbs from linear regression models developed from the same cohort. Finally, protective immunity from NAb titers was simulated from a published model. We similarly simulated 25, 50, and 75% lower T cell responses than those observed post-COVID-19 to understand how immune response variation may impact protective immunity. Results: Virus-specific T cell responses resulted in similar protective immunity across T cell subsets, but with differences in variability over time. Protective immunity for IFNγ+ S CD8 T cells spanned from 86-95%, while for IFNγ+ S CD4 T cells and IFNγ+ N CD4 T cells it ranged from 81-96% and 84-95% respectively. Further, based on simulated dampened T cell responses, protective immunity overall did not drop below 81% less than nine months after infection even with a 75% reduction in specific T cell immunity. Conclusion: NAbs are often the singular focus to predict protective immunity and the role of virus-specific T cell immunity has often been discussed as a secondary immune response. Our analysis demonstrates that for SARS-CoV-2, certain T cells responses can reliably predict protective immunity and may be intrinsically linked. Simulating dampened T cell response to mimic a more virulent strain or inadequate immune response, demonstrated that dampened T cell response may not be responsible for inadequate protective immunity in these scenarios. In the absence of prospective clinical data, similar models may be utilized to explore the impact of potential therapeutics on immune responses and resulting protective immunity.