Longitudinal Assessment of SARS-CoV-2 Specific T Cell Cytokine-Producing Responses for 1 Year Reveals Persistence of Multi-Cytokine Proliferative Responses, with Greater Immunity Associated with Disease Severity

Abstract

Cellular-mediated immunity is critical for long-term protection against most viral infections, including coronaviruses. We studied 23 SARS-CoV-2-infected survivors over a one year post symptom onset (PSO) interval by ex vivo cytokine ELISpot assay. All subjects demonstrated SARS-CoV-2-specific IFN-γ, IL-2, and Granzyme B (GzmB) T cell responses at presentation, with greater frequencies in severe disease. Cytokines, mainly produced by CD4+ T cells, targeted all structural proteins (Nucleocapsid, Membrane, Spike) except Envelope, with GzmB > IL-2 > IFN-γ. Mathematical modeling predicted that: 1) cytokine responses peaked at 6 days for IFN-γ, 36 days for IL-2, and 7 days for GzmB, 2) severe illness was associated with reduced IFN-γ and GzmB, but increased IL-2 production rates, 3) males displayed greater production of IFN-γ, whereas females produced more GzmB. Ex vivo responses declined over time with persistence of IL-2 in 86% and of IFN-γ and GzmB in 70% of subjects at a median of 336 days PSO. The average half-life of SARS-CoV-2-specific cytokine-producing cells was modelled to be 139 days (~4.6 months). Potent T cell proliferative responses persisted throughout observation, were CD4 dominant, and were capable of producing all 3 cytokines. Several immunodominant CD4 and CD8 epitopes identified in this study were shared by seasonal coronaviruses or SARS-CoV-1 in the Nucleocapsid and Membrane regions. Both SARS-CoV-2-specific CD4+ and CD8+ T cell clones were able to kill target cells, though CD8 tended to be more potent.

Determination of significant immunological timescales from mRNA-LNP-based vaccines in humans

“…In-host modelling has been extended to COVID-19 with studies looking at infection (cf. Hernandez-Vargas and Velasco-Hernandez (2020); Perelson and Ke (2021); Kim et al (2021); Néant et al (2021); Sadria and Layton (2021); Lin et al (2022); Ke et al (2022)) and vaccination (cf. Farhang-Sardroodi et al (2021); Korosec et al (2021)).…”

Multiple cohort study of hospitalized SARS-CoV-2 in-host infection dynamics: parameter estimates, sensitivity and the eclipse phase profile

“…Mathematical models at the in-host level can estimate parameters and outcomes that may be difficult to measure at the population level. For example, SARS-CoV-2 in-host models have been used to model the immune response generated by vaccines, to predict which populations vaccines are likely to impact most [10], to estimate the efficacy of vaccines in individuals [11], as well as to model T cell dynamics and cytokine secretion in mild, moderate and severe cases of COVID-19 [12]. A major focus of SARS-CoV-2 in-host modelling has been understanding viral load dynamics: examples include correlating viral load with mortality [13]; linking viral load dynamics with host transmission [14, 15]; understanding the effects of antiviral therapy on the shedding dynamics [16]; assessing individual-level heterogeneity in mild cases [17]; and relating viral load with viral replication and the immune response [18].…”