An immunodominant NP105–113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease

Abstract

NP105–113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105–113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105–113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105–113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105–113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.

Dominant CD8+ T Cell Nucleocapsid Targeting in SARS-CoV-2 Infection and Broad Spike Targeting From Vaccination

“…Overall, differences from the findings of Le Bert et al and Peng et al may result primarily from evaluation of isolated CD8 + T cells versus bulk PBMC (in which CD4 + T cells typically predominate); other studies grossly comparing CD4 + T cells to CD8 + T cells have shown that the former tend to predominate (12,46,49,(52)(53)(54), and that the two do not correlate (55). Finally, our results suggest that nucleocapsid might be a useful target for vaccine inclusion to elicit broader and more durable CD8 + T cell responses, which is also supported by a recent study suggesting that immunodominant targeting of nucleocapsid is associated with better outcome after SARS-CoV-2 infection (56).…”

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

“…T cells have been implicated in control of SARS-CoV-2 in other susceptible animal models, like the human ACE2 expressing mouse lines and Syrian hamsters [78][79][80] . Furthermore, nucleocapsid specific CD8 T cells are correlated with less severe disease in patients 20 .…”

“…In addition, preclinical studies suggest that depletion of CD8 T cells from vaccinated monkeys prior to SARS-CoV-2 challenge significantly impairs control of virus replication 60 . T cells may also play a major role in vaccine-elicited protection, and T cell targeted peptide vaccines are currently being developed 20,81,82 . Vaccine-elicited T cells may prove critical in protection against SARS-CoV-2 variants of concern that are able to evade neutralizing antibodies, as T cell epitopes are thought to be more conserved across isolates 83 .…”

“…Increased pro-inflammatory cytokines [1][2][3][4] , deficient type I interferon (IFN) responses [5][6][7] , activation of inflammasomes 8 , neutrophils [9][10][11] , and monocytes/macrophages 1,2,[11][12][13][14] have all been associated with severe COVID-19. Coordinated activation of CD8 and CD4 T cells, T cell activation state, and antigen (Ag)-specificity have all been linked to favorable outcomes of SARS-CoV-2 infection [15][16][17][18][19][20] . While neutralizing antibodies are clearly protective in immune hosts, T cell responses may also contribute to the protection provided by vaccination and natural infection [21][22][23][24] .…”

Older adults mount less durable humoral responses to two doses of COVID-19 mRNA vaccine, but strong initial responses to a third dose

“…We did not investigate vaccine-induced T-cell responses, which may play critical roles in protection against severe COVID-19, particularly in the context of variants [43][44][45][46][47][48][49][50] . Furthermore, our assays tested only the ancestral SARS-CoV-2 strain (Wuhan or USA-WA1/2020); assessments of SARS-CoV-2 variants including Omicron are in progress.…”