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Review 1: "Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection"

This reliable study finds that SARS-CoV-2 infection generates substantial immune memory. Antibody levels does not wane fast and T cell immune responses are readily detected 6 months after primary infection and correlate with disease severity.

Published onJan 17, 2021
Review 1: "Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection"
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Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection
Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection
Description

Abstract The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT and/or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

This manuscript characterizes SARS-CoV-2 specific T cells 6 months after primary infection in a cohort of 100 individuals. To accomplish this the authors, use standard IFN-g ELISPOT and intracellular cytokine stain flow cytometric assays. T cell responses to both the prime antibody target (the Spike protein) and also to Nucleocapsid and Membrane are studied, as well as responses to a range of accessory proteins. Further, T cell responses detected at 6 months are analyzed with respect to SARS-CoV-2 antibody profiles generated from serum samples obtained in the preceding months.

 

The study is of high interest as there is a fear that immunity to SARS-CoV-2 would wane very quickly; a fear that was raised by a few studies from endemic seasonal coronaviruses. This paper adds to the growing body of literature that highlights that both rigorous antibody responses and T cell responses are mounted following infection and that memory responses persist. The finding that memory T cells are readily detectable at 6 months following infection clearly emphasizes the establishment of substantial immune memory.

The finding that individuals with asymptomatic primary infection have fewer memory T cells at 6 months is of great interest and warrants further studies as to the impact of such lower levels of immune memory.

 

The study is however not equipped to extrapolate the T cell immunity data to any conclusions regarding relative protection from re-infection and the authors cannot infer any in vivo functionality from the detected responses.

 

I have some problems deciphering the data and the conclusions based on the correlations in Figure 5B+5C. On the x-axis the IFN-g ELISPOT data is depicted and on the y-axis different antibody specificities are denoted. It is well established (and the authors show the ICS data in Figure 4) that CD8 T cells primarily produce IFN-g while CD4 T cells produce primarily IL-2 (albeit some IFN-g). Further CD4 responses are necessary for B cell maturation and differentiation and these CD4 responses are obtained in the ICS assay. Therefore, I think the plots using the ELISpot data have limited value as is.

 

Minor comments

·      The RBD antibody detection scheme is not described or referenced   

·      Figure 3 could include a Figure depicting the compiled T cell data. I.e. highlighting the high proportion of individuals with positive T cell responses in the two assays

·      Were the donors verified SARS-CoV-2 positive by PCR?

·      How was the cut-off for positivity determined in ICS? And are all ICS values background subtracted from the non-peptide incubated control?

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