Review 1: "Immunological memory to SARS-CoV-2 assessed for greater than six months after infection"

RR:C19 Evidence Scale rating by reviewer:

• Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

***************************************

Review:

This study reports the simultaneous analysis of SARS-Cov2-specific serum antibodies, memory B cells, as well as memory CD8 and CD4 T cells (including TFH). While this study is mainly descriptive, it represents the follow-up of a spectacular cohort of patients: 185 patients analyzed, with 38 followed longitudinally with blood collected at 2-4 time points, up to 8 months post symptom onset.

This study is largely focused on mild cases (which represents a good overview of the global affected population with relevance for herd immunity and a more stringent evaluation since severe cases have been proposed to present stronger responses), and it might be useful to make that clear in the summary. The CD8 and CD4 study, with identification of T-cell specificity through AIM activation, is again remarkable in its information breadth. Follow-up of memory B cells was also performed for nucleocapsid-specific B cells, which is rarely done.

As mentioned by the authors, there have been few follow-up studies (including longitudinal ones) performed on primary viral infections in humans, so this study, beyond the immediate actual interest in Covid-19, has more general relevance for understanding the emergence of immune memory.

Altogether, this very complete and exhaustive study of memory constitutes a remarkable description of the different memory subsets developing after Covid-19 symptoms resolution and should be considered for publication in a top-tier journal with a medical or clinical audience, while a journal with a more scientific focus would seem less adequate.

Minor points:

- Could the authors make clear whether the MP_R peptide pool covering the SARS-Cov2 ORFeome includes Spike peptides?

- CD4 memory chapter: the authors say that "a plurality of ... memory CD4 ... are TCM", while it seems that TCM and TEM are equally represented.

- It seems that the antibodies used to characterize TFH cells are not described in Table S3 - The representation of fig.5B is a bit misleading, with lines connecting values between 1-5 (suggesting evolution). Maybe bars (or pie charts) would constitute a clearer display.

- The authors show different types of correlations between memory parameters, but not between spike-specific serum IgG and TFH. Is there something noticeable between these two parameters?

- In the first § of the discussion, the authors describe their cohort as spanning the full range of diseases, a statement that should be modulated considering the prevalence of mild cases.

- I did not see any description of age distribution. Are there correlations between age and memory persistence (according to the 0-5 criteria of memory factors)?