key: cord-284862-nhihxog0
authors: Kroemer, Marie; Spehner, Laurie; Vettoretti, Lucie; Bouard, Adeline; Eberst, Guillaume; Floury, Sebastien Pili; Capellier, Gilles; Lepiller, Quentin; Orillard, Emeline; Mansi, Laura; Clairet, Anne-Laure; Westeel, Virginie; Limat, Samuel; Dubois, Maxime; Malinowski, Léa; Bohard, Louis; Borg, Christophe; Chirouze, Catherine; Bouiller, Kevin
title: COVID-19 patients display distinct SARS-CoV-2 specific T-cell responses according to disease severity
date: 2020-08-25
journal: J Infect
DOI: 10.1016/j.jinf.2020.08.036
sha: 
doc_id: 284862
cord_uid: nhihxog0

Adaptive Immune responses generated by SARS-CoV-2 virus in convalescent patients according to disease severity remain poorly characterized. To this end, we designed a prospective study (NCT04365322) that included 60 COVID-19 convalescent patients (1-month post infection) in two cohorts respectively entitled mild illness and severe pneumonia. The monitoring of peripheral immune responses was performed using IFNᵧ ELISpot assay. The serology index of each patient was investigated at the same time. Patients with severe pneumonia were older and had more comorbidities than patients with mild illness. T-cell responses in term of frequency and intensity were clearly distinct between mild illness and severe pneumonia patients. Furthermore, our results demonstrated that recent history of COVID-19 did not hamper viral memory T-cell pool against common viruses (Cytomegalovirus, Epstein-Barr-virus and Flu-virus). The presence of potent adaptive immunity even in patients who underwent severe pneumonia sustain the rationale for the development of protective therapeutics against SARS-CoV-2.

Adaptive Immune responses generated by SARS-CoV-2 virus in convalescent patients according to disease severity remain poorly characterized. To this end, we designed a prospective study (NCT04365322) that included 60 COVID-19 convalescent patients (1month post infection) in two cohorts respectively entitled mild illness and severe pneumonia.

The monitoring of peripheral immune responses was performed using IFNᵧ ELISpot assay.

The serology index of each patient was investigated at the same time. Patients with severe pneumonia were older and had more comorbidities than patients with mild illness. T-cell responses in term of frequency and intensity were clearly distinct between mild illness and severe pneumonia patients. Furthermore, our results demonstrated that recent history of COVID-19 did not hamper viral memory T-cell pool against common viruses (Cytomegalovirus, Epstein-Barr-virus and Flu-virus) . The presence of potent adaptive immunity even in patients who underwent severe pneumonia sustain the rationale for the development of protective therapeutics against SARS-CoV-2.

SARS-CoV-2 virus induces symptoms of variable severity; some patients only have mild illness whereas other rapidly become critically ill progressing to an acute respiratory distress syndrome (ARDS). This critical state of the disease supports the immediate relevance for the development of protective therapeutics against SARS-CoV-2 but requires fundamental knowledge concerning adaptive immune responses induced by the virus.

Therefore we have read with interest the recent findings published by Xu Bo and colleagues describing in the early stage of the disease a positive correlation between T-cells decrease and COVID-19 severity 1 . However, Thijsen S and colleagues demonstrated the presence of specific T-cell responses against S and N proteins few days post onset symptoms in patients with severe pneumonia hospitalized in intensive care unit (ICU) 2 . Although the existence of SARS-CoV-2 specific T-cells has been described 2,3 , the frequency and the intensity of SARS-CoV-2 specific T-cell responses among mild illness and severe pneumonia convalescent COVID-19 patients remains to be investigated.

In this prospective study, 60 patients who had COVID-19 were enrolled in a two cohorts study that were entitled mild illness (n=30) and severe pneumonia (n=30) at least 21 days after the first symptoms of ; Table 1 for CoV-N) might be explained by the sequence homology between structural proteins from various coronavirus suggesting the existence of cross reactive memory T-cells 5 . Indeed, high degrees of similarities between coronaviruses and SARS-CoV-2 concerning S, M and N structural proteins have been recently described 6, 7 .

Beyond specific cellular responses, typical humoral responses to acute viral infection are wildly induced in COVID-19 patients 8 . Zhao et al. showed that the seroconversion rate and antibody levels increased rapidly during the first two weeks with a cumulative seropositive rate of 50.0% on the 11th-day and 100% on the 39th-day. High titers of IgG antibodies detected by Enzyme immunoassays have been shown to positively correlate with neutralizing antibodies 8, 9 . In this study, the median serology index of severe pneumonia patients was equal to 7.19 S/CO [IQR: 6. Fig. 1C) . We observed that all patients with severe pneumonia had a positive serology index and most of them had at least one specific cellular response for SARS-CoV-2 proteins (28 out of 30). In contrast, patients with mild illness had less specific cellular responses (20 out of 29) than severe pneumonia patients (P=0.0211) (Fig. 1D) . Among mild illness patients, three had a negative serology index (Fig. 1C) . Specific T-cell responses for S, M and N proteins were simultaneously shown for 70.0% of severe pneumonia patients while only for 37.9% of mild illness patients (P=0.0191) (Fig. 1E) . Of note, levels of T-cell responses were not influenced by previous exposition to a specific COVID-19 treatment (Lopinavir/ritonavir; Interferon-Beta-1A; Hydroxychloroquine and Remdesivir) (data not shown). We notice that despite a lower intensity of response in terms of INFᵧ secretion ( Fig.   1 B) , patients with severe pneumonia had frequencies of responses clearly distinct from the one of mild illness patients. 

Suppressed T cell-mediated immunity in patients with COVID-19: A clinical retrospective study in Wuhan

Elevated nucleoprotein-induced interferon-γ release in COVID-19 patients detected in a SARS-CoV-2 enzyme-linked immunosorbent spot assay

Targets of T Cell Responses to SARS-CoV-2

Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Clinical and immunological features of severe and moderate coronavirus disease 2019

Immunology of COVID-19: current state of the science

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

*ELISpot was not performed for one patient, ARDS = Acute Respiratory distress syndrome

We thank Olivier Adotévi for scientific support and proof reading. We thank Sylvie Cour (nurse) of the clinical investigation center (INSERM CIC 1431) for her help to collect blood sample. We also thank the Biomonitoring platform (Eléonore Gravelin, Adeline Renaudin, Harmonie Simonin, Caroline Laheurte) for technical support.

Authors declare no competing financial interests.
