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2.
Annals of Intensive Care ; 12(1), 2022.
Article in English | ProQuest Central | ID: covidwho-1837129

ABSTRACT

BackgroundLymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.ResultsPeripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.ConclusionsSevere COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far.Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

3.
EBioMedicine ; 78: 103967, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1757276

ABSTRACT

BACKGROUND: In critically ill COVID-19 patients, the initial response to SARS-CoV-2 infection is characterized by major immune dysfunctions. The capacity of these severe patients to mount a robust and persistent SARS-CoV-2 specific T cell response despite the presence of severe immune alterations during the ICU stay is unknown. METHODS: Critically ill COVID-19 patients were sampled five times during the ICU stay and 9 and 13 months afterwards. Immune monitoring included counts of lymphocyte subpopulations, HLA-DR expression on monocytes, plasma IL-6 and IL-10 concentrations, anti-SARS-CoV-2 IgG levels and T cell proliferation in response to three SARS-CoV-2 antigens. FINDINGS: Despite the presence of major lymphopenia and decreased monocyte HLA-DR expression during the ICU stay, convalescent critically ill COVID-19 patients consistently generated adaptive and humoral immune responses against SARS-CoV-2 maintained for more than one year after hospital discharge. Patients with long hospital stays presented with stronger anti-SARS-CoV-2 specific T cell response but no difference in anti-SARS-CoV2 IgG levels. INTERPRETATION: Convalescent critically ill COVID-19 patients consistently generated a memory immune response against SARS-CoV-2 maintained for more than one year after hospital discharge. In recovered individuals, the intensity of SARS-CoV-2 specific T cell response was dependent on length of hospital stay. FUNDING: This observational study was supported by funds from the Hospices Civils de Lyon, Fondation HCL, Claude Bernard Lyon 1 University and Région Auvergne Rhône-Alpes and by partial funding by REACTing (Research and ACTion targeting emerging infectious diseases) INSERM, France and a donation from Fondation AnBer (http://fondationanber.fr/).


Subject(s)
COVID-19 , Immunologic Memory , T-Lymphocytes , Antibodies, Viral/blood , COVID-19/immunology , Critical Illness , HLA-DR Antigens , Humans , Immunoglobulin G/blood , SARS-CoV-2 , T-Lymphocytes/immunology
4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319297

ABSTRACT

Following severe adverse reactions in patients vaccinated with the AstraZeneca ChadOx1 (Chad) vaccine, European health authorities have recommended that patients under the age of 55 who received one dose of Chad vaccine receive a second dose of Pfizer BNT162b2 (BNT) vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here, we show that the heterologous Chad/BNT combination confers better protection against SARS-CoV-2 infection than the homologous BNT/BNT combination in a population of health care workers. To understand the underlying mechanism, we monitored in a longitudinal way the anti-spike immunity conferred by each vaccinal combination. Both combinations induced strong anti-spike antibody responses after boost in all vaccinated individuals. However, sera from heterologous vaccinated individuals displayed a stronger neutralizing activity, regardless of the SARS-CoV-2 variant analyzed, and this was associated with more switched memory RBD-specific B cells with an activated phenotype and less IgA. The Chad vaccine induced a stronger T cell response than the BNT vaccine after the priming dose, and the reciprocal was true for the IgG response, which could explain the complementarity of both vaccines when used in an heterologous setting. This strongly protective vaccination regimen could be therefore particularly suitable for immunocompromised individuals.

5.
Arch Med Res ; 52(8): 850-857, 2021 11.
Article in English | MEDLINE | ID: covidwho-1631298

ABSTRACT

BACKGROUND: As COVID-19 pandemic and vaccination effects progress, research now focuses on adaptive immunological response to SARS-CoV-2. Few studies specifically investigated intensive care unit (ICU) patients, and little is known about kinetics of humoral response in such critically ill patients. In this context, the main objective of the present work was to perform a longitudinal analysis of the humoral response in critically ill COVID-19 patients with prolonged ICU stays in regard with initial inflammatory response, disease severity and mortality. METHODS: Over a 3 week period, circulating immunoglobulins (Ig) against SARS-CoV-2 along with several immunological and clinical parameters were measured in 64 ICU COVID-19 patients. RESULTS: Critically ill COVID-19 patients mounted a dynamic and sustained antibody response of both IgM and IgG as soon as the first day of ICU hospitalization. This serological response was not associated with any of the classical immunological parameters measured at ICU admission or with initial severity clinical scores. IgM and IgG levels and seroconversion trajectories were not associated with unfavourable outcome. CONCLUSION: Despite rapid seroconversion and elevated humoral response, COVID-19 patients are still characterized by elevated mortality. Additional studies, including cytotoxic T cell functions, are mandatory to understand the immunological mechanisms contributing to long stay of COVID-19 patients in ICU.


Subject(s)
COVID-19 , Critical Illness , Humans , Intensive Care Units , Pandemics , SARS-CoV-2 , Seroconversion
6.
Nature ; 600(7890): 701-706, 2021 12.
Article in English | MEDLINE | ID: covidwho-1483135

ABSTRACT

Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities recommended that patients under the age of 55 years who received one dose of ChAdOx1-S-nCoV-19 receive a second dose of the Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here we show that the heterologous ChAdOx1-S-nCoV-19 and BNT162b2 combination confers better protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the homologous BNT162b2 and BNT162b2 combination in a real-world observational study of healthcare workers (n = 13,121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody responses, but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential correlated with increased frequencies of switched and activated memory B cells that recognize the SARS-CoV-2 receptor binding domain. The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immunocompromised individuals.


Subject(s)
/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , /immunology , SARS-CoV-2/immunology , Vaccination/statistics & numerical data , Adult , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Female , France/epidemiology , Hospitals, University , Humans , Immunologic Memory/immunology , Incidence , Male , /immunology , Middle Aged , Spike Glycoprotein, Coronavirus/immunology
8.
Arch Med Res ; 52(8): 850-857, 2021 11.
Article in English | MEDLINE | ID: covidwho-1427555

ABSTRACT

BACKGROUND: As COVID-19 pandemic and vaccination effects progress, research now focuses on adaptive immunological response to SARS-CoV-2. Few studies specifically investigated intensive care unit (ICU) patients, and little is known about kinetics of humoral response in such critically ill patients. In this context, the main objective of the present work was to perform a longitudinal analysis of the humoral response in critically ill COVID-19 patients with prolonged ICU stays in regard with initial inflammatory response, disease severity and mortality. METHODS: Over a 3 week period, circulating immunoglobulins (Ig) against SARS-CoV-2 along with several immunological and clinical parameters were measured in 64 ICU COVID-19 patients. RESULTS: Critically ill COVID-19 patients mounted a dynamic and sustained antibody response of both IgM and IgG as soon as the first day of ICU hospitalization. This serological response was not associated with any of the classical immunological parameters measured at ICU admission or with initial severity clinical scores. IgM and IgG levels and seroconversion trajectories were not associated with unfavourable outcome. CONCLUSION: Despite rapid seroconversion and elevated humoral response, COVID-19 patients are still characterized by elevated mortality. Additional studies, including cytotoxic T cell functions, are mandatory to understand the immunological mechanisms contributing to long stay of COVID-19 patients in ICU.


Subject(s)
COVID-19 , Critical Illness , Humans , Intensive Care Units , Pandemics , SARS-CoV-2 , Seroconversion
9.
Eur J Immunol ; 51(12): 3239-3242, 2021 12.
Article in English | MEDLINE | ID: covidwho-1413180

ABSTRACT

Antigen-specific T-cells are essential for protective immunity against SARS-CoV-2. We set up a semi-automated whole-blood Interferon-gamma release assay (WB IGRA) to monitor the T-cell response after stimulation with SARS-CoV-2 peptide pools. We report that the WB IGRA is complementary to serological assays to assess SARS-CoV-2 immunity.


Subject(s)
COVID-19/immunology , Interferon-gamma/metabolism , SARS-CoV-2/physiology , Adult , Automation, Laboratory , Cells, Cultured , Cohort Studies , Female , Humans , Interferon-gamma Release Tests/standards , Lymphocyte Activation , Male , Middle Aged , T-Cell Antigen Receptor Specificity , Whole Body Imaging , Young Adult
11.
J Exp Med ; 218(10)2021 10 04.
Article in English | MEDLINE | ID: covidwho-1345702

ABSTRACT

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Interferon Type I/immunology , SARS-CoV-2/immunology , Adult , Aged , Animals , Antiviral Agents/immunology , Antiviral Agents/pharmacology , Autoantibodies/blood , COVID-19/blood , COVID-19/virology , Chlorocebus aethiops , Female , Humans , Interferon Type I/pharmacology , Longitudinal Studies , Male , Middle Aged , Nasal Cavity/immunology , Nasal Cavity/virology , Prospective Studies , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Viral Load/immunology , Virus Replication/drug effects , Virus Replication/immunology
12.
Sci Rep ; 11(1): 14977, 2021 07 22.
Article in English | MEDLINE | ID: covidwho-1322500

ABSTRACT

A comprehensive clinical and microbiological assessments of COVID-19 in front-line healthcare workers (HCWs) is needed. Between April 10th and May 28th, 2020, 319 HCWs with acute illness were reviewed. In addition to SARS-CoV-2 RT-PCR screening, a multiplex molecular panel was used for testing other respiratory pathogens. For SARS-CoV-2 positive HCWs, the normalized viral load, viral culture, and virus neutralization assays were performed weekly. For SARS-CoV-2 negative HCWs, SARS-CoV-2 serological testing was performed one month after inclusion. Among the 319 HCWs included, 67 (21.0%) were tested positive for SARS-CoV-2; 65/67 (97.0%) developed mild form of COVID-19. Other respiratory pathogens were found in 6/66 (9.1%) SARS-CoV-2 positive and 47/241 (19.5%) SARS-Cov-2 negative HCWs (p = 0.07). The proportion of HCWs with a viral load > 5.0 log10 cp/mL (Ct value < 25) was less than 15% at 8 days after symptom onset; 12% of HCWs were positive after 40 days (Ct > 37). More than 90% of cultivable virus had a viral load > 4.5 log10 cp/mL (Ct < 26) and were collected within 10 days after symptom onset. Among negative HCWs, 6/190 (3.2%) seroconverted. Our data suggest that the determination of viral load can be used for appreciating the infectiousness of infected HCWs. These data could be helpful for facilitating their return to work.


Subject(s)
COVID-19/diagnosis , Health Personnel , SARS-CoV-2/isolation & purification , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Female , Humans , Male , Middle Aged , Prospective Studies , Viral Load , Young Adult
13.
Eur J Immunol ; 51(4): 989-994, 2021 04.
Article in English | MEDLINE | ID: covidwho-1187983

ABSTRACT

Low concentrations of type-I interferon (IFN) in blood seem to be associated with more severe forms of Coronavirus disease 2019 (COVID-19). However, following the type-I interferon response (IR) in early stage disease is a major challenge. We evaluated detection of a molecular interferon signature on a FilmArray® system, which includes PCR assays for four interferon stimulated genes. We analyzed three types of patient populations: (i) children admitted to a pediatric emergency unit for fever and suspected infection, (ii) ICU-admitted patients with severe COVID-19, and (iii) healthcare workers with mild COVID-19. The results were compared to the reference tools, that is, molecular signature assessed with Nanostring® and IFN-α2 quantification by SIMOA® (Single MOlecule Array). A strong correlation was observed between the IR measured by the FilmArray®, Nanostring®, and SIMOA® platforms (r-Spearman 0.996 and 0.838, respectively). The FilmArray® panel could be used in the COVID-19 pandemic to evaluate the IR in 45-min with 2 min hand-on-time at hospitalization and to monitor the IR in future clinical trials.


Subject(s)
COVID-19/blood , Interferon-alpha/blood , Polymerase Chain Reaction/methods , SARS-CoV-2/immunology , Adult , Aged , COVID-19/immunology , Child , Female , Health Personnel , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-alpha/genetics , Male
14.
Crit Care ; 25(1): 140, 2021 04 12.
Article in English | MEDLINE | ID: covidwho-1181117

ABSTRACT

BACKGROUND: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved. METHODS: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements. RESULTS: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS. CONCLUSIONS: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.


Subject(s)
COVID-19/blood , Critical Illness , Intensive Care Units/trends , Interferon-alpha/blood , Respiratory Distress Syndrome/blood , Adult , Aged , Biomarkers/blood , COVID-19/epidemiology , COVID-19/immunology , Critical Illness/epidemiology , Female , Hospitalization/trends , Humans , Immunity/immunology , Longitudinal Studies , Male , Middle Aged , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/immunology
15.
J Clin Med ; 9(6)2020 Jun 16.
Article in English | MEDLINE | ID: covidwho-599307

ABSTRACT

A reliable diagnostic assay is crucial to early detect new COVID-19 cases and limit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Since the onset of the COVID-19 pandemic, the World Health Organization has published several diagnostic molecular approaches developed by referral laboratories, including Charité (Germany), HKU (Hong Kong), China CDC (China), US CDC (United States), and Institut Pasteur, Paris (France). We aimed to compare the sensitivity and specificity of these different RT-PCR assays using SARS-CoV-2 cell culture supernatants and clinical respiratory samples. Overall, the different RT-PCR assays performed well for SARS-CoV-2 detection and were all specific except the N Charité (Germany), and N2 US CDC (United States) assays. RdRp Institut Pasteur (IP2, IP4), N China CDC, and N1 US CDC were found to be the most sensitive assays. The data presented herein are of prime importance to facilitate the equipment choice of diagnostic laboratories, as well as for the development of marketed tests.

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