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1.
Vopr Virusol ; 67(6): 527-537, 2023 02 07.
Article in Russian | MEDLINE | ID: covidwho-20233326

ABSTRACT

INTRODUCTION: The development of the COVID-19 pandemic has stimulated the scientific research aimed at studying of the mechanisms of formation the immunity against SARS-CoV-2. Currently, there is a need to develop a domestic simple and cost-effective specific method suitable for monitoring of T-cell response against SARS-CoV-2 in reconvalescents and vaccinated individuals. AIM: Development of a screening method for evaluation specific T-cell immunity against SARS-CoV-2. MATERIALS AND METHODS: Total 40 individuals who had mild to moderate COVID-19 and 20 healthy volunteers who did not have a history of this disease were examined. The presence and levels of IgG and IgM antibodies to SARS-CoV-2 were identified in participants sera by ELISA using the diagnostic kits from JSC Vector-Best (Novosibirsk, Russian Federation). Antigenic stimulation of mononuclear cells was carried out on commercial plates with adsorbed whole-virion inactivated SARS-CoV-2 antigen (State Research Center of Virology and Biotechnology VECTOR Novosibirsk, Russian Federation). The concentration of IFN- was measured in ELISA using the test systems from JSC Vector-Best (Novosibirsk, Russian Federation). The immunophenotyping of lymphocytes was performed on a flow cytometer Cytomics FC500 (Beckman Coulter, USA). Statistical data processing was carried out using the Microsoft Excel and STATISTICA 10 software package. RESULTS: Stimulation of mononuclear cells isolated from the peripheral blood with whole-virion inactivated SARS-CoV-2 antigen fixed at the bottom of the wells of a polystyrene plate showed a significantly higher median response in terms of IFN- production in 40 people who had history of COVID-19 compared to 20 healthy blood donors (172.1 [34.3575.1] pg/ml versus 15.4 [6.925.8] pg/ml, p 0.0001). There was no difference in median IFN- levels in supernatants collected from unstimulated mononuclear cells from COVID-19 reconvalescents and healthy donors (2.7 [0.411.4] pg/ml versus 0.8 [0.023.3] pg/ml, p 0.05). The overall sensitivity and specificity of this method were 73% (95% CI 5888%) and 100% (95% CI 100100%), respectively, at a cut-off of 50 pg/ml. CONCLUSION: The developed method for assessment of the cellular immune response to SARS-CoV-2 can be used as a screening method for monitoring the T-cell response in a population against a new coronavirus infection in recovered people.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/diagnosis , COVID-19/epidemiology , Pandemics , T-Lymphocytes , Enzyme-Linked Immunosorbent Assay , Antibodies, Viral
2.
Clinical Immuno-Oncology ; : 289-310.e7, 2024.
Article in English | ScienceDirect | ID: covidwho-2328112

ABSTRACT

: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), identified in Wuhan, China, in December 2019, rapidly spread globally to become a devastating global pandemic. The SARS-CoV-2 (coronavirus disease 2019 [COVID-19]) respiratory illness was initially reported in the United States in the state of Washington in January 2020. COVID-19 respiratory virus proved to be an extremely contagious illness with clinical features of fever, cough, dyspnea, malaise, and rapidly progressing severe interstitial pneumonia. Since the beginning of 2020, COVID-19 has been responsible for an unimagined level of deaths and socioeconomic disruption. The patient with malignancy and a suppressed immune system was, as expected, at increased risk for contracting COVID-19. Patients with cancer, when infected, had a more difficult clinical course and an increased rate of mortality. In the intervening 2+ years, much has been learned regarding the ability of the patient with cancer's immune system to not only fight the progression of their cancer but to effectively respond to newly available mRNA vaccines against COVID-19. As the pandemic continues, careful management of the vulnerable patient with cancer is essential.

3.
BMC Pulm Med ; 23(1): 177, 2023 May 22.
Article in English | MEDLINE | ID: covidwho-2327442

ABSTRACT

OBJECTIVE: This study aimed to investigate the longitudinal circulating eosinophil (EOS) data impacted by the COVID-19 vaccine, the predictive role of circulating EOS in the disease severity, and its association with T cell immunity in patients with SARS-CoV-2 Omicron BA.2 variant infection in Shanghai, China. METHODS: We collected a cohort of 1,157 patients infected with SARS-CoV-2 Omicron/BA.2 variant in Shanghai, China. These patients were diagnosed or admitted between Feb 20, 2022, and May 10, 2022, and were classified as asymptomatic (n = 705), mild (n = 286) and severe (n = 166) groups. We compiled and analyzed data of patients' clinical demographic characteristics, laboratory findings, and clinical outcomes. RESULTS: COVID-19 vaccine reduced the incidence of severe cases. Severe patients were shown to have declined peripheral blood EOS. Both the 2 doses and 3 doses of inactivated COVID-19 vaccines promoted the circulating EOS levels. In particular, the 3rd booster shot of inactivated COVID-19 vaccine was shown to have a sustained promoting effect on circulating EOS. Univariate analysis showed that there was a significant difference in age, underlying comorbidities, EOS, lymphocytes, CRP, CD4, and CD8 T cell counts between the mild and the severe patients. Multivariate logistic regression analysis and ROC curve analysis indicate that circulating EOS (AUC = 0.828, p = 0.025), the combination of EOS and CD4 T cell (AUC = 0.920, p = 0.017) can predict the risk of disease severity in patients with SARS-CoV-2 Omicron BA.2 variant infection. CONCLUSIONS: COVID-19 vaccine promotes circulating EOS and reduces the risk of severe illness, and particularly the 3rd booster dose of COVID-19 vaccine sustainedly promotes EOS. Circulating EOS, along with T cell immunity, may have a predictive value for the disease severity in SARS-CoV-2 Omicron infected patients.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , COVID-19/prevention & control , China/epidemiology , Eosinophils , SARS-CoV-2 , Patient Acuity
4.
Front Immunol ; 14: 1046639, 2023.
Article in English | MEDLINE | ID: covidwho-2318764

ABSTRACT

Cellular immune responses are of pivotal importance to understand SARS-CoV-2 pathogenicity. Using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay with wild-type spike, membrane and nucleocapsid peptide pools, we longitudinally characterized functional SARS-CoV-2 specific T-cell responses in a cohort of patients with mild, moderate and severe COVID-19. All patients were included before emergence of the Omicron (B.1.1.529) variant. Our most important finding was an impaired development of early IFN-γ-secreting virus-specific T-cells in severe patients compared to patients with moderate disease, indicating that absence of virus-specific cellular responses in the acute phase may act as a prognostic factor for severe disease. Remarkably, in addition to reactivity against the spike protein, a substantial proportion of the SARS-CoV-2 specific T-cell response was directed against the conserved membrane protein. This may be relevant for diagnostics and vaccine design, especially considering new variants with heavily mutated spike proteins. Our data further strengthen the hypothesis that dysregulated adaptive immunity plays a central role in COVID-19 immunopathogenesis.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , T-Lymphocytes , Adaptive Immunity , Ataxia Telangiectasia Mutated Proteins , Interferon-gamma
5.
Infektsiya I Immunitet ; 12(4):701-712, 2022.
Article in English | Web of Science | ID: covidwho-2309684

ABSTRACT

SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), also known as 2019-nCoV (2019-Novel Coronavirus) is a strain of coronavirus from the genus Betacoronavirus, discovered in China at the end of 2019 in patients with pneumonia. "Coronavirus infection COVID-19" (COrona VIrus Disease 2019) caused by coronavirus 2019 (COVID-19) has spread around the world at a very fast pace, with death toll exceeding more than 5.2 million people worldwide. Limited success in developing new drugs as well as use of existing drugs for the treatment of COVID-19 resulted in situation when the main prevention measures for a long time were based on testing and isolation of sick subjects, which started to reverse due to vaccination. Monitoring the formation of humoral and T-cell population immunity against the SARS-CoV-2 virus during the COVID-19 pandemic is a necessary element for epidemiological surveillance. ELISA-based methods are widely used to assess humoral immunity, and various test systems including ELISPOT (Enzyme-Linked ImmunoSpot) are used to analyze cellular immunity. The ELISPOT assay is a highly sensitive and specific method for quantifying individual cytokine-secreting T cells after being stimulated with a specific antigen. "TigraTest (R) SARS-CoV-2" Test assessing release of interferon gamma in vitro to detect peripheral blood T-lymphocytes that specifically respond to the SARS-CoV-2 virus antigens manufactured by GENERIUM JSC, is created on the ELISPOT platform. This study describes the procedure for laboratory validation of this test system to analyze the following parameters: specificity of antibody pair, effect of interfering substances, sensitivity and specificity, precision, stability of blood samples till isolation of target cells. The developed test system showed high diagnostic sensitivity and specificity. The specificity of TigraTest (R) SARS-CoV-2 was 100%, the sensitivity for subjects immunized with the Gam-COVID-Vac vaccine (Sputnik V) was 91.67%, and the sensitivity in convalescent COVID-19 patients was 95.45%. At the same time, the data variability both during within and between series comparison did not exceed 25%, whereas 24-hour storage of peripheral blood samples at (18-25)degrees C after blood collection followed by isolation of target cells did not affect the test results.

6.
Jurnal Infektologii ; 14(1):96-104, 2022.
Article in Russian | EMBASE | ID: covidwho-2276627

ABSTRACT

Introduction. In the context of a pandemic of a new coronavirus infection (COVID-19), research on the peculiarities of the formation of an immune response to SARS-CoV-2 in patients who have been ill and vaccinated is of particular relevance. However, most studies are currently devoted to evaluating only the humoral link of immunity, and its cellular component remains insufficiently studied. The aim of the study was to evaluate the features of the formation and changes of the T-cell link of immunity in patients with a new coronavirus infection and vaccinated against this disease. Materials and methods. The study was performed on the basis of the clinical and diagnostic laboratory of the European Medical Center "UMMC-Health "LLC. Specific T-cell immunity was evaluated using ELISPOT technology. In the course of the study, 72 blood samples of employees of medical organizations were analyzed, including 26 from those who had a new coronavirus infection, 23 from persons who were intact according to COVID-19 before vaccination and 23 from the same employees after vaccination (<<Gam-Covid-Vac>>). In addition, each of the study participants was examined to determine specific class G antibodies (IgG) by solid-phase enzyme immunoassay using SARS-CoV-2-IgG-ELISA-BEST test systems (manufactured by VECTOR-BEST JSC). Results and discussion. In the group of patients (26 people), T-lymphocytes capable of specifically reacting to SARSCoV-2 antigens were detected in 100% of cases, even in individuals with IgG elimination. It should be noted that the response was more pronounced when meeting with M-and N-pepdids, compared with S-protein. 22 out of 23 COVID-19 intact individuals had no T-cell immunity to coronavirus infection before vaccination, but one employee had a response to 3 proteins-M, N, S, which indicates that he had previously encountered the SARS-CoV-2 virus. After vaccination with the drug "Gam-Covid-Vac", 22 (95.6%) employees revealed a T-cell response, while 21-only to S-protein, and an employee with a previously detected immune response-after vaccination, the response to M -, N-proteins remained almost at the same level, and the cellular response to S-peptide doubled. Conclusion. Thus, based on the results of the study, important materials were obtained on the peculiarities of the formation of a specific T-cell immune response to a new coronavirus infection. The obtained data provide a broader understanding of the immune response in new coronavirus infection in patients who have been ill and vaccinated and can be used in the future when planning preventive and anti-epidemic measures.Copyright © 2022 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved.

7.
Jurnal Infektologii ; 14(1):96-104, 2022.
Article in Russian | EMBASE | ID: covidwho-2276626

ABSTRACT

Introduction. In the context of a pandemic of a new coronavirus infection (COVID-19), research on the peculiarities of the formation of an immune response to SARS-CoV-2 in patients who have been ill and vaccinated is of particular relevance. However, most studies are currently devoted to evaluating only the humoral link of immunity, and its cellular component remains insufficiently studied. The aim of the study was to evaluate the features of the formation and changes of the T-cell link of immunity in patients with a new coronavirus infection and vaccinated against this disease. Materials and methods. The study was performed on the basis of the clinical and diagnostic laboratory of the European Medical Center "UMMC-Health "LLC. Specific T-cell immunity was evaluated using ELISPOT technology. In the course of the study, 72 blood samples of employees of medical organizations were analyzed, including 26 from those who had a new coronavirus infection, 23 from persons who were intact according to COVID-19 before vaccination and 23 from the same employees after vaccination (<<Gam-Covid-Vac>>). In addition, each of the study participants was examined to determine specific class G antibodies (IgG) by solid-phase enzyme immunoassay using SARS-CoV-2-IgG-ELISA-BEST test systems (manufactured by VECTOR-BEST JSC). Results and discussion. In the group of patients (26 people), T-lymphocytes capable of specifically reacting to SARSCoV-2 antigens were detected in 100% of cases, even in individuals with IgG elimination. It should be noted that the response was more pronounced when meeting with M-and N-pepdids, compared with S-protein. 22 out of 23 COVID-19 intact individuals had no T-cell immunity to coronavirus infection before vaccination, but one employee had a response to 3 proteins-M, N, S, which indicates that he had previously encountered the SARS-CoV-2 virus. After vaccination with the drug "Gam-Covid-Vac", 22 (95.6%) employees revealed a T-cell response, while 21-only to S-protein, and an employee with a previously detected immune response-after vaccination, the response to M -, N-proteins remained almost at the same level, and the cellular response to S-peptide doubled. Conclusion. Thus, based on the results of the study, important materials were obtained on the peculiarities of the formation of a specific T-cell immune response to a new coronavirus infection. The obtained data provide a broader understanding of the immune response in new coronavirus infection in patients who have been ill and vaccinated and can be used in the future when planning preventive and anti-epidemic measures.Copyright © 2022 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved.

8.
Viral, Parasitic, Bacterial, and Fungal Infections: Antimicrobial, Host Defense, and Therapeutic Strategies ; : 237-262, 2022.
Article in English | Scopus | ID: covidwho-2255077

ABSTRACT

The clinical outcomes in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection include asymptomatic disease or mild disease with influenza-like symptoms or severe disease condition following death by pneumonia and acute respiratory distress syndrome (ARDS). The current mRNA- and vector-based vaccines successfully addressed the antigenic challenges of the parental SARS-CoV-2 strain. However, recent concerns are being raised against some SARS-CoV-2 variants, which have the potential to escape natural immunity and vaccine-induced immune recognition partially, leading to a possible increase in transmissibility and disease severity. The coronavirus disease-19 (COVID-19)-induced rapid changes in human immune profiles might be instigating the evolution of SARS-CoV-2 with a higher propensity. Therefore, we require critical surveillance on the genomic sequence and structural conformation of the evolving variants and phenotypic impacts of the accumulating mutations on the host-immune response for possible updates in the booster vaccine sequence, if required. Here, we will highlight the role of accumulating mutations in SARS-CoV-2 genomic sequences leading to the host-immune escape by regulating the T cell- and B cell-mediated responses in infected, unvaccinated, and vaccinated individuals. © 2023 Elsevier Inc. All rights reserved.

9.
Heliyon ; 9(2): e13285, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2272510

ABSTRACT

The Omicron, the latest variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in November 2021 in Botswana, South Africa. Compared to other variants of SARS-CoV-2, the Omicron is the most highly mutated, with 50 mutations throughout the genome, most of which are in the spike (S) protein. These mutations may help the Omicron to evade host immunity against the vaccine. Epidemiological studies suggest that Omicron is highly infectious and spreads rapidly, but causes significantly less severe disease than the wild-type strain and the other variants of SARS-CoV-2. With the increased transmissibility and a higher rate of re-infection, Omicron has now become a dominant variant worldwide and is predicted to be able to evade vaccine-induced immunity. Several clinical studies using plasma samples from individuals receiving two doses of US Food and Drugs Administration (FDA)-approved COVID-19 vaccines have shown reduced humoral immune response against Omicron infection, but T cell-mediated immunity was well preserved. In fact, T cell-mediated immunity protects against severe disease, and thus the disease caused by Omicron remains mild. In this review, I surveyed the current status of Omicron variant mutations and mechanisms of immune response in the context of immune escape from COVID-19 vaccines. I also discuss the potential implications of therapeutic opportunities that are independent of SARS-CoV-2 variants, including Omicron. A better understanding of vaccine-induced immune responses and variant-independent therapeutic interventions that include potent antiviral, antioxidant, and anti-cytokine activities may pave the way to reducing Omicron-related COVID-19 complications, severity, and mortality. Collectively, these insights point to potential research gaps and will aid in the development of new-generation COVID-19 vaccines and antiviral drugs to combat Omicron, its sublineages, or upcoming new variants of SARS-CoV-2.

10.
J Formos Med Assoc ; 2023 Feb 28.
Article in English | MEDLINE | ID: covidwho-2288087

ABSTRACT

BACKGROUND: Patients with chronic kidney disease are at high risk for coronavirus disease 2019. Little is known about immune response to severe acute respiratory syndrome coronavirus 2 vaccination in patients on peritoneal dialysis (PD). METHOD: We prospectively enrolled 306 PD patients receiving two doses of vaccines (ChAdOx1-S: 283, mRNA-1273: 23) from July 2021 at a medical center. Humeral and cellular immune responses were assessed by anti-spike IgG concentration and blood T cell interferon-γ production 30 days after vaccination. Antibody ≥0.8 U/mL and interferon-γ ≥ 100 mIU/mL were defined as positive. Antibody was also measured in 604 non-dialysis volunteers (ChAdOx1-S: 244, mRNA-1273: 360) for comparison. RESULT: PD patients had less adverse events after vaccinations than volunteers. After the first dose of vaccine, the median antibody concentrations were 8.5 U/mL and 50.4 U/mL in ChAdOx1-S group and mRNA-1273 group of PD patients, and 66.6 U/mL and 195.3 U/mL in ChAdOx1-S group and mRNA-1273 group of volunteers, respectively. And after the second dose of vaccine, the median antibody concentrations were 344.8 U/mL and 9941.0 U/mL in ChAdOx1-S group and mRNA-1273 group of PD patients, and 620.3 U/mL and 3845.0 U/mL in ChAdOx1-S group and mRNA-1273 group of volunteers, respectively. The median IFN-γ concentration was 182.8 mIU/mL in ChAdOx1-S group, which was substantially lower than the median concentration 476.8 mIU/mL in mRNA-1273 group of PD patients. CONCLUSIONS: Both vaccines were safe and resulted in comparable antibody seroconversion in PD patients when compared with volunteers. However, mRNA-1273 vaccine induced significantly higher antibody and T cell response than ChAdOx1-S in PD patients. Booster doses are recommended for PD patients after two doses of ChAdOx1-S vaccination.

11.
J Med Virol ; 95(3): e28642, 2023 03.
Article in English | MEDLINE | ID: covidwho-2287827

ABSTRACT

Individuals with a recent common cold coronavirus infection, which leads to pre-existing immunity against SARS-CoV-2, displayed a less severe course of COVID-19. However, the relationship between pre-existing immunity against SARS-CoV-2 and the inactivated-vaccine-induced immune response is still unknown. Here, 31 healthcare workers who received standard two doses of inactivated COVID-19 vaccines (Weeks 0 and 4, respectively) were enrolled, vaccine-induced neutralization and T cell responses were detected, and the correlation between the pre-existing SARS-CoV-2-specific immunity was analyzed. We found the SARS-CoV-2-specific antibodies, pseudovirus neutralization test (pVNT) titers, and spike-specific interferon gamma (IFN-γ) production in CD4+ and CD8+ T cells were significantly elevated after two doses of inactivated vaccines. Interestingly, the pVNT titers after the second dose of vaccination displayed no significant correlation with the pre-existing SARS-CoV-2-specific antibodies or B cells, nor the pre-existing spike-specific CD4+ T cells. Notably, the spike-specific T cell response after the second dose of vaccination was positively correlated with the pre-existing receptor binding domain (RBD)-specific B cells and CD4+ T cells, which were documented by the frequencies of RBD-binding B cells, the breadth of RBD-specific B cell epitopes, and the frequency of IFN-γ-expressing RBD-specific CD4+ T cells. Overall, the inactivated-vaccine-induced T cell responses, not the inactivated-vaccine-induced neutralization, closely correlated with pre-existing immunity to SARS-CoV-2. Our results provide a better understanding of inactivated-vaccine-induced immunity and help predict the immunogenicity induced by inactivated vaccines in individuals.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2 , COVID-19/prevention & control , CD8-Positive T-Lymphocytes , Antibodies, Viral , Vaccination , Antibodies, Neutralizing , Vaccines, Inactivated
12.
Front Immunol ; 14: 1146196, 2023.
Article in English | MEDLINE | ID: covidwho-2287498

ABSTRACT

The devastating COVID-19 pandemic caused by SARS-CoV-2 and multiple variants or subvariants remains an ongoing global challenge. SARS-CoV-2-specific T cell responses play a critical role in early virus clearance, disease severity control, limiting the viral transmission and underpinning COVID-19 vaccine efficacy. Studies estimated broad and robust T cell responses in each individual recognized at least 30 to 40 SARS-CoV-2 antigen epitopes and associated with COVID-19 clinical outcome. Several key immunodominant viral proteome epitopes, including S protein- and non-S protein-derived epitopes, may primarily induce potent and long-lasting antiviral protective effects. In this review, we summarized the immune response features of immunodominant epitope-specific T cells targeting different SRAS-CoV-2 proteome structures after infection and vaccination, including abundance, magnitude, frequency, phenotypic features and response kinetics. Further, we analyzed the epitopes immunodominance hierarchy in combination with multiple epitope-specific T cell attributes and TCR repertoires characteristics, and discussed the significant implications of cross-reactive T cells toward HCoVs, SRAS-CoV-2 and variants of concern, especially Omicron. This review may be essential for mapping the landscape of T cell responses toward SARS-CoV-2 and optimizing the current vaccine strategy.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Epitopes , COVID-19 Vaccines , Pandemics , Proteome , T-Lymphocytes , Immunodominant Epitopes , Immunity , Receptors, Antigen, T-Cell
13.
Viruses ; 15(3)2023 03 16.
Article in English | MEDLINE | ID: covidwho-2286270

ABSTRACT

T-cell immunity plays an important role in the control of SARS-CoV-2 and has a great cross-protective effect on the variants. The Omicron BA.1 variant contains more than 30 mutations in the spike and severely evades humoral immunity. To understand how Omicron BA.1 spike mutations affect cellular immunity, the T-cell epitopes of SARS-CoV-2 wild-type and Omicron BA.1 spike in BALB/c (H-2d) and C57BL/6 mice (H-2b) were mapped through IFNγ ELISpot and intracellular cytokine staining assays. The epitopes were identified and verified in splenocytes from mice vaccinated with the adenovirus type 5 vector encoding the homologous spike, and the positive peptides involved in spike mutations were tested against wide-type and Omicron BA.1 vaccines. A total of eleven T-cell epitopes of wild-type and Omicron BA.1 spike were identified in BALB/c mice, and nine were identified in C57BL/6 mice, only two of which were CD4+ T-cell epitopes and most of which were CD8+ T-cell epitopes. The A67V and Del 69-70 mutations in Omicron BA.1 spike abolished one epitope in wild-type spike, and the T478K, E484A, Q493R, G496S and H655Y mutations resulted in three new epitopes in Omicron BA.1 spike, while the Y505H mutation did not affect the epitope. These data describe the difference of T-cell epitopes in SARS-CoV-2 wild-type and Omicron BA.1 spike in H-2b and H-2d mice, providing a better understanding of the effects of Omicron BA.1 spike mutations on cellular immunity.


Subject(s)
COVID-19 , Epitopes, T-Lymphocyte , Animals , Mice , Mice, Inbred C57BL , Epitopes, T-Lymphocyte/genetics , SARS-CoV-2/genetics , Mutation , Mice, Inbred BALB C
14.
J Hepatol ; 79(1): 150-166, 2023 Jul.
Article in English | MEDLINE | ID: covidwho-2261801

ABSTRACT

BACKGROUND & AIMS: Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD. METHODS: We combined bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver injury with vaccination or lymphocytic choriomeningitis virus infection in transgenic mice lacking IFN-I in myeloid cells (LysM-Cre IFNARflox/flox), IFNAR-induced IL-10 (MX1-Cre IL10flox/flox) or IL-10R in T cells (CD4-DN IL-10R). Key pathways were blocked in vivo with specific antibodies (anti-IFNAR and anti-IL10R). We assessed T-cell responses and antibody titers after HBV and SARS-CoV-2 vaccinations in patients with CLD and healthy individuals in a proof-of-concept clinical study. RESULTS: We demonstrate that BDL- and CCL4-induced prolonged liver injury leads to impaired T-cell responses to vaccination and viral infection in mice, subsequently leading to persistent infection. We observed a similarly defective T-cell response to vaccination in patients with cirrhosis. Innate sensing of translocated gut microbiota induced IFN-I signaling in hepatic myeloid cells that triggered excessive IL-10 production upon viral infection. IL-10R signaling in antigen-specific T cells rendered them dysfunctional. Antibiotic treatment and inhibition of IFNAR or IL-10Ra restored antiviral immunity without detectable immune pathology in mice. Notably, IL-10Ra blockade restored the functional phenotype of T cells from vaccinated patients with cirrhosis. CONCLUSION: Innate sensing of translocated microbiota induces IFN-/IL-10 expression, which drives the loss of systemic T-cell immunity during prolonged liver injury. IMPACT AND IMPLICATIONS: Chronic liver injury and cirrhosis are associated with enhanced susceptibility to viral infections and vaccine hyporesponsiveness. Using different preclinical animal models and patient samples, we identified that impaired T-cell immunity in BDL- and CCL4-induced prolonged liver injury is driven by sequential events involving microbial translocation, IFN signaling leading to myeloid cell-induced IL-10 expression, and IL-10 signaling in antigen-specific T cells. Given the absence of immune pathology after interference with IL-10R, our study highlights a potential novel target to reconstitute T-cell immunity in patients with CLD that can be explored in future clinical studies.


Subject(s)
COVID-19 , Interferon Type I , Mice , Animals , Interleukin-10 , SARS-CoV-2 , Mice, Transgenic , Liver Cirrhosis , Mice, Inbred C57BL
15.
Immunity ; 56(4): 879-892.e4, 2023 04 11.
Article in English | MEDLINE | ID: covidwho-2267119

ABSTRACT

Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Breakthrough Infections , RNA, Viral , Antibodies, Neutralizing , Antibodies, Viral , Vaccination
16.
Front Immunol ; 14: 1169034, 2023.
Article in English | MEDLINE | ID: covidwho-2264720
17.
BMC Med Genomics ; 16(1): 59, 2023 03 25.
Article in English | MEDLINE | ID: covidwho-2269158

ABSTRACT

The risk of severe condition caused by Corona Virus Disease 2019 (COVID-19) increases with age. However, the underlying mechanisms have not been clearly understood. The dataset GSE157103 was used to perform weighted gene co-expression network analysis on 100 COVID-19 patients in our analysis. Through weighted gene co-expression network analysis, we identified a key module which was significantly related with age. This age-related module could predict Intensive Care Unit status and mechanical-ventilation usage, and enriched with positive regulation of T cell receptor signaling pathway biological progress. Moreover, 10 hub genes were identified as crucial gene of the age-related module. Protein-protein interaction network and transcription factors-gene interactions were established. Lastly, independent data sets and RT-qPCR were used to validate the key module and hub genes. Our conclusion revealed that key genes were associated with the age-related phenotypes in COVID-19 patients, and it would be beneficial for clinical doctors to develop reasonable therapeutic strategies in elderly COVID-19 patients.


Subject(s)
COVID-19 , Physicians , Humans , COVID-19/genetics , Cell Differentiation , Gene Expression Profiling , Phenotype , Gene Regulatory Networks
18.
J Infect Dis ; 2022 Aug 18.
Article in English | MEDLINE | ID: covidwho-2243385

ABSTRACT

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns regarding vaccine effectiveness. We investigated humoral and cellular immune responses against SARS-CoV-2 in healthcare workers before and after a third (booster) dose of the BNT162b2 mRNA vaccine. It significantly enhanced both humoral and cellular immunity in previously uninfected individuals. However, cellular immunity was not enhanced in previously infected persons, suggesting that three antigenic stimuli by vaccination or natural infection reached a plateau of cellular immunity. Even with reinforced immunity to SARS-CoV-2, we confirmed several post-booster breakthrough cases caused by the Omicron variant.

19.
Vaccines (Basel) ; 11(2)2023 Feb 19.
Article in English | MEDLINE | ID: covidwho-2240896

ABSTRACT

SARS-CoV-2 testing is dominated by PCR to guide treatment and individual as well as public health preventive measures. Among 1700 football (soccer) players and staff of the German Bundesliga and Bundesliga 2 who were regularly tested by PCR twice weekly, 98 individuals had a positive PCR (May 2020 to mid-January 2021). A subset of these were retested shortly after the initial positive result. Among those, 11 subjects were identified who only had a transient single positive PCR of low viral load. All individuals were asymptomatic and none developed long COVID. We tested SARS-CoV-2 IgG and IgA as well as SARS-CoV-2 specific CD4 und CD8 positive T cells, and showed that only one out of 11 individuals developed SARS-CoV-2 specific cellular and humoral immunity after the positive PCR, whereas a specific immunity was undetectable in all other individuals. Thus, a single positive PCR might indicate that transient colonization of the upper respiratory tract with SARS-CoV-2 may occur without systemic induction of specific adaptive immunity. Together with test artifacts as another potential reason for a transiently positive test, this finding may favor cautious interpretation of positive PCR results or retesting before initiating intervening treatment or infection control measures in some cases.

20.
Viruses ; 15(2)2023 02 19.
Article in English | MEDLINE | ID: covidwho-2238514

ABSTRACT

People living with HIV (PLWH) may be at risk for poor immunogenicity to certain vaccines, including the ability to develop immunological memory. Here, we assessed T-cell immunogenicity following three SARS-CoV-2 vaccine doses in PLWH versus uninfected controls. Blood was collected from 38 PLWH on antiretroviral therapy and 24 age-matched HIV-negative controls, pre-vaccination and after 1st/2nd/3rd dose of SARS-CoV-2 vaccines, without prior SARS-CoV-2 infection. Flow cytometry was used to assess ex vivo T-cell immunophenotypes and intracellular Tumor necrosis factor (TNF)-α/interferon(IFN)-γ/interleukin(IL)-2 following SARS-CoV-2-Spike-peptide stimulation. Comparisons were made using Wilcoxon signed-rank test for paired variables and Mann-Whitney for unpaired. In PLWH, Spike-specific CD4 T-cell frequencies plateaued post-2nd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose. PLWH had higher frequencies of TNFα+CD4 T-cells and lower frequencies of IFNγ+CD8 T-cells than seronegative participants post-3rd dose. Regardless of HIV status, an increase in naive, regulatory, and PD1+ T-cell frequencies was observed post-3rd dose. In summary, two doses of SARS-CoV-2 vaccine induced a robust T-cell immune response in PLWH, which was maintained after the 3rd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose.


Subject(s)
COVID-19 , HIV Infections , T-Lymphocytes , Humans , CD4-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , HIV Infections/drug therapy , SARS-CoV-2 , Tumor Necrosis Factor-alpha , T-Lymphocytes/immunology
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