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1.
Cancer Discov ; 12(4): 958-983, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-2108398

ABSTRACT

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. SIGNIFICANCE: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873.


Subject(s)
COVID-19 , Neoplasms , T-Lymphocytes , Antibodies, Neutralizing , COVID-19/immunology , Humans , Neoplasms/complications , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes/immunology
2.
N Engl J Med ; 387(6): 495-505, 2022 08 11.
Article in English | MEDLINE | ID: covidwho-2031919

ABSTRACT

BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).


Subject(s)
Antibodies, Bispecific , Antineoplastic Agents, Immunological , B-Cell Maturation Antigen , CD3 Complex , Multiple Myeloma , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Cell Maturation Antigen/antagonists & inhibitors , CD3 Complex/antagonists & inhibitors , Humans , Injections, Subcutaneous , Multiple Myeloma/drug therapy , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/drug therapy , Recurrence , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
3.
Science ; 377(6608): 803, 2022 08 19.
Article in English | MEDLINE | ID: covidwho-1992931

ABSTRACT

Study implicates lack of key hormone, battle-weary immune cells, and awakened viruses.


Subject(s)
COVID-19 , COVID-19/blood , COVID-19/immunology , Humans , Hydrocortisone/blood , T-Lymphocytes/immunology
4.
Science ; 377(6608): 821-822, 2022 08 19.
Article in English | MEDLINE | ID: covidwho-1992930

ABSTRACT

T cell immunity may be critical for long-term protection by COVID-19 vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , T-Lymphocytes , Vaccine Efficacy , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , T-Lymphocytes/immunology
6.
Nat Commun ; 13(1): 4710, 2022 08 11.
Article in English | MEDLINE | ID: covidwho-1991589

ABSTRACT

Comparative analyses of the immunogenicity and reactogenicity of homologous and heterologous SARS-CoV-2 vaccine-regimens will inform optimized vaccine strategies. Here we analyze the humoral and cellular immune response following heterologous and homologous vaccination strategies in a convenience cohort of 331 healthy individuals. All regimens induce immunity to the vaccine antigen. Immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n = 66) or mRNA-1273 (n = 101) is equivalent to or more pronounced than homologous mRNA-regimens (n = 43 BNT162b2, n = 59 mRNA-1273) or homologous ChAdOx1-nCoV-19 vaccination (n = 62). We note highest levels of spike-specific CD8 T-cells following both heterologous regimens. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 are higher than respective combinations with BNT162b2. Polyfunctional T-cell levels are highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens are well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming, and ChAdOx1-nCoV-19/mRNA-1273-boosting. In conclusion, we present comparative analyses of immunogenicity and reactogenicity for heterologous vector/mRNA-boosting and homologous mRNA-regimens.


Subject(s)
2019-nCoV Vaccine mRNA-1273 , BNT162 Vaccine , COVID-19 , ChAdOx1 nCoV-19 , Immunogenicity, Vaccine , 2019-nCoV Vaccine mRNA-1273/immunology , BNT162 Vaccine/immunology , COVID-19/prevention & control , ChAdOx1 nCoV-19/immunology , Humans , Immunity, Cellular , Immunity, Humoral , SARS-CoV-2/genetics , T-Lymphocytes/immunology , Vaccination
7.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1984990

ABSTRACT

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Subject(s)
COVID-19/complications , Hepatitis A Virus Cellular Receptor 2/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Monocytes/metabolism , Receptors, IgG/metabolism , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Alveolar Epithelial Cells/pathology , B-Lymphocytes/immunology , Blood Vessels/pathology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Child , Cohort Studies , Complement Activation , Cytokines/metabolism , Enterocytes/pathology , Female , Humans , Immunity, Humoral , Inflammation/pathology , Interferon Type I/metabolism , Interleukin-15/metabolism , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/immunology , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/pathology
8.
Proc Natl Acad Sci U S A ; 119(34): e2201541119, 2022 08 23.
Article in English | MEDLINE | ID: covidwho-1984598

ABSTRACT

Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) ß and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRß and TCRδ loci, including some TCRß sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.


Subject(s)
Adaptive Immunity , COVID-19 , Immunoglobulin Heavy Chains , Receptors, Antigen, T-Cell, alpha-beta , Receptors, Antigen, T-Cell , SARS-CoV-2 , Adaptive Immunity/genetics , Aged , B-Lymphocytes/immunology , COVID-19/genetics , COVID-19/immunology , Genetic Loci , Humans , Immunoglobulin Heavy Chains/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , SARS-CoV-2/immunology , Seroconversion , T-Lymphocytes/immunology
10.
Viruses ; 12(1)2020 01 20.
Article in English | MEDLINE | ID: covidwho-1969491

ABSTRACT

Middle East respiratory syndrome (MERS) is an acute, high-mortality-rate, severe infectious disease caused by an emerging MERS coronavirus (MERS-CoV) that causes severe respiratory diseases. The continuous spread and great pandemic potential of MERS-CoV make it necessarily important to develop effective vaccines. We previously demonstrated that the application of Gram-positive enhancer matrix (GEM) particles as a bacterial vector displaying the MERS-CoV receptor-binding domain (RBD) is a very promising MERS vaccine candidate that is capable of producing potential neutralization antibodies. We have also used the rabies virus (RV) as a viral vector to design a recombinant vaccine by expressing the MERS-CoV S1 (spike) protein on the surface of the RV. In this study, we compared the immunological efficacy of the vaccine candidates in BALB/c mice in terms of the levels of humoral and cellular immune responses. The results show that the rabies virus vector-based vaccine can induce remarkably earlier antibody response and higher levels of cellular immunity than the GEM particles vector. However, the GEM particles vector-based vaccine candidate can induce remarkably higher antibody response, even at a very low dose of 1 µg. These results indicate that vaccines constructed using different vaccine vector platforms for the same pathogen have different rates and trends in humoral and cellular immune responses in the same animal model. This discovery not only provides more alternative vaccine development platforms for MERS-CoV vaccine development, but also provides a theoretical basis for our future selection of vaccine vector platforms for other specific pathogens.


Subject(s)
Coronavirus Infections/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Cell Line , Coronavirus Infections/prevention & control , Genetic Vectors , Humans , Immunization , Immunoglobulin G/blood , Immunoglobulin G/immunology , Lactococcus lactis/genetics , Mice , Mice, Inbred BALB C , Middle East Respiratory Syndrome Coronavirus/genetics , Rabies virus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , Viral Vaccines/administration & dosage
11.
Neurol Neuroimmunol Neuroinflamm ; 9(4)2022 07.
Article in English | MEDLINE | ID: covidwho-1962935

ABSTRACT

BACKGROUND AND OBJECTIVES: Evidence regarding the safety and efficacy of messenger RNA (mRNA) vaccines in patients with myasthenia gravis (MG) after immunosuppressive therapies is scarce. Our aim is to determine whether the mRNA-1273 vaccine is safe and able to induce humoral and cellular responses in patients with MG. METHODS: We performed an observational, longitudinal, prospective study including 100 patients with MG of a referral center for MG in our country, conducted from April 2021 to November 2021 during the vaccination campaign. The mRNA-1273 vaccine was scheduled for all participants. Blood samples were collected before vaccination and 3 months after a second dose. Clinical changes in MG were measured using the MG activities of daily life score at baseline and 1 week after the first and second doses. A surveillance of all symptoms of coronavirus disease 2019 (COVID-19) was conducted throughout the study. Humoral and cellular immune responses after vaccination were assessed using a spike-antibody ELISA and interferon gamma release assay in plasma. The primary outcomes were clinically significant changes in MG symptoms after vaccination, adverse events (AEs), and seroconversion and T-cell immune response rates. RESULTS: Ninety-nine patients completed the full vaccination schedule, and 98 had 2 blood samples taken. A statistically significant worsening of symptoms was identified after the first and second doses of the mRNA-1273 vaccine, but this was not clinically relevant. Mild AEs occurred in 14 patients after the first dose and in 21 patients after the second dose. Eighty-seven patients developed a humoral response and 72 patients showed a T-cell response after vaccination. A combined therapy with prednisone and other immunosuppressive drugs correlated with a lower seroconversion ratio (OR = 5.97, 95% CI 1.46-24.09, p = 0.015) and a lower T-cell response ratio (OR = 2.83, 95% CI 1.13-7.13, p = 0.024). DISCUSSION: Our findings indicate that the mRNA vaccination against COVID-19 is safe in patients with MG and show no negative impact on the disease course. Patients achieved high humoral and cellular immune response levels. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that patients with MG receiving the mRNA-1273 vaccine did not show clinical worsening after vaccination and that most of the patients achieved high cellular or immune response levels.


Subject(s)
2019-nCoV Vaccine mRNA-1273 , COVID-19 , Myasthenia Gravis , 2019-nCoV Vaccine mRNA-1273/adverse effects , 2019-nCoV Vaccine mRNA-1273/immunology , Antibodies, Viral/blood , COVID-19/prevention & control , Humans , Immunity, Cellular , Immunity, Humoral , Longitudinal Studies , Myasthenia Gravis/complications , Prospective Studies , SARS-CoV-2 , T-Lymphocytes/immunology
12.
Nature ; 609(7928): 801-807, 2022 09.
Article in English | MEDLINE | ID: covidwho-1960390

ABSTRACT

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.


Subject(s)
COVID-19 , Energy Metabolism , Ketones , Respiratory Distress Syndrome , SARS-CoV-2 , T-Lymphocytes , 3-Hydroxybutyric Acid/biosynthesis , 3-Hydroxybutyric Acid/metabolism , Amino Acids/biosynthesis , Amino Acids/metabolism , Animals , COVID-19/complications , COVID-19/immunology , COVID-19/pathology , Diet, Ketogenic , Esters/metabolism , Glutathione/biosynthesis , Glutathione/metabolism , Glycolysis , Interferon-gamma/biosynthesis , Ketone Bodies/metabolism , Ketones/metabolism , Mice , Orthomyxoviridae/pathogenicity , Oxidation-Reduction , Oxidative Phosphorylation , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
13.
Int J Mol Sci ; 21(15)2020 Jul 22.
Article in English | MEDLINE | ID: covidwho-1934093

ABSTRACT

Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.


Subject(s)
Adaptive Immunity , Fibrosis/immunology , Immunity, Innate , Signal Transduction/immunology , Animals , B-Lymphocytes/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Fibrosis/pathology , Fibrosis/therapy , Humans , Lymphopoiesis/immunology , Macrophages/immunology , Myofibroblasts/metabolism , Neutrophils/immunology , T-Lymphocytes/immunology
15.
J Cell Physiol ; 237(8): 3394-3407, 2022 08.
Article in English | MEDLINE | ID: covidwho-1905874

ABSTRACT

Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in coronavirus disease 2019 (COVID-19) patients. Mild and severe COVID-19 patients had lower extracellular adenosine triphosphate and adenosine levels, and higher cytokines than healthy controls. Mild COVID-19 patients presented lower frequencies of CD4+ CD25+ CD39+ (activated/memory regulatory T cell [mTreg]) and increased frequencies of high-differentiated (CD27- CD28- ) CD8+ T cells compared with healthy controls. Severe COVID-19 patients also showed higher frequencies of CD4+ CD39+ , CD4+ CD25- CD39+ (memory T effector cell), and high-differentiated CD8+ T cells (CD27- CD28- ), and diminished frequencies of CD4+ CD73+ , CD4+ CD25+ CD39+ mTreg cell, CD8+ CD73+ , and low-differentiated CD8+ T cells (CD27+ CD28+ ) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8+ T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4+ Annexin-V+ and CD8+ Annexin-V+ T cells, indicating increased T-cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4+ and CD8+ T cells of a healthy donor. Interestingly, the in vitro incubation of peripheral blood mononuclear cell from severe COVID-19 patients with adenosine reduced the nuclear factor-κB activation in T cells and monocytes. Together, these data add new knowledge to the COVID-19 immunopathology through purinergic regulation.


Subject(s)
5'-Nucleotidase , Apyrase , COVID-19 , T-Lymphocytes , 5'-Nucleotidase/metabolism , Adenosine/blood , Adenosine Triphosphate/blood , Annexins , Apyrase/metabolism , CD28 Antigens/metabolism , COVID-19/immunology , Cytokines/blood , GPI-Linked Proteins/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Receptors, Purinergic , Signal Transduction , T-Lymphocytes/immunology
16.
Front Immunol ; 13: 798813, 2022.
Article in English | MEDLINE | ID: covidwho-1902970

ABSTRACT

A successful vaccination would represent the most efficient means to control the pandemic of Coronavirus Disease-19 (COVID-19) that led to millions of deaths worldwide. Novel mRNA-based vaccines confer protective immunity against SARS-CoV-2, but whether immunity is immediately effective and how long it will remain in recipients are uncertain. We sought to assess the effectiveness of a two-dose regimen since the boosts are often delayed concerning the recommended intervals. Methods: A longitudinal cohort of healthcare workers (HCW, N = 46; 30.4% men; 69.6% women; mean age 36.05 ± 2.2 years) with no SARS-CoV-2 infection as documented by negative polymerase chain reaction was immunophenotyped in PBMC once a week for 4 weeks from the prime immunization (Pfizer mRNA BNT162b2) and had received 2 doses, to study the kinetic response. Results: We identified three risk groups to develop SARS-CoV-2 infection IgG+-based (late responders, R-; early responders, R+; pauci responders, PR). In all receipts, amplification of B cells and NK cells, including IL4-producing B cells and IL4-producing CD8+ T cells, is early stimulated by the vaccine. After the boost, we observed a growing increase of NK cells but a resistance of T cells, IFNγ-producing CD4+T cells, and IFNγ-producing NK cells. Also, hematologic parameters decline until the boost. The positive association of IFNγ-producing NK with IFNγ-producing CD4+T cells by the multiple mixed-effect model, adjusted for confounders (p = 0.036) as well as the correlation matrix (r = 0.6, p < 0.01), suggests a relationship between these two subsets of lymphocytes. Conclusions: These findings introduce several concerns about policy delay in vaccination: based on immunological protection, B cells and the persistent increase of NK cells during 2 doses of the mRNA-based vaccine could provide further immune protection against the virus, while CD8+ T cells increased slightly only in the R+ and PR groups.


Subject(s)
/immunology , Immunization , Interferon-gamma/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Interleukin-4/immunology , Leukocytes, Mononuclear/immunology , Lymphocyte Subsets/immunology , Male , Th1-Th2 Balance
17.
J Immunother Cancer ; 10(6)2022 06.
Article in English | MEDLINE | ID: covidwho-1902047

ABSTRACT

BACKGROUND: Patients with cancer were excluded from phase 3 COVID-19 vaccine trials, and the immunogenicity and side effect profiles of these vaccines in this population is not well understood. Patients with cancer can be immunocompromised from chemotherapy, corticosteroids, or the cancer itself, which may affect cellular and/or humoral responses to vaccination. PD-1 is expressed on T effector cells, T follicular helper cells and B cells, leading us to hypothesize that anti-PD-1 immunotherapies may augment antibody or T cell generation after vaccination. METHODS: Antibodies to the SARS-CoV-2 receptor binding domain (RBD) and spike protein were assessed in patients with cancer (n=118) and healthy donors (HD, n=22) after 1, 2 or 3 mRNA vaccine doses. CD4+ and CD8+ T cell reactivity to wild-type (WT) or B.1.617.2 (delta) spike peptides was measured by intracellular cytokine staining. RESULTS: Oncology patients without prior COVID-19 infections receiving immunotherapy (n=36), chemotherapy (n=15), chemoimmunotherapy (n=6), endocrine or targeted therapies (n=6) and those not on active treatment (n=26) had similar RBD and Spike IgG antibody titers to HDs after two vaccinations. Contrary to our hypothesis, PD-1 blockade did not augment antibody titers or T cell responses. Patients receiving B-cell directed therapies (n=14) including anti-CD20 antibodies and multiple myeloma therapies had decreased antibody titers, and 9/14 of these patients were seronegative for RBD antibodies. No differences were observed in WT spike-reactive CD4+ and CD8+ T cell generation between treatment groups. 11/13 evaluable patients seronegative for RBD had a detectable WT spike-reactive CD4+ T cell response. T cells cross-reactive against the B.1.617.2 variant spike peptides were detected in 31/59 participants. Two patients with prior immune checkpoint inhibitor-related adrenal insufficiency had symptomatic hypoadrenalism after vaccination. CONCLUSIONS: COVID-19 vaccinations are safe and immunogenic in patients with solid tumors, who developed similar antibody and T cell responses compared with HDs. Patients on B-cell directed therapies may fail to generate RBD antibodies after vaccination and should be considered for prophylactic antibody treatments. Many seronegative patients do develop a T cell response, which may have an anti-viral effect. Patients with pre-existing adrenal insufficiency may need to take stress dose steroids during vaccination to avoid adrenal crisis.


Subject(s)
COVID-19 Vaccines , COVID-19 , Neoplasms , Adrenal Insufficiency/complications , Antibodies, Viral/blood , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Neoplasms/complications , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , SARS-CoV-2 , T-Lymphocytes/immunology , Vaccination , Vaccines, Synthetic , mRNA Vaccines/immunology
18.
Immunol Med ; 45(3): 162-167, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1868228

ABSTRACT

B-cell but not T-cell responses have been extensively studied using peripheral blood mononuclear cells (PBMCs) obtained from patients with coronavirus disease 2019 (COVID-19). Our recent study showed that not only T-helper (Th) 17 but also Th1 cells directly produce interleukin (IL)-8, a major source of neutrophilic inflammation, which is also known to induce disseminated intravascular coagulation (DIC) in COVID-19 patients. Neutrophilic inflammation caused by IL-17A or IL-8 can be fatal; thus, therapeutic intervention is highly expected. The present study aimed to investigate the T-cell responses in the Japanese patients. We synthesized spike protein-derived 15-mer peptides that are expected to bind to HLA class II allelic products frequently observed in the Japanese population, and checked the T-cell responses in Japanese patients with COVID-19. We have found that (i) patients show marked IL-8 but not IL-17A responses; (ii) these responses are restricted by HLA-DR; and (iii) IL-8 responses are abrogated by a dopamine D2 like receptor (D2R) agonist, ropinirole, and an adenosine A2a receptor (A2aR) antagonist, istradefylline. Compounds used for the treatment of Parkinson's disease may ease DIC in COVID-19. (183 words).


Subject(s)
COVID-19 , Dopamine , T-Lymphocytes , COVID-19/drug therapy , Dacarbazine , Dopamine Agonists/pharmacology , Humans , Inflammation , Interleukin-8 , Leukocytes, Mononuclear/metabolism , Purinergic P1 Receptor Antagonists , Receptor, Adenosine A2A/metabolism , T-Lymphocytes/immunology
19.
J Immunol ; 208(11): 2461-2465, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1847475

ABSTRACT

Several studies have demonstrated that the SARS-CoV-2 variant-of-concern B.1.1.529 (Omicron) exhibits a high degree of escape from Ab neutralization. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron. To this purpose, we analyzed a human cohort (n = 327 subjects) of two- or three-dose mRNA vaccine recipients and COVID-19 postinfection subjects. We report that T cell responses against Omicron were largely preserved. IFN-γ-producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (∼20%) loss in IL-2 single or IL-2+IFN-γ+ polyfunctional responses. Three-dose vaccinated participants had similar responses to Omicron relative to post-COVID-19 participants and exhibited responses significantly higher than those receiving two mRNA vaccine doses. These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.


Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , T-Lymphocytes , mRNA Vaccines , Antibodies, Viral , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Interleukin-2/genetics , T-Lymphocytes/immunology , Vaccination , Vaccines, Synthetic , mRNA Vaccines/immunology
20.
Neurol Neuroimmunol Neuroinflamm ; 9(4)2022 07.
Article in English | MEDLINE | ID: covidwho-1833441

ABSTRACT

OBJECTIVES: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod. METHODS: This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2-specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated. RESULTS: In ocrelizumab-treated patients (N = 24), IFN-γ-producing SARS-CoV-2-specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2-specific T cells were detected after second (N = 12) and third (N = 9) vaccinations. DISCUSSION: In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunity, Cellular , Multiple Sclerosis , T-Lymphocytes , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Fingolimod Hydrochloride/therapeutic use , Humans , Immunization, Secondary , Interferon-gamma , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Prospective Studies , SARS-CoV-2 , T-Lymphocytes/immunology , Vaccination
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