scholarly journals Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Felipe Melo-González ◽  
Jorge A. Soto ◽  
Liliana A. González ◽  
Jorge Fernández ◽  
Luisa F. Duarte ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Cellular Responses ◽  
Interferon Γ ◽  
Phase 3 ◽  
Geometric Means ◽  
Human Use ◽  
Blocking Antibodies ◽  
Blocking Capacity ◽  
Chilean Population

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible of the current pandemic ongoing all around the world. Since its discovery in 2019, several circulating variants have emerged and some of them are associated with increased infections and death rate. Despite the genetic differences among these variants, vaccines approved for human use have shown a good immunogenic and protective response against them. In Chile, over 70% of the vaccinated population is immunized with CoronaVac, an inactivated SARS-CoV-2 vaccine. The immune response elicited by this vaccine has been described against the first SARS-CoV-2 strain isolated from Wuhan, China and the D614G strain (lineage B). To date, four SARS-CoV-2 variants of concern described have circulated worldwide. Here, we describe the neutralizing capacities of antibodies secreted by volunteers in the Chilean population immunized with CoronaVac against variants of concern Alpha (B.1.1.7), Beta (B.1.351) Gamma (P.1) and Delta (B.617.2).MethodsVolunteers enrolled in a phase 3 clinical trial were vaccinated with two doses of CoronaVac in 0-14 or 0-28 immunization schedules. Sera samples were used to evaluate the capacity of antibodies induced by the vaccine to block the binding between Receptor Binding Domain (RBD) from variants of concern and the human ACE2 receptor by an in-house ELISA. Further, conventional microneutralization assays were used to test neutralization of SARS-CoV-2 infection. Moreover, interferon-γ-secreting T cells against Spike from variants of concern were evaluated in PBMCs from vaccinated subjects using ELISPOT.ResultsCoronaVac promotes the secretion of antibodies able to block the RBD of all the SARS-CoV-2 variants studied. Seropositivity rates of neutralizing antibodies in the population evaluated were over 97% for the lineage B strain, over 80% for Alpha and Gamma variants, over 75% for Delta variant and over 60% for the Beta variant. Geometric means titers of blocking antibodies were reduced when tested against SARS-CoV-2 variants as compared to ancestral strain. We also observed that antibodies from vaccinated subjects were able to neutralize the infection of variants D614G, Alpha, Gamma and Delta in a conventional microneutralization assay. Importantly, after SARS-CoV-2 infection, we observed that the blocking capacity of antibodies from vaccinated volunteers increased up to ten times for all the variants tested. We compared the number of interferon-γ-secreting T cells specific for SARS-CoV-2 Spike WT and variants of concern from vaccinated subjects and we did not detect significant differences.ConclusionImmunization with CoronaVac in either immunization schedule promotes the secretion of antibodies able to block SARS-CoV-2 variants of concern and partially neutralizes SARS-CoV-2 infection. In addition, it stimulates cellular responses against all variants of concern.

scholarly journals Effect of Different Adjuvants on the Longevity and Strength of Humoral and Cellular Immune Responses to the HCV Envelope Glycoproteins

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 204 ◽  
Author(s):  
Bassel Akache ◽  
Lise Deschatelets ◽  
Blair A. Harrison ◽  
Renu Dudani ◽  
Felicity C. Stark ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Lipid A ◽  
Cellular Responses ◽  
Current Treatment ◽  
Water Emulsion ◽  
Treatment Regimens ◽  
Immune Parameters ◽  
Monophosphoryl Lipid A ◽  
Oil In Water Emulsion

Infection by Hepatitis C virus (HCV) can lead to liver cirrhosis/hepatocellular carcinoma and remains a major cause of serious disease morbidity and mortality worldwide. However, current treatment regimens remain inaccessible to most patients, particularly in developing countries, and, therefore, the development of a novel vaccine capable of protecting subjects from chronic infection by HCV could greatly reduce the rates of HCV infection, subsequent liver pathogenesis, and in some cases death. Herein, we evaluated two different semi-synthetic archaeosome formulations as an adjuvant to the E1/E2 HCV envelope protein in a murine model and compared antigen-specific humoral (levels of anti-E1/E2 IgG and HCV pseudoparticle neutralization) and cellular responses (numbers of antigen-specific cytokine-producing T cells) to those generated with adjuvant formulations composed of mimetics of commercial adjuvants including a squalene oil-in-water emulsion, aluminum hydroxide/monophosphoryl lipid A (MPLA) and liposome/MPLA/QS-21. In addition, we measured the longevity of these responses, tracking humoral, and cellular responses up to 6 months following vaccination. Overall, we show that the strength and longevity of anti-HCV responses can be influenced by adjuvant selection. In particular, a simple admixed sulfated S-lactosylarchaeol (SLA) archaeosome formulation generated strong levels of HCV neutralizing antibodies and polyfunctional antigen-specific CD4 T cells producing multiple cytokines such as IFN-γ, TNF-α, and IL-2. While liposome/MPLA/QS-21 as adjuvant generated superior cellular responses, the SLA E1/E2 admixed formulation was superior or equivalent to the other tested formulations in all immune parameters tested.

scholarly journals TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+ T cell and XCR1+ dendritic cell spatial co-localization

2022 ◽  
Vol 10 (1) ◽  
pp. e003571
Author(s):  
Alycia Gardner ◽  
Álvaro de Mingo Pulido ◽  
Kay Hänggi ◽  
Sarah Bazargan ◽  
Alexis Onimus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Γ ◽  
Response To Therapy ◽  
Interleukin 12 ◽  
Type I ◽  
T Cell Infiltration ◽  
Blocking Antibodies ◽  
Bone Marrow Chimeras

BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

scholarly journals Metabolic, humoral, and cellular responses in adult volunteers immunized with the genetically inactivated pertussis toxin mutant PT-9K/129G.

1990 ◽  
Vol 172 (3) ◽  
pp. 861-868 ◽  
Author(s):  
A Podda ◽  
L Nencioni ◽  
M T De Magistris ◽  
A Di Tommaso ◽  
P Bossù ◽  
...  
Keyword(s):  
T Cells ◽  
Pertussis Toxin ◽  
Neutralizing Antibodies ◽  
Cellular Response ◽  
Genetic Manipulation ◽  
Whooping Cough ◽  
Cellular Responses ◽  
Adult Volunteers

PT-9K/129G, a nontoxic mutant of pertussis toxin (PT) obtained by genetic manipulation, has been shown in animal models to be a promising candidate for new vaccines against whooping cough. To assess the safety and the immunogenicity of PT-9K/129G in humans, a pilot study has been performed in adult volunteers. The protein was found to be safe, capable of inducing high titers of toxin-neutralizing antibodies, and capable of generating immunological memory. In fact, vaccination caused an increase of cell-mediated response to PT, PT-9K/129G, S1 subunit, and B oligomer, indicating that memory T cells are induced by the vaccine. Since PT-9K/129G is mitogenic for T lymphocytes in vitro, it was investigated whether this activity is also present in vivo. No variation was observed in the proportion of T cells (CD3+), T helper cells (CD4+), and cytotoxic T cells (CD8+), as well as in that of other lymphoid populations, by FACS analysis. Interestingly, no thorough correlation was found between humoral and cellular responses. In one case, a very high cellular response was present in absence of detectable antibodies, suggesting that the antibody response, which is the only parameter measured in most clinical trials, may not give a complete picture of the response induced by a vaccine.

scholarly journals Humoral and Cellular Immunogenicity of COVID-19 Vaccinations in Patients with CLL

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3724-3724
Author(s):  
Clare Sun ◽  
Erika M Gaglione ◽  
Lauren T Vaughn ◽  
Rui Mu ◽  
Chingiz Underbayev ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Research Funding ◽  
Cellular Response ◽  
Mononuclear Cells ◽  
Humoral Response ◽  
Cellular Responses ◽  
T Cell Response ◽  
Lymphocytic Leukemia ◽  
Anti Cd20

Abstract Humoral and cellular adaptive immunity likely contribute to protection against coronavirus disease 2019 (COVID-19). Neutralizing antibodies and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells have been detected in convalescent and immunized immunocompetent individuals. Chronic lymphocytic leukemia (CLL) and its treatment, particularly anti-CD20 monoclonal antibodies and Bruton tyrosine kinase inhibitors (BTKis), blunt the antibody response to vaccines. To understand the immunogenicity of COVID-19 vaccination in patients with CLL, assessment of the T-cell response is urgently needed. Between December 22, 2020 and May 7, 2021, 57 patients with CLL were immunized with either 2 doses of BNT162b2 (n = 30) or mRNA-1273 (n = 25) or 1 dose of Ad26.COV2.S (n = 2). Qualitative and semi-quantitative anti-spike antibodies were measured with serology tests authorized by the FDA under Emergency Use Authorization. A positive humoral response to vaccination was defined as the detection of anti-spike antibodies. Ultra-deep TCRß sequencing (Adaptive Biotechnologies) was performed on total peripheral blood mononuclear cells collected before and after vaccination. These data were analyzed in the immunoSEQ Analyzer. Differential abundance was calculated using the beta-binomial model and two-sided α=.05. SARS-CoV-2 spike-specific T cells were identified in the T-MAP COVID ImmuneCODE database. A positive cellular response to vaccination was defined as significant expansion of ≥1 spike-specific clonotype. Anti-spike antibodies were detected in 61% (35/57) of patients at a median (interquartile range, IQR) of 45 (30-56) days after the last dose of vaccine. The median (IQR) antibody titer was 19.1 U/mL (3.6-150.9) among 27 patients with humoral response. There were 4 patients with titers above the upper limit of quantification (>250 U/mL) and 4 patients who had qualitative testing only. The rate of humoral response was 71% (15/21) in treatment naïve (TN) patients, 57% (16/28) in patients treated with BTKi, and 0% (0/4) in patients treated with venetoclax and anti-CD20 monoclonal antibody (mAb). Among 16 BTKi-treated patients with anti-spike antibodies, 2 interrupted BTKi during the vaccination period. One patient treated with venetoclax monotherapy and 3 previously treated patients had detectable anti-spike antibodies. The immediate prior therapies were acalabrutinib >1 year before vaccination for 2 patients and chemoimmunotherapy >8 years before vaccination for 1 patient. Vaccination with mRNA-1273 induced numerically higher titers compared to BNT162b2 (median 85.5 U/mL versus 11.0 U/mL; P=.1), but the rate of seroconversion was not significantly different (P=.4). No patients reported a history of SARS-CoV-2 infection and anti-nucleocapsid antibodies were negative in 100% (50/50) of patients tested. Circulating CD8 + T cells increased from a median (IQR) of 13.2% (7.8-18.8) at baseline to 14.3% (8.8-20.6) after vaccination (P=.015). CD3 + and CD4 + T cells did not significantly change. TCRß sequencing results are available in 7 patients (Table). The median (IQR) number of productive templates, which corresponds to the number of T cells sequenced in each sample, was 447,805 (377,738-503,097). Cellular response was observed in 57% (4/7) of patients. A total of 10 expanded spike-specific clonotypes were identified and ranged between 1 and 6 clonotypes per patient. The cumulative frequency of spike-specific clonotypes after vaccination ranged between 0.0036% and 1.55% per patient. None of these clonotypes were found at baseline despite the large number of productive templates generated in each sample. Spike-specific T cells were detected in 50% (2/4) of patients with anti-spike antibodies and 67% (2/3) of patients without seroconversion. In conclusion, patients with CLL have impaired humoral and cellular responses to COVID-19 vaccination. Seroconversion occurred less often in patients treated with BTKi than TN patients and was absent in patients treated with venetoclax and anti-CD20 mAb. Cellular responses were seen in the absence of humoral responses. TCRß sequencing is ongoing in additional patients. Updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Sun: Genmab: Research Funding. Wiestner: Merck: Research Funding; Nurix: Research Funding; Genmab: Research Funding; Verastem: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

NEUROBLASTOMA IMMUNOTHERAPY

2019 ◽  
Vol 65 (2) ◽  
pp. 181-187
Author(s):  
Aleksandr Druy ◽  
Svetlana Kuleva
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Innate And Adaptive Immunity ◽  
Car T Cells ◽  
Car T ◽  
Membrane Antigens ◽  
Theoretical Evidence ◽  
Blocking Antibodies

The recent data about innate and adaptive immunity against neuroblastoma are described in the article. The era of neuroblastoma immunotherapy started since the evidence of anti-GD2 monoclonal antibodies efficiency. Nowadays monoclonal antibodies against GD2 are introduced into schemes of maintenance therapy for high-risk neuroblastoma patients. Developing of T-cells expressing chimeric antigen receptor (CAR-T cells) directed to membrane antigens is the perspective of neuroblastoma immunotherapy. PD1/PD-L1 blocking antibodies as immune checkpoint inhibitors have the theoretical evidence of potential effectiveness. Application of immunotherapeutic approaches in high-risk neuroblastoma patients together with conventional multimodal therapies requires further investigation.

scholarly journals BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans

Nature ◽  
2021 ◽  
Author(s):  
Ugur Sahin ◽  
Alexander Muik ◽  
Isabel Vogler ◽  
Evelyna Derhovanessian ◽  
Lena M. Kranz ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies

577 Engineered non-pathogenic synthetic biotic producing L-arginine synergize with PD-1-based cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A611-A611
Author(s):  
Fernando Canale ◽  
Camilla Basso ◽  
Ning Li ◽  
Anna Sokolovska ◽  
Michela Perotti ◽  
...  
Keyword(s):  
T Cells ◽  
Synergistic Effects ◽  
Waste Product ◽  
T Cell Response ◽  
Escherichia Coli Nissle 1917 ◽  
Check Point Inhibitors ◽  
Blocking Antibodies ◽  
Metabolic Waste Product ◽  
Synthetic Biology Approach ◽  
Escherichia Coli Nissle

BackgroundThe availability of L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. Consequently, the elevation of typically low L-arginine levels within the tumor may greatly potentiate the anti-tumor responses of immune check point inhibitors, such as PD-L1 blocking antibodies. However, currently no means are available to locally increase intra-tumoral L-arginine levels.MethodsWe used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumors and continuously converts ammonia, a metabolic waste product that accumulates in tumors, into L-arginine.ResultsColonization of tumors with these bacteria elevated intra-tumoral L-arginine concentrations, increased the amount of tumor-infiltrating T cells, and had striking synergistic effects with PD-L1 blocking antibodies in the clearance of tumors. The anti-tumor effect of the living therapeutic was mediated by L-arginine and was dependent on T cells.ConclusionsThese results show that engineered microbial therapies enable metabolic modulation of the tumor microenvironment leading to enhanced efficacy of immunotherapies.

scholarly journals PD‐1‐specific “Blocking” antibodies that deplete PD‐1 + T cells present an inconvenient variable in preclinical immunotherapy experiments

2021 ◽  
Author(s):  
Fanny Polesso ◽  
Michael W. Munks ◽  
Katherine H. Rott ◽  
Savannah Smart ◽  
Ann B. Hill ◽  
...  
Keyword(s):  
T Cells ◽  
Blocking Antibodies

98 ATA3271: an armored, next-generation off-the-shelf, allogeneic, mesothelin-CAR T cell therapy for solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A109-A109
Author(s):  
Jiangyue Liu ◽  
Xianhui Chen ◽  
Jason Karlen ◽  
Alfonso Brito ◽  
Tiffany Jheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Next Generation ◽  
Phase 3 ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T

BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.

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