scholarly journals Design of T cell epitope-based vaccine candidate for SARS-CoV-2 targeting nucleocapsid and spike protein escape variants

2021 ◽  
Author(s):  
Gabriel Jabbour ◽  
Samantha Rego ◽  
Vincent Nguyenkhoa ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitopes ◽  
Clinical Predictors ◽  
Nucleocapsid Proteins ◽  
Global Concern

AbstractThe current COVID-19 pandemic continues to spread and devastate in the absence of effective treatments, warranting global concern and action. Despite progress in vaccine development, the rise of novel, increasingly infectious SARS-CoV-2 variants makes it clear that our response to the virus must continue to evolve along with it. The use of immunoinformatics provides an opportunity to rapidly and efficiently expand the tools at our disposal to combat the current pandemic and prepare for future outbreaks through epitope-based vaccine design. In this study, we validated and compared the currently available epitope prediction tools, and then used the best tools to predict T cell epitopes from SARS-CoV-2 spike and nucleocapsid proteins for use in an epitope-based vaccine. We combined the mouse MHC affinity predictor and clinical predictors such as HLA affinity, immunogenicity, antigenicity, allergenicity, toxicity and stability to select the highest quality CD8 and CD4 T cell epitopes for the common SARS-CoV-2 variants of concern suitable for further preclinical studies. We also identified variant-specific epitopes to more precisely target the Alpha, Beta, Gamma, Delta, Cluster 5 and US variants. We then modeled the 3D structures of our top 4 N and S epitopes to investigate the molecular interaction between peptide-MHC and peptide-MHC-TCR complexes. Following in vitro and in vivo validation, the epitopes identified by this study may be used in an epitope-based vaccine to protect across all current variants, as well as in variant-specific booster shots to target variants of concern. Immunoinformatics tools allowed us to efficiently predict epitopes in silico most likely to prove effective in vivo, providing a more streamlined process for vaccine development in the context of a rapidly evolving pandemic.

scholarly journals Yellow fever 17D as a vaccine vector for microbial CTL epitopes

2005 ◽  
Vol 201 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Deng Tao ◽  
Giovanna Barba-Spaeth ◽  
Urvashi Rai ◽  
Victor Nussenzweig ◽  
Charles M. Rice ◽  
...  
Keyword(s):  
T Cell ◽  
Yellow Fever ◽  
Cell Epitope ◽  
Parasite Burden ◽  
Plasmodium Yoelii ◽  
Yellow Fever Vaccine ◽  
T Cell Epitopes ◽  
High Level

The yellow fever vaccine 17D (17D) is safe, and after a single immunizing dose, elicits long-lasting, perhaps lifelong protective immunity. One of the major challenges facing delivery of human vaccines in underdeveloped countries is the need for multiple injections to achieve full efficacy. To examine 17D as a vector for microbial T cell epitopes, we inserted the H-2Kd–restricted CTL epitope of the circumsporozoite protein (CS) of Plasmodium yoelii between 17D nonstructural proteins NS2B and NS3. The recombinant virus, 17D-Py, was replication competent and stable in vitro and in vivo. A single subcutaneous injection of 105 PFU diminished the parasite burden in the liver by ∼70%. The high level of protection lasted between 4 and 8 wk after immunization, but a significant effect was documented even 24 wk afterwards. Thus, the immunogenicity of a foreign T cell epitope inserted into 17D mimics some of the remarkable properties of the human vaccine. Priming with 17D-Py followed by boosting with irradiated sporozoites conferred sterile immunity to 90% of the mice. This finding indicates that the immune response of vaccine-primed individuals living in endemic areas could be sustained and magnified by the bite of infected mosquitoes.

scholarly journals Immune Tolerance-Adjusted Personalized Immunogenicity Prediction for Pompe Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Anne S. De Groot ◽  
Ankit K. Desai ◽  
Sandra Lelias ◽  
S. M. Shahjahan Miah ◽  
Frances E. Terry ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcomes ◽  
Pompe Disease ◽  
Clinical Decision Making ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitopes ◽  
Enzyme Replacement ◽  
Hla Dr

Infantile-onset Pompe disease (IOPD) is a glycogen storage disease caused by a deficiency of acid alpha-glucosidase (GAA). Treatment with recombinant human GAA (rhGAA, alglucosidase alfa) enzyme replacement therapy (ERT) significantly improves clinical outcomes; however, many IOPD children treated with rhGAA develop anti-drug antibodies (ADA) that render the therapy ineffective. Antibodies to rhGAA are driven by T cell responses to sequences in rhGAA that differ from the individuals’ native GAA (nGAA). The goal of this study was to develop a tool for personalized immunogenicity risk assessment (PIMA) that quantifies T cell epitopes that differ between nGAA and rhGAA using information about an individual’s native GAA gene and their HLA DR haplotype, and to use this information to predict the risk of developing ADA. Four versions of PIMA have been developed. They use EpiMatrix, a computational tool for T cell epitope identification, combined with an HLA-restricted epitope-specific scoring feature (iTEM), to assess ADA risk. One version of PIMA also integrates JanusMatrix, a Treg epitope prediction tool to identify putative immunomodulatory (regulatory) T cell epitopes in self-proteins. Using the JanusMatrix-adjusted version of PIMA in a logistic regression model with data from 48 cross-reactive immunological material (CRIM)-positive IOPD subjects, those with scores greater than 10 were 4-fold more likely to develop ADA (p<0.03) than those that had scores less than 10. We also confirmed the hypothesis that some GAA epitopes are immunomodulatory. Twenty-one epitopes were tested, of which four were determined to have an immunomodulatory effect on T effector response in vitro. The implementation of PIMA V3J on a secure-access website would allow clinicians to input the individual HLA DR haplotype of their IOPD patient and the GAA pathogenic variants associated with each GAA allele to calculate the patient’s relative risk of developing ADA, enhancing clinical decision-making prior to initiating treatment with ERT. A better understanding of immunogenicity risk will allow the implementation of targeted immunomodulatory approaches in ERT-naïve settings, especially in CRIM-positive patients, which may in turn improve the overall clinical outcomes by minimizing the development of ADA. The PIMA approach may also be useful for other types of enzyme or factor replacement therapies.

scholarly journals Use of a Novel Peptide Welding Technology Platform for the Development of B- and T-Cell Epitope-Based Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 526
Author(s):  
Francesco Nicoli ◽  
Salvatore Pacifico ◽  
Eleonora Gallerani ◽  
Erika Marzola ◽  
Valentina Albanese ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
Subcutaneous Administration ◽  
T Cell Epitopes ◽  
Peptide Vaccines ◽  
Peptide Epitope ◽  
Welding Technology

Peptide vaccines incorporating B- and T-cell epitopes have shown promise in the context of various cancers and infections. These vaccines are relatively simple to manufacture, but more immunogenic formulations are considered a priority. We developed tetrabranched derivatives for this purpose based on a novel peptide welding technology (PWT). PWTs provide molecular scaffolds for the efficient synthesis of ultrapure peptide dendrimers, which allow the delivery of multiple ligands within a single macromolecular structure. Peptide vaccines incorporating T-cell epitopes derived from melanoma and B-cell epitopes derived from human immunodeficiency virus, synthesized using this approach, elicited primary immune responses in vitro and in vivo. Subcutaneous administration of the B-cell epitope-based vaccines also elicited more potent humoral responses than subcutaneous administration of the corresponding peptides alone. Highly immunogenic peptide epitope-based vaccines can therefore be generated quickly and easily using a novel PWT.

scholarly journals Identification of a Promiscuous T-Cell Epitope in Mycobacterium tuberculosis Mce Proteins

2002 ◽  
Vol 70 (1) ◽  
pp. 79-85 ◽  
Author(s):  
Maddalena Panigada ◽  
Tiziana Sturniolo ◽  
Giorgio Besozzi ◽  
Maria Giovanna Boccieri ◽  
Francesco Sinigaglia ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Hla Dr

ABSTRACT The characterization of Mycobacterium tuberculosis antigens inducing CD4+ T-cell responses could critically contribute to the development of subunit vaccines for M. tuberculosis. Here we performed computational analysis by using T-cell epitope prediction software (known as TEPITOPE) to predict promiscuous HLA-DR ligands in the products of the mce genes of M. tuberculosis. The analysis of the proliferative responses of CD4+ T cells from patients with pulmonary tuberculosis to selected peptides displaying promiscuous binding to HLA-DR in vitro led us to the identification of a peptide that induced proliferation of CD4+ cells from 50% of the tested subjects. This study demonstrates that a systematic computational approach can be used to identify T-cell epitopes in proteins expressed by an intracellular pathogen.

scholarly journals Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 295 ◽  
Author(s):  
Bernhard Wernly ◽  
Vera Paar ◽  
Achim Aigner ◽  
Patrick M Pilz ◽  
Bruno K Podesser ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T Cell ◽  
Rat Model ◽  
Mirna Expression ◽  
Cell Epitope ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Treatment ◽  
Scar Size

Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

scholarly journals T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes

Gut ◽  
2015 ◽  
Vol 66 (3) ◽  
pp. 454-463 ◽  
Author(s):  
Daniele Mennonna ◽  
Cristina Maccalli ◽  
Michele C Romano ◽  
Claudio Garavaglia ◽  
Filippo Capocefalo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Cell Epitope ◽  
Patient Specific ◽  
Cancer Genes ◽  
Healthy Donors

ObjectivePatient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies.DesignWe undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions.ResultsSeveral unique mutated antigens of CRC, shared by standard cancer and related CSC cultures, were identified by this strategy. CD8+and CD4+T cells, either autologous to the patient or derived from HLA-matched healthy donors, were readily expanded in vitro by peptides spanning different cancer mutations and specifically recognised differentiated cancer cells and CSC cultures, expressing the mutations. Neoepitope-specific CD8+T cell frequency was also increased in a patient, compared with healthy donors, supporting the occurrence of clonal expansion in vivo.ConclusionsThese results provide a proof-of-concept approach for the identification of unique neoepitopes that are immunogenic in patients with CRC and can also target T cells against the most aggressive CSC component.

scholarly journals Construction and Evaluation of a Novel Recombinant T Cell Epitope-Based Vaccine against Coccidioidomycosis

2012 ◽  
Vol 80 (11) ◽  
pp. 3960-3974 ◽  
Author(s):  
Brady J. Hurtgen ◽  
Chiung-Yu Hung ◽  
Gary R. Ostroff ◽  
Stuart M. Levitz ◽  
Garry T. Cole
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
Protein Vaccine ◽  
T Helper 1 ◽  
Human Major Histocompatibility Complex ◽  
Content Type ◽  
Mhc Ii

ABSTRACTClinical and animal studies of coccidioidomycosis have demonstrated that activated CD4+T lymphocytes are essential for protection against this fungal respiratory disease. We previously reported a vaccine againstCoccidioidesinfection which contained three recombinant CD4+T cell-reactive proteins and induced a robust, protective immune response in mice. Due to the anticipated high cost of production and clinical assessment of this multivalent vaccine, we generated a single protein which contained immunodominant T cell epitopes of the three polypeptides. Epitopes were initially identified by computational prediction of their ability to bind promiscuously to human major histocompatibility complex class II (MHC II) molecules. Cellular immunoassays confirmed the immunogenicity of the synthesized epitope peptides, whilein vitrobinding assays revealed a range of peptide affinity for MHC II. A DNA construct was synthesized for bacterial expression of a recombinant protein vaccine which contained five epitopes with the highest affinity for human MHC II, each fused with leader and spacer peptides proposed to optimize epitope processing and presentation to T cell receptors. Recall assays of immune T lymphocytes obtained from human MHC II-expressing HLA-DR4 transgenic mice confirmed that 4 of the 5 epitope peptides were processed. Mice immunized with the epitope-based vaccine admixed with a synthetic oligodeoxynucleotide adjuvant or loaded into yeast glucan particles and then challenged intranasally withCoccidioidesshowed early lung infiltration of activated T helper-1 (Th1), Th2, and Th17 cells, elevated gamma interferon (IFN-γ) and interleukin (IL)-17 production, significant reduction of fungal burden, and prolongation of survival compared to nonvaccinated mice. This is the first report of an epitope-based vaccine against coccidioidomycosis.

Peptides containing a dominant T-cell epitope from red cell band 3 have in vivo immunomodulatory properties in NZB mice with autoimmune hemolytic anemia

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3800-3806 ◽  
Author(s):  
Chia-Rui Shen ◽  
Abdel-Rahman Youssef ◽  
Anne Devine ◽  
Laura Bowie ◽  
Andrew M. Hall ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Cell Epitope ◽  
Band 3 ◽  
T Cell Epitope ◽  
Helper Epitope

Abstract The major target of the pathogenic red blood cell (RBC) autoantibodies in New Zealand black (NZB) mice is the anion channel protein band 3, and CD4+ T cells from NZB mice respond to band 3. Here, we demonstrate that a band 3 peptide 861-875, which is the predominant sequence recognized by NZB T cells in vitro, bears a dominant helper epitope able to modulate the autoimmune hemolyic anemia in vivo. The development of RBC-bound autoantibodies and anemia was accelerated in NZB mice injected with peptide 861-874, which is relatively insoluble, and inhalation of the peptide primed T cells for both peptide 861-874 and band 3 responses. By contrast, inhalation of a soluble analog (Glu861, Lys875) of peptide 861-874 deviated the autoimmune response toward a T helper-2 (Th2) profile, with marked increases in the ratio of interleukin-4 to interferon-γ produced by splenic T cells responding in vitro to either peptide 861-874 or band 3. Moreover, in mice that had received such treatment, the proportion of RBC-bound immunoglobulin G (IgG) molecules that were of the Th2-associated IgG1 isotype was also increased, and anemia was less severe. It is concluded that NZB autoimmune hemolytic anemia is helper dependent and that nasal administration of different peptides containing the dominant T-cell epitope can have potentially detrimental or beneficial effects on the disease. (Blood. 2003; 102:3800-3806)

scholarly journals TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes

2015 ◽  
Vol 112 (14) ◽  
pp. E1754-E1762 ◽  
Author(s):  
Diego Chowell ◽  
Sri Krishna ◽  
Pablo D. Becker ◽  
Clément Cocita ◽  
Jack Shu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Cell Receptor ◽  
Biochemical Properties ◽  
Immune Recognition ◽  
T Cell Epitopes ◽  
Gag Protein ◽  
Contact Residues

Despite the availability of major histocompatibility complex (MHC)-binding peptide prediction algorithms, the development of T-cell vaccines against pathogen and tumor antigens remains challenged by inefficient identification of immunogenic epitopes. CD8+ T cells must distinguish immunogenic epitopes from nonimmunogenic self peptides to respond effectively against an antigen without endangering the viability of the host. Because this discrimination is fundamental to our understanding of immune recognition and critical for rational vaccine design, we interrogated the biochemical properties of 9,888 MHC class I peptides. We identified a strong bias toward hydrophobic amino acids at T-cell receptor contact residues within immunogenic epitopes of MHC allomorphs, which permitted us to develop and train a hydrophobicity-based artificial neural network (ANN-Hydro) to predict immunogenic epitopes. The immunogenicity model was validated in a blinded in vivo overlapping epitope discovery study of 364 peptides from three HIV-1 Gag protein variants. Applying the ANN-Hydro model on existing peptide-MHC algorithms consistently reduced the number of candidate peptides across multiple antigens and may provide a correlate with immunodominance. Hydrophobicity of TCR contact residues is a hallmark of immunogenic epitopes and marks a step toward eliminating the need for empirical epitope testing for vaccine development.

scholarly journals The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo

2005 ◽  
Vol 201 (4) ◽  
pp. 567-577 ◽  
Author(s):  
Jianuo Liu ◽  
Takashi Miwa ◽  
Brendan Hilliard ◽  
Youhai Chen ◽  
John D. Lambris ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
T Cell Immunity ◽  
Cell Secretion ◽  
Inhibitory Protein ◽  
Cell Immunity ◽  
Ifn Γ ◽  
Eae Model

Decay-accelerating factor ([DAF] CD55) is a glycosylphosphatidylinositol-anchored membrane inhibitor of complement with broad clinical relevance. Here, we establish an additional and unexpected role for DAF in the suppression of adaptive immune responses in vivo. In both C57BL/6 and BALB/c mice, deficiency of the Daf1 gene, which encodes the murine homologue of human DAF, significantly enhanced T cell responses to active immunization. This phenotype was characterized by hypersecretion of interferon (IFN)-γ and interleukin (IL)-2, as well as down-regulation of the inhibitory cytokine IL-10 during antigen restimulation of lymphocytes in vitro. Compared with wild-type mice, Daf1−/− mice also displayed markedly exacerbated disease progression and pathology in a T cell–dependent experimental autoimmune encephalomyelitis (EAE) model. However, disabling the complement system in Daf1−/− mice normalized T cell secretion of IFN-γ and IL-2 and attenuated disease severity in the EAE model. These findings establish a critical link between complement and T cell immunity and have implications for the role of DAF and complement in organ transplantation, tumor evasion, and vaccine development.

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