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 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 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 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.

scholarly journals Immunoinformatics Approach Identified Two Highly Conserved B and T Cell Epitopes, LEASKRWAF and DSPLEASKRWAFRTG, for Effective Vaccine Design against Ebola and Marburg Viruses

2019 ◽  
pp. 1-16
Author(s):  
Md. Shahadat Hossain ◽  
Hasan Al. Reza ◽  
Mohammad Shahnoor Hossain
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Simulation Analysis ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Docking Simulation ◽  
Hemorrhagic Fever ◽  
Effective Vaccine ◽  
T Cell Epitopes ◽  
Mhc Molecules

Aims: Ebola and Marburg viruses cause fatal hemorrhagic fever in both human and non-human primates. Absence of any licensed vaccine has further deteriorated the problem. In the present study, we aimed to design potential epitope based vaccines against these viruses using computational approaches. Methodology: By using various bioinformatics tools and databases, we analyzed the conserved glycoprotein sequences of Ebola and Marburg viruses and predicted two potential epitopes which may be used as peptide vaccines. Results: Using various B-cell and T-cell epitope prediction servers, four highly conserved epitopes were identified. Epitope conservancy analysis showed that  “LEASKRWAF” and “DSPLEASKRWAFRTG” epitopes were 100% and 93.62% conserved and the worldwide population coverage of “LEASKRWAF” interacting with MHC class I molecules and “DSPLEASKRWAFRTG” interacting with MHC class II molecules were 78.74% and 75.75% respectively. Immunoinformatics analysis showed that they are highly immunogenic, flexible and accessible to antibody. Molecular docking simulation analysis demonstrated a very significant interaction between epitopes and MHC molecules with lower binding energy. Cytotoxic analysis and ADMET test also supported their potential as vaccine candidates. Conclusion: In sum, our in silico approach demonstrated that both “LEASKRWAF” and “DSPLEASKRWAFRTG” hold the promise for the development of common vaccine against Ebola and Marburg viruses.

scholarly journals T Cell Epitope-Based Vaccine Design for Pandemic Novel Coronavirus 2019-nCoV

2020 ◽  
Author(s):  
Dr. Seema Mishra
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Structural Proteins ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Consensus Sequences ◽  
Tight Cluster ◽  
Cell Assays ◽  
Novel Coronavirus

Immunoinformatics approach has been used to identify potential T cell epitopes from structural and non-structural proteins for immunotherapy against novel coronavirus 2019-nCoV across populations Two different prediction algorithms, NetCTLpan and Pickpocket were used to generate consensus epitopes against HLA supertypes. All of the 57 epitopes identified had no similarity/identity with the human proteome thus preventing crossreactivity. Many of these epitopes formed a tight cluster around consensus sequences <p>MGYINVFAFPFTIYSLLLC and KVSIWNLDYIINLI across proteins and alleles. These should be urgently tested in <i>in-vitro</i> MHC binding and T cell assays before being tried as vaccines to further prevent pandemic due to this lethal coronavirus.<br></p>

scholarly journals Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Aurélien Azam ◽  
Sergio Mallart ◽  
Stephane Illiano ◽  
Olivier Duclos ◽  
Catherine Prades ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Anchor Residue ◽  
Hla Dr

Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, Cα-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and priming of human T cells. Modifications are differentially accepted at multiple positions, but are all tolerated in the flanking regions. Introduction of Aib and Daa in the binding core had the most deleterious effect on binding to HLA-DR molecules and T-cell activation. Their introduction at the positions close to the P1 anchor residue abolished T-cell priming, suggesting they might be sufficient to dampen peptide immunogenicity. Other modifications led to variable effects on binding to HLA-DR molecules and T-cell reactivity, but none exhibited an increased ability to stimulate T cells. Altogether, non-natural modifications appear generally to diminish binding to HLA-DR molecules and hence T-cell stimulation. These data might guide the design of therapeutic peptides to make them less immunogenic.

scholarly journals Prediction of T and B Cell Epitopes in the Proteome of SARS-CoV-2 for Potential Use in Diagnostics and Vaccine Design

2020 ◽  
Author(s):  
Parvez Slathia ◽  
Preeti Sharma,
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Vaccine Design ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
The People ◽  
Skilled Manpower ◽  
Prophylactic Measures

<p>The world is currently battling the Covid-19 pandemic for which there is no therapy available. Prophylactic measures like vaccines can effectively thwart the disease burden. The current methods of detection are PCR based and require skilled manpower to operate. The availability of cheap and ready to use diagnostics like serological methods can ease the detection of SARS-CoV-2 virus. In the current study, immunoinformatics tools have been used to predict T and B cell epitopes present in all the proteins of this virus. NetMHCPan, NetCTL and NetMHCII servers were used for T cell epitope prediction while BepiPred and ABCPred were used for B cell epitope prediction. Population coverage analysis for T cell epitopes revealed that these could provide protection to the people throughout world. The T cell epitopes can exclusively used for vaccine design whereas B cell epitopes can be used for both vaccine design and developing diagnostic kits. </p> <p> </p>

scholarly journals Prediction of T and B Cell Epitopes in the Proteome of SARS-CoV-2 for Potential Use in Diagnostics and Vaccine Design

2020 ◽  
Author(s):  
Parvez Slathia ◽  
Preeti Sharma,
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Vaccine Design ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
The People ◽  
Skilled Manpower ◽  
Prophylactic Measures

<p>The world is currently battling the Covid-19 pandemic for which there is no therapy available. Prophylactic measures like vaccines can effectively thwart the disease burden. The current methods of detection are PCR based and require skilled manpower to operate. The availability of cheap and ready to use diagnostics like serological methods can ease the detection of SARS-CoV-2 virus. In the current study, immunoinformatics tools have been used to predict T and B cell epitopes present in all the proteins of this virus. NetMHCPan, NetCTL and NetMHCII servers were used for T cell epitope prediction while BepiPred and ABCPred were used for B cell epitope prediction. Population coverage analysis for T cell epitopes revealed that these could provide protection to the people throughout world. The T cell epitopes can exclusively used for vaccine design whereas B cell epitopes can be used for both vaccine design and developing diagnostic kits. </p> <p> </p>

scholarly journals Immunogenicity of a Recombinant Influenza Virus Bearing Both the CD4+ and CD8+ T Cell Epitopes of Ovalbumin

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Bruno Garulli ◽  
Giuseppina Di Mario ◽  
Ester Sciaraffia ◽  
Yoshihiro Kawaoka ◽  
Maria R. Castrucci
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Influenza Viruses ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Additional Tool

Recombinant influenza viruses that bear the single immunodominant CD8+ T cell epitopeOVA257−264or the CD4+ T cell epitopeOVA323−339of the model antigen ovalbumin (OVA) have been useful tools in immunology. Here, we generated a recombinant influenza virus,WSN-OVAI/II, that bears both OVA-specific CD8+ and CD4+ epitopes on its hemagglutinin molecule. Live and heat-inactivatedWSN-OVAI/IIviruses were efficiently presented by dendritic cellsin vitroto OT-I TCR transgenic CD8+ T cells and OT-II TCR transgenic CD4+ T cells.In vivo,WSN-OVAI/IIvirus was attenuated in virulence, highly immunogenic, and protected mice from B16-OVA tumor challenge in a prophylactic model of vaccination. Thus,WSN-OVAI/IIvirus represents an additional tool, along with OVA TCR transgenic mice, for further studies on T cell responses and may be of value in vaccine design.

scholarly journals EPIPOX: Immunoinformatic Characterization of the Shared T-Cell Epitome between Variola Virus and Related Pathogenic Orthopoxviruses

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Magdalena Molero-Abraham ◽  
John-Paul Glutting ◽  
Darren R. Flower ◽  
Esther M. Lafuente ◽  
Pedro A. Reche
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Variola Virus ◽  
T Cell Epitopes ◽  
Membrane Structures ◽  
Class Ii Mhc ◽  
Vaccinia Viruses ◽  
Virus Genomes

Concerns that variola viruses might be used as bioweapons have renewed the interest in developing new and safer smallpox vaccines. Variola virus genomes are now widely available, allowing computational characterization of the entire T-cell epitome and the use of such information to develop safe and yet effective vaccines. To this end, we identified 124 proteins shared between various species of pathogenic orthopoxviruses including variola minor and major, monkeypox, cowpox, and vaccinia viruses, and we targeted them for T-cell epitope prediction. We recognized 8,106, and 8,483 unique class I and class II MHC-restricted T-cell epitopes that are shared by all mentioned orthopoxviruses. Subsequently, we developed an immunological resource, EPIPOX, upon the predicted T-cell epitome. EPIPOX is freely available online and it has been designed to facilitate reverse vaccinology. Thus, EPIPOX includes key epitope-focused protein annotations: time point expression, presence of leader and transmembrane signals, and known location on outer membrane structures of the infective viruses. These features can be used to select specific T-cell epitopes suitable for experimental validation restricted by single MHC alleles, as combinations thereof, or by MHC supertypes.

Sign in / Sign up

Export Citation Format

Share Document