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Journal articles on the topic 'Epitope'
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1
Madhumathi, J., P. R. Prince, D. N. Rao, A. A. Karande, M. V. R. Reddy, and P. Kaliraj. "Epitope mapping ofBrugia malayiALT-2 and the development of a multi-epitope vaccine for lymphatic filariasis." Journal of Helminthology 91, no. 1 (February 19, 2016): 43–54. http://dx.doi.org/10.1017/s0022149x16000055.
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AbstractHuman lymphatic filariasis is a neglected tropical disease, causing permanent and long-term disability with severe immunopathology. Abundant larval transcript (ALT) plays a crucial role in parasite establishment in the host, due to its multi-faceted ability in host immune regulation. Although ALT protein is a key filarial target, its exact function is yet to be explored. Here, we report epitope mapping and a structural model ofBrugia malayiALT-2, leading to development of a multi-epitope vaccine. Structural analysis revealed that ALT represents unique parasitic defence proteins belonging to a toxin family that carries a ‘knottin’ fold. ALT-2 has been a favourite vaccine antigen and was protective in filarial models. Due to the immunological significance of ALT-2, we mapped B-cell epitopes systematically and identified two epitope clusters, 1–30 and 89–128. To explore the prophylactic potential of epitope clusters, a recombinant multi-epitopic gene comprising the epitopic domains was engineered and the protective efficacy of recombinant ALT epitope protein (AEP) was tested in the permissive model,Mastomys coucha. AEP elicited potent antibody responses with predominant IgG1 isotype and conferred significantly high protection (74.59%) compared to ALT-2 (61.95%). This proved that these epitopic domains are responsible for the protective efficacy of ALT-2 and engineering protective epitopes as a multi-epitope protein may be a novel vaccine strategy for complex parasitic infections.
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Singh, Niraj K., Anuj Tyagi, Sumit Singhal, Anjay, Yogendra Singh Jadoun, and Anuradha Kumari. "Bio-Computational Prediction of Novel Epitopes on VP2 Protein of Infectious Bursal Disease Virus." Journal of Advances in Microbiology 24, no. 5 (June 2, 2024): 26–39. http://dx.doi.org/10.9734/jamb/2024/v24i5824.
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Aim: Recently, many viral Immunogenic peptides or epitopes have been used as potential vaccine and also immuno-diagnostic candidates. In this study, we predicted different epitopic peptides on VP2 protein of infectious bursal disease virus (IBDV) using bioinformatics tools, which can be potential vaccine as well as diagnostic candidate for IBD, in future. Study Design: In the present study, B-cell epitopes (linear or continuous, and conformational) and T-cell epitopes were predicted on VP2 protein. Place and Duration of Study: Bihar Animal Sciences University, Patna, and Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, India between June and December 2023. Methodology: For the prediction of linear B-cell epitopes, Bepipred Linear Epitope Prediction 2.0, SVMTriP, and BCPred tools were used, while Ellipro was used for conformational B-cell epitopes prediction. In the absence of immune-bioinformatics tool is available to predict poultry MHC-peptide binding, only those human MHC-I/II alleles having greater than 70% identities those of poultry MHC-I/II alleles were selected. NetMHCcons 1.1 and NetMHCIIpan - 4.0 tools were used to predict strong binding affinity of peptides with MHC-I and MHC-II, respectively. Results: As per analysis by four different tools, the peptide ‘SYDLGYVRLGDPIPAIGLDPKMV ATCDSSDRPRVYTITAADDYQFSSQYQPGGV164-217’ (EpitopeL) was predicted as the most prominent linear B-cell epitope. Two peptides, i.e. ANLNSPLKIAG (EpitopeC 1) and SSQYQPGGRTSVHGLGLTTGTDKSGGQAGDQMS (EpitopeC 2) were predicted as potent conformational B-cell epitopes. During T-cell epitopes prediction, human HLA*B 40:06, HLA*B 41:03 and HLA*B 41:04 alleles chosen as homologues of poultry MHC class I alleles while DRB1:1310, DRB1:1366, DRB1:1445, and DRB1:1482 chosen as homologues of poultry MHC class II alleles. A 9-mer GELVFQTSV236-244 peptide was predicted as MHC-I strong binder ability while, two 15-mer peptides, i.e. YTKLILSERDRLGIK389-403 and QMLLTAQNLPASYNY76-90 were predicted as MHC-II strong binder ability. Conclusion: Using bio-computational analysis, one linear and two conformational B-cell epitopes were predicted on VP2 protein of IBDV. During T-cell epitopes prediction one 9-mer peptide and two 15-mer peptides were predicted as MHC-I and MHC-II strong binding peptides, respectively. After assessing protective immune responses through in vitro and in vivo studies, these predicted peptides could be potential candidates for developing subunit vaccines.
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Yuexi, Li, Wang Xingsheng, Xie Guangyan, Liao Jianming, Yin Dengke, Guan Wenyan, Pan Mingjie, and Li Jingnian. "Immunisation analysis and animal protection experiments of a recombinant multi-epitope assembly peptide from Herpes Simplex Virus Type 2 (155.35)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 155.35. http://dx.doi.org/10.4049/jimmunol.186.supp.155.35.
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Abstract Human herpes simplex virus 2 (HSV2) has been the main cause for genital herpes, causes a significant health problem worldwide, and no effective vaccine is available. Multi-epitope assembly peptides vaccination is a promising mean to achieve protective immunity and to avoid immunopathology. A recombinant Multi-Epitope Assembly Peptide (MEAP) including 12 antigen epitopies from HSV2 was expressed and purified by genetic engineering, its immunity and protection efficacy against HSV2 infection were identified in mice. The twelve epitopies contained six B cell epitopies from six envelope glycoproteins, B, C, D, E, G and I of HSV2 respectively, four CD4+ T cell epitopes from B and D, and two CD8+ T cell epitopes from D. they are responsible for the elicitation of the neutralizing antibodies and CTLs that impart protective immunity to the host. all above epitopes were inserted into the extracellular fragment of HSV-2 glycoprotein D to construct multi-epitope assembly peptides by replacing some non-epitope amino acid sequences. The MEAP could elicit high titer neutralizing antibodies and cell-mediated immune responses in mice and rabbits. The mice immunized with the MEAP were completely protected against HSV-2 infection death at a lethal dose, and the virus shedding, inflammation severity in the mice were reduced significantly compared with the control mice, which indicates that it might be a potential candidate vaccine.
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Grahadi, Rahmat, Fatchiyah Fatchiyah, and Nia Kurniawan. "Virtual prediction of potential immunogenic epitope of candoxin protein from Malayan krait (Bungarus candidus) venom." Journal of Pharmacy & Pharmacognosy Research 10, no. 6 (November 1, 2022): 1046–57. http://dx.doi.org/10.56499/jppres22.1469_10.6.1046.
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Context: Malayan krait (Bungarus candidus) is a snake that is considered highly venomous snake and widely distributed across Southeast Asia. Envenomation by this snake is characterized by facial weakness, paralysis, respiratory muscle weakness, and in most cases, it renders the victim dead. Unfortunately, there is only one antivenom for neutralizing venom that is only available from the Thai Red Cross Society. Aims: To predict the epitopes from candoxin protein of B. candidus venom that could be a candidate for vaccine-based antivenom. Methods: In this study, IEDB and SYFPHEITHI databases were utilized to predict candoxin epitope sequences and determine their immunogenicity, conservancy, and population coverage. Next, the epitopes were modeled, and the binding interactions between epitopes and MHC-II were analyzed. The epitope that binds into the active site of human and murine MHC-II proceeded to the next step. Then, the allergenic properties of the chosen epitope were assessed to ensure its safety. Lastly, the physicochemical characteristics prediction and molecular dynamics simulation were conducted to verify the epitope’s stability when produced in vivo. Results: The results showed that epitope 47-CFKESWREARGTRIE-61 has the best binding interaction when compared to others. This epitope was confirmed that did not show potential allergenic properties. The physicochemical properties and molecular dynamics simulation demonstrated that this epitope was stable. Conclusions: The results of this study will be useful in developing a novel antivenom for Bungarus candidus using a vaccine-based method.
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Zou, Wei, Roger Mackenzie, Lina Thérien, Tomoko Hirama, Qingling Yang, Margaret A. Gidney, and Harold J. Jennings. "Conformational Epitope of the Type III Group B Streptococcus Capsular Polysaccharide." Journal of Immunology 163, no. 2 (July 15, 1999): 820–25. http://dx.doi.org/10.4049/jimmunol.163.2.820.
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Abstract The protective epitope of the type III group B streptococcal polysaccharide (GBSPIII) is length dependent and conformational. To obtain a more accurate characterization of the conformational epitope, ELISA inhibition and surface plasmon resonance studies were conducted on two GBSPIII-specific mAbs using a large panel of oligosaccharide probes. The results of the studies confirmed that 2 repeating units (RU) is the minimum binding unit and that, while increases in chain length from 2 RU to 7 RU caused further optimization of the epitope, it remained monovalent. A 3-fold increase in affinity was observed between 7 RU and 20 RU, which, by surface plasmon resonance studies on a Fab, was shown to be due to both further optimization of the individual epitope and the occurrence of multivalency of epitope. The data support our hypothesis that the conformational epitope is an extended helical segment of the GBSPIII. GBSPIII exists mainly in the random coil form, which structurally mimics short oligosaccharide self Ags, but it can infrequently and spontaneously form extended helices. Although not prevalent in GBSPIII, the immune system preferentially selects these helical epitopes because they are unique to the polysaccharide. Contrary to a previously proposed model of GBSPIII binding in which the binding of the first Ab propagates a continuum of helical epitopes, our binding kinetics are consistent only with the helical epitope’s being discontinuous and infrequent.
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Potocnakova, Lenka, Mangesh Bhide, and Lucia Borszekova Pulzova. "An Introduction to B-Cell Epitope Mapping and In Silico Epitope Prediction." Journal of Immunology Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/6760830.
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Identification of B-cell epitopes is a fundamental step for development of epitope-based vaccines, therapeutic antibodies, and diagnostic tools. Epitope-based antibodies are currently the most promising class of biopharmaceuticals. In the last decade, in-depth in silico analysis and categorization of the experimentally identified epitopes stimulated development of algorithms for epitope prediction. Recently, various in silico tools are employed in attempts to predict B-cell epitopes based on sequence and/or structural data. The main objective of epitope identification is to replace an antigen in the immunization, antibody production, and serodiagnosis. The accurate identification of B-cell epitopes still presents major challenges for immunologists. Advances in B-cell epitope mapping and computational prediction have yielded molecular insights into the process of biorecognition and formation of antigen-antibody complex, which may help to localize B-cell epitopes more precisely. In this paper, we have comprehensively reviewed state-of-the-art experimental methods for B-cell epitope identification, existing databases for epitopes, and novel in silico resources and prediction tools available online. We have also elaborated new trends in the antibody-based epitope prediction. The aim of this review is to assist researchers in identification of B-cell epitopes.
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Mylin, Lawrence M. "Context-Dependent Immunogenicity of an S206G-Substituted H-2Db-Restricted Simian Virus 40 Large T Antigen Epitope I Variant." Journal of Immunology 162, no. 4 (February 15, 1999): 2171–79. http://dx.doi.org/10.4049/jimmunol.162.4.2171.
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Abstract SV40 large tumor Ag (Tag) contains four H-2b-restricted (I, II/III, IV, and V) CTL epitopes. A hierarchy exists among these CTL epitopes. CTL directed against epitopes I, II/III, and IV are readily detected following immunization of H-2b mice with SV40, Tag-transformed syngeneic cells, or a vaccinia recombinant that expresses full-length Tag, while epitope V-specific CTL are not. The mechanisms that define this hierarchy remain unknown. Initial studies have shown that the locations of epitopes I and V within SV40 Tag do not determine the immunological potencies of these epitopes. Like the wild-type Tag, derivatives in which the locations of epitopes I and V were precisely reversed within Tag failed to induce epitope V-specific CTL, but did induce epitope I-specific CTL. The use of an S206G-substituted epitope I variant (GAINNYAQKL) revealed that the S206G variant sequence induced CTL when located within the native epitope I context, but failed to do so when located within the epitope V context of Tag. Mutagenesis of residues adjacent to the S206G-substituted epitope I variant revealed that the identity of the residue flanking the amino terminus of the S206G variant was critical when it resided within the epitope V location, but not within the epitope I location. These results demonstrate that effects imposed by both regional context and adjacent residues can modulate immunogenicity, but that the relative importance of such effects varies in an epitope-dependent manner.
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Lucchese, Guglielmo, Angela Stufano, and Darja Kanduc. "Proposing Low-Similarity Peptide Vaccines againstMycobacterium tuberculosis." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/832341.
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Using the currently available proteome databases and based on the concept that a rare sequence is a potential epitope, epitopic sequences derived fromMycobacterium tuberculosiswere examined for similarity score to the proteins of the host in which the epitopes were defined. We found that: (i) most of the bacterial linear determinants had peptide fragment(s) that were rarely found in the host proteins and (ii) the relationship between low similarity and epitope definition appears potentially applicable to T-cell determinants. The data confirmed the hypothesis that low-sequence similarity shapes or determines the epitope definition at the molecular level and provides a potential tool for designing new approaches to prevent, diagnose, and treat tuberculosis and other infectious diseases.
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Tornyi, Ilona, Jozsef Lazar, Aladar Pettko-Szandtner, Eva Hunyadi-Gulyas, and Laszlo Takacs. "Epitomics: Analysis of Plasma C9 Epitope Heterogeneity in the Plasma of Lung Cancer Patients and Control Subjects." International Journal of Molecular Sciences 24, no. 18 (September 21, 2023): 14359. http://dx.doi.org/10.3390/ijms241814359.
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The human proteome is more complex than the genetic code predicts it to be. Epitomics, or protein epitome profiling, is a tool for understanding sub-protein level variation. With the ultimate goal to explore C9 proteoforms and their relevance to lung cancer, here we report plasma C9 epitope-associated molecular heterogeneity in plasma samples of lung cancer patients and control subjects. We show three C9 epitopes (BSI0449, BSI0581, BSI0639) with markedly different association with lung cancer (“unaltered”, “upregulated” and “downregulated”). In order to exclude confounding effects, we show first that the three epitope-defining mAbs recognize C9 in purified form and in the natural context, in the human plasma. Then, we present data demonstrating the lack of major epitope interdependence or overlap. The next experiments represent a quest toward the understanding of the molecular basis of apparent disparate association with lung cancer. Using immunochemistry, SDS PAGE and LC-MS/MS technologies, we demonstrate that epitope-specific immunoprecipitates of plasma C9 seem identical regarding peptide sequence. However, we found epitope-specific posttranslational modification and coprecipitated protein composition differences with respect to control and lung cancer plasma. Epitope profiling enabled the classification of hypothetical C9 proteoforms through differential association with lung cancer.
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Moriki, Takanori, Ichiro N. Maruyama, Yusuke Yamaguchi, Atsuko Igari, Yasuo Ikeda, and Mitsuru Murata. "Identification of ADAMTS13 Epitopes Required for Binding to von Willebrand Factor Using Lambda Phage Surface Display." Blood 110, no. 11 (November 16, 2007): 2707. http://dx.doi.org/10.1182/blood.v110.11.2707.2707.
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Abstract The metalloprotease ADAMTS13 cleaves multimeric von Willebrand factor (VWF) to regulate VWF-mediated thrombus formation. We planned to search core epitopes of ADAMTS13 that is required for its binding to VWF. We constructed a random cDNA fragment library expressing various peptides of ADAMTS13 on the surface of lambda phage and screened the library using immobilized VWF as a probe. After the first screening, the C-terminus of the spacer domain from Arg670 to Glu684 (termed as epitope-1) and the middle of the cysteine-rich domain from Arg484 to Arg507 (epitope-2) were determined as epitopes. When we added the synthetic epitope-1 peptide to the second screening, a new site, from Pro618 to Glu641 (epitope-3), was found in the middle of spacer domain. While the presence of synthetic epitope-2 peptide did not affect the subsequent screening, the presence of epitope-3 peptide enhanced the isolation of clones encoding epitope-1. These results suggest that ADAMTS13 epitopes-1, -2 and -3 may interact with each other for their binding to VWF. From screening in the presence of any combination or all of the three synthetic peptides, however, no new VWF binding site was uncovered. To examine the effect of divalent metal cations on the binding of ADAMTS13 epitopes to immobilized VWF, screening was carried out in the presence or absence of 5 mM of EDTA. No new epitope site was found. We next explored inhibitory effect of the synthetic epitope peptides on ADAMTS13 protease activity using recombinant ADAMTS13 and FRETS-VWF73 as a substrate. Synthetic epitopes-2 and -3 peptides markedly inhibited the cleavage of VWF by ADAMTS13, while the synthetic epitope-1 peptide did not as efficiently as epitopes-2 and -3. The stronger inhibitory effect of epitope-3 peptide than that of epitope-1 peptide was confirmed by SDS-agarose gel electrophoresis analysis of cleavage products of denatured multimeric VWF molecules by recombinant ADAMTS13. This was consistent with the dissociation constants for the three synthetic peptides with immobilized VWF determined by surface plasmon resonance, in which epitopes-2 and -3 have higher affinities for VWF than that of epitope-1. The results described above suggest that ADAMTS13 may initially bind to immobilized VWF through the sites of epitope-1 and epitope-2 with relatively weak affinity. The binding of epitope-1 to VWF may subsequently induce the conformational change of VWF, thereby exposing a binding site for epitope-3 for the efficient catalytic cleavage of VWF by ADAMTS13.
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Fairlie, W. D., P. G. Stanton, and M. T. W. Hearn. "Immunochemical characterization of two thyroid-stimulating hormone β-subunit epitopes." Biochemical Journal 308, no. 1 (May 15, 1995): 203–10. http://dx.doi.org/10.1042/bj3080203.
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The epitopes of human thyroid-stimulating hormone (hTSH) recognized by two murine monoclonal antibodies (MAbs), designated MAb 279 and MAb 299, have been characterized. These MAbs are highly specific for the beta-subunit of TSH. The epitope recognized by MAb 279 appears to be completely conserved between bovine and human TSH and partially conserved in the porcine species. The TSH beta-subunit epitope recognized by MAb 299 is only partially conserved between the human, bovine and porcine species. Both MAbs are capable of inhibiting the binding of TSH to its receptor in a TSH radioreceptor assay, indicating that the epitopes either coincide or are located close to the TSH beta-subunit receptor-binding sites. The carbohydrate moieties of the TSH beta-subunit appear to play little or no role in the epitope recognition by MAb 279 or MAb 299 while the integrity of the disulphide bonds are essential. The epitopic recognition may also involve lysine residues, as determined by the immunoreactivity with both MAbs following citraconylation of TSH. In addition, the amino acid sequence region between residues bTSH beta 34-44 could be excised by trypsin digestion of bovine TSH beta (bTSH beta) without eliminating epitopic recognition by either MAb. These results provide further insight into the relationship between the structure of the TSH beta-subunit epitopes and location of the receptor-binding sites.
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De-Simone, Salvatore G., Paloma Napoleão-Pêgo, Guilherme C. Lechuga, João P. R. S. Carvalho, Maria E. Monteiro, Carlos M. Morel, and David W. Provance. "Mapping IgA Epitope and Cross-Reactivity between Severe Acute Respiratory Syndrome-Associated Coronavirus 2 and DENV." Vaccines 11, no. 12 (November 24, 2023): 1749. http://dx.doi.org/10.3390/vaccines11121749.
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Background: The newly introduced COVID-19 vaccines have reduced disease severity and hospitalizations. However, they do not significantly prevent infection or transmission. In the same context, measuring IgM and IgG antibody levels is important, but it does not provide information about the status of the mucosal immune response. This article describes a comprehensive mapping of IgA epitopes of the S protein, its cross-reactivity, and the development of an ELISA-peptide assay. Methods: IgA epitope mapping was conducted using SPOT synthesis and sera from RT-qPCR COVID-19-positive patients. Specific and cross-reacting epitopes were identified, and an evolutionary analysis from the early Wuhan strain to the Omicron variant was performed using bioinformatics tools and a microarray of peptides. The selected epitopes were chemically synthesized and evaluated using ELISA-IgA. Results: A total of 40 IgA epitopes were identified with 23 in S1 and 17 in the S2 subunit. Among these, at least 23 epitopes showed cross-reactivity with DENV and other organisms and 24 showed cross-reactivity with other associated coronaviruses. Three MAP4 polypeptides were validated by ELISA, demonstrating a sensitivity of 90–99.96% and a specificity of 100%. Among the six IgA-RBD epitopes, only the SC/18 epitope of the Omicron variants (BA.2 and BA.2.12.1) presented a single IgA epitope. Conclusions: This research unveiled the IgA epitome of the S protein and identified many epitopes that exhibit cross-reactivity with DENV and other coronaviruses. The S protein of variants from Wuhan to Omicron retains many conserved IgA epitopes except for one epitope (#SCov/18). The cross-reactivity with DENV suggests limitations in using the whole S protein or the S1/S2/RBD segment for IgA serological diagnostic tests for COVID-19. The expression of these identified specific epitopes as diagnostic biomarkers could facilitate monitoring mucosal immunity to COVID-19, potentially leading to more accurate diagnoses and alternative mucosal vaccines.
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Soto, Luis Fernando, David Requena, and Juan Ignacio Fuxman Bass. "Epitope-Evaluator: An interactive web application to study predicted T-cell epitopes." PLOS ONE 17, no. 8 (August 26, 2022): e0273577. http://dx.doi.org/10.1371/journal.pone.0273577.
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Multiple immunoinformatic tools have been developed to predict T-cell epitopes from protein amino acid sequences for different major histocompatibility complex (MHC) alleles. These prediction tools output hundreds of potential peptide candidates which require further processing; however, these tools are either not graphical or not friendly for non-programming users. We present Epitope-Evaluator, a web tool developed in the Shiny/R framework to interactively analyze predicted T-cell epitopes. Epitope-Evaluator contains six tools providing the distribution of epitopes across a selected set of MHC alleles, the promiscuity and conservation of epitopes, and their density and location within antigens. Epitope-Evaluator requires as input the fasta file of protein sequences and the output prediction file coming out from any predictor. By choosing different cutoffs and parameters, users can produce several interactive plots and tables that can be downloaded as JPG and text files, respectively. Using Epitope-Evaluator, we found the HLA-B*40, HLA-B*27:05 and HLA-B*07:02 recognized fewer epitopes from the SARS-CoV-2 proteome than other MHC Class I alleles. We also identified shared epitopes between Delta, Omicron, and Wuhan Spike variants as well as variant-specific epitopes. In summary, Epitope-Evaluator removes the programming barrier and provides intuitive tools, allowing a straightforward interpretation and graphical representations that facilitate the selection of candidate epitopes for experimental evaluation. The web server Epitope-Evaluator is available at https://fuxmanlab.shinyapps.io/Epitope-Evaluator/
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Mylin, Lawrence M., Todd D. Schell, Debra Roberts, Melanie Epler, Alina Boesteanu, Edward J. Collins, Jeffrey A. Frelinger, Sebastian Joyce, and Satvir S. Tevethia. "Quantitation of CD8+ T-Lymphocyte Responses to Multiple Epitopes from Simian Virus 40 (SV40) Large T Antigen in C57BL/6 Mice Immunized with SV40, SV40 T-Antigen-Transformed Cells, or Vaccinia Virus Recombinants Expressing Full-Length T Antigen or Epitope Minigenes." Journal of Virology 74, no. 15 (August 1, 2000): 6922–34. http://dx.doi.org/10.1128/jvi.74.15.6922-6934.2000.
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ABSTRACT The cytotoxic T-lymphocyte response to wild-type simian virus 40 large tumor antigen (Tag) in C57BL/6 (H2b ) mice is directed against three H2-Db -restricted epitopes, I, II/III, and V, and oneH2-Kb -restricted epitope, IV. Epitopes I, II/III, and IV are immunodominant, while epitope V is immunorecessive. We investigated whether this hierarchical response was established in vivo or was due to differential expansion in vitro by using direct enumeration of CD8+ T lymphocytes with Tag epitope/major histocompatibility complex class I tetramers and intracellular gamma interferon staining. The results demonstrate that epitope IV-specific CD8+ T cells dominated the Tag-specific response in vivo following immunization with full-length Tag while CD8+ T cells specific for epitopes I and II/III were detected at less than one-third of this level. The immunorecessive nature of epitope V was apparent in vivo, since epitope V-specific CD8+ T cells were undetectable following immunization with full-length Tag. In contrast, high levels of epitope V-specific CD8+ T lymphocytes were recruited in vivo following immunization and boosting with a Tag variant in which epitopes I, II/III, and IV had been inactivated. In addition, analysis of the T-cell receptor β (TCRβ) repertoire of Tag epitope-specific CD8+ cells revealed that multiple TCRβ variable regions were utilized for each epitope except Tag epitope II/III, which was limited to TCRβ10 usage. These results indicate that the hierarchy of Tag epitope-specific CD8+T-cell responses is established in vivo.
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Ando, Takao, Rauf Latif, Samira Daniel, Katsumi Eguchi, and Terry F. Davies. "Dissecting Linear and Conformational Epitopes on the Native Thyrotropin Receptor." Endocrinology 145, no. 11 (November 1, 2004): 5185–93. http://dx.doi.org/10.1210/en.2004-0789.
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Abstract The TSH receptor (TSHR) is the primary antigen in Graves’ disease. In this condition, autoantibodies to the TSHR that have intrinsic thyroid-stimulating activity develop. We studied the epitopes on the native TSHR using polyclonal antisera and monoclonal antibodies (mAbs) derived from an Armenian hamster model of Graves’ disease. Of 14 hamster mAbs analyzed, five were shown to bind to conformational epitopes including one mAb with potent thyroid-stimulating activity. Overlapping conformational epitopes were determined by cell-binding competition assays using fluorescently labeled mAbs. We identified two distinct conformational epitopes: epitope A for both stimulating and blocking mAbs and epitope B for only blocking mAbs. Examination of an additional three mouse-derived stimulating TSHR-mAbs also showed exclusive binding to epitope A. The remaining nine hamster-derived mAbs were neutral or low-affinity blocking antibodies that recognized linear epitopes within the TSHR cleaved region (residues 316–366) (epitope C). Serum from the immunized hamsters also recognized conformational epitopes A and B but, in addition, also contained high levels of TSHR-Abs interacting within the linear epitope C region. In summary, these studies indicated that the natively conformed TSHR had a restricted set of epitopes recognized by TSHR-mAbs and that the binding site for stimulating TSHR-Abs was highly conserved. However, high-affinity TSHR-blocking antibodies recognized two conformational epitopes, one of which was indistinguishable from the thyroid-stimulating epitope. Hence, TSHR-stimulating and blocking antibodies cannot be distinguished purely on the basis of their conformational epitope recognition.
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Lim, Li Cen, Yee Ying Lim, and Yee Siew Choong. "Data curation to improve the pattern recognition performance of B-cell epitope prediction by support vector machine." Pure and Applied Chemistry 93, no. 5 (May 1, 2021): 571–77. http://dx.doi.org/10.1515/pac-2020-1107.
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Abstract B-cell epitope will be recognized and attached to the surface of receptors in B-lymphocytes to trigger immune response, thus are the vital elements in the field of epitope-based vaccine design, antibody production and therapeutic development. However, the experimental approaches in mapping epitopes are time consuming and costly. Computational prediction could offer an unbiased preliminary selection to reduce the number of epitopes for experimental validation. The deposited B-cell epitopes in the databases are those with experimentally determined positive/negative peptides and some are ambiguous resulted from different experimental methods. Prior to the development of B-cell epitope prediction module, the available dataset need to be handled with care. In this work, we first pre-processed the B-cell epitope dataset prior to B-cell epitopes prediction based on pattern recognition using support vector machine (SVM). By using only the absolute epitopes and non-epitopes, the datasets were classified into five categories of pathogen and worked on the 6-mers peptide sequences. The pre-processing of the datasets have improved the B-cell epitope prediction performance up to 99.1 % accuracy and showed significant improvement in cross validation results. It could be useful when incorporated with physicochemical propensity ranking in the future for the development of B-cell epitope prediction module.
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Liu, Jinyan, Bonnie A. Ewald, Diana M. Lynch, Anjali Nanda, Shawn M. Sumida, and Dan H. Barouch. "Modulation of DNA Vaccine-Elicited CD8+ T-Lymphocyte Epitope Immunodominance Hierarchies." Journal of Virology 80, no. 24 (September 27, 2006): 11991–97. http://dx.doi.org/10.1128/jvi.01348-06.
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ABSTRACT Generating broad cellular immune responses against a diversity of viral epitopes is a major goal of current vaccine strategies for human immunodeficiency virus type 1 (HIV-1) and other pathogens. Virus-specific CD8+ T-lymphocyte responses, however, are often highly focused on a very limited number of immunodominant epitopes. For an HIV-1 vaccine, the breadth of CD8+ T-lymphocyte responses may prove to be critical as a result of the need to cover a wide diversity of viral isolates in the population and to limit viral escape from dominant epitope-specific T lymphocytes. Here we show that epitope modification strategies can alter CD8+ T-lymphocyte epitope immunodominance hierarchies elicited by a DNA vaccine in mice. Mice immunized with a DNA vaccine expressing simian immunodeficiency virus Gag lacking the dominant Db-restricted AL11 epitope generated a marked and durable augmentation of responses specific for the subdominant Db-restricted KV9 epitope. Moreover, anatomic separation strategies and heterologous prime-boost regimens generated codominant responses against both epitopes. These data demonstrate that dominant epitopes can dramatically suppress the immunogenicity of subdominant epitopes in the context of gene-based vaccines and that epitope modification strategies can be utilized to enhance responses to subdominant epitopes.
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Kahn, S. J., and M. Wleklinski. "The surface glycoproteins of Trypanosoma cruzi encode a superfamily of variant T cell epitopes." Journal of Immunology 159, no. 9 (November 1, 1997): 4444–51. http://dx.doi.org/10.4049/jimmunol.159.9.4444.
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Abstract Trypanosoma cruzi is an obligate intracellular protozoan parasite. During mammalian infection, extracellular and intracellular parasites simultaneously express multiple members of a polymorphic surface protein superfamily. The effect of this extensive surface protein polymorphism on the mammalian host T cell response is not known. In this report, we identified a surface protein MHC class II-restricted T cell epitope (epitope 1), and cloned 10 surface protein cDNAs that encode epitope 1 variants. All these cDNA variant epitopes were processed and presented to T cells, and some functioned as partial T cell agonists. CD4 T cells primed with epitope 1, and challenged with epitope 1, proliferated and expressed IFN-gamma and IL-4. In contrast, CD4 T cells primed with a mixture of variant epitopes and epitope 1, and challenged with epitope 1, expressed IL-4, but did not proliferate or express IFN-gamma. The data suggest that the simultaneous expression of polymorphic surface proteins that encode variant T cell epitopes may limit the expression of each surface protein epitope below a threshold level required to stimulate a protective IFN-gamma response against that epitope. This system of T cell evasion is unique and contrasts with the sequential antigenic variation used by African trypanosomes to evade Abs directed against their surface proteins.
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Hayashi, Hiroki, and Tsutomu Kishi. "A Set of Plasmid-Based Modules for Easy Switching of C-Terminal Epitope Tags in Saccharomyces cerevisiae." Microorganisms 9, no. 12 (December 3, 2021): 2505. http://dx.doi.org/10.3390/microorganisms9122505.
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Epitope tagging is a powerful strategy for analyzing the functions of targeted proteins. The use of this strategy has become more convenient with the development of the epitope switch, which is another type of epitope tagging designed to convert the previously tagged epitopes on the chromosome to other epitopes of interest. Various modules for C-terminal epitope switching have been developed and amplified using the one-step polymerase chain reaction (PCR) method before transformation. However, PCR amplification occasionally generates mutations that affect the fidelity of epitope switching. Here, we constructed several plasmids to isolate modules for epitope switching through digestion by restriction enzymes. The isolated modules contained DNA sequences for homologous recombination, various epitopes (13×Myc, 6×HA, GFP, Venus, YFP, mCherry, and CFP), and a transformation marker (Candida glabrata LEU2). The restriction enzyme-digested plasmids were used to directly transform the cells for epitope switching. We demonstrate the efficient and accurate switching of the MX6 module-based C-terminal tandem affinity purification tags to each aforementioned epitope. We believe that our plasmids can serve as powerful tools for the functional analysis of yeast proteins.
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Molero-Abraham, Magdalena, John-Paul Glutting, Darren R. Flower, Esther M. Lafuente, and Pedro A. Reche. "EPIPOX: Immunoinformatic Characterization of the Shared T-Cell Epitome between Variola Virus and Related Pathogenic Orthopoxviruses." Journal of Immunology Research 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/738020.
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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.
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Friedrich, Thomas C., Adrian B. McDermott, Matthew R. Reynolds, Shari Piaskowski, Sarah Fuenger, Ivna P. de Souza, Richard Rudersdorf, et al. "Consequences of Cytotoxic T-Lymphocyte Escape: Common Escape Mutations in Simian Immunodeficiency Virus Are Poorly Recognized in Naïve Hosts." Journal of Virology 78, no. 18 (September 15, 2004): 10064–73. http://dx.doi.org/10.1128/jvi.78.18.10064-10073.2004.
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ABSTRACT Cytotoxic T lymphocytes (CTL) are associated with control of immunodeficiency virus infection but also select for variants that escape immune recognition. Declining frequencies of epitope-specific CTL frequencies have been correlated with viral escape in individual hosts. However, escape mutations may give rise to new epitopes that could be recognized by CTL expressing appropriate T-cell receptors and thus still be immunogenic when escape variants are passed to individuals expressing the appropriate major histocompatibility complex class I molecules. To determine whether peptide ligands that have been altered through escape can be immunogenic in new hosts, we challenged naïve, immunocompetent macaques with a molecularly cloned simian immunodeficiency virus (SIV) bearing common escape mutations in three immunodominant CTL epitopes. Responses to the altered peptides were barely detectable in fresh samples at any time after infection. Surprisingly, CTL specific for two of three escaped epitopes could be expanded by in vitro stimulation with synthetic peptides. Our results suggest that some escape variant epitopes evolving in infected individuals do not efficiently stimulate new populations of CTL, either in that individual or upon passage to new hosts. Nevertheless, escape variation may not completely abolish an epitope's immunogenicity. Moreover, since the mutant epitope sequences did not revert to wild type during the study period, it is possible that low-frequency CTL exerted enough selective pressure to preserve epitope mutations in viruses replicating in vivo.
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Bautista, Enrico, Young Hyun Jung, Manuela Jaramillo, Harrish Ganesh, Aryaan Varma, Kush Savsani, and Sivanesan Dakshanamurthy. "AutoPepVax, a Novel Machine-Learning-Based Program for Vaccine Design: Application to a Pan-Cancer Vaccine Targeting EGFR Missense Mutations." Pharmaceuticals 17, no. 4 (March 26, 2024): 419. http://dx.doi.org/10.3390/ph17040419.
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The current epitope selection methods for peptide vaccines often rely on epitope binding affinity predictions, prompting the need for the development of more sophisticated in silico methods to determine immunologically relevant epitopes. Here, we developed AutoPepVax to expedite and improve the in silico epitope selection for peptide vaccine design. AutoPepVax is a novel program that automatically identifies non-toxic and non-allergenic epitopes capable of inducing tumor-infiltrating lymphocytes by considering various epitope characteristics. AutoPepVax employs random forest classification and linear regression machine-learning-based models, which are trained with datasets derived from tumor samples. AutoPepVax, along with documentation on how to run the program, is freely available on GitHub. We used AutoPepVax to design a pan-cancer peptide vaccine targeting epidermal growth factor receptor (EGFR) missense mutations commonly found in lung adenocarcinoma (LUAD), colorectal adenocarcinoma (CRAD), glioblastoma multiforme (GBM), and head and neck squamous cell carcinoma (HNSCC). These mutations have been previously targeted in clinical trials for EGFR-specific peptide vaccines in GBM and LUAD, and they show promise but lack demonstrated clinical efficacy. Using AutoPepVax, our analysis of 96 EGFR mutations identified 368 potential MHC-I-restricted epitope–HLA pairs from 49,113 candidates and 430 potential MHC-II-restricted pairs from 168,669 candidates. Notably, 19 mutations presented viable epitopes for MHC I and II restrictions. To evaluate the potential impact of a pan-cancer vaccine composed of these epitopes, we used our program, PCOptim, to curate a minimal list of epitopes with optimal population coverage. The world population coverage of our list ranged from 81.8% to 98.5% for MHC Class II and Class I epitopes, respectively. From our list of epitopes, we constructed 3D epitope–MHC models for six MHC-I-restricted and four MHC-II-restricted epitopes, demonstrating their epitope binding potential and interaction with T-cell receptors. AutoPepVax’s comprehensive approach to in silico epitope selection addresses vaccine safety, efficacy, and broad applicability. Future studies aim to validate the AutoPepVax-designed vaccines with murine tumor models that harbor the studied mutations.
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Caoili, Salvador Eugenio C. "Expressing Redundancy among Linear-Epitope Sequence Data Based on Residue-Level Physicochemical Similarity in the Context of Antigenic Cross-Reaction." Advances in Bioinformatics 2016 (May 4, 2016): 1–13. http://dx.doi.org/10.1155/2016/1276594.
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Epitope-based design of vaccines, immunotherapeutics, and immunodiagnostics is complicated by structural changes that radically alter immunological outcomes. This is obscured by expressing redundancy among linear-epitope data as fractional sequence-alignment identity, which fails to account for potentially drastic loss of binding affinity due to single-residue substitutions even where these might be considered conservative in the context of classical sequence analysis. From the perspective of immune function based on molecular recognition of epitopes, functional redundancy of epitope data (FRED) thus may be defined in a biologically more meaningful way based on residue-level physicochemical similarity in the context of antigenic cross-reaction, with functional similarity between epitopes expressed as the Shannon information entropy for differential epitope binding. Such similarity may be estimated in terms of structural differences between an immunogen epitope and an antigen epitope with reference to an idealized binding site of high complementarity to the immunogen epitope, by analogy between protein folding and ligand-receptor binding; but this underestimates potential for cross-reactivity, suggesting that epitope-binding site complementarity is typically suboptimal as regards immunologic specificity. The apparently suboptimal complementarity may reflect a tradeoff to attain optimal immune function that favors generation of immune-system components each having potential for cross-reactivity with a variety of epitopes.
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Lohnas, Gerald L., Steven F. Roberts, Aprile Pilon, and Alfonso Tramontano. "Epitope-Specific Antibody and Suppression of Autoantibody Responses Against a Hybrid Self Protein." Journal of Immunology 161, no. 12 (December 15, 1998): 6518–25. http://dx.doi.org/10.4049/jimmunol.161.12.6518.
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Abstract This study addresses the relationship of epitope-specific Ab responses and alternative autoantibody responses in a model system in which an antigenized self protein serves as the carrier for a defined heterologous B cell epitope. Ubiquitin, a nonimmunogenic self protein, was engineered to present heterologous B and T cell epitopes in the recombinant molecule. Fusion to the C terminus introduced a universal T cell epitope from a Mycobacterium tuberculosis Ag. The B cell epitope was created by inserting a 12-residue loop sequence of HIV-1 gp120 at a surface-exposed position of ubiquitin. These modifications preserved the ubiquitin fold, allowing a new conformational epitope to be presented among native self epitopes. Mice immunized with the hybrid protein bearing only the mycobacterial T cell epitope elicited a strong autoantibody response to native ubiquitin. In contrast, antisera elicited against hybrid ubiquitin presenting the HIV B cell epitope reacted specifically with the foreign epitope but not with native ubiquitin. Absence of autoantibody in the response was attributed to poor competition of autoreactive B cells for limiting T cell help. Both types of responses were associated with Th responses to defined epitopes of the ubiquitin hybrid protein. These results may have implications for a tolerance mechanism dependent on B-T cell cooperation.
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Cloeckaert, Axel, Vincent Weynants, Jacques Godfroid, Jean-Michel Verger, Maggy Grayon, and Michel S. Zygmunt. "O-Polysaccharide Epitopic Heterogeneity at the Surface of Brucella spp. Studied by Enzyme-Linked Immunosorbent Assay and Flow Cytometry." Clinical Diagnostic Laboratory Immunology 5, no. 6 (November 1, 1998): 862–70. http://dx.doi.org/10.1128/cdli.5.6.862-870.1998.
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ABSTRACT Smooth Brucella strains are classified into three serotypes, i.e., A+M−, A−M+, and A+M+, according to slide agglutination with A and M monospecific polyclonal sera. The epitopes involved have been located on the O-polysaccharide (O-PS) moiety of the smooth lipopolysaccharide (S-LPS), which represents the most exposed antigenic structure on the surface ofBrucella spp. By use of monoclonal antibodies (MAbs) a number of epitope specificities on the O-PS have been reported: A, M, and epitopes shared by both A and M dominant strains, which have been named common (C) epitopes. The latter have been further subdivided, according to relative MAb binding in enzyme-linked immunosorbent assays (ELISA) to A- and M-dominant Brucella strains and to cross-reacting Yersinia enterocolitica O:9, into five epitopic specificities: C (M>A), C (M=A), C/Y (M>A), C/Y (M=A), and C/Y (A>M). In the present study, we studied the occurrence of these epitopes at the surface of representatives of all Brucellaspecies and biovars including the live vaccine strains by analyzing the levels of MAb binding to whole Brucella cells in ELISA and flow cytometry assays. In ELISA, the level of MAb binding correlated well with the previously defined epitope specificity and the serotype defined by polyclonal sera for each Brucella species, biovar, or strain. However, MAbs to the C (M=A) and C (M>A) epitopes showed insignificant binding to B. suis biovar 2 strains and bound at lower titers to B. suis biovar 3 and B. neotomae than to the other Brucella strains. Some of the flow cytometry results were contradictory to those obtained by ELISA. In fact, it appeared by flow cytometry that all O-PS epitopes, including the A and M epitopes, are shared to different degrees byBrucella spp. which nevertheless show a high degree of O-PS heterogeneity according to MAb binding intensities. The subdivision of MAb specificities and Brucella serotypes was therefore less evident by flow cytometry than by ELISA. Whereas in ELISA the MAb specific for the A epitope showed insignificant binding to Y. enterocolitica O:9, this MAb bound strongly to Y. enterocolitica O:9 in flow cytometry. One of the two MAbs specific to the C (M=A) epitope also bound at a low but significant level to B. suis biovar 2 strains. However, as in ELISA the MAb specific for the C (M>A) epitope did not bind at all to B. suis biovar 2 strains in flow cytometry. Flow cytometry provided new information regarding specificity of the MAbs and may further explain some aspects of the capacity of passive protection of some MAbs against smooth Brucella infection in mice. As shown in the present study the occurrence of Brucella strains apparently completely devoid of one specific C O-PS epitope (e.g., B. suis biovar 2 devoid of the C [M>A] epitope) offers the possibility of obtaining vaccine strains devoid of a diagnostic O-PS epitope, which could further help to resolve the problem of discriminating infected from vaccinated animals that remains a major goal in brucellosis research.
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Savsani, Kush, Gabriel Jabbour, and Sivanesan Dakshanamurthy. "A New Epitope Selection Method: Application to Design a Multi-Valent Epitope Vaccine Targeting HRAS Oncogene in Squamous Cell Carcinoma." Vaccines 10, no. 1 (December 31, 2021): 63. http://dx.doi.org/10.3390/vaccines10010063.
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We developed an epitope selection method for the design of MHC targeting peptide vaccines. The method utilizes predictions for several clinical checkpoint filters, including binding affinity, immunogenicity, antigenicity, half-life, toxicity, IFNγ release, and instability. The accuracy of the prediction tools for these filter variables was confirmed using experimental data obtained from the Immune Epitope Database (IEDB). We also developed a graphical user interface computational tool called ‘PCOptim’ to assess the success of an epitope filtration method. To validate the filtration methods, we used a large data set of experimentally determined, immunogenic SARS-CoV-2 epitopes, which were obtained from a meta-analysis. The validation process proved that placing filters on individual parameters was the most effective method to select top epitopes. For a proof-of-concept, we designed epitope-based vaccine candidates for squamous cell carcinoma, selected from the top mutated epitopes of the HRAS gene. By comparing the filtered epitopes to PCOptim’s output, we assessed the success of the epitope selection method. The top 15 mutations in squamous cell carcinoma resulted in 16 CD8 epitopes which passed the clinical checkpoints filters. Notably, the identified HRAS epitopes are the same as the clinical immunogenic HRAS epitope-based vaccine candidates identified by the previous studies. This indicates further validation of our filtration method. We expect a similar turn-around for the other designed HRAS epitopes as a vaccine candidate for squamous cell carcinoma. Furthermore, we obtained a world population coverage of 89.45% for the top MHC Class I epitopes and 98.55% population coverage in the absence of the IFNγ release clinical checkpoint filter. We also identified some of the predicted human epitopes to be strong binders to murine MHC molecules, which provides insight into studying their immunogenicity in preclinical models. Further investigation in murine models could warrant the application of these epitopes for treatment or prevention of squamous cell carcinoma.
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Mazumder, Lincon, Md Rakibul Hasan, Kanij Fatema, Shamima Begum, Abul Kalam Azad, and Mohammad Ariful Islam. "Identification of B and T Cell Epitopes to Design an Epitope-Based Peptide Vaccine against the Cell Surface Binding Protein of Monkeypox Virus: An Immunoinformatics Study." Journal of Immunology Research 2023 (February 22, 2023): 1–14. http://dx.doi.org/10.1155/2023/2274415.
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Background. Although the monkeypox virus-associated illness was previously confined to Africa, recently, it has started to spread across the globe and become a significant threat to human lives. Hence, this study was designed to identify the B and T cell epitopes and develop an epitope-based peptide vaccine against this virus’s cell surface binding protein through an in silico approach to combat monkeypox-associated diseases. Results. The analysis revealed that the cell surface binding protein of the monkeypox virus contains 30 B cell and 19 T cell epitopes within the given parameter. Among the T cell epitopes, epitope “ILFLMSQRY” was found to be one of the most potential peptide vaccine candidates. The docking analysis revealed an excellent binding affinity of this epitope with the human receptor HLA-B ∗ 15:01 with a very low binding energy (-7.5 kcal/mol). Conclusion. The outcome of this research will aid the development of a T cell epitope-based peptide vaccine, and the discovered B and T cell epitopes will facilitate the creation of other epitope and multi-epitope-based vaccines in the future. This research will also serve as a basis for further in vitro and in vivo analysis to develop a vaccine that is effective against the monkeypox virus.
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Abesamis, Lyn Marielle I., Evan Gilles A. Aliping, Fritz Khrystian Gabriel H. Armada, Mirriam F. Danao, Pamela Denise B. del Valle, Zypher Jude G. Regencia, Emmanuel S. Baja, and Antonio D. Ligsay. "In Silico Comparative Analysis of Predicted B Cell Epitopes against Dengue Virus (Serotypes 1–4) Isolated from the Philippines." Vaccines 10, no. 8 (August 5, 2022): 1259. http://dx.doi.org/10.3390/vaccines10081259.
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Dengue is a viral mosquito-borne disease that rapidly spreads in tropical and subtropical countries, including the Philippines. One of its most distinguishing characteristics is the ability of the Dengue Virus (DENV) to easily surpass the innate responses of the body, thus activating B cells of the adaptive immunity to produce virus-specific antibodies. Moreover, Dengvaxia® is the only licensed vaccine for DENV, but recent studies showed that seronegative individuals become prone to increased disease severity and hospitalization. Owing to this limitation of the dengue vaccine, this study determined and compared consensus and unique B cell epitopes among each DENV (1–4) Philippine isolate to identify potential areas of interest for future vaccine studies and therapeutic developments. An in silico-based epitope prediction of forty (40) DENV 1–4 strains, each serotype represented by ten (10) sequences from The National Center for Biotechnology Information (NCBI), was conducted using Kolaskar and Tongaonkar antigenicity, Emini surface accessibility, and Parker hydrophilicity prediction in Immune Epitope Database (IEDB). Results showed that five (5) epitopes were consensus for DENV-1 with no detected unique epitope, one (1) consensus epitope for DENV-2 with two (2) unique epitopes, one (1) consensus epitope for DENV-3 plus two (2) unique epitopes, and two (2) consensus epitopes and one (1) unique epitope for DENV-4. The findings of this study would contribute to determining potential vaccine and diagnostic marker candidates for further research studies and immunological applications against DENV (1–4) Philippine isolates.
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Manuel, Edwin R., William A. Charini, Pritha Sen, Fred W. Peyerl, Marcelo J. Kuroda, Jörn E. Schmitz, Patrick Autissier, Dennis A. Sheeter, Bruce E. Torbett, and Norman L. Letvin. "Contribution of T-Cell Receptor Repertoire Breadth to the Dominance of Epitope-Specific CD8+ T-Lymphocyte Responses." Journal of Virology 80, no. 24 (October 11, 2006): 12032–40. http://dx.doi.org/10.1128/jvi.01479-06.
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ABSTRACT Dominant epitope-specific CD8+ T-lymphocyte responses play a central role in controlling viral spread. We explored the basis for the development of this focused immune response in simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys through the use of two dominant (p11C and p199RY) and two subdominant (p68A and p56A) epitopes. Using real-time PCR to quantitate T-cell receptor (TCR) variable region beta (Vβ) family usage, we show that CD8+ T-lymphocyte populations specific for dominant epitopes are characterized by a diverse Vβ repertoire, whereas those specific for subdominant epitopes employ a dramatically more focused Vβ repertoire. We also demonstrate that dominant epitope-specific CD8+ T lymphocytes employ TCRs with multiple CDR3 lengths, whereas subdominant epitope-specific cells employ TCRs with a more restricted CDR3 length. Thus, the relative dominance of an epitope-specific CD8+ T-lymphocyte response reflects the clonal diversity of that response. These findings suggest that the limited clonal repertoire of subdominant epitope-specific CD8+ T-lymphocyte populations may limit the ability of these epitope-specific T-lymphocyte populations to expand and therefore limit the ability of these cell populations to contribute to the control of viral replication.
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Chow, SN, KW Chen, SL Su, J. Tung, and CY Lee. "Generation and epitope analysis of thyroid stimulating hormone‐specific monoclonal antibodies for enzyme immunoassays." Biotechnology and Applied Biochemistry 10, no. 2 (April 1988): 137–42. http://dx.doi.org/10.1111/j.1470-8744.1988.tb00009.x.
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By using an improved hybridoma technique with a semisolid medium of methylcellulose for initial cloning, numerous high affinity monoclonal antibodies against human thyroid stimulating hormone (TSH) were generated. These antibodies were characterized with respect to their subunit and epitope specificity. Epitope analysis of antibodies specific to the beta‐subunit of TSH was performed by a sandwich pairing procedure. Based on the results of this analysis, it was concluded that there are four distinct TSH‐specific epitopes on the beta‐subunit of TSH; these are designated a, b, c, and ab. The five antibodies binding to epitopes a, b, and c are not mutually exclusive. However, the antibody binding to epitope ab prevents further binding of other antibodies to epitope a or b, but not to epitope c. This epitope analysis enabled us to combine three high affinity monoclonal antibodies, each of which reacts with epitopes a, b, and c, respectively, in a typical sandwich enzyme immunoassay. One was immobilized on polystyrene beads and the other two were conjugated with horseradish peroxidase and served as the second antibodies. This enzyme immunoassay can be performed within 90 min and with a minimum sensitivity of 0.2‐0.3 microIU/ml.
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Lautscham, Georg, Sabine Mayrhofer, Graham Taylor, Tracey Haigh, Alison Leese, Alan Rickinson, and Neil Blake. "Processing of a Multiple Membrane Spanning Epstein-Barr Virus Protein for Cd8+T Cell Recognition Reveals a Proteasome-Dependent, Transporter Associated with Antigen Processing–Independent Pathway." Journal of Experimental Medicine 194, no. 8 (October 8, 2001): 1053–68. http://dx.doi.org/10.1084/jem.194.8.1053.
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Epstein-Barr virus (EBV) latent membrane protein (LMP)2 is a multiple membrane spanning molecule which lacks ectodomains projecting into the lumen of the endoplasmic reticulum (ER). Human CD8+ cytotoxic T lymphocytes (CTL)s recognize a number of epitopes within LMP2. Assays with epitope-specific CTLs in two different cell backgrounds lacking the transporter associated with antigen processing (TAP) consistently show that some, but not all, LMP2 epitopes are presented in a TAP-independent manner. However, unlike published examples of TAP-independent processing from endogenously expressed antigens, presentation of TAP-independent LMP2 epitopes was abrogated by inhibition of proteasomal activity. We found a clear correlation between hydrophobicity of the LMP2 epitope sequence and TAP independence, and experiments with vaccinia minigene constructs expressing cytosolic epitope peptides confirmed that these more hydrophobic peptides were selectively able to access the HLA class I pathway in TAP-negative cells. Furthermore, the TAP-independent phenotype of particular epitope sequences did not require membrane location of the source antigen since (i) TAP-independent LMP2 epitopes inserted into an EBV nuclear antigen and (ii) hydrophobic epitope sequences native to EBV nuclear antigens were both presented in TAP-negative cells. We infer that there is a proteasome-dependent, TAP-independent pathway of antigen presentation which hydrophobic epitopes can selectively access.
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Mufida, Diana Chusna, Ayu Munawaroh Aziz, and Nurrul Izza Misturiansyah. "Potential of B-Cell Epitopes Protein Ag85 Complex Mycobacterium Tuberculosis as Serodiagnostic Antigen of Tuberculosis by in Silico Study." Journal of Biomedicine and Translational Research 9, no. 1 (April 28, 2023): 7–13. http://dx.doi.org/10.14710/jbtr.v9i1.16379.
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Background: The high case of tuberculosis which isn't followed by good detection becomes an urgency for the diagnostic developments. One of them with immunodiagnostic principle uses B-cell Ag85 complex epitope. The design of the diagnostic epitope was performed by mapping the B cell epitope used in silico studies.Objective: The purpose of this research is to analyze antigenicity, physicochemical which affect immunogenicity, and homology of B-cell Ag85 complex epitope with the strain which circulates in Indonesia. Methods: The samples used were taken from the NCBI protein bank with access numbers P9WQP3 for Ag85A, P9WQP1 for Ag85B, and P9WQN9 for Ag85C. The sequences were analyzed using IEDB (Bepipred) software as the epitope prediction, VaxiJen as antigenicity prediction, ProtParam as physicochemical properties prediction, and BLASTP NCBI as sequence alignment.Results: Twenty seven epitopes were antigenic with 0.4297 to 2.6007 scores and the molecular weight was from 619.59 Da to 3145.36 Da. This research also obtained eleven stable and hydrophilic epitopes. The alignment of 11 candidate epitopes with the strain which circulates in Indonesia, had a similarity percentage of 85.71%-100% and 3 epitopes had a more significant score.Conclusion: Three epitopes of Ag85 complex; Ag85A (212-235), Ag85B (209-237), and Ag85C (283-310), were universal antigens and can be developed into diagnostic antigens in Indonesia.
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Kim, Ae, Isamu Hartman, David Lanar, Tatiana Boronina, Robert Cole, and Scheherazade Sadegh-Nasseri. "The hierarchy of two different immunodominant epitopes influences CD4+ T cell responses (APP5P.112)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 183.14. http://dx.doi.org/10.4049/jimmunol.194.supp.183.14.
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Abstract A cell-free antigen processing system for MHC class II was recently reported that has proved to be effective in identifying physiologically relevant CD4+ T cell epitopes from proteins (Hartman/Kim, et al. Nat Med. 16, pp1333-40 (2010)). This system has also provided insights into the mechanism of epitope selection (Kim, et al. Nat Commun. 5:5369 (2014)). We applied this system to a mixture of two different antigens, H5N1-HA1 and LSA-NRC of malaria to examine if there would be a competition for epitope capture. While each dominant epitope from either protein was identified in the system individually, when both proteins were simultaneously present, HA1 dominant epitope was predominantly selected. The competition between different epitopes was verified in vivo by immunizing HLA-DR1 transgenic mice with a mixture of HA1 and LSA-NRC. A recall T cell proliferation showed that T cells responded only to the HA1 and its dominant epitope. These observations did not change even when DR1 mice were immunized with increasing molar ratio of LSA-NRC to HA1 (1:1, 2:1 or 4:1). However, T cell responded to both antigens if mice were immunized first with LSA-NRC dominant epitope followed by HA1 epitope. These findings show a hierarchy for the selection of dominant epitopes from different proteins during antigen processing. Immunodominance hierarchy among different antigens influences the epitope presentation to the same MHC II, which can be important factor for designing combination vaccines.
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Lee, Sujin, Hoyin Mok, Daivd Wright, and James E. Crowe. "Modulation of the CD8+ T cell response to subdominant epitopes of respiratory syncytial virus by deletion of an immunodominant epitope (43.9)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S37—S38. http://dx.doi.org/10.4049/jimmunol.178.supp.43.9.
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Abstract Cytotoxic T lymphocytes (CTLs) are critical for control of respiratory syncytial virus (RSV) infection in humans and mice. Recently, we identified a new H-2Kd- restricted subdominant epitope in the RSV M2 protein. This finding allowed us to study the frequency of T lymphocytes responding two H-2Kd-restricted epitopes, M282–90 and M2127–135, following RSV infection in both lymphoid and non-lymphoid tissues. The ratio of T lymphocytes during the peak CTL response to RSV infection that were specific for immunodominant or subdominant was approximately 3:1 in the spleen and 10:1 in the lung. This ratio was observed consistently in primary or secondary infection. In addition, we showed that the kinetics of response against the two epitopes was regulated differently; the response to the subdominant epitope was delayed compared to the dominant epitope. In further studies, we demonstrated that modification of residues at positions 2 and 9 in the dominant M282–90 epitope altered the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 or mutant M2 proteins. Immunogenicity of the subdominant epitope M2127–135 was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to subdominant epitopes. Taken together, our findings have implications for understanding the immune response to RSV infection or vaccination and provide insight into methods for the rational design of vaccines that induce CD8+ T cells.
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Yamada, Takashi, Hiroshi Uchiyama, Toshi Nagata, Masato Uchijima, Takafumi Suda, Kingo Chida, Hirotoshi Nakamura, and Yukio Koide. "Protective Cytotoxic T Lymphocyte Responses Induced by DNA Immunization against Immunodominant and Subdominant Epitopes ofListeria monocytogenes Are Noncompetitive." Infection and Immunity 69, no. 5 (May 1, 2001): 3427–30. http://dx.doi.org/10.1128/iai.69.5.3427-3430.2001.
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ABSTRACT Taking advantage of the fact that plasmid DNA encoding a single cytotoxic T lymphocyte (CTL) epitope can induce CTLs, we examined the influence of T-cell responses to dominant epitopes on those to a subdominant epitope derived from Listeria monocytogenes. Our data suggest that interaction between T cells against dominant and subdominant epitopes does not operate in the generation of the hierarchy. Furthermore, we found that a single dominant epitope is sufficient for the induction of protective immunity.
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Biner, Daniel W., Jason S. Grosch, and Peter J. Ortoleva. "B-cell epitope discovery: The first protein flexibility-based algorithm–Zika virus conserved epitope demonstration." PLOS ONE 18, no. 3 (March 15, 2023): e0262321. http://dx.doi.org/10.1371/journal.pone.0262321.
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Antibody-antigen interaction–at antigenic local environments called B-cell epitopes–is a prominent mechanism for neutralization of infection. Effective mimicry, and display, of B-cell epitopes is key to vaccine design. Here, a physical approach is evaluated for the discovery of epitopes which evolve slowly over closely related pathogens (conserved epitopes). The approach is 1) protein flexibility-based and 2) demonstrated with clinically relevant enveloped viruses, simulated via molecular dynamics. The approach is validated against 1) seven structurally characterized enveloped virus epitopes which evolved the least (out of thirty-nine enveloped virus-antibody structures), 2) two structurally characterized non-enveloped virus epitopes which evolved slowly (out of eight non-enveloped virus-antibody structures), and 3) eight preexisting epitope and peptide discovery algorithms. Rationale for a new benchmarking scheme is presented. A data-driven epitope clustering algorithm is introduced. The prediction of five Zika virus epitopes (for future exploration on recombinant vaccine technologies) is demonstrated. For the first time, protein flexibility is shown to outperform solvent accessible surface area as an epitope discovery metric.
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Lin, Lin, Beverlie Baquir, Brandon Tan, Tiffany Ho, Paul Pantapalangkoor, Kristine Hujer, Robert A. Bonomo, and Brad Spellberg. "Vaccine Dose Alters Immunodominant Epitopes and Cytokine Profile in Response to the Acinetobacter baumannii rOmpA Vaccine (52.12)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 52.12. http://dx.doi.org/10.4049/jimmunol.188.supp.52.12.
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Abstract Background: The rOmpA vaccine protects mice from lethal infection caused by extreme-drug-resistant (XDR) Acinetobacter baumannii. The role of dose and epitope in immunology of the rOmpA vaccine was explored. Methods: The rOmpA vaccine was epitope-mapped using overlapping peptides to stimulate splenocytes from mice administered varying vaccine doses. B cell epitopes were mapped by peptide immunoblotting. Results: Vaccination with rOmpA plus Al(OH)3 adjuvant induced IFN-γ, IL-4, and IL-17+ splenocytes. Epitope mapping revealed distinct T cell epitopes that induced IFNγ+, IL-4+, and IL-17A+ splenocytes. B cell and T cell epitopes had only partial overlap, and the overlapping epitopes induced more potent IL-4 responses from splenocytes than IFN-γ responses. More than twice as many peptides induced IFN-γ, IL-4, and IL-17 responses when used to active splenocytes from high dose (100 µg) vaccinated mice versus low dose (3 µg) vaccinated mice. The IFN-γ:IL-4 ratios induced by each peptide varied depending on the dose of whole protein used to vaccinate the mice. Conclusions: rOmpA dose alters the epitope profile of responding lymphocytes, with higher vaccine doses resulting in epitope spreading. Furthermore, each individual epitope may stimulate a different cytokine profile from responding lymphocytes depending on the dose of vaccine used to immunize the mice.
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Sanchez-Trincado, Jose L., Marta Gomez-Perosanz, and Pedro A. Reche. "Fundamentals and Methods for T- and B-Cell Epitope Prediction." Journal of Immunology Research 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/2680160.
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Adaptive immunity is mediated by T- and B-cells, which are immune cells capable of developing pathogen-specific memory that confers immunological protection. Memory and effector functions of B- and T-cells are predicated on the recognition through specialized receptors of specific targets (antigens) in pathogens. More specifically, B- and T-cells recognize portions within their cognate antigens known as epitopes. There is great interest in identifying epitopes in antigens for a number of practical reasons, including understanding disease etiology, immune monitoring, developing diagnosis assays, and designing epitope-based vaccines. Epitope identification is costly and time-consuming as it requires experimental screening of large arrays of potential epitope candidates. Fortunately, researchers have developed in silico prediction methods that dramatically reduce the burden associated with epitope mapping by decreasing the list of potential epitope candidates for experimental testing. Here, we analyze aspects of antigen recognition by T- and B-cells that are relevant for epitope prediction. Subsequently, we provide a systematic and inclusive review of the most relevant B- and T-cell epitope prediction methods and tools, paying particular attention to their foundations.
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Long, H. M., T. A. Haigh, N. H. Gudgeon, A. M. Leen, C. W. Tsang, J. Brooks, E. Landais, et al. "CD4+ T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines." Journal of Virology 79, no. 8 (April 15, 2005): 4896–907. http://dx.doi.org/10.1128/jvi.79.8.4896-4907.2005.
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ABSTRACT There is considerable interest in the potential of Epstein-Barr virus (EBV) latent antigen-specific CD4+ T cells to act as direct effectors controlling EBV-induced B lymphoproliferations. Such activity would require direct CD4+ T-cell recognition of latently infected cells through epitopes derived from endogenously expressed viral proteins and presented on the target cell surface in association with HLA class II molecules. It is therefore important to know how often these conditions are met. Here we provide CD4+ epitope maps for four EBV nuclear antigens, EBNA1, -2, -3A, and -3C, and establish CD4+ T-cell clones against 12 representative epitopes. For each epitope we identify the relevant HLA class II restricting allele and determine the efficiency with which epitope-specific effectors recognize the autologous EBV-transformed B-lymphoblastoid cell line (LCL). The level of recognition measured by gamma interferon release was consistent among clones to the same epitope but varied between epitopes, with values ranging from 0 to 35% of the maximum seen against the epitope peptide-loaded LCL. These epitope-specific differences, also apparent in short-term cytotoxicity and longer-term outgrowth assays on LCL targets, did not relate to the identity of the source antigen and could not be explained by the different functional avidities of the CD4+ clones; rather, they appeared to reflect different levels of epitope display at the LCL surface. Thus, while CD4+ T-cell responses are detectable against many epitopes in EBV latent proteins, only a minority of these responses are likely to have therapeutic potential as effectors directly recognizing latently infected target cells.
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He, Shudong, Jinlong Zhao, Walid Elfalleh, Mohamed Jemaà, Hanju Sun, Xianbao Sun, Mingming Tang, Qian He, Zeyu Wu, and Florian Lang. "In Silico Identification and in Vitro Analysis of B and T-Cell Epitopes of the Black Turtle Bean (Phaseolus Vulgaris L.) Lectin." Cellular Physiology and Biochemistry 49, no. 4 (2018): 1600–1614. http://dx.doi.org/10.1159/000493496.
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Background/Aims: The incidence of lectin allergic disease is increasing in recent decades, and definitive treatment is still lacking. Identification of B and T-cell epitopes of allergen will be useful in understanding the allergen antibody responses as well as aiding in the development of new diagnostics and therapy regimens for lectin poisoning. In the current study, we mainly addressed these questions. Methods: Three-dimensional structure of the lectin from black turtle bean (Phaseolus vulgaris L.) was modeled using the structural template of Phytohemagglutinin from P. vulgaris (PHA-E, PDB ID: 3wcs.1.A) with high identity. The B and T-cell epitopes were screened and identified by immunoinformatics and subsequently validated by ELISA, lymphocyte proliferation and cytokine profile analyses. Results: Seven potential B-cell epitopes (B1 to B7) were identified by sequence and structure based methods, while three T-cell epitopes (T1 to T3) were identified by the predictions of binding score and inhibitory concentration. The epitope peptides were synthesized. Significant IgE binding capability was found in B-cell epitopes (B2, B5, B6 and B7) and T2 (a cryptic B-cell epitope). T1 and T2 induced significant lymphoproliferation, and the release of IL-4 and IL-5 cytokine confirmed the validity of T-cell epitope prediction. Abundant hydrophobic amino acids were found in B-cell epitope and T-cell epitope regions by amino acid analysis. Positively charged amino acids, such as His residue, might be more favored for B-cell epitope. Conclusion: The present approach can be applied for the identification of epitopes in novel allergen proteins and thus for designing diagnostics and therapies in lectin allergy.
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Goulder, P. J. R., A. K. Sewell, D. G. Lalloo, D. A. Price, J. A. Whelan, J. Evans, G. P. Taylor, et al. "Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation." Journal of Experimental Medicine 185, no. 8 (April 21, 1997): 1423–33. http://dx.doi.org/10.1084/jem.185.8.1423.
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Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201–restricted SLYNTVATL and HLA-A3–restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201–restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.
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Fischer, Marion F. S., James E. Crowe, and Jens Meiler. "Computational epitope mapping of class I fusion proteins using low complexity supervised learning methods." PLOS Computational Biology 18, no. 12 (December 7, 2022): e1010230. http://dx.doi.org/10.1371/journal.pcbi.1010230.
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Antibody epitope mapping of viral proteins plays a vital role in understanding immune system mechanisms of protection. In the case of class I viral fusion proteins, recent advances in cryo-electron microscopy and protein stabilization techniques have highlighted the importance of cryptic or ‘alternative’ conformations that expose epitopes targeted by potent neutralizing antibodies. Thorough epitope mapping of such metastable conformations is difficult but is critical for understanding sites of vulnerability in class I fusion proteins that occur as transient conformational states during viral attachment and fusion. We introduce a novel method Accelerated class I fusion protein Epitope Mapping (AxIEM) that accounts for fusion protein flexibility to improve out-of-sample prediction of discontinuous antibody epitopes. Harnessing data from previous experimental epitope mapping efforts of several class I fusion proteins, we demonstrate that accuracy of epitope prediction depends on residue environment and allows for the prediction of conformation-dependent antibody target residues. We also show that AxIEM can identify common epitopes and provide structural insights for the development and rational design of vaccines.
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Yuan, Tom Z., Ana G. Lujan Hernandez, Erica Keane, Qiang Liu, Fumiko Axelrod, Shweta Kailasan, Madeleine Noonan-Shueh, Mohammad Javad Aman, Aaron K. Sato, and Yasmina N. Abdiche. "Rapid exploration of the epitope coverage produced by an Ebola survivor to guide the discovery of therapeutic antibody cocktails." Antibody Therapeutics 3, no. 3 (July 2020): 167–78. http://dx.doi.org/10.1093/abt/tbaa016.
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ABSTRACT Background Development of successful neutralizing antibodies is dependent upon broad epitope coverage to increase the likelihood of achieving therapeutic function. Recent advances in synthetic biology have allowed us to conduct an epitope binning study on a large panel of antibodies identified to bind to Ebola virus glycoprotein with only published sequences. Methods and Results A rapid, first-pass epitope binning experiment revealed seven distinct epitope families that overlapped with known structural epitopes from the literature. A focused set of antibodies was selected from representative clones per bin to guide a second-pass binning that revealed previously unassigned epitopes, confirmed epitopes known to be associated with neutralizing antibodies, and demonstrated asymmetric blocking of EBOV GP from allosteric effectors reported from literature. Conclusions Critically, this workflow allows us to probe the epitope landscape of EBOV GP without any prior structural knowledge of the antigen or structural benchmark clones. Incorporating epitope binning on hundreds of antibodies during early stage antibody characterization ensures access to a library’s full epitope coverage, aids in the identification of high quality reagents within the library that recapitulate this diversity for use in other studies, and ultimately enables the rational development of therapeutic cocktails that take advantage of multiple mechanisms of action such as cooperative synergistic effects to enhance neutralization function and minimize the risk of mutagenic escape. The use of high-throughput epitope binning during new outbreaks such as the current COVID-19 pandemic is particularly useful in accelerating timelines due to the large amount of information gained in a single experiment.
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Ostrowski, M., J. A. Galeota, A. M. Jar, K. B. Platt, F. A. Osorio, and O. J. Lopez. "Identification of Neutralizing and Nonneutralizing Epitopes in the Porcine Reproductive and Respiratory Syndrome Virus GP5 Ectodomain." Journal of Virology 76, no. 9 (May 1, 2002): 4241–50. http://dx.doi.org/10.1128/jvi.76.9.4241-4250.2002.
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ABSTRACT After infection of swine with porcine reproductive and respiratory syndrome virus (PRRSV), there is a rapid rise of PRRSV-specific nonneutralizing antibodies (NNA), while neutralizing antibodies (NA) are detectable not sooner than 3 weeks later. To characterize neutralizing epitopes, we selected phages from a 12-mer phage display library using anti-PRRSV neutralizing monoclonal antibody (MAb) ISU25-C1. In addition, phages carrying peptides recognized by swine antibodies with high seroneutralizing titer were isolated after subtracting from the library those clones binding to swine anti-PRRSV serum with no neutralizing activity. Two epitopes located in the ectodomain of PRRSV GP5 were identified. One of these epitopes, which we named epitope B, was recognized both by neutralizing MAb ISU25-C1 and swine neutralizing serum (NS) but not by swine nonneutralizing serum (NNS), indicating that it is a neutralizing epitope. Epitope B is sequential, conserved among isolates, and not immunodominant. Antibodies directed against it are detected in serum late after infection. In contrast, the other epitope, which we named epitope A, is hypervariable and immunodominant. Antibodies against it appear early after infection with PRRSV. This epitope is recognized by swine NNA but is not recognized by either neutralizing MAb ISU25-C1 or swine NA, indicating that it is not involved in PRRSV neutralization. During infection with PRRSV, epitope A may act as a decoy, eliciting most of the antibodies directed to GP5 and delaying the induction of NA against epitope B for at least 3 weeks. These results are relevant to the design of vaccines against PRRSV.
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Zhai, Yougang, Zhenyu Zhong, Mohammadreza Zariffard, Gregory Spear, and Liang Qiao. "BPV VLPs presenting HIV-1 epitopes from membrane-proximal external region of gp41 induced HIV-specific mucosal and systemic cross-clade neutralizing antibodies (P4507)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 179.16. http://dx.doi.org/10.4049/jimmunol.190.supp.179.16.
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Abstract Two conserved epitopes, located in the membrane-proximal external region (MPER) of gp41 of the human immunodeficiency virus type 1 (HIV-1) envelope spike, are promising targets for vaccine design in efforts to elicit 2F5 and 4E10-like anti-HIV-1 broadly neutralizing antibodies. Since most HIV-1 infections initiate at mucosal surfaces, the induction of mucosal neutralizing antibodies is necessary and of utmost importance to counteract HIV-1 infection. Here, we utilized a mucosal vaccine vector, bovine papillomavirus (BPV) virus-like particles (VLPs), as a platform to present HIV-1 neutralizing epitopes by inserting the extended 2F5 (ELLELDKWASLWN) or 4E10 epitope (NWFDITNWLWYIK) or the MPER domain into surface loops of BPV L1 respectively. In order to enhance the presentation of the neutralizing epitopes, the modified 4E10 and 2F5 epitope were presented by inserting two alanines (AA) in N-terminal, C-terminal or both terminals of the epitopes. The chimeric VLPs presenting MPER domain resembled the HIV-1 natural epitopes better than the chimeric VLPs presenting unmodified single ones. Moreover, N-terminal modified 2F5 epitope further enhanced the epitope presentation when inserted in D-E loop. Oral immunization of mice with the chimeric VLPs displaying 2F5 or MPER elicited epitope-specific serum IgGs and mucosal secretory IgAs. The antibodies induced by chimeric VLPs presenting MPER domain are capable of neutralizing clade B and clade C HIV-1 viruses, although modest.
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Weidt, Gunnar, Olaf Utermöhlen, Jochen Heukeshoven, Fritz Lehmann-Grube, and Wolfgang Deppert. "Relationship Among Immunodominance of Single CD8+ T Cell Epitopes, Virus Load, and Kinetics of Primary Antiviral CTL Response." Journal of Immunology 160, no. 6 (March 15, 1998): 2923–31. http://dx.doi.org/10.4049/jimmunol.160.6.2923.
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Abstract The primary CTL response of BALB/c mice infected with the lymphocytic choriomeningitis (LCM) virus strain WE is directed exclusively against one major epitope, n118, whereas a viral variant, ESC, that does not express n118 induces CTL against minor epitopes. We identified one minor epitope, g283, that induces primary lytic activity in ESC-infected mice. Infections of mice with WE and ESC were used to study the hierarchical control of a T cell response. Presentation of minor epitopes is not reduced in WE-infected cells. Generation of CTL against n118 does not suppress the generation of minor epitope-specific CTL systemically, as mice coinfected with WE and ESC developed CTL against n118 and g283. However, elimination of ESC and development of minor epitope-specific CTL in ESC infection were slower than elimination of WE and development of CTL against n118. CD8+ T cells against the minor epitope were activated in ESC and WE infection, but did not expand in the latter to show lytic activity in a primary response. We explain the absence of minor epitope-specific lytic activity in WE infection by the fast reduction of virus load due to the early developing n118-specific CTL. Immunodominance of CTL epitopes in primary virus infections thus can be explained as a kinetic phenomenon composed of 1) expansion of CD8+ T cells specific for individual epitopes, 2) stimulatory effect of virus load, and 3) negative feedback control on virus load by the fastest CTL population.
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Tan, Swan, Andres Hazaet Gutiérrez, Phillip Charles Gauger, Tanja Opriessnig, Justin Bahl, Leonard Moise, and Anne Searls De Groot. "Quantifying the Persistence of Vaccine-Related T Cell Epitopes in Circulating Swine Influenza A Strains from 2013–2017." Vaccines 9, no. 5 (May 6, 2021): 468. http://dx.doi.org/10.3390/vaccines9050468.
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When swine flu vaccines and circulating influenza A virus (IAV) strains are poorly matched, vaccine-induced antibodies may not protect from infection. Highly conserved T cell epitopes may, however, have a disease-mitigating effect. The degree of T cell epitope conservation among circulating strains and vaccine strains can vary, which may also explain differences in vaccine efficacy. Here, we evaluate a previously developed conserved T cell epitope-based vaccine and determine the persistence of T cell epitope conservation over time. We used a pair-wise homology score to define the conservation between the vaccine’s swine leukocyte antigen (SLA) class I and II-restricted epitopes and T cell epitopes found in 1272 swine IAV strains sequenced between 2013 and 2017. Twenty-four of the 48 total T cell epitopes included in the epitope-based vaccine were highly conserved and found in >1000 circulating swine IAV strains over the 5-year period. In contrast, commercial swine IAV vaccines developed in 2013 exhibited a declining conservation with the circulating IAV strains over the same 5-year period. Conserved T cell epitope vaccines may be a useful adjunct for commercial swine flu vaccines and to improve protection against influenza when antibodies are not cross-reactive.
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ELKHOLY, SHEREEN F. "Using Immunoinformatics to Design a mRNA Vaccine against the Spike Glycoprotein of SARS-CoV-2." Romanian Biotechnological Letters 26, no. 5 (September 20, 2021): 2901–15. http://dx.doi.org/10.25083/rbl/26.5/2901.2915.
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The rapid outbreak of the new coronavirus SARS-COV-2 has created a major public health challenge. Immunoinformatics tools had a clear effect in tracking the genetic sequence of the virus and monitoring mutations and design vaccines that are effective enough to produce antibodies. In our study, we resorted to the emerging discipline of immunoinformatics in order to design a multi-epitope mRNA vaccine against the spike glycoprotein of SARS-CoV-2. We screened the B cell and T cell epitopes of the Spike glycoprotein. we used ABC pred server to predict B cell epitope in the spike glycoprotein sequence and we used NetMHC-4.1 server to predict the T-cell epitope. Then we selected the B cell and T cell epitopes that fulfilled the antigenicity, non-toxicity, non-allergenicity, induction of both IL4 and IFN gamma. Finally, we designed multi-epitope mRNA Vaccine construct by linking 6 B lymphocytes epitopes (BL) with 6 cytotoxic T lymphocytes epitopes (CTL) together with helper T lymphocyte (HTL) epitope up-streamed by 5’ cap and down-streamed by poly A tail. The vaccine was found to be antigenic, non-toxic, non-allergenic, capable of generating a robust immune response. Based on these parameters, this design can be considered a promising choice for a vaccine against SARS-CoV-2.
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Ma, Chenglie, Phyllis E. Whiteley, Patricia M. Cameron, Daniel C. Freed, Alison Pressey, Shiow-Ling Chen, Beth Garni-Wagner, et al. "Role of APC in the Selection of Immunodominant T Cell Epitopes." Journal of Immunology 163, no. 12 (December 15, 1999): 6413–23. http://dx.doi.org/10.4049/jimmunol.163.12.6413.
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Abstract Following antigenic challenge, MHC-restricted T cell responses are directed against a few dominant antigenic epitopes. Here, evidence is provided demonstrating the importance of APC in modulating the hierarchy of MHC class II-restricted T cell responses. Biochemical analysis of class II:peptide complexes in B cells revealed the presentation of a hierarchy of peptides derived from the Ig self Ag. Functional studies of κ peptide:class II complexes from these cells indicated that nearly 20-fold more of an immunodominant epitope derived from κ L chains was bound to class II DR4 compared with a subdominant epitope from this same Ag. In vivo, T cell responses were preferentially directed against the dominant κ epitope as shown using Ig-primed DR4 transgenic mice. The bias in κ epitope presentation was not linked to differences in class II:κ peptide-binding affinity or epitope editing by HLA-DM. Rather, changes in native Ag structure were found to disrupt presentation of the immunodominant but not the subdominant κ epitope; Ag refolding restored κ epitope presentation. Thus, Ag tertiary conformation along with processing reactions within APC contribute to the selective presentation of a hierarchy of epitopes by MHC class II molecules.
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Narita, Vanny, Asma Omar, and Agus Masduki. "Analisis Pohon Filogenik dari Protein Non-Struktural 1 (NS1) Virus Dengue di Kawasan Asia Tenggara." JURNAL Al-AZHAR INDONESIA SERI SAINS DAN TEKNOLOGI 1, no. 2 (October 3, 2011): 69. http://dx.doi.org/10.36722/sst.v1i2.28.
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<p style="text-align: justify;" align="center">Protein non-struktural 1 adalah protein Virus Dengue yang terkonservasi, tetapi protein non-struktural 1 dari Virus Dengue yang berbeda strain memiliki epitop berbeda yang dapat dikenali oleh sel-B. Epitop-epitop ini mungkin disusun oleh asam amino yang sama dalam urutan yang berbeda. Kemungkinan ini perlu dipertimbangkan dalam rangka memprediksi epitop sekuensial Virus Dengue. Tujuan penelitian kami adalah menganalisis hubungan kekerabatan dan susunan asam amino pada epitop spesifik yang telah dikonfirmasi dari sampel representatif gen protein NS1 dari Virus Dengue di kawasan Asia Tenggara. Hubungan kekerabatan protein non-struktural 1 dianalisis dengan perangkat lunak Lasergene<sup>®</sup>. Sekuen gen ditranslasi terlebih dahulu ke urutan asam amino, dan analisis pohon filogenetik kemudian dilakukan. Hasilnya menunjukkan bahwa hubungan kekerabatan protein non-struktural 1 berkisar antara 72-98%. Selanjutnya, epitop serospesifik dibandingkan berdasarkan hasil pengolahan data dnegan Lasergene. Perbandingan epitop serospesifik menunjukkan bahwa asam amino yang dominan dalam epitop adalah histidin, tirosin, glutamine dan serin</p><h6 style="text-align: center;"><em> </em><em> </em><strong>Abstract</strong></h6>Non-structural 1 protein is a conserved protein of dengue virus, but non-structural 1 proteins of dengue virus from different strains have different epitopes which can be recognized by B-cell. These epitopes may be constructed of similar amino acids in a different arrangement. This possibility must be considered in order to predict the sequencial epitope of dengue virus. The objective of our study was to analyze the phylogenetic relation and the arrangment of confirmed specific epitopes of dengue strains from representatives of South East Asia’s NS1 dengue gene samples. The phylogenetic relation of non-structural 1 protein sequences from South East Asia was analyzed with Lasergene<sup>®</sup> software. The gene sequences were translated to amino acid sequences, and phylogenetic tree analysis was performed. The results showed that the relatedness values among full sequences of non-structural 1 protein were 72-98%. Furthermore, the serospesific epitopes were compared according to the Lasergene results. The serospesific epitope comparation showed that the dominant amino acids in these epitopes were histidine, tyrosine, glutamine and serine.