In silico Designed Ebola Virus T-Cell Multi-Epitope DNA Vaccine Constructions Are Immunogenic in Mice

Background: The lack of effective vaccines against Ebola virus initiates a search for new approaches to overcoming this problem. The aim of the study was to design artificial polyepitope T-cell immunogens––candidate DNA vaccines against Ebola virus and to evaluate their capacity to induce a specific immune response in a laboratory animal model. Method: Design of two artificial polyepitope T-cell immunogens, one of which (EV.CTL) includes cytotoxic and the other (EV.Th)––T-helper epitopes of Ebola virus proteins was carried out using original TEpredict/PolyCTLDesigner software. Synthesized genes were cloned in pcDNA3.1 plasmid vector. Target gene expression was estimated by synthesis of specific mRNAs and proteins in cells transfected with recombinant plasmids. Immunogenicity of obtained DNA vaccine constructs was evaluated according to their capacity to induce T-cell response in BALB/c mice using IFNγ ELISpot and ICS. Results: We show that recombinant plasmids pEV.CTL and pEV.Th encoding artificial antigens provide synthesis of corresponding mRNAs and proteins in transfected cells, as well as induce specific responses both to CD4+ and CD8+ T-lymphocytes in immunized animals. Conclusions: The obtained recombinant plasmids can be regarded as promising DNA vaccine candidates in future studies of their capacity to induce cytotoxic and protective responses against Ebola virus.

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Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013–16 West Africa epidemic

Nature Communications ◽

10.1038/s41467-021-21411-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

T. R. W. Tipton ◽

Y. Hall ◽

J. A. Bore ◽

A. White ◽

L. S. Sibley ◽

...

Keyword(s):

T Cell ◽

West Africa ◽

Cell Response ◽

Ebola Virus ◽

Medical Condition ◽

Virus Disease ◽

T Cell Response ◽

Ebola Virus Disease ◽

Cell Phenotype ◽

T Cell Epitopes

AbstractZaireebolavirus (EBOV) is a highly pathogenic filovirus which can result in Ebola virus disease (EVD); a serious medical condition that presents as flu like symptoms but then often leads to more serious or fatal outcomes. The 2013–16 West Africa epidemic saw an unparalleled number of cases. Here we show characterisation and identification of T cell epitopes in surviving patients from Guinea to the EBOV glycoprotein. We perform interferon gamma (IFNγ) ELISpot using a glycoprotein peptide library to identify T cell epitopes and determine the CD4+ or CD8+ T cell component response. Additionally, we generate data on the T cell phenotype and measure polyfunctional cytokine secretion by these antigen specific cells. We show candidate peptides able to elicit a T cell response in EBOV survivors and provide inferred human leukocyte antigen (HLA) allele restriction. This data informs on the long-term T cell response to Ebola virus disease and highlights potentially important immunodominant peptides.

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Induction of T-cell response by a DNA vaccine encoding a novel HLA-A*0201 severe acute respiratory syndrome coronavirus epitope

Vaccine ◽

10.1016/j.vaccine.2007.05.025 ◽

2007 ◽

Vol 25 (32) ◽

pp. 6070-6077 ◽

Cited By ~ 32

Author(s):

Ying-Kit Cheung ◽

Samuel Chak-Sum Cheng ◽

Fion Wan-Yee Sin ◽

Kin-Tak Chan ◽

Yong Xie

Keyword(s):

T Cell ◽

Severe Acute Respiratory Syndrome ◽

Dna Vaccine ◽

Cell Response ◽

T Cell Response

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Vaccination with a Shigella DNA Vaccine Vector Induces Antigen-Specific CD8+ T Cells and Antiviral Protective Immunity

Journal of Virology ◽

10.1128/jvi.75.20.9665-9670.2001 ◽

2001 ◽

Vol 75 (20) ◽

pp. 9665-9670 ◽

Cited By ~ 50

Author(s):

Mohamed T. Shata ◽

David M. Hone

Keyword(s):

T Cell ◽

Dna Vaccine ◽

Protective Immunity ◽

Dna Vaccines ◽

T Cell Responses ◽

T Cell Response ◽

Vaccine Vector ◽

Host Cells ◽

Cell Responses ◽

Hiv 1

ABSTRACT A prototype Shigella human immunodeficiency virus type 1 (HIV-1) gp120 DNA vaccine vector was constructed and evaluated for immunogenicity in a murine model. For comparative purposes, mice were also vaccinated with a vaccinia virus-env(vaccinia-env) vector or the gp120 DNA vaccine alone. Enumeration of the CD8+-T-cell responses to gp120 after vaccination using a gamma interferon enzyme-linked spot assay revealed that a single intranasal dose of the Shigella HIV-1 gp120 DNA vaccine vector elicited a CD8+ T-cell response to gp120, the magnitude of which was comparable to the sizes of the analogous responses to gp120 that developed in mice vaccinated intraperitoneally with the vaccinia-env vector or intramuscularly with the gp120 DNA vaccine. In addition, a single dose of the Shigella gp120 DNA vaccine vector afforded significant protection against a vaccinia-env challenge. Moreover, the number of vaccinia-env PFU recovered in mice vaccinated intranasally with the Shigella vector was about fivefold less than the number recovered from mice vaccinated intramuscularly with the gp120 DNA vaccine. Since theShigella vector did not express detectable levels of gp120, this report confirms that Shigella vectors are capable of delivering passenger DNA vaccines to host cells and inducing robust CD8+ T-cell responses to antigens expressed by the DNA vaccines. Furthermore, to our knowledge, this is the first documentation of antiviral protective immunity following vaccination with a live Shigella DNA vaccine vector.

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Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice.

Journal of Experimental Medicine ◽

10.1084/jem.168.1.213 ◽

1988 ◽

Vol 168 (1) ◽

pp. 213-227 ◽

Cited By ~ 104

Author(s):

D H Kono ◽

J L Urban ◽

S J Horvath ◽

D G Ando ◽

R A Saavedra ◽

...

Keyword(s):

Lymph Node ◽

T Cell ◽

Autoimmune Disease ◽

Basic Protein ◽

T Cell Response ◽

T Cell Epitopes ◽

T Helper ◽

Allergic Encephalomyelitis ◽

Peptide Region ◽

Experimental Allergic

Experimental allergic encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system (CNS) that occurs after immunization of animals with myelin basic protein (MBP). The disease is a prototype model for the study of antigen-specific T helper cell-mediated autoimmune disease. In SJL/J mice, EAE is mediated by T helper cells directed against a 40-amino acid COOH-terminal peptic fragment of mouse small MBP. To identify the minimal T cell epitopes of MBP responsible for EAE, overlapping peptides completely encompassing the epitopes within this region were synthesized. A 28-residue peptide of mouse MBP spanning residues 87-114 (pM87-114) was able to elicit both a strong T cell response and chronic relapsing disease. To better localize the T cell epitopes, shorter peptides within this region were synthesized and two overlapping peptides, pM87-98 and pM91-104, were able to induce EAE. T cell clones and bulk lymph node cell populations reactive with pM87-98 did not respond to pM91-104. However, lymph node cells reactive with pM91-104 also reacted with pM87-98, thus showing that these two peptides represent contiguous, but distinct encephalitogenic epitopes and that both these epitopes may be contained within pM87-98. In addition, pM87-114 and pM87-98 were found to be minor determinants of the total T cell response to rat and rabbit MBP. The restricted response to MBP in SJL/J mice is similar to that of the PL/J mice in that each appears to have only a single peptide region in MBP that elicits encephalitogenic T cells. However, within the region studied, there were two if not more T cell epitopes. This differs from the single encephalitogenic PL/J epitope. These findings of a single encephalitogenic peptide region with multiple T cell epitopes and the fact that encephalitogenic T cell epitopes may be subdominant have implications for the design of treatments directed at the T cell receptor-MHC-peptide epitope complex in autoimmune disease.

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H-2-controlled suppression of T cell response to lactate dehydrogenase B. Characterization of the lactate dehydrogenase B suppressor pathway.

Journal of Experimental Medicine ◽

10.1084/jem.156.3.822 ◽

1982 ◽

Vol 156 (3) ◽

pp. 822-833 ◽

Cited By ~ 55

Author(s):

C N Baxevanis ◽

N Ishii ◽

Z A Nagy ◽

J Klein

Keyword(s):

Lactate Dehydrogenase ◽

T Cell ◽

Cell Response ◽

Cell Types ◽

T Cell Response ◽

T Helper ◽

Th Cells ◽

Th Cell ◽

Antigen Presenting

We characterized the cell types involved in the H-2-controlled suppression of T cell response to lactate dehydrogenase B (LDHB). The suppressor effector (Tse) was found to be an Lyt-1+2+, J+ cell that recognizes antigen together with Ek molecules of antigen-presenting cells (APC). To become functional, the Tse cell requires a second signal from a nonspecific, Lyt-1+2-, J+ suppressor-inducer (Tsi) cell. The Tsi-Tse interaction is not subject to any genetic restriction. The target cell of suppression is an Lyt-1+2-, J- (most likely T helper [Th]) cell that recognizes LDHB in the context of A molecules on APC. The suppression is manifested in inhibition of the antigen-specific, A-restricted proliferation of Th cells. The interaction between Tse and Th is restricted by the A region of the H-2 complex. Because this restriction is determined by the receptor of Th cells, the mechanism of Th-Tse interaction most likely involves a concomitant recognition of LDHB and A region-controlled molecules by Th cells on the surface of Tse cells.

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Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.9968 ◽

2009 ◽

Vol 27 (25) ◽

pp. 4047-4054 ◽

Cited By ~ 169

Author(s):

Douglas G. McNeel ◽

Edward J. Dunphy ◽

James G. Davies ◽

Thomas P. Frye ◽

Laura E. Johnson ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Acid Phosphatase ◽

T Cell ◽

Dna Vaccine ◽

Cd8 T Cells ◽

Doubling Time ◽

Prostatic Acid Phosphatase ◽

T Cell Response ◽

Psa Doubling Time

Purpose Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer. Patients and Methods Twenty-two patients were treated in a dose-escalation trial with 100 μg, 500 μg, or 1,500 μg plasmid DNA, coadministered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment. Results No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFNγ-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054). Conclusion The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.

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Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis.

Journal of Experimental Medicine ◽

10.1084/jem.174.3.593 ◽

1991 ◽

Vol 174 (3) ◽

pp. 593-601 ◽

Cited By ~ 180

Author(s):

H Yssel ◽

M C Shanafelt ◽

C Soderberg ◽

P V Schneider ◽

J Anzola ◽

...

Keyword(s):

T Cell ◽

Borrelia Burgdorferi ◽

Cell Subset ◽

Chronic Inflammatory Disease ◽

T Cell Response ◽

Lyme Arthritis ◽

T Helper ◽

Cell Clones ◽

T Cell Lines

18 cloned T cell lines reactive with Borrelia burgdorferi proteins, all CD3+4+8-TCR-alpha/beta+ and restricted by HLA class II proteins, were isolated from four patients with chronic Lyme arthritis. Analysis of these T cell clones indicated that the T cell response to the Lyme disease spirochete is not oligoclonally restricted; yet all produced the same pattern of lymphokines, resembling that of murine type 1 T helper cells, after antigen-specific or nonspecific stimulation. Therefore, a subset of human CD4+ T cells, with a distinct profile of lymphokine secretion, is selectively activated by the pathogen inciting this chronic inflammatory disease.

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