An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes
Abstract
:Simple Summary
Abstract
1. Introduction
- Conserved Fragments: Identified conserved regions in the viral polyprotein to form the basis of epitope selection;
- ADE Risk Exclusion: Excluded potential ADE-associated epitopes based on a comprehensive literature review;
- Serotype-Specific Epitopes: Combined serotype-specific B-cell epitopes from the E protein with pan-serotype T-cell epitopes from other proteins, including NS1, NS3, NS5, and Capsid;
- Molecule Integration: Integrated all selected epitopes and adjuvant proteins into a single, reasonably sized molecule rather than a complex tetravalent formulation.
2. Materials and Methods
2.1. Retrieval and Analysis of Full-Length Dengue Polyprotein Sequences
2.2. Step-by-Step Selection of Epitopes and the Estimation of the Coverage in the Population
2.2.1. Identification of B-Cell Epitopes
- Prediction: Continuous B-cell epitopes were predicted in conserved sequences of DENV-1~4 polyproteins using the IEDB database with the Bepipred2.0 method [26]. It utilizes a hidden Markov model to predict linear B-cell epitopes based on the peptide’s propensity to bind to antibodies. A threshold of 0.5 was set to determine the likelihood of an epitope being immunogenic;
- Selection criteria: Epitopes were first evaluated for their antigenicity (their ability to elicit an immune response) with the online tool VaxiJen [27], and then intra-serotyped conservancy with the IEDB database to ensure they were preserved within the same serotype of DENV. After that, allergenicity and toxicity were evaluated using Allertop v.2.0 [28] and Toxinpred [29] respectively;
- Exclusion of ADE-related epitopes: To mitigate the risk of ADE, relevant literature was collected and utilized to extract the potentially problematic epitopes, detailed in Supplementary Materials Table S11. ADE-related epitopes were then excluded accordingly from the list of predicted B-cell epitopes, mainly based on their sequence and location in the envelop protein;
- Conservancy analysis: The intra-serotype and cross-serotype conservancy of the epitopes were further analyzed to ensure they were effective across different strains within the same serotypes but not among distinct serotypes. The conservancy analysis was perfumed using the IEDB-based conservancy analysis server [30].
2.2.2. Identification of CTL and HTL Epitope
- Prediction of epitopes in given length: Epitopes were predicted using NetMHC 4.0 [31] for CTLs (MHC I) and NetMHC MHC class II 2.3v for HTLs (MHC II) [32]. These tools predict binding affinities between peptides and MHC molecules, which are critical for T-cell activation. For CTL epitopes, the length was defined as 9 amino acids, while HTL epitopes were considered 15 amino acids. These lengths corresponded to the peptide fragments that can be effectively represented by MHC molecules;
- Binding affinity-based selection of epitopes: Primary selection was conducted based on the binding affinity to MHC I/II receptors, with strong binders (SB) being those in the top <0.5% of the predicted binding scores for both CTLs and HTLs, while weak binders (WB) in the top <2% for either type. This ensured that the selected epitopes had a high likelihood of inducing a strong immune response;
- Further criteria of epitope evaluation: Epitopes with strong binding affinity were further evaluated for their antigenicity, immunogenicity, and intra- and cross-serotype conservancy while ensuring they did not possess characteristics of toxicity or allergenicity.
2.2.3. Population Coverage Analysis
2.3. Formulation and Evaluation of Vaccine Candidates
- B-cell epitopes: A flexible linker sequence, KK, was used to connect B-cell epitopes [37];
- CTL epitopes: A different flexible linker, AAY, was employed for the connection between CTL epitopes;
- HTL epitopes: A glycine–proline-rich linker, GPGPG, was used to link HTL epitopes;
- Inter-group linkers: A flexible GGGS linker was utilized to join distinct groups of epitopes, ensuring a cohesive antigen structure [33];
- Adjuvant integration: Adjuvant proteins were conjugated to the N- or C-terminus of the epitope groups via a rigid EAAAK linker.
2.4. Predictions and Validation of Molecular Structure for Vaccine Candidates
2.5. Molecular Docking and Dynamics of the Vaccine-Immune Receptor Complexes
2.6. Immune Simulation of Selected Candidate Vaccine
2.7. Codon Optimization and In Silico Cloning of Selected Candidate Vaccine
3. Results
3.1. Conserved Fragments Were Extracted from DENV Polyprotein Sequences Collected Worldwide
3.2. Effective and Non-Risky Epitopes Were Selected Stepwise from Conserved Fragments of DENV Polyprotein for B Cells, CTLs, and HTLs
3.3. Three Candidate Vaccines Composed of Selected Epitopes Were Predicted as Stable, Water Soluble, and Antigenic
- PSDV-1: Assembling the core antigen with Heparin-binding Hemagglutinin (HBHA) at the N-terminus and beta-defensin at the C-terminus;
- PSDV-2: Assembling the core antigen with HBHA at the N-terminus only;
- PSDV-3: Assembling the core antigen with beta-defensin at the N-terminus only.
3.4. PSDV-2 Was Highlighted for Further Evaluation Based on Structural Advantages and Showed a Tight Interaction with TLRs and HLAs
- Root mean square deviation (RMSD): The RMSD values for either PSDV-2–TLR4 or PSDV-2–TLR2 complexes remained consistently within the allowable range of 4 Å, and reached equilibrium within approximately 40 ns, indicating stable conformational behavior;
- Root mean square fluctuation (RMSF): As a reflection of the flexibility of residues, RMSF values for either complex were stabilized within the permissible 4 Å range, suggesting minimal fluctuations and consistent structural integrity;
- Radius of gyration (Rg): As a measure of the compactness of the protein structure, the Rg value was approximately 37 Å for the PSDV-2–TLR2 complex and 34 Å for the PSDV-2–TLR4 complex, indicating well-maintained structural compactness;
- Hydrogen bonds: The number of hydrogen bonds formed within the TLR receptors remained between 20 and 25 throughout the simulation, highlighting a strong and consistent interaction.
3.5. Robust Responses Were Induced for both Innate and Adaptive Immunity upon the Simulation of the PSDV-2 Candidate Vaccine
3.6. Codon Optimization and In Silico Cloning of the Designed Vaccines
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Features | DENV-1 | DENV-2 | DENV-3 | DENV-4 |
---|---|---|---|---|
Epitope Sequence | DEKGVT | WDFGSLGG | VTAETQN | LHWFRKGSSI |
Start | 341 | 377 | 330 | 254 |
End | 346 | 384 | 336 | 263 |
Protein region | E (ED III) | E (ED III) | E (ED III) | E (ED II) |
Epitope length | 6 | 8 | 7 | 10 |
Allergenicity | Non-Allergen | Non-Allergen | Non-Allergen | Non-Allergen |
Antigenicity Score | 0.7715 | 2.1175 | 1.2240 | 0.9330 |
Toxicity | Non-Toxic | Non-Toxic | Non-Toxic | Non-Toxic |
Intra conservancy | 100% | 100% | 100% | 100% |
Inter-DENV-1–4 conservancy | 25.00% (1/4) | 25.00% (1/4) | 25.00% (1/4) | 25.00% (1/4) |
Serotype | Protein Region | Epitope Sequence | Affinity (nM) | Antigenicity/Immunogenicity Score | Allergenicity/Toxicity Score | Intra-/Cross-Serotype Conservancy |
---|---|---|---|---|---|---|
DENV-1 | NS1 | MLMTGTLAV | 3 | 0.5611/0.20739 | Non-Allergic/Non-Toxic | 100%/25% |
NS3 | LLMRTTWAL | 4.24 | 0.9556/0.27922 | Non-Allergic/Non-Toxic | 100%/25% | |
NS5 | FMNEDHWFS | 38.43 | 0.4990/0.40604 | Non-Allergic/Non-Toxic | 100%/25% | |
DENV-2 | NS1 | LVAGGLLTV | 39.51 | 0.5463/0.08268 | Non-Allergic/Non-Toxic | 100%/25% |
NS3 | LMMRTTWAL | 4.1 | 1.1235/0.27922 | Non-Allergic/Non-Toxic | 100%/25% | |
NS5 | KLVDREREL | 3.1 | 1.4751/0.09999 | Non-Allergic/Non-Toxic | 100%/50.00% (2/4),DENV-3,-2 | |
DENV-3 | NS1 | HMIAGVTFV | 5.19 | 0.8396/0.25559 | Non-Allergic/Non-Toxic | 100%/25% |
NS3 | KLNDWDFVV | 4.15 | 2.2249/0.37972 | Non-Allergic/Non-Toxic | 100%,25% | |
DENV-4 | NS1 | GLLCLTLFV | 5.23 | 0.8159/0.02693 | Non-Allergic/Non-Toxic | 100%/25% |
NS3 | KLTDWDFVV | 4.15 | 2.6071/0.3944 | Non-Allergic/Non-Toxic | 100%/25% | |
NS5 | TTANWLWAL | 39.89 | 0.9911/0.42125 | Non-Allergic/Non-Toxic | 100%/25% |
Serotype | Epitope Sequence | Allele | Protein Region | Affinity (nM)/ Antigenicity Score | Allergenicity/Toxicity | Serotype-Specific Cross Conservancy |
---|---|---|---|---|---|---|
DENV-1 | FLRFLAIPPTAGVLA | DRB1_0101 | Capsid | 11.2/0.6827 | Non-Allergic/Non-Toxic | 100%/50.00% (2/4) DENV-1,-2 |
DENV-1 | EIVDLMCHATFTMRL | DRB1_0701 | Capsid | 6.9/0.9597 | Non-Allergic/Non-Toxic | 100%/75.00% (3/4) DENV-1,-2,-3 |
DENV-2 | WCGSLIGLTSRATWA | DRB1_0101 | Capsid | 7.4/0.8137 | Non-Allergic/Non-Toxic | 100%/50.00% (2/4) DENV-2,-3 |
DENV-3 | RDMTLIMIGSNASDR | DRB1_0401 | Capsid | 5.9/0.9291 | Non-Allergic/Non-Toxic | 100%/25% (1/4) |
DENV-4 | ITALILGAQALPVYL | DRB1_0101 | Capsid | 4.7/0.6489 | Non-Allergic/Non-Toxic | 100%/25% (1/4) |
DENV-4 | QKQSHWVEITALILG | DRB1_0701 | Capsid | 12.9/1.2944 | Non-Allergic/Non-Toxic | 100%/25% (1/4) |
DENV-4 | DFVVTTDISEMGANF | DRB1_0401 | Capsid | 33.1/0.6533 | Non-Allergic/Non-Toxic | 100%/75.00% (3/4) DENV-2,-3,-4 |
Parameter | PSDV-1 | PSDV-2 | PSDV-3 |
---|---|---|---|
No. of amino acids | 564 | 508 | 394 |
Molecular weight | 62.09 kDa | 55.2733 kDa | 42.71375 kDa |
Instability Index | 26.02 | 24.28 | 20.52 |
Aliphatic index | 86.28 | 88.33 | 85.05 |
Half-life | 30 h (mammalian reticulocytes, in vitro). >20 h (yeast, in vivo). >10 h (Escherichia coli, in vivo). | 30 h (mammalian reticulocytes, in vitro). >20 h (yeast, in vivo). >10 h (Escherichia coli, in vivo). | 30 h (mammalian reticulocytes, in vitro). >20 h (yeast, in vivo). >10 h (Escherichia coli, in vivo). |
Solubility | 0.788949 | 0.761350 | 0.569153 |
Hydropathicity (GRAVY) | −0.049 | 0.018 | 0.151 |
Theoretical pI | 8.38 | 5.76 | 9.37 |
Antigenicity | 0.6717 | 0.6727 | 0.7320 |
Allergenicity | Non-Allergenic | Non-Allergenic | Non-Allergenic |
Toxicity | Non-Toxic | Non-Toxic | Non-Toxic |
Immune Receptors | Docking Score | Res (Rec) | BFE | Res (Lig) | BFE | CBFE |
---|---|---|---|---|---|---|
TLR4 | −5386.23 | A-ARG-421 | −5.86 | B-ARG41 | −5.85 | −28.13 |
A-TYR-297 | −3.68 | B-ARG45 | −4.49 | |||
A-LYS-462 | −2.77 | B-GLU-114 | −4.15 | |||
A-TYR-350 | −2.5 | B-LEU-104 | −3.49 | |||
A-LEU-345 | −2.01 | B-LEU-107 | −3.1 | |||
TLR2 | −7330.87 | A-ARG-421 | −6.24 | B-GLU-133 | −2.15 | −29.66 |
A-ARG-460 | −4.76 | B-GLU-38 | −2.14 | |||
A-GLY-538 | −3.68 | B-THR-142 | −1.96 | |||
A-SER-539 | −3.42 | B-GLN-132 | −1.86 | |||
A-HIE-292 | −2.78 | B-ASP-115 | −1.85 |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Ullah, H.; Ullah, S.; Li, J.; Yang, F.; Tan, L. An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes. Biology 2024, 13, 681. https://doi.org/10.3390/biology13090681
Ullah H, Ullah S, Li J, Yang F, Tan L. An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes. Biology. 2024; 13(9):681. https://doi.org/10.3390/biology13090681
Chicago/Turabian StyleUllah, Hikmat, Shaukat Ullah, Jinze Li, Fan Yang, and Lei Tan. 2024. "An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes" Biology 13, no. 9: 681. https://doi.org/10.3390/biology13090681