RESUMO
BACKGROUND: The design of an epitope-based vaccine against diphtheria toxin (DT) originated from the idea that many strong binder epitopes may be structurally located in the depth of DT. Subsequently, many ineffective antibodies may be produced by the presentation of those epitopes to T and B lymphocytes. The other critical issue is the population coverage of a vaccine that has been neglected in traditional vaccines.
Objective: Given the issues above, our study aimed to design a peptide-based diphtheria vaccine, considering the issues of unwanted epitopes and population coverage. Methods: The frequencies of pre-determined HLA alleles were listed. A country in which almost all HLA alleles had been determined in almost all geographical distribution was selected. The epitopes within the sequence of diphtheria toxin were predicted by the NetMHCIIPan server based on the selected HLA alleles. Strong binder epitopes on the surface of diphtheria toxin were selected by structural epitope mapping. The epitopes, which cover almost all the human population for each of the HLA alleles in the candidate country, were then selected as epitopebased vaccines. Results: At first, 793 strong binder epitopes were predicted, of which 82 were surface epitopes. Nine surface epitopes whose amino acids had extruding side chains were selected. Finally, 2 epitopes had the most population coverage and were suggested as a di-epitope diphtheria vaccine. The population coverage of the di-epitope vaccine in France and the world was 100 and 99.24 %, respectively. HLA-DP had the most roles in epitope presentation. Conclusion: Our results indicated that 97.75 % of unwanted antibodies (791 epitopes) have been reduced. Achieving two immunodominant surface epitopes confirmed our rational filtration strategy for sequential reduction of unwanted epitopes. Our novel insight may pave a new way to designing novel peptide-based vaccines to avoid producing non-specific antibodies.RESUMO
Pertussis vaccine is produced from physicochemically inactivated toxin for many years. Recent advancements in immunoinformatics [N. Tomar and R. K. De, "Immunoinformatics: an integrated scenario," Immunology, vol. 131, no. 2, pp. 153-168, 2010] and structural bioinformatics can provide a new multidisciplinary approach to overcome the concerns including unwanted antibodies and incomplete population coverage. In this study we focused on solving the challenging issues by designing a multi-epitope vaccine (MEV) using rational bioinformatics analyses. The frequencies of All HLA DP, DQ, and DR alleles were evaluated in almost all countries. Strong binder surface epitopes on the pertussis toxin were selected based on our novel filtration strategy. Finally, the population coverage of MEV was determined in the candidate country. Filtration steps yielded 312 strong binder epitopes. Finally, 8 surface strong binder epitopes were selected as candidate epitopes. The population coverage of the MEV in France and the world was 98 and 100 percent, respectively. Our algorithm successfully filtered many unwanted strong binder epitopes. Considering the HLA type of all individuals in a country, we theoretically provided the maximum chance to all humans to be vaccinated efficiently. Application of a MEV would be led to production of highly efficient target specific antibodies, significant reduction of unwanted antibodies, and avoid possible raising of auto-antibodies as well.
Assuntos
Algoritmos , Biologia Computacional/métodos , Vacina contra Coqueluche , Anticorpos Antibacterianos/imunologia , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Epitopos/metabolismo , Humanos , Modelos Moleculares , Toxina Pertussis/química , Toxina Pertussis/genética , Toxina Pertussis/imunologia , Toxina Pertussis/metabolismo , Vacina contra Coqueluche/química , Vacina contra Coqueluche/genética , Vacina contra Coqueluche/imunologia , Vacina contra Coqueluche/metabolismoRESUMO
Presentation of many unwanted epitopes within tetanus toxoid vaccine to lymphocyte clones may lead to production of many unwanted antibodies. Moreover an ideal vaccine must cover all individuals in a population that is dependent to the kinds of human leukocyte antigen alleles. Concerning these issues, our study was aimed to in silico design of a multi-epitope tetanus vaccine (METV) in order to improve population coverage and protectivity of tetanus vaccine as well as reduction of complications. Concerning these issues, a novel rational filtration was implemented to design a novel METV using immunoinformatics and surface epitope mapping approaches. Prediction of epitopes for tetanus toxin was performed in the candidate country in which the frequency had been gathered from almost all geographical distributions. The most strong binder epitopes for major histocompatibility complex class II were selected and among them the surface epitopes of native toxin were selected. The population coverage of the selected epitopes was estimated. The final candidate epitopes had highly population coverage. Molecular docking was performed to prediction of binding affinity of our candidate epitopes to the HLA-DRB1 alleles. At first, 680 strong binder epitopes were predicted. Among them 11 epitopes were selected. Finally, 4 epitopes had the most population coverage and suggested as a tetra-epitope tetanus vaccine. 99.41% of inessential strong binders were deleted using our tree steps filtration. HLA-DP had the most roles in epitope presentation. Molecular docking analysis proved the strong binding affinity of candidate epitopes to the HLA-DRB1 alleles. In conclusion, we theoretically reduced 99.41% of unwanted antibodies using our novel filtration strategies. Our tetra-epitope tetanus vaccine showed 100% population coverage in the candidate country. Furthermore, it was demonstrated that HLA-DP and HLA-DQ had more potential in epitope presentation in comparison to HLA-DRB1.
Assuntos
Mapeamento de Epitopos/métodos , Antígenos HLA/imunologia , Toxoide Tetânico/química , Alelos , Alergia e Imunologia/instrumentação , Biologia Computacional , Desenho de Fármacos , Epitopos , Antígenos HLA-DP/imunologia , Antígenos HLA-DQ/imunologia , Cadeias HLA-DRB1/imunologia , Humanos , Conformação Molecular , Simulação de Acoplamento MolecularRESUMO
Dr. Ahmad Fayaz is one of the famous scientists in Iran in the field of rabies, and the most prominent person in controlling and prevention programs in the country in recent decades. One of his most important scientific achievements was introducing a new rabies vaccine produced in human diploid cell cultures to treat people exposed to rabies infection. Following that, anti-rabies serum therapy and injection of five doses of the cellular vaccine were entered into WHO protocol. Dr. Fayaz, as an expert and consultant of WHO, traveled to several countries and recommended appropriate ways to control rabies. This paper intends to celebrate his scientific contributions through reviewing his services and researches.
