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A New Epitope Selection Method: Application to Design a Multi-Valent Epitope Vaccine Targeting HRAS Oncogene in Squamous Cell Carcinoma.

ABSTRACT: 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.

SUBMITTER: Savsani K

PROVIDER: S-EPMC8778118 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:COVID-19 has recently become the most serious threat to public health, and its prevalence has been increasing at an alarming rate. The incubation period for the virus is ~1-14 days and all age groups may be susceptible to a fatality rate of about 5.9%. COVID-19 is caused by a novel single-stranded, positive (+) sense RNA beta coronavirus. The development of a vaccine for SARS-CoV-2 is an urgent need worldwide. Immunoinformatics approaches are both cost-effective and convenient, as in silico predictions can reduce the number of experiments needed. In this study, with the aid of immunoinformatics tools, we tried to design a multi-epitope vaccine that can be used for the prevention and treatment of COVID-19. The epitopes were computed by using B cells, cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) base on the proteins of SARS-CoV-2. A vaccine was devised by fusing together the B cell, HTL, and CTL epitopes with linkers. To enhance the immunogenicity, the β-defensin (45 mer) amino acid sequence, and pan-HLA DR binding epitopes (13aa) were adjoined to the N-terminal of the vaccine with the help of the EAAAK linker. To enable the intracellular delivery of the modeled vaccine, a TAT sequence (11aa) was appended to C-terminal. Linkers play vital roles in producing an extended conformation (flexibility), protein folding, and separation of functional domains, and therefore, make the protein structure more stable. The secondary and three-dimensional (3D) structure of the final vaccine was then predicted. Furthermore, the complex between the final vaccine and immune receptors (toll-like receptor-3 (TLR-3), major histocompatibility complex (MHC-I), and MHC-II) were evaluated by molecular docking. Lastly, to confirm the expression of the designed vaccine, the mRNA of the vaccine was enhanced with the aid of the Java Codon Adaptation Tool, and the secondary structure was generated from Mfold. Then we performed in silico cloning. The final vaccine requires experimental validation to determine its safety and efficacy in controlling SARS-CoV-2 infections.

Dataset Information

A New Epitope Selection Method: Application to Design a Multi-Valent Epitope Vaccine Targeting HRAS Oncogene in Squamous Cell Carcinoma.

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