Modeling mRNA-based vaccine YFV.E1988 against yellow fever virus E-protein using immuno-informatics and reverse vaccinology approach

Abstract

To surmount constraints of live-attenuated vaccines we have in silico designed mRNA vaccine using envelope protein as a target antigen. From the alignment of 216 envelope proteins, a consensus sequence was obtained which was used for codon optimization. The secondary structure was predicted using Mfold and RNAfold tool. IEDB server was used to predict T-cell and B-cell epitopes, epitope conservancy, immunogenicity, and population coverage. Antigenicity, allergenicity, and toxicity were predicted using Vaxijen, AllerTOP, and ToxinPred tools, respectively. Interactions between MHC and identified epitopes were confirmed by docking and molecular dynamics simulation. In silico immune simulation was done using the C-ImmSim server. Vaccine peptide 3D structure was predicted and validated based on the Ramachandran plot. Finally, we designed the vaccine construct for simulating restriction cloning using the SnapGene tool. Our optimization of consensus E protein is highly immunogenic, conserved, has immune-dominance characteristics, and suggests high translational efficiency in the host cell. We validated the presence of T and B cell epitopes and interestingly we found one CD4+ and four CD8+ T-cell epitopes that satisfied all the criteria of an effective vaccine candidate. We found high-affinity interactions between epitope and HLA alleles that can stimulate the T-cell response. The immune simulation verified the immune cell response to eliminate the antigen. To ensure effective expression of the vaccine, a circular plasmid has been designed using in silico cloning approach for the in vitro transcription process. Obtained results suggest that the vaccine YFV.E1988 will elicit specific immune responses against YFV and it is a potential model ready for laboratory testing.

Highlights

• The envelope (E) protein was found to be highly conserved and it has the potential to protect individuals against YFV infection.

• YFV.E1988 vaccine has been capable to stimulate both the CD8+ and CD4+ T cell, solving the major limitations of the current live-attenuated vaccines against YFV.

• Presence of T- and B-cell epitopes across the antigen have been validated using several computational tools.

• Molecular docking ensured the epitope-allele binding and protein-TLR/MR interaction. The vaccine was found to be immune-stimulatory, safe, and stable.

• The codons were optimized for efficient translation and increased stability into the human host. The UTR regions and poly (A) tail used for the development of YFV.E1988 showed immune stimulatory potential in several experiments.

Communicated by Ramaswamy H. Sarma

Keywords:

• mRNA Vaccine
• codon optimization
• yellow fever
• Epitope
• Immune system

Acknowledgements

We acknowledge high-performance computing facility support from the Centre for Bioinformatics Learning Advancement and Systematics Training (cBLAST), University of Dhaka for MD analysis. We also acknowledge the support of Biomolecular Research Foundation (BMRF), Dhaka, Bangladesh.

Author contributions

ABMMKI conceived the project. NTK collected the data. NTK, MAZ and ABMMKI performed the analyses. NTK and ABMMKI wrote the manuscript. The manuscript was reviewed and approved by all authors.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data and software availability

All data added Table, figures and supplementary file and supplementary tables. In this research work publicly available free mostly online and few offline software/tools were used. Necessary link, reference of the software/tools provided in the method section.

Funding

The author(s) reported there is no funding associated with the work featured in this article.