Immunoinformatics Approach to Develop a Novel Chimeric L1/L2 Messenger RNA-based Vaccine Targeting a Broad Spectrum of Human Papillomavirus Species

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Abstract
Papillomaviruses can infect animals and humans, causing benign lesions and cancer. Chimeric vaccines may address the limited coverage of current papillomavirus vaccines by providing cross-type immunity. The present study focused on the in silico design of a chimeric mRNA vaccine targeting a wide range of human papillomaviruses (HPV). The study incorporated 25 amino acid sequences derived from L1 and L2 capsid proteins of 14 high-risk and 11 low-risk HPV strains. These sequences underwent multiple sequence alignment, and the resulting sequences were used to develop consensus sequences. Computational approaches were then applied to predict and identify immunodominant T-cell and B-cell epitopes. The mRNA vaccine structure was designed by merging codon-optimized multi-epitope chimeric peptides with regulatory components that enhance both transcription and translation efficiency. The present study identified 19 T and 6 B cell epitopes, which were evaluated as non-toxic, non-allergenic, highly antigenic, and fully or partially conserved. The final multi-epitope peptide vaccine had a molecular weight of 60,161.29 kDa, a theoretical isoelectric point (pI) of 9.44, a solubility index of 0.451, and an antigenicity score of 0.9178. The mRNA vaccine exhibited a stable mRNA structure with a minimum free energy of -731.10 kcal/mol and an estimated molecular weight of 644.98 kDa. The proposed vaccine demonstrated no cross-affinity with the human genome and attained a worldwide population coverage rate of 86.24%. The vaccine formed a stable docking complex and exhibited strong interactions with major histocompatibility class I and class II molecules, as well as Toll-like receptor 4 (TLR4), Toll-like receptor 9 (TLR9), and the B-cell receptor. Binding affinities were assessed based on free energy (ΔG) values of -34.01 kcal/mol and -20.77 kcal/mol for major histocompatibility complex (MHC) class I and II, respectively, -1377.5 kcal/mol for TLR4, -24.19 kcal/mol for TLR9, and -34.41 kcal/mol for the B-cell receptor. This vaccine triggered both antibody and cell-mediated immune responses and increasing levels of IFN-γ and the interleukins IL-2, IL-10, and IL-12. This vaccine is considered preventive against multiple HPV infections. Nonetheless, in vitro and in vivo investigations are necessary to validate the safety and efficacy of this vaccine.

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