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<p>Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i>, remains a major global health challenge due to the limited efficacy of the Bacillus Calmette–Guérin (BCG) vaccine. Using an immunoinformatics-driven strategy, we designed and evaluated three distinct multi-epitope vaccine constructs (MEVCs) derived from PPE68, IrtA, and PE9, which were subsequently developed into an mRNA vaccine construct. T-cell and B-cell epitopes were predicted using IEDB tools and BepiPred-3.0, and the designed constructs were systematically evaluated for antigenicity, allergenicity, toxicity, and physicochemical characteristics. Structural modeling with AlphaFold3, followed by epitope mapping and molecular docking with TLR2 and TLR4/MD-2, identified Pattern 3 (PPE68–IrtA–PE9) as the most promising construct. It exhibited the highest antigenicity score (0.6122), a high abundance of B-cell epitopes (0.865), and demonstrated predicted binding to the TLR4/MD-2 complex (ΔG =  − 12.2&#xa0;kcal/mol), forming 12 hydrogen bonds and engaging both receptor components, as well as to TLR2 (ΔG =  − 10.4&#xa0;kcal/mol) with nine hydrogen bonds. In silico immune simulations of Pattern 3 predicted strong T-cell responses, elevated IFN-γ levels, and high IgG1, IgG2, and IgM titers, while the codon-optimized mRNA exhibited a stable secondary structure (ΔG =  − 2,217.20&#xa0;kcal/mol). These results suggest that antigen domain arrangement may influence predicted immunogenicity and structural stability, and exhibit a favorable in silico safety profile, supporting PPE68–IrtA–PE9 as a promising mRNA vaccine design for further experimental evaluation.</p>

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Domain arrangement–driven immunogenicity of a computationally designed mRNA vaccine targeting PPE68, IrtA, and PE9 of Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Theerawat Dorbutr,
  • Elena Stylianou,
  • Helen McShane,
  • Nawamin Pinpathomrat

摘要

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health challenge due to the limited efficacy of the Bacillus Calmette–Guérin (BCG) vaccine. Using an immunoinformatics-driven strategy, we designed and evaluated three distinct multi-epitope vaccine constructs (MEVCs) derived from PPE68, IrtA, and PE9, which were subsequently developed into an mRNA vaccine construct. T-cell and B-cell epitopes were predicted using IEDB tools and BepiPred-3.0, and the designed constructs were systematically evaluated for antigenicity, allergenicity, toxicity, and physicochemical characteristics. Structural modeling with AlphaFold3, followed by epitope mapping and molecular docking with TLR2 and TLR4/MD-2, identified Pattern 3 (PPE68–IrtA–PE9) as the most promising construct. It exhibited the highest antigenicity score (0.6122), a high abundance of B-cell epitopes (0.865), and demonstrated predicted binding to the TLR4/MD-2 complex (ΔG =  − 12.2 kcal/mol), forming 12 hydrogen bonds and engaging both receptor components, as well as to TLR2 (ΔG =  − 10.4 kcal/mol) with nine hydrogen bonds. In silico immune simulations of Pattern 3 predicted strong T-cell responses, elevated IFN-γ levels, and high IgG1, IgG2, and IgM titers, while the codon-optimized mRNA exhibited a stable secondary structure (ΔG =  − 2,217.20 kcal/mol). These results suggest that antigen domain arrangement may influence predicted immunogenicity and structural stability, and exhibit a favorable in silico safety profile, supporting PPE68–IrtA–PE9 as a promising mRNA vaccine design for further experimental evaluation.