TZ1391: a computationally designed circular mRNA multi-epitope vaccine candidate against Mycobacterium tuberculosis via TLR3 immunomodulation

Ali A. Alamri A. Mishra V.K. Utegenova A. Askarova G. Baiduissenova A. Dusmagambetova A.
December 2026 BioMed Central Ltd

BMC Immunology
2026 #27 Issue 1

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health burden due to latent infection, multidrug resistance, and the limited efficacy of the BCG vaccine. To address this challenge, we computationally designed and evaluated a circular mRNA-based multi-epitope vaccine candidate, TZ1391. Five experimentally validated M. tuberculosis antigens (ESAT-6, CFP-10, Ag85B, PPE18, and HspX) were used to predict immunodominant cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B-cell epitopes. Three vaccine constructs (MTB-C1, MTB-C2, and MTB-C3) were assembled by integrating 20 CTL, 20 HTL, and 20 B-cell epitopes with appropriate linkers, PADRE sequence, and innate immune adjuvants. Structural modeling using AlphaFold2 and GalaxyRefine confirmed stable, native-like conformations for all constructs, with MTB-C3 showing the highest structural quality (GDT-HA = 0.8782; RMSD = 0.646 Å) and the greatest number of stabilizing disulfide bonds. Molecular docking against TLR3, TLR4, and TLR8 identified two top-performing candidates. MTB-C3 exhibited the strongest interaction with TLR3, achieving the lowest HDock score (− 480.53) and highest confidence score (0.9987), while MTB-C2 showed optimal binding to TLR4 (ClusPro score − 1488.6; confidence 0.9700). Despite favorable TLR4 engagement by MTB-C2, MTB-C3 was prioritized as the lead candidate (TZ1391) due to its superior structural stability, reduced conformational fluctuations during molecular dynamics simulations, and stronger TLR3 binding free energy (ΔG_bind = − 173.25 ± 7.9 kcal/mol). Immune simulations further predicted that TZ1391 elicits a robust Th1-biased response, characterized by sustained IgG production, strong IFN-γ and IL-2 induction, and durable immune memory. Overall, the strong TLR3-mediated interaction, combined with enhanced structural stability and favorable immunogenic profiles, establishes TZ1391 as a promising multi-epitope vaccine candidate for further experimental validation against tuberculosis.

Circular mRNA vaccine , Immune simulations , Molecular dynamics simulations , Multi-epitope vaccine , Mycobacterium tuberculosis (MTB)

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Immunology, Diagnostics & Research Discovery Lab (IDRDL), Department of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23200, Pakistan
Department of Biochemistry, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
Chemistry Division, School of Advance Sciences and Languages, VIT Bhopal University, Bhopal- Kothri Kalan, Sehore, India
Department of Microbiology and Virology, Astana Medical University, Astana, Kazakhstan
Department of Dermatovenereology, Head of the Department, Faculty of Medicine and Public Health, Al- Farabi Kazakh National University, Almaty, Kazakhstan
Laboratory Department of City Polyclinic №5 of the Akimat of Astana, Astana Medical University, Astana, Kazakhstan

Immunology
Department of Biochemistry
Chemistry Division
Department of Microbiology and Virology
Department of Dermatovenereology
Laboratory Department of City Polyclinic №5 of the Akimat of Astana

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