Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, originating in the exocrine cells of the pancreas and accounting for over 90% of all pancreatic cancers. It is largely considered one of the deadliest malignancies with a 5-year survival rate of less than 10%. Currently, chemotherapy and surgery are the most common treatments; however, few cases are suitable for safe resection and relapse rates are high even with radiation-based treatment. Immunotherapy, specifically vaccine administration, has emerged as a promising method for PDAC prevention and treatment. Compared to other types of vaccines (DNA, protein subunit, etc.), mRNA vaccines are more promising due to their enhanced immune response, faster development time, and more targeted delivery. This study uses immunoinformatic tools to design a safe, efficacious, soluble, and non-toxic multivalent mRNA PDAC vaccine by assembling antigenic, immunogenic, and non-allergenic B- and T-cell (CTL and HTL) epitopes specifically targeting the S100 protein family, Mucin-1 (MUC-1) protein, and Wilm’s Tumor gene 1 (WT-1); the S100 proteins are all linked to organoid morphology and PDAC progression; MUC-1 is over-expressed in all epithelial cancers including PDAC; WT-1 acts as a tumor suppressor in a wide range of cancers, and its overexpression makes it a clear target in PDAC. 7 CTL, 6 HTL, and 4 B-cell epitopes were successfully identified and conjugated. We ordered the epitopes with 5′ cap, 5′ UTR, Kozak sequence, signal peptide (tPA), stop codon, 3′ UTR, and a 120-nucleotide long poly(A) tail at the C-terminal with linker sequences (AAY, GGGGS, KK). The computational findings (physicochemical, structural (secondary and tertiary), 3D refinement analyses, MD simulations, and docking analyses) corroborated the stability, high quality, and hydrophilicity of the proposed construct. The final mRNA construct had a molecular weight of 40403.03 kPA and was deemed soluble (grand average of hydropathicity of -0.516); a high level of thermostability was also observed with a stability index of 25.75 and an aliphatic index of 69.29. Molecular docking and immune simulation revealed a high binding affinity (below -700 kcal/mol) of the in silico vaccine with artificial toll-like-receptors (TLR4, TLR6, TLR7, and TLR9). Immune simulations showed a robust immune response. A slow but consistent increase in immunoglobulins (IgG and IgM) and cytokines (IL-4, IL-10, etc.) was observed. Codon optimization showed further success, yielding a codon adaptation index (CAI) of 1. This immunoinformatic study presents a viable multivalent PDAC vaccine candidate, suggesting that this mRNA construct can now be validated experimentally and be compared to other vaccine candidates to assess its possible impact in human health. This in silico vaccine offers a groundbreaking platform for further research and therapeutic intervention for pancreatic cancer. Citation Format: Ridhi Gutta, Sreelasya Polavarapu, Suhani Garg. In silico design of a multi-epitope mRNA vaccine for pancreatic ductal adenocarcinoma by targeting S100 proteins, MUC-1, and WT-1 abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C072.
Gutta et al. (Wed,) studied this question.