<p>Dengue Virus Serotype 2 (DENV-2) is increasingly impacting public health, especially in South and Southeast Asia. Bangladesh faced its most severe dengue outbreak in 2023, reporting 318,623 cases and over 1,700 deaths, with the DENV-2 Cosmopolitan genotype responsible for 70.2% of cases. To better understand this event, we utilized in silico methods to explore mutational trends and epitope dynamics in global and Bangladeshi sequences from 2017 to 2023. The study aimed to provide insights into viral evolution and hypothesize how specific mutations might theoretically affect immune recognition. We analyzed 2,118 DENV-2 sequences from Bangladesh and other countries, focusing on the Cosmopolitan genotype. Using multiple sequence alignment against a reference sequence (Accession ID: NC_001474.2), we identified mutations. BepiPred2, BcePred, and IEDB tools were used to predict B-cell and T-cell (MHC-I and MHC-II) epitopes, while antigenicity was assessed with VaxiJen v2.0. Structural modeling of mutations in these epitopes was performed using PEPstrMOD and TM-align to evaluate potential impacts on immune recognition. The modeled epitopes were optimized and validated using UCSF Chimera and MolProbity, respectively. This step allowed us to verify the structural integrity of our models, helping to confirm that the predicted epitopes remain biologically relevant and stable.” Significant mutations were found in both structural and non-structural proteins, with distinct patterns between Bangladesh and global sequences. Mutations like K9R in the capsid and I164V in the envelope protein showed a striking increase in 2023 Bangladesh samples, with others like L247F in NS1 and I140V in NS3 also linked to structural changes that could affect immune recognition. Globally, mutations such as H148Y in prM and K388E in NS5 were more common in previous years but less so in 2023. Newly observed mutations in Bangladesh, like V64I in NS4A and Y201H in NS5, indicate local adaptation. We also noted shifts in antigenicity, where certain epitopes switched from antigenic to non-antigenic (e.g., T244A) and vice versa (e.g., I18V), potentially impacting vaccine efficacy. Our structural analysis revealed that these mutations could induce conformational changes in B-cell and T-cell epitopes, potentially influencing immune responses and facilitating immune evasion. All models generated during the structural analysis were validated using MolProbity to evaluate their accuracy and structural stability. Furthermore, despite the widespread mutations, we identified multiple conserved epitopes across B-cell, MHC-I, and MHC-II categories that maintained stable antigenicity and minimal structural deviation, suggesting their potential as stable immunogenic targets for future experimental validation and vaccine development against DENV-2 Cosmopolitan strains. This study highlights DENV-2’s evolving nature in Bangladesh and globally, underscoring the need for ongoing surveillance and consideration of these mutations in vaccine design. Insights from this analysis may inform public health strategies to reduce dengue impacts in endemic areas.</p>