Streptococcus pneumoniae is a leading cause of some diseases such as pneumonia, sepsis, and meningitis mostly in children less than 5 years of age. Presently, two types of pneumococcal vaccine are available on the market: polysaccharide vaccines (PPV) that are based on capsular polysaccharides of at least 92 different serotypes, and protein-conjugated polysaccharide vaccine (PCV). The PPVs such as PPV23 do not stimulate efficient protective immunity in children under 2 years old, while the PCVs such as PCV7, PCV10, and PCV13 that cover 7, 10, and 13 serotypes, respectively, highly protect newborns, but have some disadvantages such as complications in manufacturing, costly production, and also requires refrigeration and multiple injections. Epitope-based vaccines, including varied mixtures of conserved virulence proteins, are a promising alternative to the existing capsular antigen vaccines. In this study, it has been tried to design an efficient subunit vaccine in order to elicit both CTL and HTL responses. The immunodominant epitopes from highly protective antigens of S. pneumoniae (PspA, CbpA, PiuA, and PhtD) were selected from different databanks, such as IEDB, PROPRED, RANKPEP, and MHCPRED. The PspA and CbpA were chosen as CTL epitope stimulants, and PhtD and PiuA were defined as helper epitopes. Because of low immunogenicity of epitope vaccines, PorB protein as a TLR2 agonist was employed to increase the immunogenicity of the vaccine. All the peptide segments were fused to each other by proper linkers, and the physicochemical, structural, and immunological characteristics of the construct were also evaluated. To achieve a high-quality 3 D structure of the protein, modeling, refinement, and validation of the final construct were done. Docking and molecular dynamics analyses demonstrated an appropriate and stable interaction between the vaccine and TLR2 during the simulation period. The computational studies suggested the designed vaccine as a novel construct, capable to elicit efficient humoral and cellular immunities, which are crucial for protection against S. pneumoniae. Communicated by Ramaswamy H. Sarma