Puja Jaishwal, Satarudra Prakash Singh
ABSTRACT Existing spike protein‐based COVID‐19 vaccines have significantly prevented SARS‐CoV‐2 infection in most of the world's population. However, challenges remain regarding production costs, scalability, global efficacy, and safety. The current study aims to design a novel, conserved, and promiscuous B‐ and T‐lymphocyte epitope‐based universal COVID‐19 vaccine derived from the spike protein. The designed monomeric self‐assembling peptide vaccine (SAPV) constructs (with and without adjuvant/TAT/PADRE sequences) involving pentameric and trimeric coiled‐coil motifs were evaluated for self‐assembly through homo‐oligomer modeling. The screened SAPV constructs (SAPVb3 and SAPVa5) were subsequently analyzed for their physicochemical properties and potential allergenicity, toxicity, subcellular localization, antigenicity, solubility, and antioxidative properties. Finally, the interaction, specificity, and stability analysis were performed through docking and simulation studies of the macromolecular complexes formed between the SAPV constructs and broadly neutralizing human monoclonal antibody (K501SP6) as well as toll‐like receptors (TLR)‐2/4. In the case of TLR‐4, SAPVa5 demonstrated the strongest binding affinity (−1623.9 kcal/mol) compared to SAPVb3 (−1447.1 kcal/mol), control C3 (−1488.3 kcal/mol), and the reference immunogenic peptide of RBD (−954.4 kcal/mol). Moreover, immune simulations of SAPVb3/SAPVa5 and the self‐assembling polypeptide nanoparticle vaccine (FMP014) yielded comparable results and elicited robust immune responses against SARS‐CoV‐2 variants. However, before conducting a clinical trial, SAPV constructs must be evaluated in a wet laboratory for immunogenicity and safety.