Abstract The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a pathogenic virus responsible for the coronavirus disease 2019 (COVID-19) outbreak. The virus has rapidly spread worldwide and caused serious global health and economic issues. The World Health Organization has declared COVID-19 a pandemic and suggested that all countries should take extreme countermeasures to stop it from spreading. SARS-CoV-2 targets the angiotensin-converting enzyme 2 (ACE2) receptor on human lung cells through receptor binding domain on the spike proteins (S-RBD) via N487, Y489, and G496 residues as previously reported. The virus uses ACE2 to inoculate mRNA and to replicate inside the cells, which results in a severe respiratory syndrome. Patients might experience serious symptoms including fever, cough, inability to taste, shortness of breath, and sometimes respiratory failure. Therefore, developing a vaccine is highly necessary to control the outbreak, which led to our goal in this study to identify antigenic peptide sequences on the S-RBD domain that may induce the immune response to provide protection from the virus. We virtually analyzed S-RBD protein structure by multiple sequence alignment (MSA) via CLUSTAL OMEGA to study the homology of the S-RBD domain in both strains (SARS-CoV and SARS-CoV-2), and the results showed 76% identical shared amino acids. Moreover, the S-RBD sequence for SARS-CoV-2 was blasted against the sequence “486-FNCYFPLQSYGFQ-498” on Drugbank database with a penalty of -1 for each indel, -3 for the mismatch, and with an expected value of 8 to screen for potential molecules that might interact with the target sequence. The blast results showed a possible alignment with complement component 4A (C4-A) protein, a protein involved in autoimmunity and antibody signaling, on the residues F490, C488, P491, Y495, G496, F497, and Q498. Lastly, a molecular docking analysis was performed by ClusPro 2.0 docking system to analyze the binding affinity of C4-A protein to the S-RBD-protein, and the results of the docking analysis showed 30 different bindings with different weighted energy coefficient scores. The top 10 binding conformations were chosen based on the coefficient score values between -856.2 to -985.4. The highest binding affinity of C4-A protein was observed on the target sequence, which might be a therapeutic approach for a possible COVID-19 vaccine. Further experiments are required to synthesize recombinant peptides for S-RBD protein and test it on animal models to check if it will induce C4-A production in response to recombinant S-RBD peptide and antibodies signaling to counter SARS-CoV-2 virus and, hopefully, competing with ACE2 binding to S-protein. Citation Format: Majid Al-Zahrani. A computational approach to identify a possible SARS-CoV-2 vaccine from receptor binding domain peptide sequence on spike glycoproteins [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S03-03.