AbstractWe have developed a serology test platform for identifying individuals with prior exposure to specific viral infections and provide data to help reduce public health risks. The serology test composed of a pair of cell lines engineered to express either a viral envelop protein (Target Cell) or a receptor to recognize the Fc region of an antibody (Reporter Cell), that is,Diagnostic‐Cell‐Complex (DxCell‐Complex). The formation of an immune synapse, facilitated by the analyte antibody, resulted into a dual‐reporter protein expression by the Reporter Cell. We validated it with human serum with confirmed history of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. No signal amplification steps were necessary. The DxCell‐Complex quantitatively detected the target‐specific immunoglobulin G (IgG) within 1 h. Validation with clinical human serum containing SARS‐CoV‐2 IgG antibodies confirmed 97.04% sensitivity and 93.33% specificity. The platform can be redirected against other antibodies. Self‐replication and activation‐induced cell signaling, two attributes of the cell, will enable rapid and cost‐effective manufacturing and its operation in healthcare facilities without requiring time‐consuming signal amplification steps.