In this study, a UCSF research group developed lower-cost spLUC (simple split luciferase) biosensors to rapidly (<30 minutes) and more precisely identify SARS-CoV-2 antibodies compared to other assays. The antibody sensors were created by binding coronavirus antigens with nanoluciferase fragments (SmBiT, LgBiT). When mixed with a sample containing SARS-CoV-2 antibodies, the sensors colocalize between the antibodies’ Fab fragment, restore luciferase enzyme function, and signal the presence of antibodies via bioluminescence. The sensors are specifically tuned to detect S and N viral proteins, which are often implemented in other COVID-19 tests as antigens. Based on the direct relationship between luciferase signal and antibodies present, the sensors can test patient serum samples and generate signals that correspond in strength to varying antibody concentrations. A competitive spLUC assay could differentiate between antibody epitope classes, such as specific epitopes of S-RBD and C135, and could be further used to study how epitope variations relate to patients’ symptoms. After developing the assay, the researchers tested its specificity on serum samples of six cohorts, 150 patients with a wide range symptoms. The results from testing the serum samples demonstrated the precision of the assay, which was comparable to other COVID-19 diagnostic tests.