Synthetic proteins for COVID-19 diagnostics

•Synthetic protein (JS7) and peptides bind serum antibodies of COVID-19 patients.•JS7 represents the interface of SARS-CoV-2 receptor binding domain with ACE2.•Antibody binding to JS7 or recombinant RBD is proportional to disease severity.•RBD/ACE2 interface peptides block antibody binding to JS7 or recombinant RBD.•JS7 variants could be rapidly synthesized for diagnostics or vaccine boosters. There is an urgent need for inexpensive, rapid and specific antigen-based assays to test for vaccine efficacy and detect infection with SARS-CoV-2 and its variants. We have identified a small, synthetic protein (JS7), representing a region of maximum variability within the receptor binding domain (RBD), which binds antibodies in sera from nine patients with PCR-verified COVID-19 of varying severity. Antibodies binding to either JS7 or the SARS-CoV-2 recombinant RBD, as well as those that disrupt binding between a fragment of the ACE2 receptor and the RBD, are proportional to disease severity and clinical outcome. Binding to JS7 was inhibited by linear peptides from the RBD interface with ACE2. Variants of JS7, such as E484K or N501Y, can be quickly synthesized in pure form in large quantities by automated methods. JS7 and related synthetic antigens can provide a basis for specific diagnostics for SARS-CoV-2 infections.