Immunologic Testing for SARS-CoV-2 Infection from the Antigen Perspective

Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally as a severe pandemic. SARS-CoV-2 infection stimulates antigen-specific antibody responses. Multiple serologic tests have been developed for SARS-CoV-2. However, which antigens are most suitable for serological testing remains poorly understood. Specifically, which antigens have the highest sensitivity and specificity for serological testing and which have the least cross-reactivity with other coronaviruses are currently unknown. Previous studies have shown that the S1 domain of the spike (S) protein has very low cross-reactivity between epidemic coronaviruses and common human coronaviruses, whereas the S2 domain of the S protein and the nucleocapsid protein (N protein) show low-level cross-reactivity. Therefore, S1 is considered more specific than the native homotrimer of the S protein, and the receptor-binding domain as an antigen to test patient antibodies is more sensitive than the native N protein. In addition, an increasing number of studies have used multiantigen protein arrays to screen serum from convalescent patients with COVID-19. Antigen combinations demonstrated improved performance compared to each individual antigen. For rapid antigen detection, the sensitivity of the test is higher in the first week of onset of the disease with high viral loads. Highly sensitive and specific immunological diagnostic methods for antibodies or those that directly detect viral antigens in clinical samples would be beneficial for the rapid and accurate diagnosis of SARS-CoV-2 infection.