Next-generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire

Melani, R. D.; Des Soye, B. J.; Kafader, J. O.; Forte, E.; Hollas, M.; Blagovich, V.; Negrao, F.; McGee, J. P.; Drown, B.; Lloyd-Jones, C.; Seckler, H. S.; Camarillo, J. M.; Compton, P. D.; LeDuc, R. D.; Early, B.; Fellers, R. T.; Cho, B.-K.; Baby Mattamana, B.; Goo, Y. A.; Thomas, P. M.; Ash, M. K.; Bhimalli, P. P.; Al-Harthi, L.; Sha, B. E.; Schneider, J. R.; Kelleher, N. L.

Methods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we present Ig-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multi-parametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We apply Ig-MS to plasma from subjects with severe & mild COVID-19, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, with compatibility to any recombinant antigen to gauge our immune responses to vaccination, pathogens, or autoimmune disorders.