Previously unrecognized non-reproducible antibody-antigen interactions and their implications for diagnosis of viral infections including COVID-19

Pan, Jiaojiao; Yang, Lan; Deng, Yi; Sun, Baoqing; Zhang, Li; Wu, Wenya; Li, Jingzhi; Cheng, Hu; Li, Yiting; Xu, Wenwen; Yang, Jiao; Sun, Yiyue; Fei, Hao; Xue, Qinghong; Zhou, Youxin; Wang, Hui; Zheng, Peiyan; Chen, Hao; Zhu, Fengcai; Peng, Daxin; Gu, Dayong; Han, Jun; Qiu, Jiwan; Ma, Hongwei

Antibody-antigen (Ab-Ag) interactions are canonically described by a model which exclusively accommodates non-interaction (0) or reproducible-interaction (RI) states, yet this model is inadequate to explain often-encountered non-reproducible signals. Here, by monitoring diverse experimental systems and confirmed COVID-19 clinical sera using a peptide microarray, we observed that non-specific interactions (NSI) comprise a substantial proportion of non-reproducible antibody-based results. This enabled our discovery and capacity to reliably identify non-reproducible Ab-Ag interactions (NRI), as well as our development of a powerful explanatory model (“0-RI-NRI-Hook four-state model”) that is [mAb]-dependent, regardless of specificity, which ultimately shows that both NSI and NRI are not predictable yet certain-to-happen. In experiments using seven FDA-approved mAb drugs, we demonstrated the use of NSI counts in predicting epitope type. Beyond challenging the centrality of Ab-Ag interaction specificity data in serology and immunology, our discoveries also facilitated the rapid development of a serological test with uniquely informative COVID-19 diagnosis performance.