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

Pan, J.; Yang, L.; Deng, Y.; Sun, B.; Zhang, L.; Wu, W.; Li, J.; Cheng, H.; Li, Y.; Xu, W.; Yang, J.; Sun, Y.; Fei, H.; Xue, Q.; Zhou, Y.; Wang, H.; Zheng, P.; Chen, H.; Zhu, F. C.; Peng, D.; Gu, D.; Han, J.; Qiu, J.; Ma, H.

doi:10.1101/2021.07.20.453011

bioRxiv · 10.1101/2021.07.20.453011

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

Pan, J.·Yang, L.·Deng, Y.·Sun, B.·Zhang, L.·Wu, W.·Li, J.·Cheng, H.·Li, Y.·Xu, W.·Yang, J.·Sun, Y.·Fei, H.·Xue, Q.·Zhou, Y.·Wang, H.·Zheng, P.·Chen, H.·Zhu, F. C.·Peng, D.·Gu, D.·Han, J.·Qiu, J.·Ma, H.

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Abstract

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.

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Pan, J., Yang, L., Deng, Y., Sun, B., Zhang, L., Wu, W., Li, J., Cheng, H., Li, Y., Xu, W., Yang, J., Sun, Y., Fei, H., Xue, Q., Zhou, Y., Wang, H., Zheng, P., Chen, H., Zhu, F. C., Peng, D., Gu, D., Han, J., Qiu, J., Ma, H.. 2021-07-20. Previously unrecognized non-reproducible antibody-antigen interactions and their implications for diagnosis of viral infections including COVID-19. https://doi.org/10.1101/2021.07.20.453011

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