Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift

Song, G.; Yuan, M.; Liu, H.; Capozzola, T.; Lin, R. N.; Torres, J. L.; He, W.-t.; Musharrafieh, R.; Dueker, K.; Zhou, P.; Callaghan, S.; Mishra, N.; Yong, P.; Anzanello, F.; Avillion, G.; Vo, A. L.; Li, X.; Makhdoomi, M.; Feng, Z.; Zhu, X.; Peng, L.; Nemazee, D.; Safonova, Y.; Briney, B.; Ward, A. B.; Burton, D. R.; Wilson, I. A.; Andrabi, R.

doi:10.1101/2023.04.26.538488

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bioRxiv · 10.1101/2023.04.26.538488

Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift

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Abstract

Developing broad coronavirus vaccines requires identifying and understanding the molecular basis of broadly neutralizing antibody (bnAb) spike sites. In our previous work, we identified sarbecovirus spike RBD group 1 and 2 bnAbs. We have now shown that many of these bnAbs can still neutralize highly mutated SARS-CoV-2 variants, including the XBB.1.5. Structural studies revealed that group 1 bnAbs use recurrent germline encoded CDRH3 features to interact with a conserved RBD region that overlaps with class 4 bnAb site. Group 2 bnAbs recognize a less well-characterized "site V" on the RBD and destabilize spike trimer. The site V has remained largely unchanged in SARS-CoV- 2 variants and is highly conserved across diverse sarbecoviruses, making it a promising target for broad coronavirus vaccine development. Our findings suggest that targeted vaccine strategies may be needed to induce effective B cell responses to escape resistant subdominant spike RBD bnAb sites.

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Song, G., Yuan, M., Liu, H., Capozzola, T., Lin, R. N., Torres, J. L., He, W.-t., Musharrafieh, R., Dueker, K., Zhou, P., Callaghan, S., Mishra, N., Yong, P., Anzanello, F., Avillion, G., Vo, A. L., Li, X., Makhdoomi, M., Feng, Z., Zhu, X., Peng, L., Nemazee, D., Safonova, Y., Briney, B., Ward, A. B., Burton, D. R., Wilson, I. A., Andrabi, R.. 2023-04-27. Broadly neutralizing antibodies targeting a conserved silent face of spike RBD resist extreme SARS-CoV-2 antigenic drift. https://doi.org/10.1101/2023.04.26.538488

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