Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein

Malladi, S. K.; Jaiswal, D.; Ying, B.; Alsoussi, W.; Darling, T.; Dadonaite, B.; Civljak, A.; Horvath, S.; Zhou, J.; Kim, W.; Turner, J.; Schmitz, A.; Han, F.; Scheaffer, S.; Farnsworth, C.; Nachbagauer, R.; Nestorova, B.; Chalkias, S.; Klebert, M.; Edwards, D.; Paris, R.; Strnad, B.; Middleton, W.; OHalloran, J.; Presti, R.; Bloom, J. D.; Boon, A. C. M.; Diamond, M. S.; Bajic, G.; Ellebedy, A. H.

doi:10.1101/2024.12.06.625234

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bioRxiv · 10.1101/2024.12.06.625234

Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein

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Abstract

SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of the virus impacts the breadth of the induced GC B cell response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes of nine healthy adults following bivalent booster immunization. We show that 77.8% of the B cell clones in the GC expressed as representative monoclonal antibodies recognized the spike protein, with a third (37.8%) of these targeting the receptor binding domain (RBD). Strikingly, only one RBD-targeting mAb, mAb-52, neutralized all tested SARS- CoV-2 strains, including the recent KP.2 variant. mAb-52 utilizes the IGHV3-66 public clonotype, protects hamsters challenged against the EG.5.1 variant and targets the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Finally, we show that the remarkable breadth of mAb-52 is due to the somatic hypermutations accumulated within vaccine-induced GC reaction. One Sentence SummaryBooster SARS-CoV-2 mRNA vaccine recruits and broadens GC B cell responses targeting a highly conserved site on receptor binding domain of spike glycoprotein.

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Malladi, S. K., Jaiswal, D., Ying, B., Alsoussi, W., Darling, T., Dadonaite, B., Civljak, A., Horvath, S., Zhou, J., Kim, W., Turner, J., Schmitz, A., Han, F., Scheaffer, S., Farnsworth, C., Nachbagauer, R., Nestorova, B., Chalkias, S., Klebert, M., Edwards, D., Paris, R., Strnad, B., Middleton, W., OHalloran, J., Presti, R., Bloom, J. D., Boon, A. C. M., Diamond, M. S., Bajic, G., Ellebedy, A. H.. 2024-12-09. Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein. https://doi.org/10.1101/2024.12.06.625234

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