SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback

Coelho, C. H.; Bloom, N.; Ramirez, S. I.; Parikh, U. M.; Heaps, A.; Sieg, S. F.; Greninger, A.; Ritz, J.; Moser, C.; Eron, J. J.; Currier, J. S.; Klekotka, P.; Wohl, D. A.; Daar, E. S.; Li, J.; Hughes, M. D.; Chew, K. W.; Smith, D. M.; Crotty, S.; Accelerating COVID-19 Therapeutic Interventions and Vaccines: 2/A5401 (ACTIV-2/A5401) Study Team,

doi:10.1101/2023.11.21.567575

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bioRxiv · 10.1101/2023.11.21.567575

SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback

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Abstract

Therapeutic anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been extensively studied in humans, but the impact on immune memory of mAb treatment during an ongoing immune response has remained unclear. Here, we evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific defect in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating human memory B cell responses, both to infection and vaccination. These data indicate that mAb administration can promote alterations in the epitopes recognized by the B cell repertoire, and the single administration of mAb can continue to determine the fate of B cells in response to additional antigen exposures months later. SIGNIFICANCE STATEMENTEvaluating the therapeutic use of monoclonal antibodies during SARS-CoV-2 infection requires a comprehensive understanding of their impact on B cell responses at the cellular level and how these responses are shaped after vaccination. We report for the first time the effect of bamlanivimab on SARS-CoV-2 specific human memory B cells of COVID-19 infected humans receiving, or not, mRNA immunization.

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Coelho, C. H., Bloom, N., Ramirez, S. I., Parikh, U. M., Heaps, A., Sieg, S. F., Greninger, A., Ritz, J., Moser, C., Eron, J. J., Currier, J. S., Klekotka, P., Wohl, D. A., Daar, E. S., Li, J., Hughes, M. D., Chew, K. W., Smith, D. M., Crotty, S., Accelerating COVID-19 Therapeutic Interventions and Vaccines: 2/A5401 (ACTIV-2/A5401) Study Team,. 2023-11-22. SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback. https://doi.org/10.1101/2023.11.21.567575

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