Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination

Adams, L. E.; Leist, S. R.; Dinnon, K. H.; West, A.; Gully, K. L.; Anderson, E.; Loome, J. F.; Madden, E.; Powers, J.; Schaefer, A.; Sarkar, S.; Castillo, I.; Maron, J.; McNamara, R. P.; Bertera, H. L.; Zweigart, M. R.; Higgins, J. S.; Hampton, B. K.; Lakshmanane, P.; Alter, G.; Montgomery, S.; Baxter, V.; Heise, M. T.; Baric, R. S.

doi:10.1101/2022.11.28.518175

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bioRxiv · 10.1101/2022.11.28.518175

Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination

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Abstract

Two group 2B {beta}-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. The mechanisms of cross protection driven by the sarbecovirus spike, a dominant immunogen, are less clear yet critically important for pan-sarbecovirus vaccine development. We evaluated the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination did not prevent virus replication, it protected against lethal heterologous disease outcomes in both SARS-CoV-2 and clade 2 bat sarbecovirus HKU3-SRBD challenge models. The spike vaccines tested primarily elicited a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. We found non-neutralizing antibody functions that mediated cross protection in wild-type mice were mechanistically linked to FcgR4 and spike S2-binding antibodies. Protection was lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.

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Adams, L. E., Leist, S. R., Dinnon, K. H., West, A., Gully, K. L., Anderson, E., Loome, J. F., Madden, E., Powers, J., Schaefer, A., Sarkar, S., Castillo, I., Maron, J., McNamara, R. P., Bertera, H. L., Zweigart, M. R., Higgins, J. S., Hampton, B. K., Lakshmanane, P., Alter, G., Montgomery, S., Baxter, V., Heise, M. T., Baric, R. S.. 2022-11-28. Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination. https://doi.org/10.1101/2022.11.28.518175

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