Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

Lee, J.; Zepeda, S.; Park, Y.-J.; Taylor, A. L.; Quispe, J.; Stewart, C.; Leaf, E. M.; Treichel, C.; Corti, D.; King, N. P.; Starr, T. N.; Veesler, D.

doi:10.1101/2023.09.12.557371

bioRxiv · 10.1101/2023.09.12.557371

Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

Lee, J.·Zepeda, S.·Park, Y.-J.·Taylor, A. L.·Quispe, J.·Stewart, C.·Leaf, E. M.·Treichel, C.·Corti, D.·King, N. P.·Starr, T. N.·Veesler, D.

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Abstract

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with the antigenicity of their spike (S) glycoproteins remain uncharacterized. Here, we show that the African Rinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad ACE2 usage and that RBD mutations further expand receptor promiscuity and enable human ACE2 utilization. We determined a cryoEM structure of the PRD-0038 RBD bound to R. alcyone ACE2, explaining receptor tropism and highlighting differences with SARS-CoV-1 and SARS-CoV-2. Characterization of PRD-0038 S using cryoEM and monoclonal antibody reactivity revealed its distinct antigenicity relative to SARS-CoV-2 and identified PRD-0038 cross-neutralizing antibodies for pandemic preparedness. PRD-0038 S vaccination elicited greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses compared to SARS-CoV-2 S due to broader antigenic targeting, motivating the inclusion of clade 3 antigens in next-generation vaccines for enhanced resilience to viral evolution.

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Lee, J., Zepeda, S., Park, Y.-J., Taylor, A. L., Quispe, J., Stewart, C., Leaf, E. M., Treichel, C., Corti, D., King, N. P., Starr, T. N., Veesler, D.. 2023-09-13. Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus. https://doi.org/10.1101/2023.09.12.557371

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