Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines

Addetia, A.; Schaefer, A.; Sprouse, K.; Valdez, A.; Taylor, A.; Navarro, M.-J.; Brown, J. T.; Leaf, E.; Miranda, M.; Walls, A. C.; Lee, J.; Catanzaro, N. J.; Treichel, C.; Willoughby, I.; Powers, J.; Martinez, D. R.; Vesari, B.; Ravichandran, R.; Seo, A. J.; Stewart, C.; Merz, B.; Beirne, E.; Zepeda, S.; Cook, A.; Pessaint, L.; Sharma, A.; Edwards, D.; Lee, K.; Smith, K.; Starr, T. N.; Baric, R.; King, N. P.; Veesler, D.

doi:10.1101/2025.05.11.652904

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bioRxiv · 10.1101/2025.05.11.652904

Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines

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Abstract

Vaccines against emerging SARS-CoV-2 variants and sarbecoviruses with pandemic potential must elicit a robust humoral immune response in a population imprinted with the SARS-CoV-2 spike (S) protein. Here, we designed protein nanoparticle (NP) vaccines co-displaying the SARS-CoV-2 BA.5, SARS-CoV-1, and BtKY72 receptor-binding domains (RBDs) with or without the Wuhan-Hu-1 (Wu) RBD. We show that these vaccines elicit cross-reactive and broadly neutralizing plasma antibody responses against SARS-CoV-2 variants and sarbecoviruses in naive and pre-immune animals. Immunization with multivalent RBD-NPs overcomes immune imprinting and elicits neutralizing antibodies and memory B cells specific for the BA.5, SARS-CoV-1, and BtKY72 RBDs in mRNA-1273-vaccinated non-human primates. Multivalent RBD-NPs outperform a monovalent Wu RBD-NP vaccine by providing superior protection in mice and non-human primates challenged with the vaccine-mismatched SARS-CoV-2 XBB.1.5 or the pre-emergent RsSHC014. These data support the use of multivalent RBD-NP vaccines for SARS-CoV-2 variants and sarbecoviruses in naive and pre-immune populations.

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Addetia, A., Schaefer, A., Sprouse, K., Valdez, A., Taylor, A., Navarro, M.-J., Brown, J. T., Leaf, E., Miranda, M., Walls, A. C., Lee, J., Catanzaro, N. J., Treichel, C., Willoughby, I., Powers, J., Martinez, D. R., Vesari, B., Ravichandran, R., Seo, A. J., Stewart, C., Merz, B., Beirne, E., Zepeda, S., Cook, A., Pessaint, L., Sharma, A., Edwards, D., Lee, K., Smith, K., Starr, T. N., Baric, R., King, N. P., Veesler, D.. 2025-05-13. Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines. https://doi.org/10.1101/2025.05.11.652904

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