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

Amin Addetia; Alexandra Schäfer; Kaitlin R. Sprouse; Adian Valdez; Ashley Taylor; Mary-Jane Navarro; Jack T Brown; Elizabeth M. Leaf; Marcos C. Miranda; Alexandra C. Walls; Jimin Lee; Nicholas Catanzaro; Catherine Treichel; Isabelle Willoughby; John Powers; David R Martinez; Blue Vesari; Rashmi Ravichandran; Albert J. Seo; Cameron Stewart; Benjamin Merz; Emily Beirne; Samantha K. Zepeda; Anthony Cook; Laurent Pessaint; Ankur Sharma; Darin K. Edwards; Kunse Lee; Kelly D. Smith; Tyler N. Starr

doi:10.1101/2025.05.11.652904

ImmunologybioRxivMay 11, 2025

Preprint

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

Amin Addetia iD, Alexandra Schäfer iD, Kaitlin R. Sprouse iD, Adian Valdez, Ashley Taylor, Mary-Jane Navarro iD, Jack T Brown iD, Elizabeth M. Leaf iD, Marcos C. Miranda iD, Alexandra C. Walls iD, Jimin Lee iD, Nicholas Catanzaro iD, Catherine Treichel iD, Isabelle Willoughby, John Powers iD, David R Martinez, Blue Vesari, Rashmi Ravichandran iD, Albert J. Seo, Cameron Stewart iD, Benjamin Merz, Emily Beirne iD, Samantha K. Zepeda iD, Anthony Cook iD, Laurent Pessaint iD, , David Veesler iD

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.

PDF DOI